Epidemiology, Diagnosis and Prognosis

Schwabkey Z, et al. Impact of obesity on survival of patients with myelodysplastic syndromes. Hematol, 2021; 26(1): 393-397 (DOI: 1080/16078454.2021.1929692)

• In a retrospective single institution database analysis (Moffitt, USA) of 3089 men with known body mass index (BMI), 31% (n=963) were regarded as obese. While no significant difference was noted in baseline characteristics between groups of BMI < or ≥30, the median overall survival (OS) was better for those with BMI <30 (37mo vs 34mo, p=0.04), particularly in lower risk patients (57mo vs 52mo, p=0.08) or those with age <45yrs (116mo vs 25mo, p=0.034). BMI retained association with OS in a multivariate analysis as well. Also, for patients with BMI<30 the rate of AML transformation was lower (32% vs 36%, p=0.009).

Baba Y, et al. Increased serum C-reactive protein is an adverse prognostic factor in low-risk myelodysplastic syndromes. Int J Hematol, 2021; 114(4): 441-448. (DOI: 1007/s12185-021-03187-7)

• The study investigated the significance of inflammation in MDS by utilizing serum CRP levels as an indication of the degree of systemic inflammation. Traditionally, inflammatory cytokines are correlated with low survival in MDS patients. A retrospective analysis was conducted on 90 IPSS classified low-risk MDS patients. After examining CRP in the context of other known prognostic factors at diagnosis, it was concluded that serum CRP ≥ 0.58 mg/dL was associated with poor survival – both in the overall study as well as particularly in the 73 low-risk MDS patients defined by the revised IPSS. The study concluded that increased CRP may be a predictor of poor prognosis, and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in low-risk MDS patients.

Kanagal-Shamanna R, et al. Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes. Cancer, 2021;127(19):3552-3565. (DOI: 1002/cncr.33745)

• A multivariate analysis including 55 MDS patients demonstrated that the previously known good prognosis with SF3B1^mut may be limited to SF3B1^mutK700E as the non-K700E variants showed comparatively lower survival similar to SF3B1^wt. This was especially the case with lower risk MDS patients and those with ringed sideroblasts.

Natchkamp K, et al. Eligibility for clinical trials is unsatisfactory for patients with myelodysplastic syndromes, even at a tertiary referral center. Leuk Res, 2021, May 11 [Online ahead of print] (DOI: 1016/j.leukres.2021.106611)

• A simulation exercise from Düsseldorf MDS registry with historical 1809 patients and 47 clinical trials logged into the database, reevaluated eligibility of patients if all trials were to take place in 2016 with all patients as potential candidates for eligibility. On an average for any trial in general only 18% patients would be eligible, while 34% patients would be eligible for at least 1 of 9 trials from 2016. Further, the eligibility rates for pharma led studies were half of those for investigator led studies (10% vs 21%). The main reasons for exclusion were karyotype (58%), comorbidities (40%) and prior therapies (55%). Authors concluded that pharma study eligibility appeared to be more restrictive and not reflective of the real-life patients.

Kuendgen A, et al. Therapy-related Myelodysplastic Syndromes deserve specific diagnostic sub-classification and risk-stratification – An approach to classification of patients with t-MDS. Leukemia, 2021; 35(3): 835– (DOI: 10.1038/s41375-020-0917-7)

• An analysis of 2087 patients with therapy related MDS (t-MDS) from different international groups evaluating classification and prognostication tools, it was found that application of WHO classification for primary MDS (pMDS) could successfully predict time to leukemic transformation and survival both (p<0.001). t-MDS were found to be equally heterogeneous as p-MDS in terms of cytogenetics and prognostic score distribution. Clinical outcomes however were less favorable in each t-MDS group as compared to p-MDS (IWG p-MDS data were used for comparison). These observations strongly suggest that t-MDS should be classified as a distinct group in WHO-classification of therapy related myeloid neoplasms.

Schwabkey Z, et al. Impact of obesity on survival of patients with myelodysplastic syndromes. Hematol, 2021; 26(1): 393-397 (DOI: 1080/16078454.2021.1929692)

• In a retrospective single institution database analysis (Moffitt, USA) of 3089 men with known body mass index (BMI), 31% (n=963) were regarded as obese. While no significant difference was noted in baseline characteristics between groups of BMI < or ≥30, the median overall survival (OS) was better for those with BMI <30 (37mo vs 34mo, p=0.04), particularly in lower risk patients (57mo vs 52mo, p=0.08) or those with age <45yrs (116mo vs 25mo, p=0.034). BMI retained association with OS in a multivariate analysis as well. Also, for patients with BMI<30 the rate of AML transformation was lower (32% vs 36%, p=0.009).

Baba Y, et al. Increased serum C-reactive protein is an adverse prognostic factor in low-risk myelodysplastic syndromes. Int J Hematol, 2021; 114(4): 441-448. (DOI: 1007/s12185-021-03187-7)

• The study investigated the significance of inflammation in MDS by utilizing serum CRP levels as an indication of the degree of systemic inflammation. Traditionally, inflammatory cytokines are correlated with low survival in MDS patients. A retrospective analysis was conducted on 90 IPSS classified low-risk MDS patients. After examining CRP in the context of other known prognostic factors at diagnosis, it was concluded that serum CRP ≥ 0.58 mg/dL was associated with poor survival – both in the overall study as well as particularly in the 73 low-risk MDS patients defined by the revised IPSS. The study concluded that increased CRP may be a predictor of poor prognosis, and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in low-risk MDS patients.

Kanagal-Shamanna R, et al. Only SF3B1 mutation involving K700E independently predicts overall survival in myelodysplastic syndromes. Cancer, 2021;127(19):3552-3565. (DOI: 1002/cncr.33745)

• A multivariate analysis including 55 MDS patients demonstrated that the previously known good prognosis with SF3B1^mut may be limited to SF3B1^mutK700E as the non-K700E variants showed comparatively lower survival similar to SF3B1^wt. This was especially the case with lower risk MDS patients and those with ringed sideroblasts.

Natchkamp K, et al. Eligibility for clinical trials is unsatisfactory for patients with myelodysplastic syndromes, even at a tertiary referral center. Leuk Res, 2021, May 11 [Online ahead of print] (DOI: 1016/j.leukres.2021.106611)

• A simulation exercise from Düsseldorf MDS registry with historical 1809 patients and 47 clinical trials logged into the database, reevaluated eligibility of patients if all trials were to take place in 2016 with all patients as potential candidates for eligibility. On an average for any trial in general only 18% patients would be eligible, while 34% patients would be eligible for at least 1 of 9 trials from 2016. Further, the eligibility rates for pharma led studies were half of those for investigator led studies (10% vs 21%). The main reasons for exclusion were karyotype (58%), comorbidities (40%) and prior therapies (55%). Authors concluded that pharma study eligibility appeared to be more restrictive and not reflective of the real-life patients.

Kuendgen A, et al. Therapy-related Myelodysplastic Syndromes deserve specific diagnostic sub-classification and risk-stratification – An approach to classification of patients with t-MDS. Leukemia, 2021; 35(3): 835– (DOI: 10.1038/s41375-020-0917-7)

• An analysis of 2087 patients with therapy related MDS (t-MDS) from different international groups evaluating classification and prognostication tools, it was found that application of WHO classification for primary MDS (pMDS) could successfully predict time to leukemic transformation and survival both (p<0.001). t-MDS were found to be equally heterogeneous as p-MDS in terms of cytogenetics and prognostic score distribution. Clinical outcomes however were less favorable in each t-MDS group as compared to p-MDS (IWG p-MDS data were used for comparison). These observations strongly suggest that t-MDS should be classified as a distinct group in WHO-classification of therapy related myeloid neoplasms.

Nitecki R, et al. Incidence of myelodysplastic syndrome and acute myeloid leukemia in patients receiving poly-ADP ribose polymerase inhibitors for the treatment of solid tumors: A meta-analysis of randomized trials. Gynecol Oncol, 2021; Mar 15 [Online ahead of print] (https://doi.org/10.1016/j.ygyno.2021.03.011)

• Fourteen randomized trials with a total of 5739 patients with solid tumors were the subject of this pooled incidence rate ratio (IRR) analysis for MDS/AML cases post PARP-inhibitor treatment. Generally, the risk of MDS/AML post PARP-inhibitor therapy was not elevated as compared to control arm treatments (IRR=1.32). However, when assessed in studies with front-line treatment only, the risk was clearly evident (IRR= 5.43). Also, the risk of MDS/AML was not observed in studies including patients with BRCA mutations only (IRR= 0.83), while studies including broader patients did show the risk (IRR=2.43).

Rozema J, et al. Comorbidities and malignancies negatively affect survival in myelodysplastic syndromes: a population based study. Blood Adv, 2021; 5(5): 1344-1351. (https://doi.org/10.1182/bloodadvances.2020003381)

• A population based study using the Dutch province HemoBase registry of 291 MDS patients diagnosed between 2005 and 2017 with a f/u till 2019 showed that, the overall survival (OS) was better for patients with Charlson Comorbidity Index (CCI) <4, age<65 yrs, female sex and low-risk disease. Therapy related and secondary MDS were associated with worse OS as compared to de novo MDS (HR=1.51, p=0.04). Patients in remission at the time of MDS diagnosis, after therapy for prior malignancy, showed comparable OS to de novo MDS (25.5mo vs 28.3mo).

Jiang Y, et al. Asian population is more prone to develop high-risk myelodysplastic syndrome, concordantly with their propensity to exhibit high-risk cytogenetic aberrations. Cancers, 2021;13(3):481.  (https://doi.org/10.3390/cancers13030481)

• The study systematically examined the differences between western versus Asian MDS patients over last 20 years with respect to epidemiological, clinical, biological and genetic characteristics. Asian cases tended to be lower in incidence, almost 10 years younger at the disease onset, and diagnosed with int- to high-risk MDS (vs higher proportion of low risk MDS diagnoses in western population). Also, while the common genetic anomalies among western patients were del(5q), mutations in TET2, SF3B1, SESF2 and IDH1/2 , in Asian patients trisomy 8, del(20q), U2AF1 and ETV6 mutations were more common. Despite these differences, within each individual prognostic category, the OS was comparable between western and Asian patients.

Siddon AJ and Hasserjian RP. How I diagnose low-grade myelodysplastic syndromes. Am J Clin Pathol, 2020; 154(1): 5-14. (1093/ajcp/aqaa046 )

• This expert pathologist’s perspective discusses diagnostic challenge for differential diagnosis of low grade MDS from other causes of peripheral blood cytopenia by integrating cytogenetics and next generation sequencing data along with morphologic dysplasia. The review also discusses how important it is to include the emerging knowledge of clonal hematopoiesis of indeterminate potential. The review provides a diagnostic algorithm and discusses illustrative cases.

Winter S, et al. Integrating the “Immunome” in the stratification of myelodysplastic syndromes and future clinical trial design. J Clin Oncol, 2020; 38(15): 1723-1735. (1200/JCO.19.01823 )

• MDS risk stratification currently does not account for patient’s immune status or molecular abnormalities. The review discusses immune monitoring strategies for refinement of patient stratification to enable predicting for response to treatment in MDS. The review also provides a proposal for a multicenter study to test their hypotheses.

Liang S, et al. Prognostic value of DNMT3A mutations in myelodysplastic syndromes: a meta-analysis. Hematology, 2019;24(1):613-622. (https://pubmed.ncbi.nlm.nih.gov/31482762/)

• The meta-analysis included 12 studies with 2236 MDS patients. A pooled HR for overall survival and leukemia free survival showed significantly adverse prognostic impact of DNMT3A mutations, (OS- HR-1.65, p<0.001; LFS- HR-4.62, p<0.001)

Kurumaddali A, Salem AH and Agarwal AK. Spanish guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Cancer, 2019; 10(22): 5427-5433. (https://pubmed.ncbi.nlm.nih.gov/31632487/)

• Using a pre-established clinical trial database and linear regression analysis of 25 trials with 38 cohorts, the authors found that ≥PR (PR+CR+Marrow CR) was a strong predictor of OS (adjusted R2=0.64). Furthermore, for a given response rate (≥PR) or treatment group, the survival was longer in treatment naïve vs previously treated patients.

McDonald LS, et al. A multicenter report on the natural history of myelodysplastic syndromes in very old patients (aged over 85 years). Leuk Lymphoma 2019; 60(5):1324-1327. (https://pubmed.ncbi.nlm.nih.gov/30632846/)

• Data on 47 men and 37 women aged ≥85 yrs demonstrated that 93% patients were anemic at diagnosis with a med Hb level of 9.5g/dL. Sixty four percent of patients had more than one cytopenia, 53% patient shad elevated serum ferritin levels, and 88% patients had one or more significant comorbidities (cardiac, renal, or diabetes). Of the patients with significant anemia (Hb <10 g/dL), 42% received erythropoietin. Of the 29 transfusion-dependent patients only 48% received erythropoietin. The AML transformation rate was 7%. The median Overall survival was 16 mo in men and 27 mo in women. In 34 patients with IPSS-R classification, the med survival was 31.5 mo in very good risk, 41.5 mo in good risk, and 8mo in int risk patients.

Starkman R, et al. An MDS-Specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring. Leukemia, 2019: Dec 6 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31811236/)

• A frailty Index (FI) based on impact of deficits on likelihood of adverse outcomes was calculated in 440 MDS patients. The median FI was 0.25 and FI was correlated with age, IPSS-/-R risk. The FI ≤0.2 vs >0.2-0.3 vs >0.3 demonstrated significantly different OS with a median 55.6mo, 24mo and 10.9mo respectively (p<0.0001). FI remained as a significant covariate of OS in a multivariate analysis as well. Additionally, FI discriminated OS within each of the IPSS-/-R categories.

Palomo L et al. Spanish guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukemia. Br J Haematol, 2019; Oct 16 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31621063)

• The revised guidelines of the Spanish MDS Group (GESMD) have aimed at establishing quality standards for implementation and interpretation of next generation sequencing in myeloid malignancies.

Sekeres M et al. The national MDS natural history study: design of an integrated data and sample biorepository to promote research studies in myelodysplastic syndromes. Leuk Lymphoma, 2019; 21: 1-11. (https://www.ncbi.nlm.nih.gov/pubmed/31111762)

• This NCI supported study facilitates availability of MDS biospecimens for scientific discovery. The study plans to recruit up to 2000 MDS/MPN patients and up to 500 cases of idiopathic cytopenia of undetermined significance (ICUS). The present report details study design and plans for specimens and data collection.

Valent P et al. Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions. Oncotarget, 2017; 8(43):73483-73500 (https://www.ncbi.nlm.nih.gov/pubmed/29088721)

• The detection of MDS-related molecular abnormalities or incidence of peripheral blood cytopenias in individuals without any pathological diagnosis yet, and with a possibility of developing bone marrow conditions other than MDS in some of such individuals, have posed new challenges to MDS diagnosis. The 2016 working conference of the international consensus group discussed such challenges and developed a proposal for classification of pre-MDS conditions and also updated the minimal diagnostic criteria for MDS. In addition, the report defines diagnostic standards for differentiating normal, pre-MDS and MDS conditions.

Duong VH et al. The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes. Ann Hematol, 2018; 97(2): 247-254. (https://www.ncbi.nlm.nih.gov/pubmed/29167940)

• An institutional database review identified 223 patients with a primary diagnosis of MDS and ≥1% bone marrow blasts in peripheral blood, while 1535 MDS patients did not have blasts in blood. When compared, the patients with blasts in blood tended to be younger with frequent trilineage cytopenia, complex karyotype, higher IPSS score, transfusion dependence and therapy related MDS. Moreover, the rates of leukemic transformation were significantly higher and overall survival significantly shorter in those with blasts in blood than those without (AML-49% vs 26%, p<0.005; med OS- 16.5 mo vs 45.8 mo, p<0.005, respectively). The Cox regression analysis identified presence of blasts in blood as independent prognostic factor.

Borges DP et al. Prognostic importance of aurora kinases and mitotic spindle gene transcript levels in myelodysplastic syndrome. Leuk Res, 2018; 64: 61-70. (https://www.ncbi.nlm.nih.gov/pubmed/29220700)

• Proteins related to the mitotic spindle (AURKA, AURKB, TPX2), to the mitotic checkpoint (MAD2, CDC20) and the regulation of the cell cycle (p21) are directly related to chromosomal stability and tumor development. CDC20 expression were significantly increased in patients with dysmegakaryopoiesis, thrombocytopenia and high-risk patients. MAD2 expression were decreased in patients with 2 or 3 cytopenias and neutrophil below 800/mm³. TPX2 was overexpressed in patients presenting dysmegakaryopoiesis. A decrease in AURKA and AURKB expression was observed in patients with altered karyotype, who presented dysplasia in 3 lineages and hemoglobin below 8g/dL (p=0.024). The expression of AURKA, AURKB and MAD2 were decreased in patients with hypoplastic MDS, associated with high frequency of chromosomal alterations and high mortality rate. This study confirmed the importance of aurora kinases and mitotic spindle genes in the pathogenesis and clinical evolution of MDS.

Kobayashi T et al. A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study). Am J Hematol, 2017; Sept 11. [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28891083)

• A central review was conducted of 129 hypoplastic MDS cases from 20 institutions in Japan over a period of 10 years (Apr 2003-Mar 2012). A comparison was made to 115 non-hypoplastic MDS patients. This retrospective assessment showed that hypoplastic MDS group had a preponderance of RA subtype, and tended to have higher overall survival and leukemia-free survival.

Bennett JM. Changes in the updated 2016: WHO classification of the myelodysplastic syndromes and related myeloid neoplasms. Clin Lymphoma Myeloma Leuk 2016; 16(11): 607-609. (https://www.ncbi.nlm.nih.gov/pubmed/27693133)

• This article highlights diagnostic dilemmas in the 2008 WHO classification and the changes made in 2016 update to resolve them. In MDS, dysplasias and cytopenias in individual lineages involved are not always concordant. The 2016 classification uses general term MDS with single or multiple lineage dysplasias to create diagnostic categories. In addition, for higher risk MDS, the disease with excess blasts is categorized as MDSEB 1 or MDSEB 2.

Strupp C et al. New proposals of the WHO working group (2016) for the diagnosis of myelodysplastic syndromes (MDS): characteristics of refined MDS types. Leu Res 2017;57:78-84. (https://www.ncbi.nlm.nih.gov/pubmed/28324772)

• A validation of the new 2016 WHO classification of MDS was conducted with centrally diagnosed 3528 patients in the Düsseldorf registry, showing MDS single lineage dysplasia (MDS SLD) in 7.3%, multilineage dysplasia (MDS MLD) in 27.7%, MDS RS SLD in 6.4%, MDS RS MLD in 9.1%, Del(5q) in 4.5%, MDS with excess blasts 1 (MDSEB 1) in 13.6% and MDSEB 2 in 17.6% patients. The overall survival and AML transformation were also in line with the risk categorization. When compared to WHO 2008 classification, a major shift was observed in approx. 17% non-blastic patients from RCMD (2008) to MDS RS MLD or MDS Del(5q) (2016). Survival was higher in SLD and Del(5q) patients than MLD or EB1/2 patients. For AML progression rate, as compared to SLD, MLD and del(5q) categories, EB1 showed nearly 2x higher and EB2 had 3x higher rates.

Xavier AC et al. Incidence and outcomes of paediatric myelodysplastic syndrome in the United States. Br J Haematol 2017; Feb 27 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28240841)

• The analysis of SEER database records between 2001 and 2011 revealed an incidence of pediatric MDS at 1.16 cases/million population/year. Furthermore, similar to adult MDS, the 5-year survival of therapy-related pediatric MDS (41.2%) was significantly poorer as compared to de novo pediatric MDS (71.3%, p=0.004).

Steensma DP et al. Connect MDS/AML: Design of the myelodysplastic syndromes and acute myeloid leukemia disease registry, a prospective observational cohort study BMC Cancer 2016;16:652 (https://www.ncbi.nlm.nih.gov/pubmed/27538433)

• The present report provides design of the first prospective non-interventional observational registry for MDS/AML that will enroll approximately 1500 US patients from 150 community and academic centers. The disease diagnosis will be based on a central pathological review and the study will include 4 patient cohorts- lower risk MDS (low/int-1), higher risk MDS (int-2/high), AML and ICUS (idiopathic cytopenia of undetermined significance),

Arber DA et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127(20):2391-2405. (https://www.ncbi.nlm.nih.gov/pubmed/27069254)

• Gene expression arrays and next-generation sequencing have brought to light several new molecular biomarkers for myeloid neoplasms especially in acute leukemias. In light of this knowledge the 2008 WHO classification is revised to reflect the consensus opinions of hematopathologists, hematologists, oncologists and geneticists. The present article details major changes and specific rationale behind them.

Greenberg PL et al. Cytopenia levels for aiding establishment of the diagnosis of myelodysplastic syndromes. Blood 2016 Aug 17 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27535995)

• This letter to editor provides clarification on recently revised WHO criteria regarding the thresholds to be used for determining milder cytopenia when definitive morphologic and/or cytogenetic features of MDS are present. The authors recommend the use of standard hematologic values rather than the IPSS prognostic cutoff values to define such cytopenias for the diagnosis of MDS.

Yao CY et al. Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS). Oncotarget 2016 Aug 4 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27527853)

• In a series of 369 MDS patients classified per WHO 2008 criteria, 100 patients (approx. 27%) were diagnosed as hypocellular subtype. As compared to normo-/hyper-cellular MDS cases, these hypocellular patients tended to be lower risk with lower bone marrow and peripheral blood blast counts, had significantly lower incidence of RUNX1, ASKL1, DNMT3, EZH2 and TP53 mutations and demonstrated relatively longer overall survival.

Pfeilstöcker M et al. Time-dependent changes in mortality and transformation risk in MDS. Blood 2016; 128(7): 902-910 (https://www.ncbi.nlm.nih.gov/pubmed/27335276)

• A retrospective study of 7212 primary untreated MDS cases from the IWG database for prognosis in MDS, showed that mortality and leukemic transformation rates diminished over time in higher risk patients, while remained stable in lower risk patients with hazards in different prognostic categories becoming similar after approximately 3.5 years essentially reaching equivalence after 5 years.

Bennett JM et al. Dysplastic erythroid precursors in the myelodysplastic syndromes and the acute myeloid leukemias: is there biologic significance (How should blasts be counted?). Leuk Res 2016; 47: 63-69. (https://www.ncbi.nlm.nih.gov/pubmed/27258735)

• A study of % erythroid precursors (EP) within bone marrow aspirate blast count from >1400 MDS patients enrolled in Dusseldorf, Germany Adult MDS registry, showed no impact of % EP (including the FAB group’s recommendation of “50% rule”) on overall survival or leukemic transformation rates.

Buckstein R et al. Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study Br J Haematol2016 March 15, [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26991631)

• In 445 consecutive patients with MDS or CMML within a multicenter national registry in Canada, clinical outcomes were assessed in relation to frailty, disability, and physical functioning. Overall survival was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. The multivariate analysis demonstrated independent prognostic value of adding frailty (HR- 2.7,p<0.0001) and Charlson comorbidity score (HR-1.8, p=0.01) to revised IPSS (IPSS-R).

Park E et al. Nationwide statistical analysis of myeloid malignancies in Korea: incidence and survival rate from 1999-2012. Blood Res= 2015; 50(4): 204-217 (http://www.ncbi.nlm.nih.gov/pubmed/26770948)

• With overall 3771 cases of myeloid diseases (1.7% of all cancers) within the Korea Central Cancer Registry, the present study compared five year survival rates between 2001-2005 vs 2008-2012 periods. While the survival rates appeared to improve with Acute Myeloid Leukemia (AML-26.3% to 34.8%), Acute Promyelocytic Leukemia (APL-51.6% to 69.6%) and myeloproliferative neoplasms (MPN-81.8% to 87.1%). In contrast for the same time intervals survival did not change for MDS (45.6% and 44.4% respectively)

Wlodarski M et al. Prevalence, clinical characteristics and prognosis of GATA-2 related myelodysplastic syndromes (MDS) in children and adolescents. Blood 2016; 127(11):1387-1397 (http://www.ncbi.nlm.nih.gov/pubmed/26702063)

• Germline GATA-2 mutations were investigated in 426 children and adolescents with primary MDS and in 82 cases with secondary MDS from two consecutive studies of the European Working Group of MDS in childhood occurring over a period of 15 years. The incidence of germline GATA-2 mutations in primary MDS was 7% among all cases (and 15% in advanced disease), but completely absent in children with MDS secondary to therapy or acquired aplastic anemia. When data from additional 108 children was combined, Germline GATA-2 mutations were highly prevalent in patients with monosomy 7 (37% in all ages and 72% in adolescents). The overall survival and outcomes of hematopoietic stem cell transplantation did not have impact of the mutational status. Thus, germline GATA-2 mutation may not confer poor prognosis in childhood MDS.

Clinical Management During SARS-CoV-2 Pandemic

Patnaik MM, et al. Special considerations in the management of patients with myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes during the SARS-CoV-2 Pandemic. Am J Hematol, 2020; 95(8): E203-E208. (1002/ajh.25853 )   

• This letter to editor highlights the shared risks of the MDS/MPN overlap patients with SARS-CoV-2 infection, stemming from the increased proinflammatory milieu in these patients. The letter also provides a list of cytokine signaling directed ongoing clinical trials in SAR-CoV-2 patients. In addition, the authors share a best practice of forming a special emergency response expert panel at their institute to handle COVID- 19 in MDS/MPN patients.

Raza A, et al. Rewriting the rules for care of MDS and AML patients in the time of COVID-19. Leuk Res Rep, 2020; 13: 100201. (1016/j.lrr.2020.100201 )

• The report discusses the major changes occurring in the medical care of MDS and AML patients in the epicenter of pandemic with increasing remote management to save the patients from overly exposure to infection risk, and the unique challenges/management of transfusion and transplant. The report also throws light on challenges faced by the research laboratories working with precious patient specimens.

Paul S, et al. Targeting leukemia in the time of COVID-19. Acta Haematol, 2020: May 11 [Online ahead of print]. (1159/000508199 )

• The report focuses on evaluating alternatives to reduce clinic visits and hospitalizations while enabling critical systemic therapies for leukemias to continue uninterrupted and makes recommendations on how to manage leukemia amidst the SARS-CoV-2 pandemic.

Boyd K, Parcell B and Tauro S. Immunosuppression in hematological cancer patients with Covid-19-uncomplicated infections but delayed viral clearance? Leuk Res, 2020; 96:106407. ( 1016/j.leukres.2020.106407 )

• This report discusses leukemia cases that tested positive for COVID-19. The report discusses their immune status and kinetics of viral clearance over a period of time.

Willan J, et al. Assessing the impact of lockdown: fresh challenges for the care of haematology patients in the COVID-19 pandemic. Br J Haematol, 2020; 189(6): e224-e227. (1111/bjh.16782 )

• The report provides a quantitative estimation of a reduction in the frequencies of routine hematology-oncology diagnoses, blood transfusions and a variety of other services during a transition period and while in the lockdown phase versus the time prior to COVID-19.   

Diagnosis & Prognosis

Johnson RC et al. Mesenchymal stromal cell density is increased in higher grade myelodysplastic syndromes and independently predicts survival. Am J Clin Pathol 2014; 142 (6):795-802. http://www.ncbi.nlm.nih.gov/pubmed/25389333

• Automated image analysis of tissue microarray was performed to determine CD271+ mesenchymal stromal cell (MSC) density in 125 cytopenic patients. The results demonstrated significantly increased density of MSC in higher grade MDS (n=24) as compared to lower grade MDS (n=40, p=0.02) and benign cytopenias (n=61, p<0.006). Furthermore, the MSC density predicted survival independent of revised IPSS, transfusion history, status of therapy related MDS and fibrosis (HR 3.4, p<0.001).

Della Porta MG et al. Validation of WHO classification-based prognostic scoring system (WPSS) for myelodysplastic syndromes and comparison with the revised international prognostic scoring system (IPSS-R). A study of the international working group for prognosis in myelodysplasia (IWG-PM). Leukemia 2015, Feb 27. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25721895

• An assessment of individual WPSS parameters in 5326 untreated MDS patients revealed a strong correlation between WPSS and IPSS-R. Discrepancies were noted in some low risk cases where morphologic assessment of marrow dysplasia in individual hematopoietic lineages did not reflect peripheral cytopenias and/or blast count in the marrow. Lastly, anemia severity prognostically weighted higher in WPSS vs. IPSS-R.

Schemenau J et al. Cellularity, characteristics of hematopoietic parameters and prognosis in myelodysplastic syndromes. Eur J Haematol 2015, Jan 20 [Epub ahead of Print] (http://www.ncbi.nlm.nih.gov/pubmed/25600827)

The median survival and rates of leukemic transformation after 2 years were significantly higher for hypercellular MDS (25 months, p<0.0005; and 33%, p=0.018 respectively), as compared to hypocellular and normocellular MDS (survival-38 and 42 months respectively and leukemic transformation rate- 19% for both).

Zeiden AM et al. (on Behalf of ECOG and North American Leukemia Intergroup). Comparison of the prognostic utility of the revised international prognostic scoring system and the French prognostic scoring system in azacitidine-treated patients with myelodysplastic syndromes. Br J Haematol 2014, 166: 352-359. (http://www.ncbi.nlm.nih.gov/pubmed/24712482)

• A comparison of IPSS-R with FPSS in 150 MDS patients treated with azacytidine alone or in combination with entinostat showed that both systems differentiated survival in different prognostic categories. Statistically however, FPSS had no further advantage over IPSS-R.

Johnson RC et al. Mesenchymal stromal cell density is increased in higher grade myelodysplastic syndromes and independently predicts survival. Am J Clin Pathol 2014; 142 (6):795-802. http://www.ncbi.nlm.nih.gov/pubmed/25389333

• Automated image analysis of tissue microarray was performed to determine CD271+ mesenchymal stromal cell (MSC) density in 125 cytopenic patients. The results demonstrated significantly increased density of MSC in higher grade MDS (n=24) as compared to lower grade MDS (n=40, p=0.02) and benign cytopenias (n=61, p<0.006). Furthermore, the MSC density predicted survival independent of revised IPSS, transfusion history, status of therapy related MDS and fibrosis (HR 3.4, p<0.001).

Epidemiology and Outcomes Research

Prica A, Sholzberg M, and Buckstein R. Safety and efficacy of thrombopoietin-receptor agonists in myelodysplastic syndromes: a systemic review and meta-analysis of randomized controlled trials. J. Haematol. 2014; Aug 26 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25155450

• This meta-analysis of randomized placebo controlled trials included a total of 384 patients from five clinical studies (4 with romiplostim and 1 with eltrombopag). Overall, romiplostim was found to have a significantly lower risk of exposure-adjusted bleeding rates and platelet transfusion rates, both of which are important from patient perspective. However, apparently, the effect on leukemic progression could not be ascertained conclusively in this meta-analysis.

Cogle CR. Incidence and burden of the myelodysplastic syndromes. Curr Hematol Malig Rep 2015; 10(3): 272-281. http://www.ncbi.nlm.nih.gov/pubmed/26134527

• The review compared the US population based registry estimates of MDS incidence vs. those seen with the searches conducted on electronic pathology reports or other novel case capture methods and demonstrated that the population based registries may underestimate the incidence. The medicare billing claims data review estimated MDS prevalence at 60,000-170,000 in the USA with a projection to grow in future. A cost burden of MDS related transfusions estimated as a 3-year mean was at $88,824 for those who needed transfusion vs. $29,519 for the non-transfused MDS cases.

Loghavi S et al. TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis. Br J Hematol 2015; 171(1):91-99. http://www.ncbi.nlm.nih.gov/pubmed/26123119

• Sixty seven cases of de novo MDS with moderate to severe reticulin fibrosis (MDS-F) were the subject of this investigation. TP53 overexpression was assessed by dual color CD34/TP53 immunohistochemistry. TP53 mutations assayed with next generation- or Sanger- sequencing methods showed mutations in approximately 47% cases. TP53 overexpression correlated with TP53 mutations, blast count, abnormal cytogenetics and high/very-high IPSS-R groups. In a multivariate analysis, TP53 expression independently predicted shorter survival (p≤0.001) and particularly in CD34+ cells, was associated with shorter overall and leukemia-free survival.

Belli CB et al. Myelodysplastic syndromes in South America: A multinational study of 1080 patients. Am J Heamtol 2015; 90(10): 851-858. http://www.ncbi.nlm.nih.gov/pubmed/26104573

• A first epidemiological study from South America retrospectively compared MDS patients, primarily from three countries, Argentina (n=635), Brazil (n=345) and Chile (n=100). Chilean cohort showed higher preponderance of younger patients with higher F/M ratio, while Brazilian group had higher incidence of RARS category. As compared to Argentinian series, both Brazilian and Chilean patients had significantly lower Hb levels. The overall survival was significantly lower in Chilean patients (35 mo, p=0.03), as compared to Argentinian (56 mo) or Brazilian (55 mo) patients.

Fega KR et al. Non-hematologic predictors of mortality improve the prognostic value of the international prognostic scoring system for MDS in older adults. J Geriatr Oncol 2015; 6(4): 288-298. http://www.ncbi.nlm.nih.gov/pubmed/26073533

• A single institution retrospective study of 114 consecutive MDS patients with ≥ 65 years of age between 2006-2011 who had quality of life assessment at baseline showed an ‘ease of taking long walk’ as one of the significant predictors of mortality (HR=0.44) in a multivariate analysis among the other clinical predictors including serum albumin, therapy related MDS and IPSS score.

Efficace F. Prognostic value of self-reported fatigue on overall survival in patients with myelodysplastic syndromes: a multicentre, prospective, observational, cohort study. Lancet Oncol 2015 Set 21 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26404501

• This study aimed to assess if self-reported fatigue severity can help predict survival for MDS. Adult patients from 37 centers in Europe, USA and East Asia with intermediate-2 / high risk MDS were asked to complete a quality of life assessment, indicating their fatigue score using EORTC questionnaire-core 30. Between Nov 10, 2008 and Aug 13, 2012, 280 patients (median age 71 yrs) had median overall survival from diagnosis of 17 months. In analysis, overall survival was associated with higher self-reported fatigue score among the other predictors like increasing age, transfusion dependency, ≥ 2 ECOG performance status, increased WBC count, high-risk IPSS score.

de Swart et al. Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukemiaNet MDS (EUMDS) registry. Br J Haematol 2015; 170(3): 372-783. http://www.ncbi.nlm.nih.gov/pubmed/25907546

• This report described baseline characteristics, disease management and outcome of 1000 EUMDS registry based lower-risk MDS patients. The assessment identified low/very low (n=247) or high/very high (n=32) risk patients within intermediate-1 category. The revised IPSS scoring (IPSS-R) was superior to IPSS in both predicting disease progression and survival. The distribution of supportive care (transfusion/growth factors/iron) vs. monitoring within 2 years of diagnosis was 70:30.

Koenecke C et al. Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: A retrospective multicenter study of the European Society of Blood and Marrow Transplantation. Hematologica 2015; 100(3): 400-408. http://www.ncbi.nlm.nih.gov/pubmed/25552702

• Among the total of 903 patients classified in 5 risk groups of IPSS-cytogenetic classification, poor and very poor categories had an independent impact on shorter relapse free and overall survival compared to very good, good and intermediate categories. The study thus provided an important validation for the revised five- group classification.

Pathobiology

Aoyagi Y, et al. Mitochondrial fragmentation triggers ineffective hematopoiesis in myelodysplastic syndromes. Cancer Discov, 2021; Aug 30 [Online ahead of print] (DOI: 1158/2159-8290.CD-21-0032)

• Dynamin-related protein-1 (DRP1)-dependent excessive mitochondrial fragmentation in hematopoietic stem cells/progenitor cells was shown to lead to reactive oxygen species (ROS) production, and inflammatory signaling activation eventually causing dysplasia and impairment of granulopoiesis in the bone marrow of mouse models. Furthermore, pharmacological inhibition of DRP-1 attenuated mitochondrial fragmentation and rescued ineffective hematopoietic phenotype.

Aoyagi Y, et al. Mitochondrial fragmentation triggers ineffective hematopoiesis in myelodysplastic syndromes. Cancer Discov, 2021; Aug 30 [Online ahead of print] (DOI: 1158/2159-8290.CD-21-0032)  

• Dynamin-related protein-1 (DRP1)-dependent excessive mitochondrial fragmentation in hematopoietic stem cells/progenitor cells was shown to lead to reactive oxygen species (ROS) production, and inflammatory signaling activation eventually causing dysplasia and impairment of granulopoiesis in the bone marrow of mouse models. Furthermore, pharmacological inhibition of DRP-1 attenuated mitochondrial fragmentation and rescued ineffective hematopoietic phenotype.

Fang H, et al. Myelodysplastic syndrome with t(6;9)(p22;q34.1)/DEK-NUP214 better classified as acute myeloid leukemia? A multicenter study of 107 cases. Mod Pathol, 2021; Feb 8 [Online ahead of print] (https://doi.org/10.1038/s41379-021-00741-w)

• Contrary to the prior suggestion in literature to regard MDS with t(6;9)(p22;q34.1)/DEK-NUP214 as AML, when this study compared clinicopathological features of 107 cases (33MDS and 74 AML) with this genetic anomaly, the MDS cases tended to be older, had significantly lower WBC, lower blast count in blood and marrow, higher platelet count and a lower frequency of FLT3-ITD mutation. Multivariate analyses showed that initial diagnosis of MDS vs AML and allogeneic hematopoietic stem cell transplant were prognostic for overall survival (p=0.008 and p<0.0001 respectively) underscoring the distinct nature of MDS cases vs AML.

Riabov V, et al. High erythroferrone expression in CD71+ erythroid progenitors predicts superior survival in myelodysplastic syndromes. Br J Haematol, 2021; 192(5): 879-891. (https://doi.org/10.1111/bjh.17314)

• Both Erythroferrone (ERFE) and growth/differentiation factor 15 (GDF15), the regulators of iron homeostasis in erythroid progenitors, were studied in 111 MDS patients. Both showed prognostic value independent of the IPSS-R risk category. ERFE overexpression in low-/int-1 patients predicted superior OS. Also, although EREF expression was increased in patients with SF3B1 mutations, it predicted OS regardless of SF3B1 mutant or wild type status.

Van Zeventer IA, et al. Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals. Blood, 2020;135(14):1161-1170. (https://doi.org/10.1182/blood.2019004362)

• From a population-based Lifeline cohort, a group of individuals ≥60 yr age with anemia (n=676) was selected with 1:1 matched control participants. Peripheral blood analysis at variant allele frequency (VAF) of 1% for 27 driver genes was undertaken to evaluate clonal hematopoiesis (CH). The results showed higher frequency of individuals with CH in the group with anemia versus the matched controls (46.6% vs 39.1% respectively, p<0.007). Subsequent analyses revealed waxing and waning of CH over a subsequent 44mo period regardless of anemia. Also, it was noted that while VAF <5% did not impact overall survival, that >5% showed increased risk of death.

Wouters HJCM, et al. Association of anemia with health-related quality of life and survival: a large population-based cohort study. Haematologica, 2019; 104(3): 468-476. (https://doi.org/10.3324/haematol.2018.195552)

• The assessment of anemia and health related quality of life (HRQOL) measured by RAND-36 questionnaire in a population-based cohort demonstrated that anemia in individuals over 60 years of age has impact on their overall survival as well as HRQOL. While subjects younger that 60 years did not show similar correlation. Also, based on the impact on HRQOL and survival, the report identifies a need for considering the threshold of hemoglobin below 13g/dL in women 60 yrs or older as anemic.

Oh YJ, et al. Mutation of ten-eleven translocation-2 is associated with increased risk of autoimmune disease in patients with myelodysplastic syndrome. Korean J Intern Med, 2020; 35(2):457-464. ( 3904/kjim.2018.247 )

• This study explored if genetic mutations are linked with autoimmune disorders in MDS patients. Eighty-eight mutations were sequenced for 73 MDS patients (median age 70 y/o, 67.1% male). Autoimmune disorders (AID) were found in 16 (21.9%) patients and mutations were detected in 57 (78.1%) of patients. MDS patients with or without AID did not differ in percentage (68.8% vs. 80.7%) or mean number of mutations (1.8 ± 1.6 vs. 2.2 ± 1.8) with significance. Ten-eleven translocation-2 (TET2) mutation however was significantly higher in patients with AID vs without (31.3% vs. 5.3%). Thus, TET2 mutations in MDS patients may be linked to increased AID risk.

Elvarsdóttir EM, et al. A three dimensional in vitro model of erythropoiesis recapitulates erythroid failure in myelodysplastic syndromes. Leukemia, 2020;34(1):271-282. (https://pubmed.ncbi.nlm.nih.gov/31375745/)

• Using a modified scaffolding of collagen coated polyurethane 3D cultures were established with mononuclear cells (MNC) and CD34+ enriched bone marrow cells from healthy volunteers and MDS-RS patients. Such 3D cultures supported proliferation and differentiation of erythroid cells from CD34+ cells and multilineage growth from MNC for more than 4 weeks. Importantly, the cultures demonstrated significant erythroid differentiation including erythroid islands and enucleated erythrocytes, preserved RS phenotype and the SF3B1mutated clone. This technology could have significant implication in drug development for MDS.

Behbehani GK, et al. Profiling myelodysplastic syndromes by mass cytometry demonstrates abnormal progenitor cell phenotype and differentiation. Clin Cytometry, 2020; 98: 131-145. (https://pubmed.ncbi.nlm.nih.gov/31917512/)

• A high-dimensional single cell mass cytometry (MCM) in addition to previously reported surface anomalies also detected increased CD321 and CD99 expression and decreased CD47 expression. In hematopoietic stem progenitor compartment differentiated between MDS vs cytopenia of undetermined significance and finally the high-parameter MCM data identified abnormal differentiation patterns of myeloid cells that were immunophenotypically closer to myeloid derived suppressor cells.

Lin P et al. Isocitrate dehydrogenase 2 mutations correlate with leukemic transformation and are predicted by 2-hydroxyglutarate in myelodysplastic syndromes. J Cancer Res Clin Oncol, 2018; Mar 16 [Epub ahead of print]( https://www.ncbi.nlm.nih.gov/pubmed/29549529)

• In a genetic profiling study of 281 MDS patients, elevated levels of an oncogenic protein, 2-hydroxyglutarate (2HG) were found to correlate with inferior overall and leukemia-free survival as well as with the presence of IDH mutations. IDH2 mutations in particular, demonstrated a link with additional simultaneous mutations in DNMT3A and SRSF2 genes and showed higher rates of leukemic transformation. Lastly, IDH2 mutations were prognostic in low-risk MDS.

Montalban-Bravo G et al. Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. Oncotarget, 2018; 9(11): 9714-9727 ( https://www.ncbi.nlm.nih.gov/pubmed/29515765)

• The present report on whole exome sequencing of bone marrow samples from 83 MDS and 31 MDS/MPN patients detected mutations cumulatively in 31 genes in 86% patients. The multivariate analysis showed the impact of TP53 mutations (HR=3.1, p=0.011) and ≥3 concurrent mutations (HR=2.5, p=0.005) in predicting a shorter survival.

Schwartz JR et al. The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun, 2017; 8(1): 1557. (https://www.ncbi.nlm.nih.gov/pubmed/29146900)

• A genomic sequencing of 77 pediatric bone marrow samples with diagnosis of primary MDS, MDS/MPN or AML with MDS related changes revealed preponderance of RAS/MAPK pathway mutations (45% of Primary MDS), while mutations in RNA splicing genes were rare (2% of primary MDS). Newly in pediatric samples, germline variants were detected in SAMD9 and SAMD9L genes in 17% of primary MDS.

Balaian E et al. Erythropoietin inhibits osteoblast function in myelodysplastic syndromes via the canonical Wnt pathway. Haematologica, 2018; 103(1):61-68 (https://www.ncbi.nlm.nih.gov/pubmed/29079596)

• Upon in vitro erythropoietin (EPO) treatment, the expression of osteoblast specific genes and subsequent osteoblast mineralization increased in mesenchymal stromal cells from young healthy donors, while in the cells from old healthy donors and MDS patients, EPO did not have the same increase, rather inhibited cell differentiation and inhibited canonical Wnt pathway gene expression. Activation of Wnt pathway with lithium chloride or parathyroid hormone could rescue EPO inhibition of differentiation. EPO thus seems to uniquely modulate the osteo-hematopoietic niche in young age, vs old age donors and MDS patients.

Cull AH et al. Overexpression of arginase 1 is linked to DNMT3A and TET2 mutations in lower-grade myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Res, 2018; 65:5-13 (https://www.ncbi.nlm.nih.gov/pubmed/29227812)

• The report found elevated relative arginase-1 activity  in marrow mononuclear cells from patients with CMML (n=15), low grade MDS (n=12) and high grade MDS (n=12) compared to controls (n=8). This corresponded to the overexpression of arginase-1 protein in patients’ cells. Furthermore, immunohistochemistry showed higher protein expression in CMML and low grade MDS than the high grade MDS marrow biopsies. Lastly, DNMT3A and/or TET2 mutations were significantly enriched in patients with elevated arginase-1 activity (p=0.0386).

Ribeiro HL Jr et al. DNA repair gene expressions are related to bone marrow cellularity in myelodysplastic syndrome. J Clin Pathol, 2017; 70: 970-980 (https://www.ncbi.nlm.nih.gov/pubmed/28554891)

• The expression of genes related to nuclear excision (ERCC8, XPA and XPC), homologous recombination and non-homologous end-joining (ATM, BRCA1, BRCA2 and LIG4) repair mechanisms was evaluated in 51 MDS cases. Patients with hypocellular marrows showed decreased expression of ATM, BRCA1, BRCA2 and LIG4 (DNA double stranded repair genes), and increased expression of XPA and XPC (DNA single stranded repair genes). In hypoplastic marrows lower expression of the ATM, LIG4 and ERCC8 was associated with higher preponderance of chromosomal abnormalities as well.

Tefferi A et al. Targeted next-generation sequencing in myelodysplastic syndromes and prognostic interaction between mutations and IPSS-R. Am J Hematol, 2017; Sept 5 [Epub ahead of print]( https://www.ncbi.nlm.nih.gov/pubmed/28875545)

• Using a 27-gene next generation sequencing (NGS) panel in 179 cases of primary MDS, 82% patients were found to have at least one mutation/variant detectable with 23% harboring ≥ 3 mutations/variants. The top three frequent mutations/variants were ASXL1 (30%), TET2 (25%) and SF3B1 (20%). The three mutations that particularly showed impact on survival were ASXL1, SETBP1 and TP53 in the overall study population, however had no impact in IPSS-R low/very low subgroup. The report concludes that the number of mutations/variants did not add to conventional prognostication.

Neukirchen J et al. Cytogenetic clonal evolution in myelodysplastic syndromes is associated with inferior prognosis. Cancer, 2017; July 26. [Epub ahead of print] ( https://www.ncbi.nlm.nih.gov/pubmed/28746789)

• A longitudinal karyotype analysis of 549 patients from the Dusseldorf MDS registry demonstrated clonal evolution in 24% patients (18% among those treated with best supportive care). The clonal evolution was associated with an increased risk of leukemic transformation (HR=2.23, p=0.036) and poorer survival (HR=3.68, p<0.001). Similarly, detectability of cytogenetic subclones at diagnosis had a similar impact on survival and 5-year probability of leukemic transformation.

McGraw K and List A. Erythropoietin receptor signaling and lipid rafts. Vitam Horm, 2017; 105: 79-100. (https://www.ncbi.nlm.nih.gov/pubmed/28629526)

• The intactness of lipid bilayer membrane may be quintessential for EPO receptor signaling. Lipid rafts composed of densely packed sphingolipids and cholesterol provide a membrane microdomain for understanding the mechanics of EPO signaling. Disruption of lipid rafts impair EPO signaling which may thus help in a therapeutic assessment of EPO signaling deficiencies.

Hlaváčková A et al. Enhanced plasma protein carbonylation in patients with myelodysplastic syndromes.  Free Radic Biol Med 2017 Mar 12 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28300669)

• A total of 32 patients with MDS (RARS, RCMD, RAEB 1, or RAEB 2) were examined for protein carbonylation, indicative of reactive oxygen radical activity. These MDS patients and, in particular, the RARS category, showed elevated protein carbonylation as compared to healthy controls. Additionally, using tandem mass spectrometry, 27 uniquely carbonylated proteins were identified in RARS patients, the pathobiologic significance of which needs further exploration.

Diamantopoulos P et al. Poly(ADP-ribose) polymerase-1 mRNA levels strongly correlate with the prognosis of myelodysplastic syndromes. Blood Cancer J 2017; 7(2):e533. (https://www.ncbi.nlm.nih.gov/pubmed/28212373)

• The median PARP1 mRNA levels correlated with advanced disease among WHO 2008/2016 categories as well as among IPSS/IPSS-R categories. Moreover, the median overall survival and 5-yr survival rates were worse in patients with high vs. low PARP1 mRNA levels (OS- 37.4 mo vs not reached, p=0.0001, and 29.8% vs 88.9% respectively).

Makishima H et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet 2017; 49(2): 204-212. (https://www.ncbi.nlm.nih.gov/pubmed/27992414)

• Clonal dynamics were studied using whole exome and/or targeted sequencing of 699 patients (122/699 studied longitudinally). The number of mutations, their diversity and clone size increased at progression. A set of mutations including FLT3, PTPN11, WT1, IDH1/2, NPM1 and N-RAS grouped as Type 1, were found to be newly acquired at AML transformation, related to faster progression and poorer survival. On the other hand, another set of mutations enriched in higher risk MDS like TP53, GATA2, KRAS, RUNX1, ASXL1, ZRSF2, STAG2, and TET2 (Type2) did not correlate with AML progression or survival.

Westers TM et al. Immunophenotypic analysis of erythroid dysplasia in myelodysplastic syndromes. A report from the IMDS Flow working group. Haematologica 2017; 102(2):308-319. (https://www.ncbi.nlm.nih.gov/pubmed/27758818)

• This multicenter study of the IMDS Flow working group attempted to define flow parameters to distinguish MDS associated dyserythropoiesis from non-clonal cytopenias. In a multivariate analysis, expression of CD36 and CD71, intensity of CD71, and % CD117+ erythroid progenitors best discriminated MDS from non-clonal cytopenias. The high specificity (92%) of this marker set was verified in a validation cohort.

Cremers EM et al. Implementation of erythroid lineage analysis by flow cytometry in diagnostic models for myelodysplastic syndromes. Haematologica 2017; 102(2):320-326. (https://www.ncbi.nlm.nih.gov/pubmed/27658438)

• The study analyzed 167 bone marrow aspirates (106 MDS and 61 cytopenic controls). The results showed a correlation of the presence of erythroid aberrancies with MDS diagnosis and the addition of erythroid aberrancies to two different flow cytometric models increased sensitivity of detecting MDS.

Li B et al. Colony-forming unit cell (CFU-C) assays at diagnosis: CFU-GM cluster predicts survival in myelodysplastic syndrome patients independently of IPSS-R. Oncotarget 2016 Sept 18 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27655727)

• CFU-C assays of bone marrow samples from 365 consecutive newly diagnosed MDS patients with a median survival follow up of 22 mo, in multivariate analyses demonstrated that a cluster to CFU-G/M ratio of >0.6 was an independent risk factor for overall survival after adjusting for IPSS-R (HR-3.3, p=0.005). Additionally the study also showed significantly lower BFU-E, CFU-E and CFU-G/M in MDS than normal bone marrows

Obeng EA et al. Physiologic expression of SF3B1 (K700E) causes impaired erythropoiesis, aberrant splicing and sensitivity to therapeutic spliceosome modulation. Cancer Cell 2016; 30(3):404-417 (https://www.ncbi.nlm.nih.gov/pubmed/27622333)

• − SF3B1 mutations are frequent in MDS especially in RARS patients. The present study showed that introduction of a specific high frequency mutation SF3B1 (K700E) using a knockin mouse technique, caused erythroid dysplasia and macrocytic anemia. The spliceosome modulator, E7017 selectively killed the cells expressing SF3B1 (K700E), which may have therapeutic implications.

Hilgendorf S et al. Loss of ASXL1 triggers an apoptotic response in human hematopoietic stem and progenitor cells. Exp Hematol 2016, Sept 8 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27616637)

• ASXL1 is frequently mutated in MDS. Using a specific small interfering RNA transduced in human cord blood CD34+ cells, ASXL1 expression was knocked down. This resulted in a significant reduction in myeloid stem cell number as well as their expansion potential and in particular caused apoptosis of erythroid progenitors at all stages of differentiation.

Novakova M et al. Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome. Haematologica 2016 March 24 [Epub ahead of print](http://www.ncbi.nlm.nih.gov/pubmed/27013649)

• In pediatric population, the present study reported a 14% incidence of GATA-2 mutations in advanced MDS (RAEB/RAEB-t and MDS related AML) as compared to 17% in refractory cytopenia of childhood and 0% in aplastic anemia. The GATA-2-deficient MDS patients showed profound B cell lymphopenia including B cell progenitors in blood and bone marrow.

Zhang X et al. T-cell large granular lymphocyte proliferation in myelodysplastic syndromes: clinicopathological features and prognostic significance. Leuk Res 2016; 43:18-23. (http://www.ncbi.nlm.nih.gov/pubmed/26927701)

• A study comparing 35 MDS patients with T-cell large granular lymphocyte proliferation (T-LGL) with 36 patients without T-LGL demonstrated a significant difference in peripheral blood CD3+/CD157+ cell count (p<0.01). The presence of T-LGL proliferation in bone marrow was correlated with hypocellularity and erythroid hypoplasia. However, immunosuppressive treatment for T-LGL did not result in survival benefit.

Raimbault A et al. APG101 efficiently rescues erythropoiesis in lower risk myelodysplastic syndromes with severe impairment of hematopoiesis. Oncotarget 2016, Feb 18 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26910909)

• Two thirds of the low-risk MDS patients may overexpress CD95 correlating with poor erythropoiesis and that CD95 overexpression may indicate resistance to Erythropoiesis Stimulating Agents (ESAs). APG101, a fusion protein of the extracellular domain of CD95 conjugated with Fc portion of human IgG1 increased the number of burst forming units-erythroid (BFU-E) derived from CD34+ cells in vitro.

Komrokji R et al. Autoimmune diseases and myelodysplastic syndromes. Am J Hematol 2016, Feb 13 [Epub ahead of Print] (http://www.ncbi.nlm.nih.gov/pubmed/26875020)

• Among 1408 MDS patients, 391 (28%) patients had autoimmune diseases with hypothyroidism in 12% of total MDS patients as the highest incidence. Other frequently seen conditions (≥ 5% prevalence) were idiopathic thrombocytopenic purpura, rheumatoid arthritis, and psoriasis. Autoimmune diseases were most common in RA or RCMD and those with low blood transfusion dependency. Overall survival (60 mo) was better and rates of leukemic transformation (23%) was lower in patients with autoimmune diseases vs. those without (45 mo, p=0.006; 30%, p=0.011 respectively).

Patnaik M and Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer J 2016;6:e393 (http://www.ncbi.nlm.nih.gov/pubmed/26849014)

• This report reviewed frequent cytogenetic and genetic abnormalities observed in CMML patients and suggested that only nonsense and frameshift ASXL1 mutations might negatively impact overall survival. Based on such results, the current prognostic models including Molecular Mayo model and Groupe Francais des Myelodysplasies model have incorporated ASXL1 mutations as a prognostic factor.

Myelodysplastic syndrome macrophages have aberrant iron storage and heme oxygenase-1 expression. Leuk Lymphoma 2016 Jan 12 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26758041)

• Marrow iron was found to be elevated in MDS marrows (n=67) as compared to the age-matched cytopenic marrows (n=62) and was found to colocalize with heme oxygenase (HO1) protein expression and H-ferritin in CD163+ macrophages within MDS marrows. Moreover, high HO1 expression was significantly associated with shorter overall survival among MDS patients independent of IPSS-R and transfusion history.

Genga KR et al. Proteins of the mitotic checkpoint and spindle are related to chromosomal instability and unfavorable prognosis in patients with myelodysplastic syndrome. J Cell Pathol 2015;Jan 30 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25637637

• Immunohistochemistry for proteins, cell division cycle 20 (CDC20), mitotic arrest deficient 2 (MAD2) and the mitotic spindle kinase (Aurora B) in the bone marrow specimens from MDS patients revealed increased expression of all three proteins in patients with

Gjini E et al. A zebrafish model of myelodysplastic syndrome produced through tet2 genomic editing. Mol Cell Biol 2015; 35(5):789-804 http://www.ncbi.nlm.nih.gov/pubmed/25512612

• Somatic loss-of-function mutations in TET2 gene are frequently observed in MDS which impacts normal demethylation process. Using genome editing technology to disrupt Tet2 catalytic domain via homozygous mutation, authors created a zebrafish model that was viable and fertile with normal embryonic- and at-birth- hemopoiesis, but developed myeloid dysplasia and anemia with age.

Woll PS et al. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell 2014;25: 794-808. http://www.ncbi.nlm.nih.gov/pubmed/24835589

• In this seminal study, an assessment was made of somatic mutations observed in the MDS cases studied, via sequentially back-tracing in myeloid committed progenitors, to common progenitors to early stem cells. The study underscored Lin¯CD34⁺CD38¯CD90⁺ phenotype as the earliest stem cell that could propagate MDS phenotype in vivo. The study further focused on del5q- cases and found that it could be the isolated genetic abnormality in the stem cells as well as committed progenitors particularly early in the disease. The study also alluded to additional driver mutations like TP53 gene mutations occurring in the stem cell itself and/or in downstream progenitors that may offer self-renewal ability and may coincide with the process of disease progression and leukemic transformation.

Chen X et al. Induction of myelodysplasia by myeloid-derived suppressor cells. Clin Invest. 2013; 123(11): 4595-4611. http://www.ncbi.nlm.nih.gov/pubmed/?term=Chen+X+and+myelodysplasia

• The study demonstrated expansion of myeloid-derived suppressor cells typically linked with immunosuppression/inflammation, that via S100A9-CD33 ligand receptor pathway engage other immature myeloid cells into secreting suppressive cytokines like IL10 and TGFβ, which in turn may lead to marrow failure and multilineage cytopenia as shown by the study in a transgenic mouse model. Lastly, the study also demonstrated that disruption of CD33 signaling or all trans retinoic acid-induced maturation of these suppressor cells, could rescue the MDS phenotype in mice.

Scopim-Ribeiro R et al. Ten-Eleven-Translocation 2 (TET2) is downregulated in myelodysplastic syndromes. J.Haematol. 2014; Sept 8 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25200248

• As compared to normal bone marrows (n=22), the bone marrow cells of MDS (n=64) and AML (n=53) showed significantly decreased TET2 expression. Among MDS patients, RAEB-1/RAEB-2 patients especially showed lower expression of TET2 as compared to the other WHO 2008 MDS classification categories. Also, the leukemic progression coincided with a further drop in TET2 expression and in a multivariate analysis along with the WHO 2008 classification categories and male gender, loss of TET2 expression too predicted poorer overall survival.

Ganster C et al. New data shed light on Y-loss-related pathogenesis in myelodysplastic syndromes. Genes Chromosomes Cancer 2015 Sept 23 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26394808

•  The significance of Loss of Y-chromosome (LOY) in MDS was tested by determining the percentage of LOY in clonal CD34+ peripheral blood cells in comparison to normal CD3+ T-cells of 27 MDS patients using FISH analysis. The results were compared to those of 32 elderly men without hematologic diseases and 25 young blood donors. LOY was found in CD3+ cells of 5.8% of elderly MDS patients and 2.5% elderly men without hematologic diseases. In contrast LOY was significantly higher in CD34+ cells of the MDS patients versus the elderly men without hematologic disease (43.3% vs. 13.2%, p=0.005) indicating that LOY has age related basis but is also associated with MDS.

Malcovati L et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ringsideroblasts. Blood 2015;126(2):233-241. http://www.ncbi.nlm.nih.gov/pubmed/25957392

• A mutation analysis in relation to disease characteristics and patient outcome was performed on 293 patients with myeloid neoplasm with ≥ 1% ring sideroblasts. Particularly, SF3B1 mutation was evident in 81% of RARS/RCMD-RS. A multivariate analysis showed lower cumulative incidence of disease progression (p=0.018) and better overall survival (p=0.003). A co-existing mutation in DNA methylation gene was correlated to multilineage dysplasia in SB3F1 mutated patients without any further impact on patient outcome.

Reviews, Perspectives and Guidelines

The following articles provide significant review of literature and/or innovative perspective on the state-of-the-art in MDS or discuss therapeutic management guidelines and identify need for additional prospective studies.

• Kontandreopoulou C-N. Poly (ADP-ribose) polymerase-1 (PARP-1) as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood Adv, 2021; Sept 16 [Online ahead of print]. (DOI: 1182/bloodadvances.2021004638)

• Komrokji R, et al. Validation of the international working group proposal for SF3B1 mutant myelodysplastic syndromes. Blood, 2021; 138(11):989-992.  (DOI: 1182/blood.2021010831)

• Parker WB and Thottassery JV. 5-Aza-4’-thio-2’-deoxycytidine, a new orally bioavailable non-toxic “best-in-class” DNMT1 depleting agent in clinical development. J Pharmacol Exp Ther, 2021; Sept 9 [Online ahead of print]. (DOI: 1124/jpet.121.000758)

• Santini V. Advances in myelodysplastic syndrome. Curr Opin Oncol, 2021; Sept 1 [Online ahead of print] (DOI: 1097/CCO.0000000000000790)

• Hecker JS, Paschzelt L, and Götze KS. Are myelodysplastic syndromes ready for venetoclax? Exploring future potential and considerations. Expert Rev Hematol, 2021; 14(9):789-793. (DOI: 1080/17474086.2021.1968822)

• Patel SS. Pediatric myelodysplastic syndromes Clin Lab Med, 2021; 41(3):517-528. (DOI: 1016/j.cll.2021.03.015)

• Schiffer M, et al. The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: Dawn of the total oral therapy era. Expert Rev Anticancer Ther, 2021; 21(9):989-1002. (DOI: 1080/14737140.2021.1918002)

• Platzbecker U, Kubasch AS, Bouthiette CH, and Prebet T. Current challenges and unmet medical needs in myelodysplastic s Leukemia, 2021; 35(8): 2182-2198. (DOI: 10.1038/s41375-021-01265-7)

• Kasprzak A, et al. Guidelines for myelodysplastic syndromes: converting evidence into action? Int J Environ Res Public Health, 2021; 18(14): 7629. (DOI: 3390/ijerph18147629)

• Ferrara F and Bernardi M. 2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease. Br J Haematol, 2021; 194(2):235-237. (DOI: 1111/bjh.17640)

• Killick SB, et al. British society for haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol, 2021; 194(2): 267-281. (DOI: 1111/bjh.17612)

• Killick SB, et al. British society for haematology guidelines for the diagnosis and evaluation of prognosis of adult myelodysplastic syndromes. Br J Haematol, 2021; 194(2): 282-293. (DOI: 1111/bjh.17621)

• Hellstrom-Lindberg E, Tobiasson M, Greenberg PL. Centenary Review: Myelodysplastic Syndromes: Moving towards personalized management. Haematologica, 2020; 105:1765-1769. (DOI: 3324/haematol.2020.248955)

• Greenberg PL. Metchnikoff’s Inflamed Legacy: The Dysplastic Nature of Myelodysplastic Syndrome’s Innate Immunity (Editorial). Haematologica 2021; Aug 5 [Online ahead of print] (DOI: 3324/haematol.2021.279419)

• Kontandreopoulou C-N. Poly (ADP-ribose) polymerase-1 (PARP-1) as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome. Blood Adv, 2021; Sept 16 [Online ahead of print]. (DOI: 1182/bloodadvances.2021004638)

• Komrokji R, et al. Validation of the international working group proposal for SF3B1 mutant myelodysplastic syndromes. Blood, 2021; 138(11):989-992.  (DOI: 1182/blood.2021010831)

• Parker WB and Thottassery JV. 5-Aza-4’-thio-2’-deoxycytidine, a new orally bioavailable non-toxic “best-in-class” DNMT1 depleting agent in clinical development. J Pharmacol Exp Ther, 2021; Sept 9 [Online ahead of print]. (DOI: 1124/jpet.121.000758)

• Santini V. Advances in myelodysplastic syndrome. Curr Opin Oncol, 2021; Sept 1 [Online ahead of print] (DOI: 1097/CCO.0000000000000790)

• Hecker JS, Paschzelt L, and Götze KS. Are myelodysplastic syndromes ready for venetoclax? Exploring future potential and considerations. Expert Rev Hematol, 2021; 14(9):789-793. (DOI: 1080/17474086.2021.1968822)

• Patel SS. Pediatric myelodysplastic syndromes Clin Lab Med, 2021; 41(3):517-528. (DOI: 1016/j.cll.2021.03.015)

• Schiffer M, et al. The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: Dawn of the total oral therapy era. Expert Rev Anticancer Ther, 2021; 21(9):989-1002. (DOI: 1080/14737140.2021.1918002)

• Platzbecker U, Kubasch AS, Bouthiette CH, and Prebet T. Current challenges and unmet medical needs in myelodysplastic s Leukemia, 2021; 35(8): 2182-2198. (DOI: 10.1038/s41375-021-01265-7)

• Kasprzak A, et al. Guidelines for myelodysplastic syndromes: converting evidence into action? Int J Environ Res Public Health, 2021; 18(14): 7629. (DOI: 3390/ijerph18147629)

• Ferrara F and Bernardi M. 2021 BSH guidelines for the management of adult myelodysplastic syndromes: a practical approach to a challenging disease. Br J Haematol, 2021; 194(2):235-237. (DOI: 1111/bjh.17640)

• Killick SB, et al. British society for haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol, 2021; 194(2): 267-281. (DOI: 1111/bjh.17612)

• Killick SB, et al. British society for haematology guidelines for the diagnosis and evaluation of prognosis of adult myelodysplastic syndromes. Br J Haematol, 2021; 194(2): 282-293. (DOI: 1111/bjh.17621)

• Hellstrom-Lindberg E, Tobiasson M, Greenberg PL. Centenary Review: Myelodysplastic Syndromes: Moving towards personalized management. Haematologica, 2020; 105:1765-1769. (DOI: 10.3324/haematol.2020.248955)

• Greenberg PL. Metchnikoff’s Inflamed Legacy: The Dysplastic Nature of Myelodysplastic Syndrome’s Innate Immunity (Editorial). Haematologica 2021; Aug 5 [Online ahead of print] (DOI: 10.3324/haematol.2021.279419)

• Kipp D and Wei AH. The path to approval for oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes. Future Oncol, 2021; Mar 26 [Online ahead of print]. (https://doi.org/10.2217/fon-2020-1318)

• Bewersdorf JP and Zeidan AM. Management of patients with higher-risk myelodysplastic syndromes after failure of hypomethylating agents: what is on the horizon? Best Pract Res Clin Haematol, 2021; 34(1):101245. (https://doi.org/10.1016/j.beha.2021.101245)

• Hasserjian RP. Controversies in the recent (2016) world health organization clarification of acute myeloid leukemia. Best Pract Res Clin Haematol, 2021; 34(1):101249. (https://doi.org/10.1016/j.beha.2021.101249)

• Kantarjian HM, et al. Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach. Cancer, 2021; Mar 18 [Online ahead of print] (https://doi.org/10.1002/cncr.33477)

• Schwotzer N, et al. Spectrum of kidney involvement in patients with myelodysplastic syndromes. Kidney Int Rep, 2021; 6(3):746-754. (https://doi.org/10.1016/j.ekir.2020.12.030)

• Kubasch AS, Fenaux P and Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv, 2021; 5(5):1565-1575. (https://doi.org/10.1182/bloodadvances.2020002177)

• Feld J, Silverman L and Navada SC. Forsaken pharmaceutical: Glasdegib in acute myeloid leukemia and myeloid diseases Clin Lymphoma Myeloma Leuk, 2021;21(4): e415-e422. (https://doi.org/10.1016/j.clml.2020.12.007)

• Garcia JS. Prospects for Venetoclax in myelodysplastic syndromes. Hematol Oncol Clin North Am, 2020; 34(2):441-448. (https://doi.org/10.1111/bjh.16206)

• Hunter AM and Sallman DA. Targeting TP53 mutations in myelodysplastic syndromes. Hematol Oncol Clin North Am, 2020; 34(2):421-440.  (https://doi.org/10.1016/j.hoc.2019.11.004)

• McCullough KB and Patnaik MM. Myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes-Advances in treatment. Best Pract Res Clin Haematol, 2020; 33(2): 101130. (https://doi.org/10.1016/j.beha.2019.101130)   

• Hellström-Lindberg E, Tobiasson M and Greenberg P. Myelodysplastic syndromes: Moving towards personalized management. Haematologica, 2020; 105(7):1765-1779. (https://doi.org/10.3324/haematol.2020.248955)    

• Komrokji R. Luspatercept in myelodysplastic syndromes: Who and When? Hematol Oncol Clin North Am, 2020; 34(2):393-400.( https://doi.org/10.1016/j.hoc.2019.10.004)

• Park S et al., The prognostic value of serum erythropoietin in patients with lower-risk myelodysplastic syndromes: a review of the literature and expert opinion. Ann Hematol, 2020;9(1): 7-19. (https://doi.org/10.1007/s00277-019-03799-4)

• Bewersdorf JP and Zeidan AM. Following in the footsteps of acute myeloid leukemia: are we witnessing the start of a therapeutic revolution for higher risk myelodysplastic syndromes? Leuk Lymphoma, 2020; 61(10): 2295-2312. (1080/10428194.2020.1761968 )

• Mittelman M. Balanced translocations in myelodysplastic syndromes (MDS)- an unrecognized MDS patient subgroup? Br J Haematol, 2020; 190(2): 141-142. (1111/bjh.16641 )

• Fenaux P, Platzbecker U and Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol, 2019; Sept 30 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31568568/)

• Fenaux P, Kiladjian J and Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood, 2019; 133(8): 790-794. (https://pubmed.ncbi.nlm.nih.gov/30602619/)

• Komrokji R. Luspatercept in myelodysplastic syndromes: Who and When?. Hematol Oncol Clin North Am, 2020; 34(2): 393-400. (https://pubmed.ncbi.nlm.nih.gov/32089218/)

• Santini V. How I treat MDS after hypomethylating agent failure. Blood, 2019; 133(6):521-529. (https://pubmed.ncbi.nlm.nih.gov/30545832/)

• Komrokji R. Activin receptor II ligand traps: new treatment paradigm for low-risk MDS. Curr Hematol Malig Rep, 2019;14(4):346-351. (https://pubmed.ncbi.nlm.nih.gov/31203517/)

• Spaulding TP et al. The evolving role of next generation sequencing in myelodysplastic syndromes. Br J Haematol, 2019; Oct 1 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31571207)

• Kubasch AS and Platzbecker U. The wolf of hypomethylating agent failure: what comes next? Haematologica, 2019; 104(8): 1505-1508.  (https://www.ncbi.nlm.nih.gov/pubmed/31366462)

• Germing U et al. Novel therapies in low- and high-risk myelodysplastic syndrome. Expert Rev Hematol 2019; 12(10): 893-908. (https://www.ncbi.nlm.nih.gov/pubmed/31353975)

• Loghavi S and Wang SA. Defining boundary between myelodysplastic syndromes and myeloproliferative neoplasms. Surg Pathol Clin, 2019; 12(3):651-669. (https://www.ncbi.nlm.nih.gov/pubmed/31352979)

• Gil-Perez A and Montalban-Bravo G. Management of myelodysplastic syndromes after failure of response to hypomethylating agents. Ther Adv Hematol 2019; 10 eCollection. (https://www.ncbi.nlm.nih.gov/pubmed/31156799)

• Kaplan HG, Malmgren JA and Calip GS. Granulocyte colony-stimulating factors in therapy-related myelodysplastic syndrome and acute myeloid leukemia. JAMA Oncol, 2019; 5(7):1065-1066. (https://www.ncbi.nlm.nih.gov/pubmed/31070689)

• Adés L, Serbet M, Fenaux P. Guadecitabine in myelodysplastic syndromes: promising but there is still progress to be made. Lancet Haematol, 2019;6(6):e290-e291. (https://www.ncbi.nlm.nih.gov/pubmed/31060978)

• Valent P et al. Proposed diagnostic criteria for Classical chronic myelomonocytic leukemia (CMML), CMML Variants and Pre-CMML Conditions. Haematologica, 2019, 104(10):1935-1949. (https://www.ncbi.nlm.nih.gov/pubmed/31048353)

• Daver N et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia, 2018; Feb 22, [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/29487386)

• Steensma DP. Prognosis in myelodysplastic syndromes: The attractions and limitations of simplicity. Am J Hematol, 2018; Feb 16, [Epub ahead of print]  (https://www.ncbi.nlm.nih.gov/pubmed/29451319)

• List A, Ebert BL and Fenaux P. A decade of progress in myelodysplastic syndrome with chromosome 5q deletion. Leukemia, 2018; Jan 30, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29445113)

• Shallis RM and Zeidan AM. Lenalidomide in non-deletion 5q lower-risk myelodysplastic syndromes: a glass quarter full or three quarters empty? Leuk Lymphoma, 2018; Feb 7, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29411698)

• Montalban-Bravo G and Garcia-Manero G. Myelodysplastic syndromes: 2018 update on diagnosis, risk stratification and management. Am J Hematol, 2018; 93(1):129-147. (https://www.ncbi.nlm.nih.gov/pubmed/29214694)

• Steensma DP. The evolving role of genomic testing in assessing prognosis of patients with myelodysplastic syndromes. Best Pract Res Clin Haematol, 2017; 30(4):295-300. (https://www.ncbi.nlm.nih.gov/pubmed/29156198)

• Sallman DA, Tanaka TN, List A and Bejar R. SOHO state of the art update and next questions: Biology and treatment of myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk, 2017; 17(10):613-620. (https://www.ncbi.nlm.nih.gov/pubmed/29025689)

• Furutani E and Shimamura A. Germline genetic predisposition to hematologic malignancy. J Clin Oncol, 2017:35(9):1018-1028 (https://www.ncbi.nlm.nih.gov/pubmed/28297620)

• Galán-Díez, Cuesta-Domínguz Á, and Kousteni S. The bone marrow microenvironment in health and myeloid malignancy Cold Spring Harb Perspect Med, 2017; Sept 29, [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28963115)

• Cargo C and Bowen D. Individual risk assessment in MDS in the era of genomic medicine. Semin Hematol, 2017; 54(3): 133-140. (https://www.ncbi.nlm.nih.gov/pubmed/28958286)

• Miles A and Platzbecker U. Increasing effectiveness of hematopoiesis in myelodysplastic syndromes: erythropoiesis stimulating agents and transforming growth factor-β superfamily inhibitors. Semin Hematol, 2017; 54(3):141-146. (https://www.ncbi.nlm.nih.gov/pubmed/28958287)

• Madanat Y and Sekeres MA. Optimizing the use of hypomethylating agents in myelodysplastic syndromes: selecting the candidate, predicting the response and enhancing the activity. Semin Hematol, 2017; 54(3):147-153. (https://www.ncbi.nlm.nih.gov/pubmed/28958288)

• Pardo-Pastor J et al. Image gallery: Pyoderma gangrenosum in a patient with myelodysplastic syndrome treated with azacitidine. Br J Dermatol, 2017; 177(3):e68. (https://www.ncbi.nlm.nih.gov/pubmed/28940271)

• Zeidan AM, Pullarkat VA and Komrokji RS. Overcoming barriers to treating iron overload in patients with lower risk myelodysplastic syndrome. Crit Rev Oncol Hematol, 2017; 117:57-66. (https://www.ncbi.nlm.nih.gov/pubmed/28807236)

• Santini V. First-line therapeutic strategies for myelodysplastic syndromes. Clin Lymphoma Myeloma, 2017; 17S:S31-S36. (https://www.ncbi.nlm.nih.gov/pubmed/28760300)

• Boddu P et al. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma, 2017: Jul 6. [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28679300)

• Stahl M and Zeidan AM. Management of lower-risk myelodysplastic syndromes without del 5q; current approach and future trends. Exp Rev Hematol 2017; 10(4): 345-364. (https://www.ncbi.nlm.nih.gov/pubmed/2827785)

• Greenberg PL et al. Myelodysplastic syndromes, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2017; 15(1):60-87. (https://www.ncbi.nlm.nih.gov/pubmed/28040720)

• Almeida A et al. Recent advances in the treatment of lower-risk non del(5q) myelodysplastic syndromes (MDS). Leuk Res 2017;52:50-57. (https://www.ncbi.nlm.nih.gov/pubmed/27883945)

• Bejar R and Greenberg PL. The impact of somatic and germline mutations in myelodysplastic syndromes and related disorders. J Natl Compr Canc Netw 2017; 15(1): 131-135. (https://www.ncbi.nlm.nih.gov/pubmed/28040723)

• Bejar R. Implications of molecular genetic diversity in myelodysplastic syndromes. Curr Opin Hematol. 2017;24(2):73-78. (https://www.ncbi.nlm.nih.gov/pubmed/27875374)

• Wlodarski MW et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood, 2016; 127 (11): 1387-1397. (https://www.ncbi.nlm.nih.gov/pubmed/26702063)

• Bigenwald C et al. Are myelodysplastic syndromes and acute myeloid leukemia occurring during the course of lymphoma always therapy related? Br J Haematol 2016 Sept 23 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27662562)

• Bhatt VR and Steensma DP. Hematopoietic cell transplantation for myelodysplastic syndromes. J Oncol Pract 2016; 12(9):786-792. (https://www.ncbi.nlm.nih.gov/pubmed/27621329)

• Zeidan AM, Stahl M and Komrokji R. Emerging biologic therapies for the treatment of myelodysplastic syndromes. Expert Opin Emerg Drugs 2016; 21(3): 283-300 (https://www.ncbi.nlm.nih.gov/pubmed/27486848)

• Platzbecker U and Fenaux P. Recent frustration and innovation in myelodysplastic syndrome. Haematologica 2016; 101(8):891-893 (https://www.ncbi.nlm.nih.gov/pubmed/27478197)

• Navada SC and Silverman LR. The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther 2016; 16(8): 805-810 (https://www.ncbi.nlm.nih.gov/pubmed/27400247)

• Malcovati L and Cazzola M. Recent advances in the understanding of myelodysplastic syndromes with ring sideroblasts. Br J Haematol 2016; 174(6): 847-858 (https://www.ncbi.nlm.nih.gov/pubmed/27391606)

• Rivera G, Saramipoor Behbahan I and Greenberg P. Immune checkpoint pathways: perspectives on myeloid malignancies. Leuk Lymphoma 2016 Feb 25 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26916355)

• Stahl M et al. Lost in translation? Ten years of development of histone deacetylase inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Expert Opin Investig Drugs 2016; 25(3):307-317. (http://www.ncbi.nlm.nih.gov/pubmed/26807602)

• Niscola P, Mandelli F and Efficace F. Improving accuracy of prognosis in patients with myelodysplastic syndromes using self-reported quality of life data. Opportunities for a new research agenda in developing prognostic models. Exp Rev Hematol 2016 Mar 24 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26954305)

The present editorial provides commentary on these researchers’ prior study demonstrating value of adding patient self-reported fatigue to existing prognostic tools such as IPSS, IPSS-R, and WPSS with a significant benefit in overall survival.

• Mughal TI et al. An international MDS/MPN working group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2015; 100(9): 1117-1130. http://www.ncbi.nlm.nih.gov/pubmed/26341525

• Komrokji RS. Treatment of higher-risk myelodysplastic syndromes after failure of hypomethylating agents. Clin Lymphoma Myeloma Leuk 2015 June 15 Suppl: S56-S59. http://www.ncbi.nlm.nih.gov/pubmed/26297279

• Greenberg PL. Synergistic interactions of molecular and clinical advances for characterizing the myelodysplastic syndromes. J Natl Compr Netw 2015; 13(7):829-832. http://www.ncbi.nlm.nih.gov/pubmed/26150576

• Steensma DP. Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc 2015; 90(7): 969-983. http://www.ncbi.nlm.nih.gov/pubmed/26141335

• Deeg J. Treatment ethics, quality of life and health economics in the management of hematopoietic malignancies in older patients. Bone Marrow Transplant 2015; 50(9): 1145-1149. http://www.ncbi.nlm.nih.gov/pubmed/26052908

• Jonas BA and Greenberg PL. MDS Prognostic Scoring Systems – Past, Present and Future. In Best Practice & Research, Clinical Haematology, Editor-in-Chief: M. Tallman, 
Virginia Klimek, Elsevier, Inc: Myelodysplastic syndrome. Vol 28 (1): 3-13, 2015. http://www.ncbi.nlm.nih.gov/pubmed/25659725

• Greenberg PL et al. Myelodysplastic syndromes: version 2.2015 J Natl Compr Canc Netw. 2015; 13(3): 261-272. (http://www.ncbi.nlm.nih.gov/pubmed/25736003)

• Sekeres MA and Gerds AT. Established and novel agents for myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program 2014; 1: 82-89 (http://www.ncbi.nlm.nih.gov/pubmed/25696839)

• Klimek V (Ed). Myelodysplastic Syndromes. Best Practice Res Clin Hematol 2015; 28(1):1-68. (Special Issue with several pertinent review articles)

• Santini V and Fenaux P. Treatment of myelodysplastic syndrome with thrombomimetic drugs. Semin Hematol 2015; 52(1); 38-45http://www.ncbi.nlm.nih.gov/pubmed/25578418

• Zeidan AM et al. Current state of prognostication and risk stratification in myelodysplastic syndromes. Curr Opin. Hematol. 2015; 22(2): 146-154 http://www.ncbi.nlm.nih.gov/pubmed/25575032

• Jhanwar S. Genetic and epigenetic pathways in myelodysplastic syndromes: a brief overview. Adv Biol Regul. 2014, Nov 20 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25499150

• Fenaux P et al. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Oncol. 2014; 25(suppl.3): iii57-iii69 http://www.ncbi.nlm.nih.gov/pubmed/25185242

• Porwit A et al. Revisiting guidelines for integration of flow cytometry results in the WHO classification of myelodysplastic syndromes- proposal from the International/European LeukemiaNet Working Group for flow cytometry in MDS. Leukemia 2014; 28(9):1793-1798. http://www.ncbi.nlm.nih.gov/pubmed/24919805

• Bejar R and Steensma DP. Recent developments in myelodysplastic syndromes. Blood 2014; Sept 18 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25237199

• Tefferi A. Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. J. Hematol. 2014; 89(9): 915-925 http://www.ncbi.nlm.nih.gov/pubmed/25124313

• Duong VH, Komrokji RS and List AF. Update on the pharmacotherapy for myelodysplastic syndromes. Expert Opin. Pharmacother. 2014; 15(13): 1811-1825 http://www.ncbi.nlm.nih.gov/pubmed/25080144

• Gale RP, Bennett JM, and Hoffman FO. Therapy-related AML: A slip of the lip can sink a ship. Res. 2014;38(3):418-420. http://www.ncbi.nlm.nih.gov/pubmed/24439054

Quality of Life

Luskin MR et al. Self-reported sleep disturbance and survival in myelodysplastic syndromes. Br J Haematol 2017 Mar 8 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28272741)

• In a single institution study with MDS patients, using the “European organization for research and treatment of cancer quality of life questionnaire,” multivariable models showed that anemia and sleep disturbance were both associated with fatigue (p<0.001). Additionally, sleep disturbance (p=0.002) and fatigue (p=0.04) were individual predictors of overall survival.

Treatment:

Stojikov I, et al. Core set of patient-reported outcomes for myelodysplastic syndromes- EUMDS Delphi study in patients and hematologists. Blood Adv, 2021; Sept 7 [Online ahead of print] (DOI: 1182/bloodadvances.2021004568)

• As a part of the prospective European LeukemiaNet MDS (EUMDS) registry, a 2-round survey was conducted with MDS patients and hematologists for the selection of preferred PRO measures out of 40 well selected instruments based on a systematic MDS literature search. Per the agreement between patients and hematologists, and based on predefined inclusion criteria, “general quality of life” was chosen by both patients and hematologists. Whereas, hematologists also selected two additional measures, “transfusion-dependency burden” and “ability to work/activities of daily living.”

Abel GA, et al. Peri-transfusion quality of life assessment for patients with myelodysplastic syndromes. Transfusion, 2021; July 12 [Online ahead of print] (DOI: 1111/trf.16584)

• A total of 62 MDS patients were enrolled in the study, of which 37 completed 1-day- pre- and 7-day-post- RBC transfusion questionnaires (QOL in myelodysplasia scale (QUALMS)). Among these 37 patients, 35% reported increased QUALMS score, 46% had no change and 19% reported a decrease post transfusion. Also, 23% reported that their physician discussed the results before next transfusion.

Amitai I, et al. Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study. Br J Haemaol, 2021; 194(2): 319-324. (DOI: 1111/bjh.17537)

• This analysis of Canadian MDS registry attempted to validate the Fatigue-international prognostic scoring system among higher risk MDS patients. The use of EORTC Quality of life-core 30 (QLQ-C-30) instrument with threshold of ≥45 points, in higher IPSS risk group stratified patients into distinct groups with different survival outcomes. These findings were further validated with Revised IPSS and other fatigue scales.

Uckun FM, et al. A clinical phase 1B study of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancers (Basel), 2021; 13(16): 4113. (DOI: 3390/cancers13164113)

• A total of 46 RR AML/MDS patients who had failed multiple lines of prior therapy received APVO436 weekly as iv infusion at 10 dose levels between 0.3mcg to 60mcg. Maximum tolerable dose (MTD) was not reached at 60mcg weekly. Infusion related reaction was the most common AE seen in 28.3% patients, along with cytokine release syndrome (CRS) in 21.7% patients. The recommended phase 2 dose was determined at 0.2mcg/kg which showed appreciable clinical response including a CR.

Bewersdorf JP, et al. Venetoclax-based combination in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant. Leuk Lymphoma, 2021; Sept 3 [Online ahead of print] (DOI: 1080/10428194.2021.1966788)

• A retrospective study of AML/High-risk MDS patients from Memorial Sloan Kettering Cancer Center and Yale University, who received venetoclax either prior to or after allo-HCT between 2016 and 2020 showed 1-year OS rate of 79% in those receiving venetoclax before and 43.4% in those receiving after allo-HCT. These results demonstrate the feasibility of venetoclax therapy as a salvage regimen.

Kantarjian H, et al. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer, 2021; Aug 23 [Online ahead of print] (DOI: 1002/cncr.33828)

• An oral nucleoside analogue, Sapacitabine was tested in an alternating cycles with decitabine. In a phase 3 randomized multicenter international study, elderly patients of ≥ 70 years age who were not candidates for standard induction chemotherapy were randomized 1:1 to receive decitabine (20 mg/m² 1-hr iv qd x 5 d every 8wk) in alternating cycles with sapacitabine in the test arm or decitabine alone in the control arm with same dosing in a every 4 week cycle. Patients with prior hypomethylating agent exposure were excluded. The primary endpoint was OS. A total of 482 patients were randomized to decitabine-sapacitabine vs decitabine monotherapy (n=241 each). The OS and CR rates were comparable between arms (OS: 5.9 mo vs 5.7 mo respectively, p=0.8902; CR: 16.6% vs 10.8% respectively, p=0.1468). However, in patients with low baseline WBC <10×10⁹/L, OS and CR were higher with sequential therapy than control monotherapy (n=321) (OS: 8.0mo vs 5.8mo respectively, p=0.145 and CR: 21.5% vs 8.6% respectively, p=0.0017).

Swaminathan M, et al. A phase I/II study of the combination of quizartinib with azacytidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome. Haematologica, 2021; 106(8):2121-2130. (DOI: 3324/haematol.2020.263392)

• AML patients FLT3-like tyrosine kinase-3-internal tandem duplication (FLT3-ITD) mutations receiving first salvage therapy (n=39) or previously untreated MDS/AML patients with >60 years age (n=34) were treated with quizartinib plus azacytidine (AZA) or low dose cytarabine (LDAC). The composite response rate among previously untreated patients was 87% (13/15; CR-8) with quizartinib+AZA and 74% (14/19; CR=1) in quizartinib+LDAC with median OS/relapse free survival (RFS) of 19.2/10.5 mo and 8.5/6.4 mo respectively. Among previously treated patients the composite response rate and median OS with two treatments were, 64%/12.8mo vs 29%/4mo respectively.

Shimoni A, et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT. Br J Haematology, 2021; Sept 12 [Online ahead of print] (DOI: 1111/bjh.17817 )

• Reduced intensity conditioning (RIC) is known for lower non-relapse mortality and higher relapse rates as compared to myeloablative conditioning (MAC). The assessment of post-allogeneic transplant outcomes, compared a type of RIC with Fludarabine/treosulfan (FT, n=367), with traditional RIC (n=687) and MAC(n=668). Besides the older age in FT and RIC compared to MAC, there were no other differences in baseline characteristics among the three groups. After a median f/u of over 5 years (64mo), FT matched RIC in lower NRM (30% and 27% respectively) vs MAC (34%, p=0.008), while it showed lower 5-year relapse comparable to MAC (25% for both) vs RIC (38%). In a multivariate analysis, FT was associated with lower risk of relapse (HR=0.55, p<0.001) and better OS (HR=0.72, p<0.01). Authors concluded that FT may a preferred regimen for allogeneic-hematopoietic cell transplant in MDS.

Kurosawa S et al, Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis. Bone Marrow Transplant, 2021; Sept 7 [Online ahead of print] (DOI: 1038/s41409-021-01447-y)

• While Fludarabine/busulfan (Flu/Bu4) is effective in myeloablation prior to allo-HSCT in AML, it is not established in MDS. The nationwide registry data from Japan between 2006 and 2018 was reviewed (N=2482) for comparison of allo-HSCT outcomes with Flu/Bu4 (n=153) versus Busulfan/Cyclophosphamide (Bu4/Cy, n=153) conditioning in MDS patients. The cumulative non-relapse mortality, cumulative incidence of relapse, the 3-year progression free survival or the 3-year OS were not significantly different with the two conditioning regimens.

Wei Y, et al. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci, 2021; 112(9): 3636-3644. (DOI: 1111/cas.15048)

• A combination of Low dose decitabine (LDEC, 15mg/m² day 1-3) with venetoclax (VEN, 200mg day 1-21) in a 2 mo cycle x 10 cycles, was tested in a prospective study of 20 AML/high-risk MDS patients starting approximately on day 100 post-transplantation. The median follow up was approximately 20 mo. For primary end points, the median 2-year event-free survival (EFS) was 17.5mo (525 days) with 17 patients event free. The most common adverse events (AEs) were neutropenia, anemia, thrombocytopenia, neutropenic fever and fatigue. No >3 grade AEs were observed. GVHD of any grade was observed in 55% patients.

Modi D, et al. Post-transplant cyclophosphamide versus thymoglobulin in HLA-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transplant Cell Ther, 2021;27(9): 760-767. (DOI: 1016/j.jtct.2021.06.018)

• This retrospective study of 76 patients with AML or MDS assessed (2006-2019) the efficacy and safety of two GVHD prophylaxis regimens post-transplant with HLA mismatched unrelated donor. Cyclophosphamide (50mg/kg on day 3 and 4) treatment was compared with thymoglobulin (total dose 4.5 mg/kg). Although, the grade 3-4 acute GVHD at day 100 did not show significant difference (12% vs 19,6%, p=0.38), chronic GVHD at 1 year was significantly lower with cyclophosphamide (16% vs 49%, p=0.006). Also with cyclophosphamide, the median time to engraftment was shorter for both neutrophils (15 vs 11days, p<0.001) and platelets (21 vs 15 days, p=0.002). No difference in OS, relapse rate, relapse free survival or GVHD-free relapse-free survival were noted with the two agents tested. In a propensity-score-based multivariate analysis, besides higher acute and chronic GVHD incidence, higher non-relapse mortality was demonstrated with thymoglobulin compared to cyclophosphamide.

Rozema J, et al. Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study. Transfusion, 2021; Sept 3 [Online ahead of print] (DOI: 1111/trf.16631)

• An observational, retrospective, population-based study of MDS patients (n=292) from the HemoBase registry in a Friesland province of the Netherlands (2005-2017), showed high RBC transfusion burden (HTB >8units/16wk) in 46.6% patients and low transfusion burden (LTB) in 5.8% patients. Once univariate and multivariable regression analyses were performed, the odds ratio for HTB was particularly high in patients aged 75-84 years, or those with high risk MDS or MDS-EB-2.

Komrokji R, et al. Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Leuk Lymphoma, 2021; Aug 27 [Online ahead of print] (DOI: 1080/10428194.2021.1971217)

• MDS/MPN-RS-T is characterized by anemia, ring sideroblasts, and persistent thrombocytosis. 167 MDS/MPN-RS-T patients at a single institute (Moffitt, USA) were evaluated to compare the hematological improvement (HI) response rates among different therapies, including lenalidomide. 84% patients had SF3B1 mutations and 43% had JAK2 V617F mutations. Overall, 46% patients received erythropoiesis stimulating agents (ESA), 28% had lenalidomide and 27% got hypomethylating agents (HMA). The HI rate with the three treatments were 58%, 53% and 24% respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMA.

Stojikov I, et al. Core set of patient-reported outcomes for myelodysplastic syndromes- EUMDS Delphi study in patients and hematologists. Blood Adv, 2021; Sept 7 [Online ahead of print] (DOI: 1182/bloodadvances.2021004568)

• As a part of the prospective European LeukemiaNet MDS (EUMDS) registry, a 2-round survey was conducted with MDS patients and hematologists for the selection of preferred PRO measures out of 40 well selected instruments based on a systematic MDS literature search. Per the agreement between patients and hematologists, and based on predefined inclusion criteria, “general quality of life” was chosen by both patients and hematologists. Whereas, hematologists also selected two additional measures, “transfusion-dependency burden” and “ability to work/activities of daily living.”

Abel GA, et al. Peri-transfusion quality of life assessment for patients with myelodysplastic syndromes. Transfusion, 2021; July 12 [Online ahead of print] (DOI: 1111/trf.16584)

• A total of 62 MDS patients were enrolled in the study, of which 37 completed 1-day- pre- and 7-day-post- RBC transfusion questionnaires (QOL in myelodysplasia scale (QUALMS)). Among these 37 patients, 35% reported increased QUALMS score, 46% had no change and 19% reported a decrease post transfusion. Also, 23% reported that their physician discussed the results before next transfusion.

Amitai I, et al. Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study. Br J Haemaol, 2021; 194(2): 319-324. (DOI: 1111/bjh.17537)

• This analysis of Canadian MDS registry attempted to validate the Fatigue-international prognostic scoring system among higher risk MDS patients. The use of EORTC Quality of life-core 30 (QLQ-C-30) instrument with threshold of ≥45 points, in higher IPSS risk group stratified patients into distinct groups with different survival outcomes. These findings were further validated with Revised IPSS and other fatigue scales.

Uckun FM, et al. A clinical phase 1B study of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancers (Basel), 2021; 13(16): 4113. (DOI: 3390/cancers13164113)

• A total of 46 RR AML/MDS patients who had failed multiple lines of prior therapy received APVO436 weekly as iv infusion at 10 dose levels between 0.3mcg to 60mcg. Maximum tolerable dose (MTD) was not reached at 60mcg weekly. Infusion related reaction was the most common AE seen in 28.3% patients, along with cytokine release syndrome (CRS) in 21.7% patients. The recommended phase 2 dose was determined at 0.2mcg/kg which showed appreciable clinical response including a CR.  

Bewersdorf JP, et al. Venetoclax-based combination in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant. Leuk Lymphoma, 2021; Sept 3 [Online ahead of print] (DOI: 1080/10428194.2021.1966788)

• A retrospective study of AML/High-risk MDS patients from Memorial Sloan Kettering Cancer Center and Yale University, who received venetoclax either prior to or after allo-HCT between 2016 and 2020 showed 1-year OS rate of 79% in those receiving venetoclax before and 43.4% in those receiving after allo-HCT. These results demonstrate the feasibility of venetoclax therapy as a salvage regimen.

Kantarjian H, et al. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer, 2021; Aug 23 [Online ahead of print] (DOI: 1002/cncr.33828)

• An oral nucleoside analogue, Sapacitabine was tested in an alternating cycles with decitabine. In a phase 3 randomized multicenter international study, elderly patients of ≥ 70 years age who were not candidates for standard induction chemotherapy were randomized 1:1 to receive decitabine (20 mg/m² 1-hr iv qd x 5 d every 8wk) in alternating cycles with sapacitabine in the test arm or decitabine alone in the control arm with same dosing in a every 4 week cycle. Patients with prior hypomethylating agent exposure were excluded. The primary endpoint was OS. A total of 482 patients were randomized to decitabine-sapacitabine vs decitabine monotherapy (n=241 each). The OS and CR rates were comparable between arms (OS: 5.9 mo vs 5.7 mo respectively, p=0.8902; CR: 16.6% vs 10.8% respectively, p=0.1468). However, in patients with low baseline WBC <10×10⁹/L, OS and CR were higher with sequential therapy than control monotherapy (n=321) (OS: 8.0mo vs 5.8mo respectively, p=0.145 and CR: 21.5% vs 8.6% respectively, p=0.0017).

Swaminathan M, et al. A phase I/II study of the combination of quizartinib with azacytidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome. Haematologica, 2021; 106(8):2121-2130. (DOI: 3324/haematol.2020.263392)

• AML patients FLT3-like tyrosine kinase-3-internal tandem duplication (FLT3-ITD) mutations receiving first salvage therapy (n=39) or previously untreated MDS/AML patients with >60 years age (n=34) were treated with quizartinib plus azacytidine (AZA) or low dose cytarabine (LDAC). The composite response rate among previously untreated patients was 87% (13/15; CR-8) with quizartinib+AZA and 74% (14/19; CR=1) in quizartinib+LDAC with median OS/relapse free survival (RFS) of 19.2/10.5 mo and 8.5/6.4 mo respectively. Among previously treated patients the composite response rate and median OS with two treatments were, 64%/12.8mo vs 29%/4mo respectively.

Shimoni A, et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT. Br J Haematology, 2021; Sept 12 [Online ahead of print] (DOI: 1111/bjh.17817 )

• Reduced intensity conditioning (RIC) is known for lower non-relapse mortality and higher relapse rates as compared to myeloablative conditioning (MAC). The assessment of post-allogeneic transplant outcomes, compared a type of RIC with Fludarabine/treosulfan (FT, n=367), with traditional RIC (n=687) and MAC(n=668). Besides the older age in FT and RIC compared to MAC, there were no other differences in baseline characteristics among the three groups. After a median f/u of over 5 years (64mo), FT matched RIC in lower NRM (30% and 27% respectively) vs MAC (34%, p=0.008), while it showed lower 5-year relapse comparable to MAC (25% for both) vs RIC (38%). In a multivariate analysis, FT was associated with lower risk of relapse (HR=0.55, p<0.001) and better OS (HR=0.72, p<0.01). Authors concluded that FT may a preferred regimen for allogeneic-hematopoietic cell transplant in MDS.

Kurosawa S et al, Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis. Bone Marrow Transplant, 2021; Sept 7 [Online ahead of print] (DOI: 1038/s41409-021-01447-y)

• While Fludarabine/busulfan (Flu/Bu4) is effective in myeloablation prior to allo-HSCT in AML, it is not established in MDS. The nationwide registry data from Japan between 2006 and 2018 was reviewed (N=2482) for comparison of allo-HSCT outcomes with Flu/Bu4 (n=153) versus Busulfan/Cyclophosphamide (Bu4/Cy, n=153) conditioning in MDS patients. The cumulative non-relapse mortality, cumulative incidence of relapse, the 3-year progression free survival or the 3-year OS were not significantly different with the two conditioning regimens.

Wei Y, et al. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci, 2021; 112(9): 3636-3644. (DOI: 1111/cas.15048)

• A combination of Low dose decitabine (LDEC, 15mg/m² day 1-3) with venetoclax (VEN, 200mg day 1-21) in a 2 mo cycle x 10 cycles, was tested in a prospective study of 20 AML/high-risk MDS patients starting approximately on day 100 post-transplantation. The median follow up was approximately 20 mo. For primary end points, the median 2-year event-free survival (EFS) was 17.5mo (525 days) with 17 patients event free. The most common adverse events (AEs) were neutropenia, anemia, thrombocytopenia, neutropenic fever and fatigue. No >3 grade AEs were observed. GVHD of any grade was observed in 55% patients.

Modi D, et al. Post-transplant cyclophosphamide versus thymoglobulin in HLA-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transplant Cell Ther, 2021;27(9): 760-767. (DOI: 1016/j.jtct.2021.06.018)

• This retrospective study of 76 patients with AML or MDS assessed (2006-2019) the efficacy and safety of two GVHD prophylaxis regimens post-transplant with HLA mismatched unrelated donor. Cyclophosphamide (50mg/kg on day 3 and 4) treatment was compared with thymoglobulin (total dose 4.5 mg/kg). Although, the grade 3-4 acute GVHD at day 100 did not show significant difference (12% vs 19,6%, p=0.38), chronic GVHD at 1 year was significantly lower with cyclophosphamide (16% vs 49%, p=0.006). Also with cyclophosphamide, the median time to engraftment was shorter for both neutrophils (15 vs 11days, p<0.001) and platelets (21 vs 15 days, p=0.002). No difference in OS, relapse rate, relapse free survival or GVHD-free relapse-free survival were noted with the two agents tested. In a propensity-score-based multivariate analysis, besides higher acute and chronic GVHD incidence, higher non-relapse mortality was demonstrated with thymoglobulin compared to cyclophosphamide.

Rozema J, et al. Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study. Transfusion, 2021; Sept 3 [Online ahead of print] (DOI: 1111/trf.16631)

• • An observational, retrospective, population-based study of MDS patients (n=292) from the HemoBase registry in a Friesland province of the Netherlands (2005-2017), showed high RBC transfusion burden (HTB >8units/16wk) in 46.6% patients and low transfusion burden (LTB) in 5.8% patients. Once univariate and multivariable regression analyses were performed, the odds ratio for HTB was particularly high in patients aged 75-84 years, or those with high risk MDS or MDS-EB-2.

Komrokji R, et al. Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Leuk Lymphoma, 2021; Aug 27 [Online ahead of print] (DOI: 1080/10428194.2021.1971217)

• • MDS/MPN-RS-T is characterized by anemia, ring sideroblasts, and persistent thrombocytosis. 167 MDS/MPN-RS-T patients at a single institute (Moffitt, USA) were evaluated to compare the hematological improvement (HI) response rates among different therapies, including lenalidomide. 84% patients had SF3B1 mutations and 43% had JAK2 V617F mutations. Overall, 46% patients received erythropoiesis stimulating agents (ESA), 28% had lenalidomide and 27% got hypomethylating agents (HMA). The HI rate with the three treatments were 58%, 53% and 24% respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMA.

Sallman DA, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol, 2021; Jan 15 [Online ahead of print] (https://doi.org/10.1200/jco.20.02341)

• This phase Ib/II study assessed a small molecule APR-246 which restores wild-type p53 function. This novel compound was used in combination with azacitidine in 55 patients with at least one TP53 mutation (40MDS, 11AML, 4 MDS/MPN). The response among all patients/MDS/AML patients included, ORR-71%/73%/64%, CR-44%/50%/36% respectively. The responding patients showed lowered p53 expression with 38% achieving molecular remission and OS of 14.6 mo compared to 7.5 mo in non-responding patients (p=0.0005). Common adverse events for the combination were febrile neutropenia (33%), leukopenia (29%) and neutropenia (29%).

Wan Z, and Han B. High-dose regimens of hypomethylating agents promote transfusion independence in IPSS lower-risk myelodysplastic syndromes: a meta-analysis of prospective studies. Ageing, 2021; Mar 26 [Online ahead of print] (https://doi.org/10.18632/aging.202767)

• A literature meta-analysis of prospective studies published between Jan 1990 and Jul 2020 compared different dosing regimens of two hypomethylating agents, azacytidine and decitabine in lower-risk MDS. No differences were noted between regimens of individual agents or between two agents with respect to response rates and OS. Safety profile too did not have significant differences besides decitabine (20mg/m2/day x 3days) showing higher rates of Grade 3/4 anemia and lower rates of diarrhea/constipation. The transfusion independence rate was higher with AZA (75mg/m2/day x 7day; p<0.025).

Garcia-Manero G, et al. Phase III randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol, 2021; Mar 25 [Online ahead of print] (https://doi.org/10.1200/jco.20.02619)

• Lower risk MDS patients were randomized to receive CC-486 300mg/day for 21 days in a 28 day cycle (n=216) or placebo. The RBC transfusion-independence (TI) rate, and median duration of TI were higher in CC-486 treated patients (31%, and approx. 11mo) versus the placebo group (11%, p=0.0002, approx. 5mo). The rate of patients with >1.5mg increase in HB and the rate of platelet improvement were higher in CC-486 treated patients (23.4% vs 4.6% and 24.3% vs 6.5%). Furthermore, although overall death rate was similar in the two arms, the number of deaths in the first 56 days were higher in the treatment arm primarily due to infections in patients with notable pretreatment neutropenia (n=16 ) vs placebo (n=6).

Clavio M, et al. Overall survival of myelodysplastic syndrome patients after azacitidine discontinuation and applicability of the North American MDS Consortium Scoring System in clinical practice. Cancer, 2021; Mar 19 [Online ahead of print] (https://doi.org/10.1002/cncr.33472)

• This Italian registry study of 402 consecutively enrolled MDS patients showed that while 80% patients discontinued due to primary or adaptive resistance, 20% were responsive to AZA at treatment discontinuation. Among the latter, those who subsequently received hematopoietic stem cell transplant, had significantly improved survival. Furthermore, when assessed with North American MDS Consortium scoring system (n=278), the low-risk patients showed better survival vs high-risk patients (p<0.001) regardless of whether they received best supportive care (5mo vs 2mo respectively) or active treatment including transplant (16mo vs 8mo).

Feld J et al. Safety and Efficacy: Clinical experience of venetoclax in combination with hypomethylating agents in both newly diagnosed and relapsed/refractory advanced myeloid malignancies. Hemasphere, 2021; 5(4):e549 (https://doi.org/10.1097/hs9.0000000000000549)

• This retrospective analysis of a total of 72 patients (AML, n=65 and MDS, n=7), treated with a combination of venetoclax and hypomethylating agent showed CR/CRi in 53.8% newly diagnosed AML, and in 38.5% relapsed/recurrent AML. The responders to combination were enriched for TET2, IDH1 and IDH2 mutations, while non-responders showed enrichment for FLT3 and RAS mutations. Approx. 59% patients developed infections, and approx. 47% had neutropenic fever.

Garcia JS, et al. A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival. Leuk Res, 2021; Mar 2 [Online ahead of print] (https://doi.org/10.1016/j.leukres.2021.106555)

• This study level systematic review of literature included 237 clinical studies to assess outcomes with azacitidine in higher-risk MDS. The pooled marrow CR was 9%, overall CR-17%, and median overall survival of 18.6 mo. While the CR rate showed a weak correlation with median OS (Pearson’s r=0.315), it correlated strongly with median progression free survival (r=0.88) across studies.

Scott BL, et al. Myeloablative versus reduced-intensity conditioning for hematopoietic cell transplantation in acute myelogenous leukemia and myelodysplastic syndromes-long-term follow-up of the BMT CTN 0901 clinical trial. Transplant Cell Ther, 2021; Feb 26 [Online ahead of print] (https://doi.org/10.1016/j.jtct.2021.02.031)

• AML/MDS patients (18-65 yr age) with <5% marrow myeloblasts were randomized between myeloablative conditioning (MAC, n=135) and reduced-intensity conditioning (RIC, n=137) prior to receiving hematopoietic cell transplant (HCT) from HLA-matched donor. Median f/u was 51mo. At four years, treatment related mortality was higher in MAC (approx. 25%) compared to RIC (approx. 10%, p<0.001). On the other hand, relapse rate was significantly higher in RIC vs MAC (HR-4.06, p<0.001). At 3 years, the post-relapse survival rate was comparable between MAC and RIC (approx. 25%). The OS upon long term f/u though, was superior with MAC versus RIC (HR-1.54, p=0.03).

List A, et al. Lenalidomide-epoetin alfa versus lenalidomide monotherapy in myelodysplastic syndromes refractory to recombinant erythropoietin. J Clin Oncol, 2021; 39(9): 1001-1009. (https://doi.org/10.1200/jco.20.01691)

• A total of 195 non-del(5q) low risk patients with low probability of response to erythropoietin therapy (based on sEPO levels and/or prior erythropoietin treatment), were randomized to receive a combination of LEN+EPO alfa (n=99) or LEN alone (n=96). After 4 cycles, Major erythroid response (MER) was higher with the combination (28.3%, p=0.004) vs LEN alone (11.5%). At 16 wks too, the MER and overall erythroid response were higher with combination (38.9%/46.5% respectively) vs LEN monotherapy (15.5%/32.3% respectively). Lastly, the MER observed with the combination was also more durable versus LEN monotherapy (23.8 mo vs 13mo).

Boyko O, et al. Erythropoietin as an independent prognostic factor in myelodysplastic syndromes. Exp Oncol, 2021; 43(1): 41-45. (https://doi.org/10.32471/exp-oncology.2312-8852.vol-43-no-1.15914)

• Elevated serum EPO levels were observed in MDS patients as compared to healthy individuals (p<0.01). However, the difference in sEPO between low versus high-risk patients was not significant. sEPO levels correlated negatively with Hb levels and bone marrow blast counts in high risk patients. Also, an inverse correlation was seen between sEPO and sTNFα in low-risk patients.

Stauder R, et al. Patient-reported outcome measures in studies of myelodysplastic syndromes and acute myeloid leukemia: Literature review and landscape analysis. Eur J Haematol, 2020; 104(5): 476-487. (1111/ejh.13389 )

• This extensive review noted that across studies in MDS and AML, the most frequently used patient reported outcome measures (PROMs) were generic like SF-36 or EQ-5D or cancer specific like EORTC QLQ-C30, and FACT-An. However, MDS specific PROMS like QUALMS or QOL-E and AML specific PROMS like FACT-Leu or EORTC QLQ-Leu were used only in a minority of studies. The review underscores the need to use MDS/AML specific PROMS in future studies.

Fenaux P et al. Luspatercept in patients with lower risk myelodysplastic syndrome. N Engl J Med, 2020;382(2):140-151. (https://doi.org/10.1056/nejmoa1908892)      

• This double blind placebo controlled ph 3 study assessed luspaterept (1mg up to 1.75 mg per Kg body weight sc every 3 weeks) vs placebo in patients with very-low, low or intermediated risk MDS patients with ringed sideroblasts and who were transfusion dependent (N=229; 2:1:: luspatercept: placebo).Primary end-point was transfusion independence for ≥8 weeks in first 24 weeks of treatment which was seen in 38% on luspatercept versus 13% with placebo (p<0.001). The most common adverse events were fatigue, diarrhea, asthenia, nausea, and dizziness.

Stein EM et al. Enasidenib in patients with IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicenter, AG221-C-001 trial. Lancet Haematol, 2020;7(4):e309-e319. (https://doi.org/10.1016/s2352-3026(19)30284-4)

• Seventeen previously treated patients with IDH2 mutation received a median 3 cycles of Enasidenib, an IDH2 inhibitor; 5 with ≥12 cycles (60-300 mg QD PO in 28 day cycle). After median follow up of 11mo no dose limiting toxicities were observed. The most common grade 3-4 treatment emergent adverse events were indirect hyperbilirubinaemia (35%), pneumonia (29%) and thrombocytopenia (24%), and no treatment related deaths. The overall response was seen in 9/17 (53%) patients with median duration of response of 9.2mo and median overall survival was 16.9mo.

Navada SC, et al. Rigosertib in combination with azacytidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study. Leuk Res, 2020;94: 106369 (1016/j.leukres.2020.106369 )

1. The phase 1 part of this phase 1/2 study involved 9MDS, 1CMML and 8AML patients. An oral Ras-inhibitor, rigosertib was given twice daily at 140mg or 280 mg or 560mg morning+280mg evening doses for 3 weeks of the 4week cycle. A standard dose azacytidine was given in the second week of the cycle. No dose limiting toxicities were noted and hence no maximum tolerated dose could be determined. The most frequent adverse events were diarrhea, constipation, fatigue, nausea, pneumonia and back pain. The majority of responses were in MDS/CMML patients (7/9) with only 2/7 responses in AML.

Taylor J, et al. Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukemia refractory to hypomethylating agents: a single-center, single arm, phase 2 trial. Lancet Haematol, 2020; 7(8):e566-e574. ( 1016/S2352-3026(20)30209-X )

• There is no current therapy for MDS refractory to hypomethylating agents under 6 months. This study aimed safety and activity of selinexor in MDS patients or oligoblastic acute myeloid leukemia (OAML). A phase 2 trial (18 y/o or older up to 30% MDS/OAML) received a 3-week long cycle of selinexor (60mg twice/week for 2 weeks, 1 week off). From the 23 patients evaluated, overall response rate was 26% (95% Cl 10-48) in 6 patients with marrow complete remission and 12 patients (52%, 95% Cl 31-73) had stable disease.

Kubasch AS, et al. Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia, 2020; 34(4): 1182-1186. (1038/s41375-019-0645-z )

• SAMBA study assessing anti-CD123 therapeutic monoclonal called talacotuzumab in 19AML and 5 High-Risk MDS patients was terminated as a part of discontinuation of the drug development program by the manufacturer. 16/24 patients were resistant including 8/24 patients who relapsed after initial response to prior HMA therapy. The treatment related toxicity was significant including 2 deaths with pneumonia possibly related to treatment. The eight-week mortality was 25% and overall response rate was 8.3% including one complete remission. The benefit/risk ratio for talacotuzumab was determined to be unfavorable and hence the study was terminated.

Stahl M, et al. Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis. Haematologica, 2020; 105(1):102-111. (3324/haematol.2019.219345 )

• A systematic literature review identified nine prospective cohort studies and 12 clinical trials using immunosuppressive therapy, mostly anti-thymocyte globulin ± cyclosporin A. The overall response rate was 42.5% with 12.5% CR and RBC transfusion independence rate of 33.4%. The leukemic transformation rate was 8.6% per patient year. The review highlights the immunosuppressive therapy as a therapeutic option to low-risk MDS patients. 

Yalniz FF, et al. A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy. Br J Haematol, 2020;188(3): 404-412. (https://doi.org/10.1111/bjh.16173)

• This phase II study assessed the addition of pracinostat to hypomethylating agent (HMA) in MDS patients who showed primary or secondary failure on HMA or had stable disease without a clinical response. Forty five patients receiving a median 3 cycles showed one CR and 7 marrow CR with a median overall survival of 5.7 mo in previous HMA failure or 5.6mo in previous stable disease on HMA. Grade ≥3 adverse events were seen in 84% patients with 33% discontinuing treatment. The study concluded with the need to optimize the dose of pracinostat.

Cai L, et al. Role of TP53 mutations in predicting the clinical efficacy of hypomethylating therapy in patients with myelodysplastic syndrome and related neoplasms: a systematic review and meta-analysis. Clin Exp Med, 2020; 20(3): 361-371 (1007/s10238-020-00641-4 )   

• This systematic review and meta-analysis report on 22 original studies demonstrates that while MDS patients with TP53 mutations respond to hypomethylating agents well, their overall survival may still be poor regardless of their response.

Vicente A, et al. Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndromes. Haematologica, 2020; May 21 [Online ahead of print]. (3324/haematol.2020.249995 )

• A phase 2 dose escalation study in Low/int-1 risk MDS patients assessed eltrombopag (EPAG) at 50 mg/day to a maximum of 150mg/day over 16 weeks. Eleven of twenty five patients (44%) had hematologic response; 5 had uni-lineage and 6 bi-lineage. Presence of PNH clone, marrow hypocellularity, thrombocytopenia ± other cytopenia and elevated plasma thrombopoietin predicted response. The safety profile was consistent with previous experience of EPAG. Ten patients discontinued after med time on treatment of 16 months and having a response. Four of them restarted EPAG later and had a robust second response.

Duong Vu H, et al. A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure. Leuk Lymphoma, 2020; 61(8): 1901-1907. ( 1080/10428194.2020.1751841 )

• Thrombocytopenia is seen often in MDS patients and this study conducted a trial of eltrombopag in MDS and MPN or AML patients after hypomethylating agent failure. They had a mean baseline platelet count <50 x 10⁹ /L. The dose was upped from 50 mg to 200 mg daily. The maximally tolerated dose was determined with 37 patients, but it was not reached. In 9 patients (24%), 2 achieved marrow CR with hematologic improvement, 1 marrow CR without HI, and 6 HI. The median overall survival for these patients was 7.5 months and eltrombopag yielded modest results for mostly high-risk MDS patients post HMA failure.

Barot SV, Patel BJ, and Gerds AT. Patient-reported outcomes in myelodysplastic syndromes: the move from life span to health span (MDS). Current Hematol Malig Rep, 2020; Feb 11 [Online ahead of print] (https://pubmed.ncbi.nlm.nih.gov/32048198/)

• Although PRO measurement is less common in clinical studies in MDS, when conducted have demonstrated positive results with growth factors, HMS and IMiDs. Many new clinical studies have begun to incorporate a prospective PRO assessment using broad metrics such as EORTC-QLQ-C30, the previously reported FACT-An and MDS specific tools like QUALMS (Quality of life in Myelodysplasia Scale).

Sekeres M and Steensma D. Rethinking clinical trial end points in myelodysplastic syndrome. Leukemia, 2019;33(3):570-575. (https://pubmed.ncbi.nlm.nih.gov/30700839/)

• The review evaluates challenges to drug development and emphasizes the meaningfulness of study end points relevant to patients. The report also underscores the importance of assessing longer term end points such as response duration, quality of life and overall survival in addition to the currently common end points of hematologic and bone marrow response rates.

Mozessohn L, et al. Healthcare utilization in patients with higher-risk MDS/low-blast count AML treated with azacytidine in the real-world. Leuk Lymphoma, 2020; Feb 8 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/32036719/)

• The Ontario AZA-MDS registry linked to population based administrative databases showed approx. 80% patients (705/877) had at least one emergency clinic visit; 33% in their first cycle. Also, approx. 77% had at least one hospitalization with a mean length approx. 18 days. A greater comorbidity, non-response to AZA and transfusion dependence were associated with both emergency room visits and hospitalizations. Also, among patients with ≥ 3 cycles of treatment hospitalization during first cycle was associated with an increased risk of death.

Chandhok N, et al. Hypomethylating agent- based combinations in higher risk myelodysplastic syndrome. Leuk Lymphoma, 2019; Dec 9 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31814484/)

• The authors argue that there continues to exist an unmet need to improve upfront treatment of higher risk MDS patients as only a proportion of patients respond to hypomethylating agents and the responses are less durable. Authors propose upfront combinations with other agents as a way to improve outcomes of HMA and list venetoclax and rigosertinib as promising agents for such combination.

Ren Y, et al. Decitabine for myelodysplastic syndromes: Dose comparison in a real world clinical setting. Leuk Lymphoma, 2019; 60(7): 1731-1739. (https://pubmed.ncbi.nlm.nih.gov/30616472/)

• This was a retrospective study with 133 MDS patients. The study demonstrated that in real world patients 15 mg/m2/day dose vs. 20mg/m2/day dose resulted in a comparable response rates (ORR-51.8% vs 52%, CR-15.7% vs 22% respectively), longer survival (21.6 mo vs 15.2 mo respectively), and lower hematologic toxicity (Gr3/4 neutropenia- 60% vs 88%; thrombocytopenia- 65% vs 88% respectively). Additionally, the report also found that the overall survival benefit with 15 mg/m2/day was primarily associated with lower risk patients.

Ades L, et al. A phase II study of efficacy and safety of an intensified schedule of azacytidine in intermediate-2 and high-risk patients with myelodysplastic synromes: A study by the Groupe Francophone Des Myelodysplasies (GFM). Heamatologica, 2019; 104(4):e131-e133. (https://pubmed.ncbi.nlm.nih.gov/30381302/)

• A azacytidine treatment intensification tested using a schedule leading to 20% higher number of days with azacytidine (75mg/m2/day x5 days in 14-day cycle) administration during first 8 weeks of treatment. Patients who achieved CR/PR received additional aza at 21-day cycles x 4 followed by std 7-day dosing in a 28-day cycle until progression. For patient not achieving CR or PR after first 8 weeks, additional 8 weeks of intensified treatment was given. The primary end point was response by IWG 2006 criteria after first 4 and 8 dose intensified cycles (15-day cycles). The int-2- and high-risk proportions were 65:35 among the 26 evaluable patients. The overall marrow response after 4- or 8-weeks intensified treatment was 22% (6/27). The marrow CR+ hematologic improvement (HI) was 65% after week 4 and 62% after week 8. With a f/u of approx. 42 mo, median duration of CR/PR was 10.5 mo, duration of overall response was 14 mo, and overall survival was 21.5 mo. Treatment intensification was not associated with increased toxicity.

Zeidan A, et al. Treatment sequence of lenalidomide and hypomethylating agents and the impact on clinical outcomes for patients with myelodysplastic syndromes. Leuk Lymphoma 2019;60(8):2050-2055. (https://pubmed.ncbi.nlm.nih.gov/30636526/)

• A US claims database study (Inovalon MORE2 registry) comparing outcomes of treatment sequence Len- HMA vs HMA-Len demonstrated longer time to discontinue second treatment (HR-0.52, p=0.023), and to disenroll from insurance used as proxy for survival (HR-0.64, p=0.017).

Stanworth SJ, et al. Red cell transfusion in outpatients with myelodysplastic syndromes: A feasibility and exploratory randomized trial. Br J Haematol, 2020; Jan 20 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31960409/)

• This multinational study randomized 38 patients in outpatient clinic to initiate RBC transfusion at standard threshold of Hb ≤8.0 g/dL (n=20) vs a liberal threshold of Hb≤10.5 g/dL (n=18). The compliance for transfusion threshold was 86% vs 99% in the standard vs liberal groups and the mean pre-transfusion Hb was 8.0 g/dL and 9.7 g/dL respectively. Using EORTC QLQ-C30 and EQ-5D-5L tools, the quality of life was found to be better in patients on liberal Hb threshold arm.

de Swart L, et al. Impact of red blood cell transfusion dose density on progression free survival in lower-risk myelodysplastic syndromes patients. Haematologica, 2020; 105(3): 632-639. (https://pubmed.ncbi.nlm.nih.gov/31171638/)

• The analysis based on European MDS registry included 1267 lower risk MDS patients: 317 had died without progression and 162 had disease progression. When assessed for the impact of blood transfusions on overall progression-free survival (PFS), the transfusion density as low as 3 units/16 weeks was associated with poorer PFS that continued to increase beyond 8 units/16 weeks.

Kaphan E, et al. Impact of transfusion on survival in patients with myelodysplastic syndromes: current knowledge, new insights and transfusion clinical practice. Blood Rev, 2019; Dec 18 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31918886/)

• Patients treated with red blood cell (RBC) transfusions experience shorter survival as compared to those treated with erythropoiesis stimulating agents (ESAs). The report has attempted to list the physiologic impacts of chronic RBC transfusion strategy highlighting iron toxicity, cardiac event rate, oxidative stress and RBC storage lesions due to physicochemical changes in RBCs.

Swaminathan M, et al. A phase 2 clinical trial of eltrombopag for treatment of patients with myelodysplastic syndromes after hypomethylating-agent failure. Leuk Lymphoma, 2019; 60(9):2207-2213. https://pubmed.ncbi.nlm.nih.gov/30773968/)

• Eltrombopag was given at a starting dose of 200mg orally per day either as monotherapy (n=7) or was added to HMA (n=22) after the failure of initial HMA therapy of high risk MDS. There was one early death (<30 days) due to infection/sepsis, an overall 11% (3/28) platelet improvement rate and a med survival of 12 mo. Addition of eltrombopag to HMA did not show additive toxicity.

Faraoni I et al. Cytotoxicity and differentiating effect of the poly (ADP-Ribose) polymerase inhibitor Olaparib in myelodysplastic syndrome. Cancer, 2019; 11(9):E1373. (https://www.ncbi.nlm.nih.gov/pubmed/31527467)

• In primary cultures of bone marrow mononuclear cells from 28 MDS patients, olaparib showed cytotoxic effects with a median IC50 of 5.4µM, which is lower than the peak in vivo concentration reached with standard olaparib dose. Moreover, the cytotoxicity appeared specific to myeloid blasts and simultaneously an increase in metamyelocytes and mature granulocytes was noted while sparing the uninvolved lymphoid cells. These cytotoxic and differentiation effects were further augmented in combination with decitabine.

Santini V et al. Phase 2 study of the ALK5 inhibitor Galunisertib in very low-, low- and intermediate-risk myelodysplastic syndromes. Clin Cancer Res, 2019; Sept 3 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31481511)

• Galunisertib, an oral inhibitor of TGF beta receptor type I kinase (ALK5), was evaluated in a phase 3 study at twice daily 150 mg dose in 14 days on/14 days off schedule in VLR, LR and IR MDS patients (n=41). The hematologic improvement- erythroid was seen in 24.4% patients per IWG 2006. Among transfusion dependent patients HI-E was seen in 32.1%. Overall median duration of response in all patients was 90 days. The adverse events were grade 1/2 in 49% patients (fatigue, diarrhea, pyrexia, and vomiting).

Sallman DA et al. A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS). Leuk Res, 2019; 81:56-61 (https://www.ncbi.nlm.nih.gov/pubmed/31030089)

• Glasdegib was assessed in higher risk MDS patients (n=35) with hypomethylating agent. The overall response was seen in 2 patients (6%) with marrow CR with HI as the best response. The median overall survival was 10.4 mo. ≥3 infections occurred in 11% with non-hematologic toxicities generally being rare.

Qin Y et al. Hypomethylating agents for patients with myelodysplastic syndromes prior to hematopoietic stem cell transplantation: a systematic review and meta-analysis. Ann Hematol, 2019; Oct 22 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31637485)

• A meta-analysis of 6 cohort studies with MDS patients demonstrated that overall survival and relapse free survival were comparable regardless of the use of hypomethylating agents compared to chemotherapy or best supportive care prior to HSCT (OS- HR=0.81, p-0.104 and RFS- HR=0.96, p-0.749).

Reilly B et al. DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes. Blood Adv, 2019; 3(19): 2845-2858. (https://www.ncbi.nlm.nih.gov/pubmed/31582393)

• Bone marrow DNA samples from 141 MDS patients showed 5 distinct CG methylation clusters which demonstrated distinct subtypes of patients otherwise not distinguished by mutations or clinical features. Patients with diverse genetic lesions converge into single methylation group who may share pathogenic mechanisms and clinical outcomes.

Vij R et al. A phase II multicenter study of the addition of azacitidine to reduced-intensity conditioning allogeneic transplant for high-risk myelodysplasia (and older patients with acute myeloid leukemia): Results of CALGB 100801 (Alliance). Biol Blood marrow Transplant, 2019; 25(10):1984-1992. (https://www.ncbi.nlm.nih.gov/pubmed/31212080)

• A total of 63 patients (40 unrelated and 23 matched related donors) received Fludarabine iv d -7 to d-3, busulfan daily to AUC 4000 µM/min d -6 to d -3 (after a prior test dose) and ATG d -6 to d -4. All patients also received up to 6 cycles of Azacitidine starting between d +42 to d +90. In total 41patients received AZA starting on median day 61 post-transplant of whom 17 completed 6 cycles. The 2-year cumulative rates of non-relapse mortality was 33.4%, and relapse of 25%. At med f/u of approx. 59 mo, the estimated PFS was approx. 41% at 2 year and 27% at 5 year. For the entire group of patients, the overall median PFS was 15.8mo and median overall survival was 19.2mo.

Garcia-Manero G et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicenter, open-label, randomized phase 1/2 trial. Lancet Haematol 2019;6(6):e317-e327. (https://www.ncbi.nlm.nih.gov/pubmed/31060979)

• Int-1, Int-2 or High risk MDS patients with or without prior exposure to hypomethylating agents were randomized to sc guadecitabine 60 mg/m2 (n=55) or 90 mg/m2 (n=50) on d1-5 in 28 d cycle. With median 3.2 yr f/u, the overall response (a composite of CR, PR, Marrow CR and HI) did not differ between the two dose levels (40% vs 55% respectively). For patients who were treatment naïve and those who were relapsing after previous exposure to hypomethylating agents, the overall response rates were 51% vs 43% respectively. The grade ≥3 adverse events included thrombocytopenia, neutropenia, febrile neutropenia, anemia and infections. The deaths due to adverse event were 7%. The recommended dose for future studies thus is 60 mg/m2.

Qin T et al. Risk of disease progression in low-risk MDS is linked to distinct epigenetic subtypes. Leukemia 2019; Jul 22 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Qin+T+and+Nimer+SD)

• A set of paired diagnostic and f/u samples were assessed in a cohort of 20 patients (13 with stable MDS and 7 with progressive MDS). Targeted sequencing was carried out with a panel of 59 genes frequently mutated in myeloid malignancies. The progressive disease patients had higher frequency of mutations/patient (3.2) vs stable disease patients (1.2, p=0.01). Furthermore, the study identified 356 differentially methylated regions (DMRs) between progressive and stable low-risk MDS. Whereas the methylation pattern of stable disease patients was closer to normal, that for progressive disease patients was significantly divergent. Supervised analysis showed that the number of DMRs nearly doubled (681) with progressive disease.

Beelan DW et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic hematopoietic stem cell transplantation for older patients with acute myeloid leukemia or myelodysplastic syndrome (MC-FludT.14/L): a randomized, non-inferiority, phase 3 trial. Lancet Haematol, 2019; Oct 9 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31606445)

• This report is based on the final analysis of the study with a median f/u of 15.4mo for treosulfan and 17.4mo for busulfan. AML patients in first or consecutive complete remission (marrow blasts <5%) or MDS with marrow blasts <20% were randomized in this open label study to receive Treosulfan (iv 10g/m2 daily x 3d) or busulfan (0.8 mg/kg). Both groups received iv fludarabine 30mg/m2 daily x5d. The treosulfan arm had higher 2-year event-free survival rate (64%) compared to the busulfan arm (50.4%, HR=0.65, p=0.0051 for superiority). The safety profiles were similar in the two groups. Treosulfan -fludarabine may therefore hold the promise of standard preparative regimen for allogeneic HSCT in AML.

Hoeks M et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica, 2019; Jul 5 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31278207)

• Low risk MDS patients with iron chelation therapy (224/2200 or approx. 10.2%) within European MDS registry were compared to contemporary non-chelated patients. After adjustment for demographic and disease characteristics the chelated patient showed 50% risk reduction in overall survival (HR=0.50), which improved further in propensity-score analysis of matched cases (HR=0.42). Approximately 39% chelated patients had erythroid response.

Savona MR et al. Phase 1b study of Glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high risk MDS. Clin Cancer Res, 2018; Feb 20, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29463550)

• An open label dose finding phase 1b study in newly diagnosed high risk MDS/AML (N=52) assessed Glasdegib at 100 or 200 mg daily po in 28-day cycle in combination with low-dose cytarabine or decitabine in patients not suitable for induction chemotherapy or in combination with cytarabine/daunorubicin in fit patients. Whereas no dose limiting toxicities (DLT) were observed with combination treatments in unfit patients, there was one DLT of grade 4 neuropathy noted for combination in fit patients. Overall 16/52 (31%) patients achieved CR/CR-with incomplete hematopoietic recovery. The RP2D of 100mg was selected for combination with standard chemotherapy.

Komrokji R et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol, 2018; 5(2):e63-e72. (https://www.ncbi.nlm.nih.gov/pubmed/29331635)

• RBC-transfusion dependent low/int-1 risk MDS patients refractory or ineligible to ESAs who were either non-del(5q) or were del(5q) but refractory to lenalidomide, were randomly assigned to receive sotatercept subcutaneously at 0.1 mg/kg (n=7) or 0.3 mg/kg (n=6) or non-randomly assigned to 0.5mg/kg(n=21), 1mg/kg (n=35) or 2mg/kg (n=5). HI-E, the primary end-point was achieved in 29/62 patients (47%) with high baseline transfusion burden and 7/12 (58%) patients with low transfusion burden. The most commonly reported AEs were fatigue (26%) and peripheral edema (24%). Among the grade 3/4 treatment emergent AEs reported (5%), most common were lipase increase and anemia. One death was noted due to treatment emergent hematoma and fall.

Deeg HJ et al. Transplant conditioning with Treosulfan/fludarabine with or without total body irradiation: a randomized phase II trial in patients with myelodysplastic syndrome and acute myeloid leukemia. Biol Blood Marrow Transplant, 2017; Dec 20 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/29274396)

• In a prospective randomized ph 2 study assessing transplant conditioning with treosulfan (iv 14g/m²/day days -6 to -4) + fludarabine(iv 30mg/m²/day days -6 to -2) with or without 2Gy total body irradiation (TBI) in reducing post-transplant relapse in MDS, CMML and AML patients (N=100; med age- 57 yr). Donors were related in 43 patients and unrelated in 57 patients. With a median follow up of 20 months, the rate of 1-yr survival was 80% in the TBI arm vs 69% for non-TBI conditioning. The 1-yr relapse rates for MDS and AML with TBI vs non-TBI regimens were 27% vs 33% and 16% vs 35% respectively. The report concluded that treosulfan/fludarabine/low-dose TBI provides effective conditioning for allogeneic hematopoietic cell transplantation

Schmid C et al. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis of 698 patients by the chronic malignancies working party of the European society of blood and marrow transplantation. Haematologica, 2018; 103(2):237-245. (https://www.ncbi.nlm.nih.gov/pubmed/29101205)

• This retrospective registry analysis explored post relapse therapeutic practices used for MDS patients who had allogeneic HSCT. Generally, the overall survival from relapse was short (median-4.7 months, 2-yr OS-17.7%). Shorter remission post-transplant (p<0.001), advanced disease (p=0.001), older age (p=0.007), unrelated donor (p=0.008), GVHD prior to relapse (p<0.001) were adversely related to OS. Among the three major practices noted at 6mo post-relapse, the OS (median and 2-yr %OS) rates were as follows- palliative chemotherapy and/or supportive care (n=375, med OS 8.9mo and 2-yr OS-29.7%), Donor lymphocyte infusion (n=213, med OS-6.0mo and 2-yr OS 27.6%) or second transplant (n=110, med OS-4.2mo and 2-yr OS-17%). For second transplant, longer remission after the first transplant, complete remission after second transplant and change to a new donor were of prognostic value.

Almeida A et al. Safety profile of lenalidomide in patients with lower-risk myelodysplastic syndromes without del (5q): results of a phase 3 trial. Leuk Lymphoma, 2018; Jan 11, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29322849)

• This report presents the safety profile of lenalidomide treatment of low risk non-del(5q) ESA refractory/ineligible MDS patients (n=239) from a phase 3 study. Compared to the placebo, lenalidomide had higher incidence of grade 3/4 treatment emergent AEs (TEAE-44% vs 86% respectively). The risk of infection or hemorrhagic events, however, were not increased. Grade 3/4 non-hematologic events were rare. The report also provides guidance on managing lenalidomide related TEAEs.

Sekeres MA et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol, 2017; 35(24):2745-2753.( https://www.ncbi.nlm.nih.gov/pubmed/28486043)

• In the phase II part of this phase II/III study, 277 high risk MDS/CMML patients were randomized to receive azacitidine alone (75 mg/m2/d 1-7 of 28 d cycle, n=92), or in combination with lenalidomide (10mg/d1-21, n=93)or with vorinostat (300mg bid d3-9, n=92). At a median follow up of 23 months, the ORR was 38% with azacitidine alone as compared to 49% with azacitidine+lenalidomide (p=0.14) and 27% with azacitidine+vorinostat (p=0.16). CMML patients showed higher ORR with lenalidomide combination than azacitidine alone (68% vs 28%, p=0.02).

Shapiro RM and Lazo-Langner A. Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia. BMC Hematol, 2018; Jan 31 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29435331)

• A metaanalysis of RCTs showed higher pooled proportion of overall response rate (ORR) with two 7-day schedules, 44.8% for 7-0-0 and 45.8% for 5-2-2, as compared to 41.2% on 5-day schedule (5-0-0).

Sohn SK et al. No benefit of hypomethylating agents compared to supportive care for higher risk myelodysplastic syndrome. Korean J Intern Med, 2017; Dec 15 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/29232940)

• A retrospective analysis of 279 high/very high MDS patients from the Korean MDS working party database estimated 3-yr survival rate of 53.1% with allogeneic HCT + HMA, 75% with allogeneic HCT without HMA, 17.3% with HMA alone and 20.8% with best supportive care. The multivariate analysis demonstrated association of OS with only allogeneic HCT alone (HR=0.36, p=0.002).

Komrokji R et al. Azacitidine in lower-risk myelodysplastic syndromes: a meta-analysis of data from prospective studies. Oncologist, 2018; 23(2):159-170. (https://www.ncbi.nlm.nih.gov/pubmed/29118268)

• A 15-yr retrospective search for ph 2/3 studies with azacitidine and patient level data from identified relevant studies led to analysis of 233 selected patients; approx. 90% non-del(5q) low risk MDS. The pooled estimates of RBC-transfusion independence and overall clinical benefit were approx. 39% and 42% respectively. Also, in a multivariate analysis, a planned use of ≥6 cycles was predictive of a response.

Medeiros BC et al. Randomized study of continuous high dose lenalidomide, sequential azacytidine and lenalidomide, or azacitidine in persons 65 years and over with newly diagnosed acute myeloid leukemia. Haematologica, 2018; 103(1):101-106. (https://www.ncbi.nlm.nih.gov/pubmed/29097499)

• A randomized open-label ph 2 study compared three therapeutic strategies in patients newly diagnosed with AML and ≥ 65 yrs of age; continuous high dose lenalidomide (n=15), sequential azacytidine and lenalidomide (n=39), or azacitidine (n=34) and demonstrated 1-yr survival rates of 21%, 44% and 52% respectively. Also, the hazard of death was greatest with continuous high dose lenalidomide.

Platzbecker U et al. A phase 3 randomized placebo-controlled trial of darbepoietin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia, 2017; 31(9): 1944-1950. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Platzbecker+and+Darbepoietin)

• Low/Int-1 risk MDS patients with Hb ≤10 g/dL, sEPO ≤500 mU/mL and low transfusion burden (N=147) were randomized 2:1 to receive 500μg darbepoietin alfa sc q3w or placebo for 24 weeks, followed by 48 week of open label darbepoietin alfa. Between week 5 and 24, darbepoietin alfa treated patients had lower transfusion incidence (36.1% vs 59.2%, p=0.008) and higher erythroid response (14.7% vs 0%, p=0.016). In the open label 48 weeks phase, darbepoietin dosing increased from q3w to q2w with a corresponding higher erythroid response rate of 34.7%. Safety of darbepoietin was consistent with previous reports.

Kantarjian HM et al. Long-term follow up for up to 5 years on the risk of leukemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim vs placebo in randomized double-blind trial. Lancet Haematol 2018; 5(3):e117-e126. (https://www.ncbi.nlm.nih.gov/pubmed/29396092)

• A ph 2 study with 58 wk romiplostim treatment in low/int-1 risk MDS with thrombocytopenia (n=250) demonstrated clinical benefits in reducing platelet transfusions and with respect to HI-platelet response rate. However, based on the potential risk of progression to AML noted in initial analysis treatment was discontinued and patients were followed for long term outcomes. Among 210/250 patients (84%) who entered a 5-yr follow up phase (139 treated with romiplostim and 83 with placebo), AML progression occurred in 12% patients from romiplostim arm vs 11% from the placebo arm (HR=1.06, p=0.88), while 56% vs 54% patients died respectively on the two arms (HR=1.03, p=0.89). These long-term data may thus warrant an in-depth reassessment of benefit/risk profile of romiplostim.

Troy JD et al. Patient-reported distress in myelodysplastic syndromes and its association with clinical outcomes: A retrospective cohort study. J Natl Compr Cancer Netw, 2018; 16(3):267-273. (https://www.ncbi.nlm.nih.gov/pubmed/29523665)

• NCCN defines distress as a multifunctional unpleasant emotional experience of a psychologic nature that may interfere with patient’s ability to cope with cancer symptoms and treatment. A single center retrospective 2-yr study on patient-reported distress demonstrated increased risk for death with even a single point increase on the distress scale used (HR=1.18) suggesting a need for further exploration of this topic.

Cogle CR et al. Early treatment initiation in lower-risk myelodysplastic syndromes produces an earlier and higher rate of transfusion independence. Leuk Res 2017; 60:123-128. (https://www.ncbi.nlm.nih.gov/pubmed/28818807)

• This American retrospective study based on SEER registry and Medicare claims database assessed the impact of a timing of initiating treatment with approved agents (azacytidine, decitabine or lenalidomide) since the date of transfusion dependence. Among the 508 transfusion dependent patients included in the study, 351 received approved therapies early at a median of 28 days since transfusion dependence while 157 patients had delayed initiation of treatment (median 187 days from transfusion dependence). In a multivariate analysis, early treatment predicted transfusion independence and also showed higher rates of transfusion independence.

Ramos F et al. Multidimentional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS Group. Am J Hematol, 2017; 92(9):E534-E541. (https://www.ncbi.nlm.nih.gov/pubmed/28612357)

• This study evaluated the prospects of adding patient condition and peripheral blood mutational status to IPSS-R, in a ten-year prospective cohort of 200 consecutive MDS patients. Patients originally categorized per IPSS-R were stratified by patient condition (per Lee Index) and mutations detected in peripheral blood with next generation sequencing. The addition of patient condition significantly improved overall survival (HR=3.02, p<0.001), while mutational status improved prediction of leukemic transformation (HR=2.71, p<0.001).

Drusbosky L et al. Computational drug treatment simulations on projections of dysregulated protein networks derived from the myelodysplastic mutanome match clinical response in patients. Leuk Res 2017; 52:1-7. (https://www.ncbi.nlm.nih.gov/pubmed/27855285)

• Drug response was simulated for lenalidomide or hypomethylating agents (HMA) or for HMA+Lenalidomide. Using computational biology of genomic abnormalities in each patient intracellular pathway map was computed for individual patients. The computational model matched clinical responses in 80% MDS patients treated with lenalidomide (37/46) or HMAs (12/15) while the matching was 100% (10/10) in patients treated with HMA + Lenalidomide.

Santini V et al. The effect of lenalidomide on health-related quality of life in patients with lower-risk non-del (5q) myelodysplastic syndromes: results from the MDS-005 Study. Clin Lymphoma Myeloma Leuk, 2018; 18(2):136-144. (https://www.ncbi.nlm.nih.gov/pubmed/29429612)

• MDS-005 study in RBC-transfusion dependent low risk non-del(5q) MDS had previously shown effectiveness of lenalidomide in achieving RBC-transfusion independence (TI ≥8wks) in approx. 27% patients (p<0.001) vs placebo (2.5%). EORTC QOL questionnaire-core 30 tool was used in the current investigation to assess HRQOL. At week 24, after adjusting for baseline score, emotional functioning showed benefit with lenalidomide treatment. Also, a positive correlation with all 5 preselected scales (fatigue, dyspnea, global QOL, physical functioning and emotional functioning) was observed with achieving TI ≥8wks (p<0.01) and with all except emotional functioning in case of increased Hb (p<0.05).

Ueda Y et al. A phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with myelodysplastic syndrome.  Cancer Sci, 2017; Sept 26 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/28949050)

• In a dose finding study transfusion dependent MDS patients were administered with a synthetic peptide vaccine WT4869 derived from WT1 gene at 5-1200 μg/dose intradermally every 2 weeks. Among the 25 enrolled patients, dose limiting toxicity was observed in one patient at 50 μg/dose level and in another patient at 400 μg/dose level. With overall response rate of approximately 18% and median survival of 65 weeks, the MTD remained undetermined.  WT1-specific cytotoxic T cells were detectable in 11/25 evaluable patients.

Efficace F et al. Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes. Cancer 2018; 124(6):1251-1259. (https://www.ncbi.nlm.nih.gov/pubmed/29231969)

• A new prognostic index adding patient-reported fatigue severity to IPSS [FA-IPSS(h)- Fatigue-IPSS (high risk)] was developed based on previously untreated MDS patients who completed EORTC QOL questionnaire-core 30 at baseline. The index estimated median overall survival in FA-IPSS-risk-1 or -2 or -3 as 23,16, and 10 months respectively. The predictive accuracy of this new index was higher than conventional IPSS alone in development cohort as well as in a subsequent validation cohort that in addition included previously treated patients

Aldoss I et al. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status. Haematologica, 2017; Sept 29 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28971906)

• The present report evaluates the impact of pre-transplant genetics and other clinical characteristics on allogeneic HSCT in 67 therapy-related MDS (t-MDS) patients compared to 199 patients with de novo MDS receiving allogeneic HSCT. Despite the higher proportion of Int-2/High risk disease and high-risk cytogenetics in t-MDS, the 5-yr overall survival was comparable in t-MDS and de novo MDS patients (49.9% vs 53.9% respectively, p=0.61). Moreover, neither the presence of TP53 mutation nor the mutations of other high-risk genes like EZH2, ASXL1 etc. showed any impact on overall or relapse-free survival.

Ciurea SO et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant, 2017; Sept 14. [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28918304)

• The report describes a single center experience with 43 AML/MDS patients (median age- 61 yr.) undergoing haploidentical SCT with fludarabine-melphalan based conditioning and post-transplant cyclophosphamide based GVHD prophylaxis. All but one patient engrafted donor cells very well. The rates of acute gr 2-4 GVHD at 6 months was 35% and of overall chronic GVHD at 2 yrs. was 9%. At a median 19 mo. follow up both OS and PFS rates were 42%.

Scheid C et al. Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation: a retrospective analysis of the EBMT chronic malignancies working party. Bone Marrow Transplant, 2017; Sept 11. [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/28892084)

• A retrospective analysis of the EBMT database was conducted to understand the impact of the IPSS-R score immediately prior to a transplantation rather than abiding by the score assigned at diagnosis. The multivariate analysis highlighted IPSS-R, graft source, age, and prior treatment as prognostic factors. IPSS-R at transplant showed significant difference in OS and in relapse free survival (Low risk with 55mo/24.8mo as the highest and Very High risk with 7.8 mo./5.5 mo. as the lowest respectively, p<0.001).

Talati C, Sallman D and List A. Lenalidomide: myelodysplastic syndromes with del (5q) and beyond. Semin Heamtol, 2017; 54(3):159-166. (https://www.ncbi.nlm.nih.gov/pubmed/28958290)

• The article describes the differential mechanism of action for lenalidomide in del (5q) MDS vs non-del (5q) MDS. While lenalidomide may lead to elimination of the involved clone in patients with del (5q), it may enhance EPO receptor signaling in non-del(5q) patients. In the latter case, therefore, lenalidomide therapy may work better in combination with EPO-alfa.

Kantarjian HM et al. Guadecitabine (SGI-110) in treatment-naïve patients with acute myeloid leukemia: phase 2 results from a multicenter, randomized, phase 1/2 study. Lancet Oncol, 2017; 18(10): 1317-1326. (https://www.ncbi.nlm.nih.gov/pubmed/28844816)

• This cohort report focuses on outcomes in treatment naïve AML patients from a large randomized phase 1/2 study with AML and MDS patients. The patients were ≥65 yrs old and were not eligible to receive intensive chemotherapy. A total of 107 patients received Guadecitabine in a 28-day cycle on three schedules; 60mg/m² d1-5 (n=26), 90mg/m² d1-5 (n=28), or 60mg/m² d1-10 (n=53). Efficacy seemed comparable across the three schedules, with a composite complete response attained in approximately half the patients. The most frequent grade 3 AEs were febrile neutropenia, thrombocytopenia, neutropenia, pneumonia, anemia and sepsis. The 5-day vs 10-day schedule remained comparable. 22% deaths were related to AEs, were mainly due to sepsis. The recommended dose for future studies is 60mg/m² d1-5 in a 28-day cycle.

Houston BL et al. A predictive model of response to erythropoiesis-stimulating agents in myelodysplastic syndrome: from the Canadian MDS patient registry. Ann Hematol 2017, Oct 3 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28975386)

• Using WHO 2008 criteria, response was evaluated in a total of 208 ESA-treated patients from a prospective Canadian registry. The patients were primarily low/int-1 per IPSS or low/very low per IPSS-R. The erythroid response rate with Epoetin alfa was 50%, while darbepoietin was 39% (p=0.2). The multivariate analysis underscored independent predictive value of low-risk IPSS score (p=0.0016) and serum EPO <100mIU/mL (p<0.0001). Using a score of 1 for low risk and 2 for serum EPO<100mIU/mL, the authors suggest to have improved sensitivity with higher response rate seen in the best risk group as compared to the previously established Nordic score.

Lin Y et al. Prophylactic RhCE and Kell antigen matching; impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes. Vox Sang 2017; 112(1):79-86. (https://www.ncbi.nlm.nih.gov/pubmed/28097704)

• A study of 176 transfusion dependent MDS patients reveals importance of an institutional policy for prophylactic antigen matching for RhCE and Kell antigens. Overall, 17% of the patients developed alloantibodies, with the majority showing at least one anti-RhCE or Kell antigens. When assessed for the prophylactic matching policy before transfusion, the rate was significantly lower (11%) vs. when no policy was applied (23%).

Platzbecker U et al. Luspatercept for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicenter, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol, 2017; 18(10):1338-1347. (https://www.ncbi.nlm.nih.gov/pubmed/28870615)

• Luspatercept is postulated to relieve the TGFβ protein superfamily imposed inhibition of erythropoiesis and hence may have a therapeutic role in treating MDS related anemia. PACE-MDS is a phase 2 study in low/int-1 MDS patients or non-proliferative CMML who had persistent anemia with or without RBC transfusion support at the time of enrollment. In this dose-finding study, Luspatercept was administered subcutaneously every 3 weeks (dose range- 0.125 mg/kg to 1.75 mg/kg for first 5 doses and then in extension study starting at 1 mg/kg titrated up to 1.75 mg/kg). The base study with 27 patients receiving a range of doses, safety and responses were assessed at week 12. Further, 31 patients were enrolled in the extension study cohort. 32/51 (63%) total patients receiving higher doses (0.75- 1.75 mg/kg) achieved HI-E per IWG criteria vs. only 2/9 responders among patients receiving lower doses. With three treatment-related Gr 3 AEs, the treatment was overall well-tolerated.

Sanchez-Garcia J et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma, 2017; Aug 24 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28836866)

• The efficacy of azacitidine was tested against the best supportive care in a prospective study with 36 lower-risk non-del (5q), transfusion dependent MDS patients subsequent to ESAs. The HI-E rate in azacitidine group after nine cycles was 44.4% vs 5.5% in the control group (p<0.01). Transfusion independence was noted with extended azacitidine treatment (median duration of 50 weeks).

Fenaux P et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol, 2017; 178(6):906-913. (https://www.ncbi.nlm.nih.gov/pubmed/28616874)

• This was an open label extension study in 60 patients with lower risk MDS and platelet counts ≤ 50×10⁶/L. The median extension study treatment time was 25 weeks and subsequent observations for 57 weeks. Treatment related AEs were seen in 23% patients. Median duration of platelet response was 33 weeks with 82% patients showing continuous response. 15% (5/34) of the platelet responders had grade ≥ 3 bleeding events.

Martino R et al. Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes. Bone Marrow Transplant 2017; Mar 20 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28319072)

• A multicenter retrospective study involving 843 MDS patients received allogeneic marrow transplant from HLA-matched sibling donor. This study showed that a 13 year relapse rate was significantly higher after reduced conditioning regimen (48%) vs standard myeloablative regimen (31%, p=0.04), without any impact on overall survival. However, non-relapse mortality was higher in myeloablation group as compared to reduced-intensity regimen (40% vs 31%, p=0.1).

Prebet T et al. Outcome of patients treated for myelodysplastic syndromes without deletion 5q after failure of lenalidomide therapy. Oncotarget 2017, Feb 8 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28184031)

• An international retrospective study assessed lenalidomide treated lower risk non-del(5q) MDS patients (n=384). Among these patients, 55% were treated with ESAs and 23% with hypomethylating agents (HMA) before lenalidomide treatment. The response to lenalidomide was seen in 17% patients with amedian lenalidomide treatment duration of 15 mo. Conversely, for the 64% who did not respond to lenalidomide, the median duration of treatment was only 4 mo . When HMA were used after lenalidomide, the overall survival was 51 mo vs. 31 mo with the best supportive care after lenalidomide (p=0.01).

Jabbour E et al. Randomized phase 2 study of low-dose decitabine vs Low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood, 2017; 130(13):1514-1522. (https://www.ncbi.nlm.nih.gov/pubmed/28774880)

• Low/Int-1 risk MDS and MDS/MPN patients (n=113) were randomly assigned to receive decitabine 20mg/m² IV daily (n=73) or azacitidine 75mg/m² IV or SC daily (n=40) for 3 consecutive days in a 28-day cycle for a median of 9 cycles. When decitabine was compared with azacitidine, the ORR was 70% vs 49% (p=0.03), transfusion independence rates were 32% vs 16% (p=0.2), cytogenetic response was 61% vs 25% (p=0.02), overall event-free survival at a follow up of 20 months was 20 mo. vs 13 mo. (p=0.1), respectively. Both treatments were well tolerated.

Wermke M et al. Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the german MDS study group (D-MDS). Br J Haematol 2016; 175(5):917-924. (https://www.ncbi.nlm.nih.gov/pubmed/27714772)

• A prospective study enrolled lower risk MDS patients with transfusion dependent anemia and/or neutropenia and higher risk patients relapsed/refractory to 5-azacitidine. A total of 20 patients (9 lower- and 11 higher-risk) were treated with a weekly 25mg dose of Temsirolimus. Only four patients showed stable disease without HI after four months. The remaining patients discontinued early due to adverse events. A significant decline in marrow vascularization was seen with treatment without impact on the balance of peripheral blood T-cell populations.

Park S et al. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol 201, Mar 28 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28350519)

• Using an international retrospective cohort of 1698 patients with non-del(5q) lower risk MDS treated with ESA, the effect of second line treatment subsequent to ESAs was assessed. The HI-E in frontline with ESA treatment was 61.5% with a median response duration of 17 months. Patients without any response to ESAs had a higher rate of AML transformation than those who initially responded to ESA and then relapsed. Nearly 40% patients received second line therapy after ESA failure including Hypomethylating agents, and lenalidomide, while approx. 60% patients received RBC transfusion only. The HMA and Lenalidomide treated patients had higher propensity for AML transformation and lower 5year survival rates as compared to those receiving transfusions only or treatment with other agents.

Santini V et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents J Clin Oncol 2016; 34(25): 2988-2996 (https://www.ncbi.nlm.nih.gov/pubmed/27354480)

• A phase III randomized placebo controlled double blind study with 239 ESA refractory or ineligible lower risk patients assessed efficacy and safety of lenalidomide in non-del(5q) MDS. The primary end point of ≥ 8 wk transfusion independence was achieved with lenalidomide treatment in 26.9% patients vs. 2.5% on the placebo arm (p<0.001). The median duration of TI with lenalidomide was 30.9 wks. Additionally ≥4 units reduction in PRBC transfusion at 112 days assessment time point was seen in 22% with lenalidomide, compared to none on the placebo arm. Neutropenia and thrombocytopenia were the most common adverse events.

Daver N et al. Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia and high-risk myelodysplastic syndrome. Haematologica, 2017; 102(10):1709-1717. (https://www.ncbi.nlm.nih.gov/pubmed/28729302)

• Vosaroxin and decitabine combination was tested in ≥60 yr. old patients with newly diagnosed AML (n=58) or high risk MDS (n=7). Decitabine was given at 20mg/m² d1-5 every 4-6 weeks up to 7 cycles. In combination, the initial dose of Vosaroxin 90mg/m² d1 and d4 in first 22 patients showed high incidence of Mucositis and was reduced in latter 43 patients to 70mg/m² d1 and d4. The ORR with combination was 74% including CR in 48%, and CRi Platelet in 17%. The 70mg/m² dose of Vosaroxin showed comparable ORR (74% vs 73%), better CR (51% vs 41%), better survival (14.6 mo. vs 5.5 mo., p=0.007) and significantly reduced the incidence of Mucositis (30% vs 59%, p=0.02) as well as lowered 8 week-mortality (9% vs 23%, p=0.14) when compared to 90mg/m² dose respectively. The multiparametric MRD negative status achieved in 54% subjects was correlated to improved survival (34 mo. in MRD neg. vs 8.3 mo. MRD pos., p=0.023)

Swords RT et al. KB004, a first-in-class monoclonal antibody targeting the receptor tyrosine kinase EphA3 in patients with advanced hematologic malignancies: results from a phase 1 study. Leuk Res 2016; 50:123-131. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Sword+RT+and+EphA3)

• An anti-Ephrin receptor tyrosine kinase monoclonal antibody was tested in a phase 1 study with multiple hematologic malignancies including MDS and AML. The most common toxicities were grade 1/2 infusion reactions in approx. 80% treated patients becoming dose limiting beyond 250 mg. The weekly schedule of the drug was found to be well tolerated with clinical responses noted in all the hematologic conditions tested.

Oliva EN et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single blind, randomized controlled phase 2 superiority trial. Lancet Haematol 2017; 4(3):e127-e136. (https://www.ncbi.nlm.nih.gov/pubmed/28162984)

• Eltrombopag (50mg to 300 mg) treatment for at least 24 weeks and until disease progression versus placebo, showed platelet response (HI-plt) in 47% (24/59) patients as compared to 3% of the total 31 patients on placebo arm. Nearly 42% of the placebo patients had bleeding events versus 14% with eltrombopag treated patients (p=0.0025). The AML transformation and disease progression rates were comparable in the two groups.

McGraw KL et al. Lenalidomide Induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One 2014; 9(12): e114249 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25469886

• Localization of erythropoietin receptor (EpoR) within lipid raft microdomains is essential for its signaling. The present report demonstrated that the lipid raft assembly was significantly diminished in number and size in MDS erythroid progenitors as compared to normal controls. Lenalidomide rapidly induced raft assembly, recruitment of EpoR and its signaling upon EPO stimulation with JAK2/STAT5 phosphorylation in UT7 cell line and primary MDS erythroid progenitors. The raft assembly was also associated with F-actin polymerization.

Zhang Z et al. Decitabine treatment sensitizes tumor cells to T-cell mediated cytotoxicity in patients with myelodysplastic syndromes. Am J Transl Res 2017; 9(2): 454-465. (https://www.ncbi.nlm.nih.gov/pubmed/28337274)

• Decitabine treatment of MDS-derived cell lines significantly improved surface expression of cancer-testis antigens (CTAs) and also led to incremental recognition of CTA expressing MDS derived cells by cytotoxic T cells. There was increased HLA and ICAM-1expression specific to cytotoxic T cells. These data may support a role of decitabine in active adaptive immunity in MDS.

Garelius HK et al. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in non-transfused patients with lower-risk myelodysplastic syndrome. J Intern Med 2017; 28(3):284-299. (  https://www.ncbi.nlm.nih.gov/pubmed/27926979)

• The clinical impact of ESA use was evaluated among 1696 subjects registered in EUMDS registry between 2008 and 2014. Nearly 46% patients received ESAs for a median duration of 27.5 months. When compared with non-ESA patients, those treated with ESAs showed a trend of survival benefit (HR=0.82, p=0.09) with the best results in patients not needing transfusions prior to ESA treatment. Among the latter group of patients, post-ESA treatment, first transfusion was needed after a median of 23.3 months (p<0.0001), while in those with prior transfusions, the time to post-ESA first transfusion was significantly shorter (median 6.1 month). Additionally, the responding patients showed significantly lower risk of death (HR=0.065, p=0.018).

Schuler MK et al. Effects of a home-based exercise program on physical capacity and fatigue in patients with low to intermediate risk myelodysplastic syndrome- pilot study. Leuk Res 2016; 47:128-135 (https://www.ncbi.nlm.nih.gov/pubmed/27326698)

• A prospective non-randomized feasibility study assessed evaluating safety and efficacy of home-based exercise intervention to overcome fatigue and build physical capacity was a subject of the present report. In a strength and endurance building training, of 21 total MDS patients, 15 (71%) continued on study till week 12 with 11 completing the program. Significant improvement in 6 min-walking distance exercise was seen. However no improvement was noted in fatigue scores.

Jonasova A et al. High level of full length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. J. Haematol. 2014: Oct 4 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25284710

• Previously down-regulation of cereblon (CRBN) gene expression was associated with resistance to lenalidomide treatment in myeloma. The present study demonstrated that del 5q low risk MDS patients had significantly higher levels of CRBN mRNA as compared to other low risk MDS patients or healthy controls. Furthermore, the CRBN expression was especially higher in responders to lenalidomide, which dropped coincidentally with MDS progression.

Apuri S et al. Evidence for selective benefit of sequential treatment with hypomethylating agents in patients with myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 2017 Jan 10 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28185797)

• A single institution study evaluated effectiveness of sequencing the two hypomethylating agents with each other. In the first line HI rates were comparable with both agents 63% with Azacytidine and 50% with decitabine. In the second line though, decitabine post azacitidine showed 19% HI as the best response compared to 40% with azacitidine post-decitabine. In line with these results, AML transformation was lower with the latter (29% vs 20% respectively). The median survival from the initiation of second line however was comparable (17.8 mo vs 22 mo).

Deshet-Unger N et al. Erythropoietin administration is associated with improved T-cell properties in patients with myelodysplastic syndromes. Leuk Res 2017; 52: 20-27 (https://www.ncbi.nlm.nih.gov/pubmed/27870945)

• In this study, MDS patients treated with ESA were compared to non-ESA treated MDS patients or healthy donors. At baseline, all MDS patients showed reduced number and function of CD4+ T cells and elevated CD8+ T cell number/activity. Post ESA, the CD4+CD25+ cell counts were normalized in the periphery. Also, in vitro activation of both T cell populations, CD4+ and CD8+ with phytohemagglutinin as measured by CD69 expression, nearly doubled after ESA treatment compared to non-ESA treated patients.

Zeidan AM et al. Lenalidomide treatment for lower risk nondeletion 5q myelodysplastic syndromes patients yields higher response rates when used before azacitidine Clin Lymphoma Myeloma Leuk 2015 Sept 2 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26440749

• In a study of 63 low risk MDS patients without 5q deletion, subsequent to ESA failure, a significantly higher Hematopoietic Improvement in Erythroid lineage (HI-E) was found when lenalidomide was administered before vs. after azacytidine (38% vs. 12 %, p = 0.04). No additional benefit in terms of leukemic transformation or overall survival was noted with a specific sequence of the two agents.

Garcia-Manero G et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher risk myelodysplastic syndromes. Cancer 2017; 123(6):994-1002. (https://www.ncbi.nlm.nih.gov/pubmed/28094841)

• Int-2/high-risk MDS patients (n=102) were randomized 1:1 between azacitidine + pracinostat vs azacitidine + placebo. Respectively in the two groups, the CR rate by cycle 6 was 18% vs 33% (p=0.07), median overall survival of 16 and 19 months, and progression free survival of 11 and 9 months.

Beier F et al. Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide. Leuk Res 2015 Sept 21 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26427727

• Telomere length (TL) dynamics were assessed in 5q del MDS patients enrolled in the LEMON-5 study. Compared to age-matched healthy controls, the peripheral blood and/or bone marrow hematopoietic cells from patients showed significant loss of TL, which correlated with the duration of disease from diagnosis and extent of cytopenias. With respect to a corresponding baseline TL, following 6 months of lenalidomide treatment and attaining cytogenetic response, a significant recovery of TL was noted indicative of a shift toward normalization of hematopoiesis.

Welch JS et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016; 375(21):2023-2036. (https://www.ncbi.nlm.nih.gov/pubmed/27959731)

• This single institution trial enrolled a total of 116 subjects with AML or MDS with 46% patients clearing marrow blasts to <5% level. The unfavorable cytogenetic profile patients had better response (67%) with 20 mg/ m2 x 10 days administration of decitabine than those with intermediate or favorable cytogenetics (34%, p<0.001). Moreover, specifically in patients with TP53 mutations the response was 100% (21/21 patients) vs. 41% in wild type TP53 patients (p<0.001).

Weiss L et al. Real-world analysis of the Celgene Global Drug Safety database: Early discontinuation of lenalidomide in patients with myelodysplastic syndromes due to non-serious rash. Ther Clin Risk Manag 2015; 11:1355-1360. http://www.ncbi.nlm.nih.gov/pubmed/26379438

• The study examined rash in MDS patients treated with lenalidomide in real-world as documented in the Celgene Global Drug Safety database in comparison with MDS-003/004 clinical trials. Most rash adverse events were nonserious (CGDSD, 91%) or grade 1/2 (MDS-003/004, 87%-93%). Rash occurring at a median of 9 days after treatment initiation was the leading cause of permanent discontinuation of lenalidomide within 2 two cycles in 72% patients in the real world. In contrast, only 2-3% rash adverse events led to treatment discontinuation in MDS-003/004 trials.

Pappa V et al. A retrospective study of azacitidine treatment in patients with intermediate-2 or high risk myelodysplastic syndromes in a real-world clinical setting in Greece. Int J Hematol 2017; 105(2):184-195. (https://www.ncbi.nlm.nih.gov/pubmed/27815858)

• A single country, multicenter, retrospective chart review study (RETRO-AZA-MDS-001) conducted between Feb-Nov 2012 assessed clinical benefit/risk profile of azacitidine in routine practice in int-2/high risk MDS. A total of 88 patients with a median of 6.6 month treatment duration showed ORR- approx. 38%, HI rate of 33%, AML transformation in 6.8%, transfusion independence in 7.3% among transfusion-dependent patients, and serious adverse events in 42%. Patients with no prior ESA were nearly 8 times more likely to achieve a clinical response with azacitidine (p=0.012).

Tinsley SM, Kurtin SE and Ridgeway JA. Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma, Leuk 2015 June 15 Suppl: S64-S69. http://www.ncbi.nlm.nih.gov/pubmed/26297281

• The registration clinical trial toxicity profile of lenalidomide across all indications noted most common adverse events of hematologic nature with grade 3 or more events as a reason for drug discontinuation. However, in the postmarketing setting an analysis of the Celgene Global Drug Safety database brought to light a nonserious rash as the leading cause of permanent drug discontinuation. The rarity of ≥grade 3 rash in registration trial may highlight differences in the management of rash in the real world. The rash observed was mild to moderate presenting as patchy, raised, macular skin lesions or sometimes as localized urticaria, which might be associated with pruritus.

Thépot S et al. A randomized phase II trial of azacitidine +/- epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica 2016; 101(8): 918-925. (https://www.ncbi.nlm.nih.gov/pubmed/27229713)

• The study prospectively compared outcomes of lower risk MDS relapsing after or refractory to ESA, if they were randomly treated with azacitidine or azacitidine + epoietin-β. Among the 98 patients randomized 1:1, transfusion independence was achieved after 6 cycles in comparable number of patients in both groups (approx. 16% with azacitidine alone or 14% with combination). So was the overall erythroid response similar in the two cohorts studied.

Zhang Z et al. increased PD-1/STAT1 ratio may account for the survival benefit in decitabine therapy for lower risk myelodysplastic syndrome. Leuk Lymphoma 2016 Aug 11 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27686004)

• Among the 44 lower risk MDS patients treated with decitabine, 59.1% achieved overall response, and 53.8% achieved reduction in PRBC/Platelet transfusion burden with a median overall survival of 19 mo for the group. An increase in type1 CD8+ population was noted and amplification of PD-1/STAT1 ratio of 2-4 was associated with longer survival.

Zeidan A et al. Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes. Br J Haematol 2016 Sept 21 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27650975)

• The study identified patients diagnosed with MDS between 2004-2011 in the US based SEER registry, who received ≥10 doses of either azacitidine or decitabine. With a median survival estimate of 15 mo (RAEB subset -12 mo), the study did not find significant difference with respect to the hypomethylating agent used (HR=1.06, p=0.37). A significantly shorter survival was noted in the present study with azacitidine treated RAEB patients as compared to previously reported survival for the same MDS subset in AZA-001 clinical study (11mo vs. 24.5mo, respectively).

Mittleman M et al. Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndrome (MDS)-ViLen-01 protocol. Ann Hematol 2016; 95(11)-1811-1818 (https://www.ncbi.nlm.nih.gov/pubmed/27546027)

• ViLen-01, a phase IIa study included treatment of high risk MDS with 6 month induction regimen of Azacitidine +lenalidomide followed by consolidation using azacitidine and maintenance with lenalidomide. A total of 25 subjects with significant co-morbidities in 88% were treated on the study (13 completing induction, 7 entered consolidation and 2 went into maintenance). Using IWG criteria, the authors reported 72% (18/25) ORR, 24% (6/25) CR, 12% (3/25) marrow CR, 36% (9/25) HI, PFS and OS both 12 mo. The safety profile was acceptable without any new signal for the combination over the expected AEs for individual agents.

Takahashi K et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.Oncotarget2016 Feb 9 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26871476)

• One hundred sixty eight MDS patients treated with hypomethylating agents were screened for TP53 mutations. Although the overall response rate did not vary, the response duration and overall survival were significantly shorter in patients with TP53 mutations as compared to those with wild type gene (DOR- 5.7 mo vs 28.5 mo, p=0.003; OS- 9.4 mo vs 20.7 mo, p<0.001 respectively). Additionally, at leukemic progression post hypomethylating agent treatment, TP53 mutations persisted.

Nazha A et al. Outcomes of patients with myelodysplastic syndromes who achieve stable disease after treatment with hypomethylating agents. Leuk Res2016; 41:43-47 (http://www.ncbi.nlm.nih.gov/pubmed/26777537)

• Within a MDS clinical research consortium database, stable disease (SD) was defined as no evidence of progression and without achievement of any other response. While 55% patients demonstrated best response to Azacytidine or Decitabine (AZA/DAC) at 4-6 mo, additional 20% achieved response at a later time point. Patients with SD at 4-6 mo who eventually achieved CR also had a superior survival vs. those who never improved beyond SD (28.1 mo vs 14.4 mo, p=0.04)

Borthakur G et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in Ras-mutant relapsed or refractory myeloid malignancies. Cancer 2016 March 18 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26990290)

• This phase 1/2 study evaluated relapsed/ refractory AML, high risk-MDS and CMML patients with or without N-RAS or K-RAS mutations. The most common treatment related adverse events were diarrhea, rash, nausea and increased aminotransferase levels. The phase 2 recommended dose was 2 mg PO daily. Patients with N-RAS or K-RAS mutations showed response- 20% in AML/high risk MDS and 27% in CMML as compared to 3% in patients without N-RAS/K-RAS mutations. These results thus validated targeted activity of trametinib in RAS mutated patients.

Garcia-Manero G et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomized controlled phase 3 trial. Lancet Oncol 2016, March 8 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26968357)

• A total of 299 RAEB1, RAEB 2, RAEB-t and CMML patients were randomized 2:1 (199 treated with Rigosertib vs. 100 on best supportive care). With a median follow up of 19.5 months, rigosertib treatment resulted in an overall survival of 8.2 months vs. 5.9 months on control arm (HR=0.87, p=0.33). The most common adverse events with rigosertib were anemia, thrombocytopenia, neutropenia, febrile neutropenia, and pneumonia. With the lack of survival benefit in this trial, the future studies will focus on individual high risk subgroups

Brierley C and Steensma D. Allogeneic stem cell transplantation in myelodysplastic syndromes: does pretreatment clonal burden matter?. Curr Opin Hematol 2016; 23(2): 167-174 (http://www.ncbi.nlm.nih.gov/pubmed/26717194)

• This review surmises that patients with more than 10% marrow blasts should be considered for cytoreduction with therapies like hypomethylating agents prior to allogeneic SCT transplant whereas those with less than 10% blasts could proceed to transplant directly.

Hutzschenreuter F et al. Granulocyte and granulocyte-macrophage colony stimulating factors for newly diagnosed patients with myelodysplastic syndromes. Cochrane Database Syst Rev2016, Feb 16 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26880256)

• A meta-analysis of five randomized controlled (RCT) trials for G-CSF (N=337) and two RCTs for GM-CSF (N=149) demonstrated no benefit in overall survival, progression free survival, progression to AML or in incidence of infections and PRBC transfusions. Larger data is needed to ascertain these observations.

Brayer J et al. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides. Am. J. Hematol 2015: Mar 19 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25802083

• The present study assessed safety, tolerability and immunogenicity of a polyvalent WT1 peptide vaccine. Previously treated high risk MDS patients and AML patients in remission were treated with a mixture of peptides from WT1 protein along with GMCSF. Six biweekly vaccinations followed by a maximum of 12 monthly doses were administered. Vaccinations were well tolerated with no discontinuation due to toxicity. One of the two MDS patients showed sustained transfusion independence and 2 of the 14 AML patients showed >1 year relapse free survival.

Di Stasi A et al. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front Immunol 2015; 6: 36 http://www.ncbi.nlm.nih.gov/pubmed/25699052

• A total of 51 eligible MDS/AML patients from 9 studies reported between 2004-2012 showed clinical benefit with WT1 peptide vaccination demonstrating its safety and clinical benefit including some patients who achieved and maintained remission long term over 8 years. The emergence of WT-1 specific T cells, and normalization/reduction of WT-1 mRNA levels were both associated with progression free survival.

Garcia-Manero G et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clin Cancer Res 2015; 21(5): 985-994 http://www.ncbi.nlm.nih.gov/pubmed/25480830

• A dose finding study with 45 patients receiving oral study medication at 400 to 1200 mg once daily or 200 or 300 mg twice daily. MTD was not reached with once daily dosing, but 300 mg twice daily was not tolerated. The most common side effects were primarily grade 1-2 including rash, diarrhea, dry skin, fatigue and anorexia. Disease response was seen in 14 evaluable cases (32%), all but one of whom were previously treated with hypomethylating agents. Five had bilineage response and 3 of the 25 RBC- and 5 of 7 platelet- transfusion dependent patients achieved transfusion independence.

Thepot S et al. A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure. Leuk Res 2014; 38(12): 1430-1434 http://www.ncbi.nlm.nih.gov/pubmed/25449687

• In this study, 18 patients with higher risk MDS and 12 with AML received 100 mg/day or 150 mg/day PO dose of erlotinib. Generally the treatment was well-tolerated with limited non-hematologic toxicities (common grade III/IV events being skin reactions or diarrhea). The 20% overall response rate was comprised of, 1 CR, 1 marrow CR and 4 hematologic improvement. The median duration of response was 5 months.

Jabbour EJ et al. Outcome of patients with low-risk and intermediate-1 risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS clinical research consortium. Cancer 2015; 121(6): 876-882 (http://www.ncbi.nlm.nih.gov/pubmed/25410759)

• The overall response to hypomethylating agents (HMA) was 35% with average 6 cycles and median duration of response being 7 months. Only 7% patient showed leukemic transformation while on therapy. Of the total 290 evaluable patients failing HMA, 77% remained low-risk MDS. With a 16 month follow up, median transformation-free survival and overall survival after HMA failure were 15 and 17 months respectively.

Santini V et al. Minimizing risk of hypomethylating agent failure in patients with higher risk MDS and practical management recommendations. Leuk Res 2014; 38(12): 1381-1391 http://www.ncbi.nlm.nih.gov/pubmed/25444075

• A perspective is provided specifically on optimizing the benefits of first-line hypomethylating agent use and on the management of azacitidine failure.

Jilg S et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high risk myelodysplastic syndromes patients. Leukemia 2015 Jul 8 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26153654

• Bone marrow mononuclear cells from primary samples of 124 MDS or secondary AML patients and 57 age-matched healthy volunteers were subjected to a treatment with anti-BCL2 agents ABT-737 or ABT-199. The drug sensitivity read as reduction in CD34+ cell number or colony forming capacity, could be demonstrated in high-risk/sAML samples, whereas the low-risk MDS or healthy donor samples remained unaffected.

Latagliata R et al. Erythropoietin treatment in patients with myelodysplastic syndromes and type 2 diabetes. Diabetes 2014: Jul 25 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25060764

• A high dose erythropoietin alfa treatment (2 x 40,000 IU s.c./week) was administered to 140 low risk MDS patients, of which 27 had concomitant type-2 diabetes. The erythroid response rates were comparable between diabetic (17/27 or 62.9%) and non-diabetic patients (62/113 or 54.8%, p=0.446). Neither did the two groups differ with respect to response duration, relapse rate or overall survival.

Ørskov AD et al.Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget 2015; Mar 18[Epub ahead of print].(http://www.ncbi.nlm.nih.gov/pubmed/25823822)

• Most patients with higher-risk myelodysplastic syndrome (MDS) at some point lose response to hypomethylating agents (HMAs). In the present study, T cell expression of immunoinhibitory receptor PD-1, that is regulated by DNA methylation, was associated with a worse overall response rate and low survival. HMAs induced PD-1 expression on T cells in treated MDS patients, thus hindering immune response against MDS blasts. So, the activation of PD-1 checkpoint in HMA treatment can serve as resistance which may be overcome by a combination therapy with PD-1 pathway inhibitor

Ofran Y et al. Higher infection rate after 7- compared with 5-day cycle of azacytidine in patients with higher risk myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 2015; Mar 5 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/25823643)

• Infectious complications may be dose-related in azacytidine (AZA) treatment. Higher-risk patients with MDS or AML treated with AZA in 18 Israeli hospitals from 2008 to 2011 participated in a survey study. The limited analysis of infection rates following the first AZA dose displayed more frequent events with a dose of 75 mg/m2 for 7 days than 75 mg/m2 for 5 days. Of the 46 total events, the pathogen was bacterial in 25 and viral or fungal in 2 each respectively. No pathogen was detected in 17 cases. Infections were common in patients with platelet counts <20,000 or with poor risk cytogenetics.

Strati P et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol 2015; 90(4):276-281. (http://www.ncbi.nlm.nih.gov/pubmed/25530214)

• Patients with AML or high risk MDS received 75 mg/m2 azacytidine on day 1-7 of 21 day cycle in combination with midostaurin at 25 mg or 50 mg bid on days 8-21 of the first cycle and continuously thereafter. Phase I and II enrolled 14 and 40 patients respectively. The overall response rate was 26% and remission duration of 20 weeks. Best response was seen in FLT-3 mutated patients previously not treated with another FLT3 inhibitor or in patients not transplanted previously.

Issa JP et al. Results of Phase 2 randomized study of low dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 2014; Oct 21 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25336333

• Decitabine as a single agent (20 mg/m2 x 5 d every 4-6 weeks) was tested against its combination with oral dose of valproic acid (50 mg/kg x 7 d every 4-6 weeks). The rates of complete remission, overall response and overall survival were comparable between the groups. The study concluded that addition of valproic acid did not improve the outcomes of decitabine treatment

Lübbert M and Kuendgen A. Combining DNA methyltransferase and histone deacetylase inhibition to treat acute myeloid leukemia/myelodysplastic syndrome: achievements and challenges Cancer 2014; Mar 24 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25336205

• In the light of previous data on the combination of hypomethylating agents with HDAC inhibitors, the present editorial provides potential arguments for the lack of combination benefit described in the study of Issa et al. The editorial suggests that valproic acid may not be a strong HDAC inhibitor, the intermittent schedule of valproic acid used might have led to suboptimal systemic drug exposure as compared a continuous regimen used otherwise, and importantly, the HDAC inhibition may arrest DNA synthesis and hence lowering the incorporation of decitabine and reducing the therapeutic index of the latter.

Duong VH et al. Lack of objective response of myelodysplastic syndromes and acute myeloid leukemia to decitabine after failure of azacitidine. Leuk Lymphoma 2014; Sept 27 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25263320

• A single center study with 25 MDS/AML/ MDS-MPN patients administered decitabine subsequent to primary or secondary azacitidine failure, and yielded stable disease in 5 patients and no complete/ partial response nor hematologic improvement in any patient. Median number of decitabine cycles administered was 2 and disease progression was rapid.

Bejar R et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014; 124(17): 2705-2712. http://www.ncbi.nlm.nih.gov/pubmed/25224413

The study sequenced 40 recurrently mutated myeloid malignancy specific genes in 213 patients prior to treatment with azacitidine or decitabine. The response to treatment correlated with TET2 mutations especially in the absence of ASXL1 mutations. Furthermore, the TET2 null cells lost engraftment advantage in murine bone marrow in presence of azacitidine. The TET2 mutations may thus predict response to hypomethylating agents. Besides, mutations in TP53 and PTPN11 associated with poor survival but not with drug response.

Xie M, Jiang Q and Xie Y. Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: a meta-analysis with 1392 participants. Lymphoma Myeloma Leuk. 2014; Jun 12 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25042977

• The meta-analysis included a total of 1392 MDS patients (decitabine, n=768; azacitidine, n=624), from 11 clinical trials. The pooled estimates of complete response rates, PRBC transfusion rates and incidence of grade 3/4 toxicities were comparable between the two drugs. However, rates of partial response, hematologic improvement and overall response were higher with azacitidine as compared to decitabine. Azacitidine also showed superior outcome in patients with high risk features or age >75 years.

Müller-Thomas C. Response to azacitidine is independent of p53 expression in high-risk myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica 2014; 99(10): e179-181. http://www.ncbi.nlm.nih.gov/pubmed/24972774

• The present retrospective study assessed p53 expression by immunohistochemistry in bone marrow biopsies of 100 MDS/secondaryAML/MDS-MPN patients prior to the start of azacitidine treatment. p53-positive patients mostly belonged to the poor risk category and often had a simultaneous presence of chromosome 5 abnormalities. MDS patients with strong p53 expression showed higher response rates to azacitidine as compared to p53-negative patients (p=0.033). No such difference was noted in secondary AML cases studied. However in MDS, the overall survival was shorter in p53 positive patients despite responding to azacitidine.

Grinblatt DL et al. Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA^® Leuk. Lymphoma 2014;Aug 20 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/24956145

• A community practice registry provides real world evidence supporting the efficacy and safety of azacitidine in 421 MDS patients with lower as well as higher risk disease.

Svensson T et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. Eur J. Haematol. 2014; 93(5):439-445. http://www.ncbi.nlm.nih.gov/pubmed/24853277

• Previously untreated MDS patients (n=12) eligible for azacitidine treatment and who had < 75 x 10⁹/L platelet count were included in this study. The severe adverse events included infections, deep vein thrombosis and transient ischemic attack. The MTD was determined at 200 mg qd. Complete remission or bone marrow remission was seen in 4/12 while platelet improvement was seen sustainably in 9/12 patients.

Seymour JF et al. Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes. J. Haematol. 2014; 165(1): 49-56. http://www.ncbi.nlm.nih.gov/pubmed/?term=Seymour+JF+and+hypocellularity

• The present report was a post-hoc analysis of AZA-001 (azacitidine vs. conventional care regimen) clinical trial that assessed the impact of baseline bone marrow cellularity on overall survival. Of the total 299 patients randomized, 13% (n=39) were hypocellular (<30% marrow cellularity). Azacytidine telerability was comparable between hypocellular patients and others. At 33 months, the median overall survival was not reached in hypocellular patients while it was 21.1 mo in non-hypocellular patients treated with azacitidine with the treatment outcome being significantly superior than the conventional care group in each of the two cellularity cohorts.

Narayan R et al. Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leuk Lymphoma 2015 Sept 16 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26374199

• A phase II study with elderly AML/MDS patients who had previous exposure to a hypomethylating agent and/or immunomodulatory agent, assessed treatment with azacitidine at 75 mg/m2 SQ/IV daily for day 1-7 and with lenalidomide at 50 mg PO daily on day 8-28 for a median of 2 cycles. In 32 evaluable patients overall response rate was 25% with overall survival of 9.8 months in responders vs. 4 months in non-responders (p=0.016). Neutropenic fever was the major adverse event.

Papageorgiou SG et al. Treatment with 5-azacytidine improves clinical outcome in high-risk MDS patients in the real-life setting: A single center observational study. Hematology 2015 Jul 28 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26218077

• A retrospective study evaluated 56 high-risk MDS patients who received 5-AZA between 2005-2013 in an outpatient clinic at 75 mg/m2 sc, 7 total doses (5 week days on, 2 week-end days off, 2 week days on). The results showed overall response rate of 50% with CR in 21.2%, PR 3.8%, HI 25% and stable disease in 34.6%. The estimated event free and overall survival were at 11 mo and 17 mo respectively. Survival was especially improved in responding patients.

 

Ye XN et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma 2015 Sept 15. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26372888

• A sequential combination of decitabine 20 mg/m2/day on day1- 3 followed by Idarubicin 3mg/m2/day on day 5-7, with cytarabine 30mg/ m2/day on day 7-14, was administered to 30 patients with high-risk MDS or AML evolved from MDS, or relapsed/refractory AML. The significantly high complete remission rate of approximately 67% was postulated to be indicative of a priming effect of decitabine on conventional chemotherapy.

Danylesko I et al. Biosimilar filgrastim (Tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant Sept 4. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26343949

• A prospective study with HLA-matched healthy sibling donors of 24 AML/MDS patients evaluated a biosimilar human GCSF, Tevagrastim, in comparison with a historical control of sibling donors treated with filgrastim (Neupogen). Mobilization of CD34+ hematopoietic stem cells in peripheral blood was assessed with a 10 μg/kg sc dose for 4 days. The yield of CD34+ stem cell mobilization in healthy donors and engraftment in corresponding patients included in tevagrastim group were comparable to the filgrastim historical controls. No new safety signal was noted with tevagrastim.

Giordano G et al. Biosimilar epoetin α is as effective as originator epoetin α plus liposomal iron (Sideral®), vitamin B12 and folates in patients with refractory anemia: A retrospective real-life approach. Mol Clin Oncol 2015; 3(4): 781-784

• In a retrospective study, 92 MDS patients were treated between 2008-2012, with 40,000 IU weekly sc of a biosimilar epoetin α currently approved in Europe, HX575 (n=46) or established original epoetin α.(n=46). Adequate iron, vitamin B12 and folate support was provided. The study showed comparable results between the biosimilar and original epoetin groups with respect to time for 1g/dL increase in serum hemoglobin (4 vs 5 weeks), time to attain 12 g/dL serum hemoglobin (10.5 vs 12 weeks), transfusions required (7 vs 5 patients) and median cost of therapy ( 1354 vs 1536 Euros/mo).

Sandhu KS et al. Umbilical cord blood transplantation outcomes in acute myelogenous leukemia/myelodysplastic syndromes patients ≥ 70 years old. Biol Blood Marrow Transplant 2015 Sept. 25 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26415559

• In a four year period within single institute, of the 70 total transplant patients with ≥ 70 years of age, 10 patients received umbilical cord blood (UCB) transplant. In these UCB patients, at 2 years, non-relapse mortality (20%), relapse (30%), disease free survival (50%) and overall survival (60%), were similar to those in another series of 60-69 years old patients indicating the feasibility of UCB transplant in ≥ 70 years old.

Guièze R et al. Management of myelodysplastic syndrome relapsing after allogeneic hematopoietic stem cell transplantation: A study by the French Scociety of Bone Marrow Transplantation and Cell Therapies. Biol Blood Marrow Transplant 2015 Aug 6. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26256942

• One hundred forty seven consecutive patients relapsing after allogeneic HSCT for MDS were studied. The post-transplant treatments included immunotherapy (2^nd transplant or donor lymphocyte infusion, n=62) or cytoreductive treatment (n=39) or palliative/supportive care (n=46) with 2 year survival rates of 32%, 6% and 2% respectively in these three groups (p<0.001 for immunotherapy).

Robin M et al. Comparison of unrelated cord blood and peripheral blood stem cell transplantation in adults with myelodysplastic syndrome after reduced-intensity conditioning regimen: a collaborative study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party. Biol Blood Marrow Transplant 2015; 21(3):489-495 http://www.ncbi.nlm.nih.gov/pubmed/25529382

• In a large series of high risk MDS patients (n=631), post reduced-intensity conditioning, mobilized peripheral blood stem cells (n=502) from unrelated donor as compared to umbilical cord blood transplant (n= 129) showed superior neutrophil engraftment (98% vs. 78%, p<0.001), lower 2 year non-relapse mortality (31% vs. 42%, p=0.03), better overall survival (49% vs. 30%, p<0.001) and Disease free survival (44% vs. 28%, p<0.001). The report suggested 10/10 HLA matched unrelated donor as an alternative when matched sibling is unavailable.

Treatment:

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Allogeneic Bone Marrow Transplant

Deeg HJ et al. Transplant conditioning with Treosulfan/fludarabine with or without total body irradiation: a randomized phase II trial in patients with myelodysplastic syndrome and acute myeloid leukemia. Biol Blood Marrow Transplant, 2017; Dec 20 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/29274396)

• In a prospective randomized ph 2 study assessing transplant conditioning with treosulfan (iv 14g/m²/day days -6 to -4) + fludarabine(iv 30mg/m²/day days -6 to -2) with or without 2Gy total body irradiation (TBI) in reducing post-transplant relapse in MDS, CMML and AML patients (N=100; med age- 57 yr). Donors were related in 43 patients and unrelated in 57 patients. With a median follow up of 20 months, the rate of 1-yr survival was 80% in the TBI arm vs 69% for non-TBI conditioning. The 1-yr relapse rates for MDS and AML with TBI vs non-TBI regimens were 27% vs 33% and 16% vs 35% respectively. The report concluded that treosulfan/fludarabine/low-dose TBI provides effective conditioning for allogeneic hematopoietic cell transplantation

Schmid C et al. Outcome after relapse of myelodysplastic syndrome and secondary acute myeloid leukemia following allogeneic stem cell transplantation: a retrospective registry analysis of 698 patients by the chronic malignancies working party of the European society of blood and marrow transplantation. Haematologica, 2018; 103(2):237-245. (https://www.ncbi.nlm.nih.gov/pubmed/29101205)

• This retrospective registry analysis explored post relapse therapeutic practices used for MDS patients who had allogeneic HSCT. Generally, the overall survival from relapse was short (median-4.7 months, 2-yr OS-17.7%). Shorter remission post-transplant (p<0.001), advanced disease (p=0.001), older age (p=0.007), unrelated donor (p=0.008), GVHD prior to relapse (p<0.001) were adversely related to OS. Among the three major practices noted at 6mo post-relapse, the OS (median and 2-yr %OS) rates were as follows- palliative chemotherapy and/or supportive care (n=375, med OS 8.9mo and 2-yr OS-29.7%), Donor lymphocyte infusion (n=213, med OS-6.0mo and 2-yr OS 27.6%) or second transplant (n=110, med OS-4.2mo and 2-yr OS-17%). For second transplant, longer remission after the first transplant, complete remission after second transplant and change to a new donor were of prognostic value.

Aldoss I et al. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status. Haematologica, 2017; Sept 29 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28971906)

• The present report evaluates the impact of pre-transplant genetics and other clinical characteristics on allogeneic HSCT in 67 therapy-related MDS (t-MDS) patients compared to 199 patients with de novo MDS receiving allogeneic HSCT. Despite the higher proportion of Int-2/High risk disease and high-risk cytogenetics in t-MDS, the 5-yr overall survival was comparable in t-MDS and de novo MDS patients (49.9% vs 53.9% respectively, p=0.61). Moreover, neither the presence of TP53 mutation nor the mutations of other high-risk genes like EZH2, ASXL1 etc. showed any impact on overall or relapse-free survival.

Ciurea SO et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant, 2017; Sept 14. [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28918304)

• The report describes a single center experience with 43 AML/MDS patients (median age- 61 yr.) undergoing haploidentical SCT with fludarabine-melphalan based conditioning and post-transplant cyclophosphamide based GVHD prophylaxis. All but one patient engrafted donor cells very well. The rates of acute gr 2-4 GVHD at 6 months was 35% and of overall chronic GVHD at 2 yrs. was 9%. At a median 19 mo. follow up both OS and PFS rates were 42%.

Scheid C et al. Validation of the revised IPSS at transplant in patients with myelodysplastic syndrome/transformed acute myelogenous leukemia receiving allogeneic stem cell transplantation: a retrospective analysis of the EBMT chronic malignancies working party. Bone Marrow Transplant, 2017; Sept 11. [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/28892084)

• A retrospective analysis of the EBMT database was conducted to understand the impact of the IPSS-R score immediately prior to a transplantation rather than abiding by the score assigned at diagnosis. The multivariate analysis highlighted IPSS-R, graft source, age, and prior treatment as prognostic factors. IPSS-R at transplant showed significant difference in OS and in relapse free survival (Low risk with 55mo/24.8mo as the highest and Very High risk with 7.8 mo./5.5 mo. as the lowest respectively, p<0.001).

Martino R et al. Long-term follow-up of a retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic transplantation from matched related donors in myelodysplastic syndromes. Bone Marrow Transplant 2017; Mar 20 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28319072)

• A multicenter retrospective study involving 843 MDS patients received allogeneic marrow transplant from HLA-matched sibling donor. This study showed that a 13 year relapse rate was significantly higher after reduced conditioning regimen (48%) vs standard myeloablative regimen (31%, p=0.04), without any impact on overall survival. However, non-relapse mortality was higher in myeloablation group as compared to reduced-intensity regimen (40% vs 31%, p=0.1).

Biosimilars

Danylesko I et al. Biosimilar filgrastim (Tevagrastim, XMO2) for allogeneic hematopoietic stem cell mobilization and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. Biol Blood Marrow Transplant Sept 4. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26343949

• A prospective study with HLA-matched healthy sibling donors of 24 AML/MDS patients evaluated a biosimilar human GCSF, Tevagrastim, in comparison with a historical control of sibling donors treated with filgrastim (Neupogen). Mobilization of CD34+ hematopoietic stem cells in peripheral blood was assessed with a 10 μg/kg sc dose for 4 days. The yield of CD34+ stem cell mobilization in healthy donors and engraftment in corresponding patients included in tevagrastim group were comparable to the filgrastim historical controls. No new safety signal was noted with tevagrastim.

Giordano G et al. Biosimilar epoetin α is as effective as originator epoetin α plus liposomal iron (Sideral®), vitamin B12 and folates in patients with refractory anemia: A retrospective real-life approach. Mol Clin Oncol 2015; 3(4): 781-784

• In a retrospective study, 92 MDS patients were treated between 2008-2012, with 40,000 IU weekly sc of a biosimilar epoetin α currently approved in Europe, HX575 (n=46) or established original epoetin α.(n=46). Adequate iron, vitamin B12 and folate support was provided. The study showed comparable results between the biosimilar and original epoetin groups with respect to time for 1g/dL increase in serum hemoglobin (4 vs 5 weeks), time to attain 12 g/dL serum hemoglobin (10.5 vs 12 weeks), transfusions required (7 vs 5 patients) and median cost of therapy ( 1354 vs 1536 Euros/mo).

Demethylating Agents

Ørskov AD et al.Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget 2015; Mar 18[Epub ahead of print].(http://www.ncbi.nlm.nih.gov/pubmed/25823822)

• Most patients with higher-risk myelodysplastic syndrome (MDS) at some point lose response to hypomethylating agents (HMAs). In the present study, T cell expression of immunoinhibitory receptor PD-1, that is regulated by DNA methylation, was associated with a worse overall response rate and low survival. HMAs induced PD-1 expression on T cells in treated MDS patients, thus hindering immune response against MDS blasts. So, the activation of PD-1 checkpoint in HMA treatment can serve as resistance which may be overcome by a combination therapy with PD-1 pathway inhibitor

Ofran Y et al. Higher infection rate after 7- compared with 5-day cycle of azacytidine in patients with higher risk myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 2015; Mar 5 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/25823643)

• Infectious complications may be dose-related in azacytidine (AZA) treatment. Higher-risk patients with MDS or AML treated with AZA in 18 Israeli hospitals from 2008 to 2011 participated in a survey study. The limited analysis of infection rates following the first AZA dose displayed more frequent events with a dose of 75 mg/m2 for 7 days than 75 mg/m2 for 5 days. Of the 46 total events, the pathogen was bacterial in 25 and viral or fungal in 2 each respectively. No pathogen was detected in 17 cases. Infections were common in patients with platelet counts <20,000 or with poor risk cytogenetics.

Strati P et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol 2015; 90(4):276-281. (http://www.ncbi.nlm.nih.gov/pubmed/25530214)

• Patients with AML or high risk MDS received 75 mg/m2 azacytidine on day 1-7 of 21 day cycle in combination with midostaurin at 25 mg or 50 mg bid on days 8-21 of the first cycle and continuously thereafter. Phase I and II enrolled 14 and 40 patients respectively. The overall response rate was 26% and remission duration of 20 weeks. Best response was seen in FLT-3 mutated patients previously not treated with another FLT3 inhibitor or in patients not transplanted previously.

Issa JP et al. Results of Phase 2 randomized study of low dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer 2014; Oct 21 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25336333

• Decitabine as a single agent (20 mg/m2 x 5 d every 4-6 weeks) was tested against its combination with oral dose of valproic acid (50 mg/kg x 7 d every 4-6 weeks). The rates of complete remission, overall response and overall survival were comparable between the groups. The study concluded that addition of valproic acid did not improve the outcomes of decitabine treatment

Lübbert M and Kuendgen A. Combining DNA methyltransferase and histone deacetylase inhibition to treat acute myeloid leukemia/myelodysplastic syndrome: achievements and challenges Cancer 2014; Mar 24 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25336205

• In the light of previous data on the combination of hypomethylating agents with HDAC inhibitors, the present editorial provides potential arguments for the lack of combination benefit described in the study of Issa et al. The editorial suggests that valproic acid may not be a strong HDAC inhibitor, the intermittent schedule of valproic acid used might have led to suboptimal systemic drug exposure as compared a continuous regimen used otherwise, and importantly, the HDAC inhibition may arrest DNA synthesis and hence lowering the incorporation of decitabine and reducing the therapeutic index of the latter.

Duong VH et al. Lack of objective response of myelodysplastic syndromes and acute myeloid leukemia to decitabine after failure of azacitidine. Leuk Lymphoma 2014; Sept 27 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25263320

• A single center study with 25 MDS/AML/ MDS-MPN patients administered decitabine subsequent to primary or secondary azacitidine failure, and yielded stable disease in 5 patients and no complete/ partial response nor hematologic improvement in any patient. Median number of decitabine cycles administered was 2 and disease progression was rapid.

Bejar R et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 2014; 124(17): 2705-2712. http://www.ncbi.nlm.nih.gov/pubmed/25224413

The study sequenced 40 recurrently mutated myeloid malignancy specific genes in 213 patients prior to treatment with azacitidine or decitabine. The response to treatment correlated with TET2 mutations especially in the absence of ASXL1 mutations. Furthermore, the TET2 null cells lost engraftment advantage in murine bone marrow in presence of azacitidine. The TET2 mutations may thus predict response to hypomethylating agents. Besides, mutations in TP53 and PTPN11 associated with poor survival but not with drug response.

Xie M, Jiang Q and Xie Y. Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: a meta-analysis with 1392 participants. Lymphoma Myeloma Leuk. 2014; Jun 12 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25042977

• The meta-analysis included a total of 1392 MDS patients (decitabine, n=768; azacitidine, n=624), from 11 clinical trials. The pooled estimates of complete response rates, PRBC transfusion rates and incidence of grade 3/4 toxicities were comparable between the two drugs. However, rates of partial response, hematologic improvement and overall response were higher with azacitidine as compared to decitabine. Azacitidine also showed superior outcome in patients with high risk features or age >75 years.

Müller-Thomas C. Response to azacitidine is independent of p53 expression in high-risk myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica 2014; 99(10): e179-181. http://www.ncbi.nlm.nih.gov/pubmed/24972774

• The present retrospective study assessed p53 expression by immunohistochemistry in bone marrow biopsies of 100 MDS/secondaryAML/MDS-MPN patients prior to the start of azacitidine treatment. p53-positive patients mostly belonged to the poor risk category and often had a simultaneous presence of chromosome 5 abnormalities. MDS patients with strong p53 expression showed higher response rates to azacitidine as compared to p53-negative patients (p=0.033). No such difference was noted in secondary AML cases studied. However in MDS, the overall survival was shorter in p53 positive patients despite responding to azacitidine.

Grinblatt DL et al. Patients with myelodysplastic syndromes treated with azacitidine in clinical practice: the AVIDA^® Leuk. Lymphoma 2014;Aug 20 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/24956145

• A community practice registry provides real world evidence supporting the efficacy and safety of azacitidine in 421 MDS patients with lower as well as higher risk disease.

Svensson T et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. Eur J. Haematol. 2014; 93(5):439-445. http://www.ncbi.nlm.nih.gov/pubmed/24853277

• Previously untreated MDS patients (n=12) eligible for azacitidine treatment and who had < 75 x 10⁹/L platelet count were included in this study. The severe adverse events included infections, deep vein thrombosis and transient ischemic attack. The MTD was determined at 200 mg qd. Complete remission or bone marrow remission was seen in 4/12 while platelet improvement was seen sustainably in 9/12 patients.

Seymour JF et al. Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes. J. Haematol. 2014; 165(1): 49-56. http://www.ncbi.nlm.nih.gov/pubmed/?term=Seymour+JF+and+hypocellularity

• The present report was a post-hoc analysis of AZA-001 (azacitidine vs. conventional care regimen) clinical trial that assessed the impact of baseline bone marrow cellularity on overall survival. Of the total 299 patients randomized, 13% (n=39) were hypocellular (<30% marrow cellularity). Azacytidine telerability was comparable between hypocellular patients and others. At 33 months, the median overall survival was not reached in hypocellular patients while it was 21.1 mo in non-hypocellular patients treated with azacitidine with the treatment outcome being significantly superior than the conventional care group in each of the two cellularity cohorts.

Narayan R et al. Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leuk Lymphoma 2015 Sept 16 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26374199

• A phase II study with elderly AML/MDS patients who had previous exposure to a hypomethylating agent and/or immunomodulatory agent, assessed treatment with azacitidine at 75 mg/m2 SQ/IV daily for day 1-7 and with lenalidomide at 50 mg PO daily on day 8-28 for a median of 2 cycles. In 32 evaluable patients overall response rate was 25% with overall survival of 9.8 months in responders vs. 4 months in non-responders (p=0.016). Neutropenic fever was the major adverse event.

Papageorgiou SG et al. Treatment with 5-azacytidine improves clinical outcome in high-risk MDS patients in the real-life setting: A single center observational study. Hematology 2015 Jul 28 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26218077

• A retrospective study evaluated 56 high-risk MDS patients who received 5-AZA between 2005-2013 in an outpatient clinic at 75 mg/m2 sc, 7 total doses (5 week days on, 2 week-end days off, 2 week days on). The results showed overall response rate of 50% with CR in 21.2%, PR 3.8%, HI 25% and stable disease in 34.6%. The estimated event free and overall survival were at 11 mo and 17 mo respectively. Survival was especially improved in responding patients.

 

Ye XN et al. Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma 2015 Sept 15. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26372888

• A sequential combination of decitabine 20 mg/m2/day on day1- 3 followed by Idarubicin 3mg/m2/day on day 5-7, with cytarabine 30mg/ m2/day on day 7-14, was administered to 30 patients with high-risk MDS or AML evolved from MDS, or relapsed/refractory AML. The significantly high complete remission rate of approximately 67% was postulated to be indicative of a priming effect of decitabine on conventional chemotherapy.

ESAs and Growth factors

Platzbecker U et al. A phase 3 randomized placebo-controlled trial of darbepoietin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia, 2017; 31(9): 1944-1950. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Platzbecker+and+Darbepoietin)

• Low/Int-1 risk MDS patients with Hb ≤10 g/dL, sEPO ≤500 mU/mL and low transfusion burden (N=147) were randomized 2:1 to receive 500μg darbepoietin alfa sc q3w or placebo for 24 weeks, followed by 48 week of open label darbepoietin alfa. Between week 5 and 24, darbepoietin alfa treated patients had lower transfusion incidence (36.1% vs 59.2%, p=0.008) and higher erythroid response (14.7% vs 0%, p=0.016). In the open label 48 weeks phase, darbepoietin dosing increased from q3w to q2w with a corresponding higher erythroid response rate of 34.7%. Safety of darbepoietin was consistent with previous reports.

Kantarjian HM et al. Long-term follow up for up to 5 years on the risk of leukemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim vs placebo in randomized double-blind trial. Lancet Haematol 2018; 5(3):e117-e126. (https://www.ncbi.nlm.nih.gov/pubmed/29396092)

• A ph 2 study with 58 wk romiplostim treatment in low/int-1 risk MDS with thrombocytopenia (n=250) demonstrated clinical benefits in reducing platelet transfusions and with respect to HI-platelet response rate. However, based on the potential risk of progression to AML noted in initial analysis treatment was discontinued and patients were followed for long term outcomes. Among 210/250 patients (84%) who entered a 5-yr follow up phase (139 treated with romiplostim and 83 with placebo), AML progression occurred in 12% patients from romiplostim arm vs 11% from the placebo arm (HR=1.06, p=0.88), while 56% vs 54% patients died respectively on the two arms (HR=1.03, p=0.89). These long-term data may thus warrant an in-depth reassessment of benefit/risk profile of romiplostim.

Houston BL et al. A predictive model of response to erythropoiesis-stimulating agents in myelodysplastic syndrome: from the Canadian MDS patient registry. Ann Hematol 2017, Oct 3 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28975386)

• Using WHO 2008 criteria, response was evaluated in a total of 208 ESA-treated patients from a prospective Canadian registry. The patients were primarily low/int-1 per IPSS or low/very low per IPSS-R. The erythroid response rate with Epoetin alfa was 50%, while darbepoietin was 39% (p=0.2). The multivariate analysis underscored independent predictive value of low-risk IPSS score (p=0.0016) and serum EPO <100mIU/mL (p<0.0001). Using a score of 1 for low risk and 2 for serum EPO<100mIU/mL, the authors suggest to have improved sensitivity with higher response rate seen in the best risk group as compared to the previously established Nordic score.

Fenaux P et al. Romiplostim monotherapy in thrombocytopenic patients with myelodysplastic syndromes: long-term safety and efficacy. Br J Haematol, 2017; 178(6):906-913. (https://www.ncbi.nlm.nih.gov/pubmed/28616874)

• This was an open label extension study in 60 patients with lower risk MDS and platelet counts ≤ 50×10⁶/L. The median extension study treatment time was 25 weeks and subsequent observations for 57 weeks. Treatment related AEs were seen in 23% patients. Median duration of platelet response was 33 weeks with 82% patients showing continuous response. 15% (5/34) of the platelet responders had grade ≥ 3 bleeding events.

Park S et al. Outcome of lower-risk patients with myelodysplastic syndromes without 5q deletion after failure of erythropoiesis-stimulating agents. J Clin Oncol 201, Mar 28 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28350519)

• Using an international retrospective cohort of 1698 patients with non-del(5q) lower risk MDS treated with ESA, the effect of second line treatment subsequent to ESAs was assessed. The HI-E in frontline with ESA treatment was 61.5% with a median response duration of 17 months. Patients without any response to ESAs had a higher rate of AML transformation than those who initially responded to ESA and then relapsed. Nearly 40% patients received second line therapy after ESA failure including Hypomethylating agents, and lenalidomide, while approx. 60% patients received RBC transfusion only. The HMA and Lenalidomide treated patients had higher propensity for AML transformation and lower 5year survival rates as compared to those receiving transfusions only or treatment with other agents.

Oliva EN et al. Eltrombopag versus placebo for low-risk myelodysplastic syndromes with thrombocytopenia (EQoL-MDS): phase 1 results of a single blind, randomized controlled phase 2 superiority trial. Lancet Haematol 2017; 4(3):e127-e136. (https://www.ncbi.nlm.nih.gov/pubmed/28162984)

• Eltrombopag (50mg to 300 mg) treatment for at least 24 weeks and until disease progression versus placebo, showed platelet response (HI-plt) in 47% (24/59) patients as compared to 3% of the total 31 patients on placebo arm. Nearly 42% of the placebo patients had bleeding events versus 14% with eltrombopag treated patients (p=0.0025). The AML transformation and disease progression rates were comparable in the two groups.

Garelius HK et al. Erythropoiesis-stimulating agents significantly delay the onset of a regular transfusion need in non-transfused patients with lower-risk myelodysplastic syndrome. J Intern Med 2017; 28(3):284-299. (  https://www.ncbi.nlm.nih.gov/pubmed/27926979)

• The clinical impact of ESA use was evaluated among 1696 subjects registered in EUMDS registry between 2008 and 2014. Nearly 46% patients received ESAs for a median duration of 27.5 months. When compared with non-ESA patients, those treated with ESAs showed a trend of survival benefit (HR=0.82, p=0.09) with the best results in patients not needing transfusions prior to ESA treatment. Among the latter group of patients, post-ESA treatment, first transfusion was needed after a median of 23.3 months (p<0.0001), while in those with prior transfusions, the time to post-ESA first transfusion was significantly shorter (median 6.1 month). Additionally, the responding patients showed significantly lower risk of death (HR=0.065, p=0.018).

Deshet-Unger N et al. Erythropoietin administration is associated with improved T-cell properties in patients with myelodysplastic syndromes. Leuk Res 2017; 52: 20-27 (https://www.ncbi.nlm.nih.gov/pubmed/27870945)

• In this study, MDS patients treated with ESA were compared to non-ESA treated MDS patients or healthy donors. At baseline, all MDS patients showed reduced number and function of CD4+ T cells and elevated CD8+ T cell number/activity. Post ESA, the CD4+CD25+ cell counts were normalized in the periphery. Also, in vitro activation of both T cell populations, CD4+ and CD8+ with phytohemagglutinin as measured by CD69 expression, nearly doubled after ESA treatment compared to non-ESA treated patients.

Growth Factors

Swaminathan M, et al. A phase 2 clinical trial of eltrombopag for treatment of patients with myelodysplastic syndromes after hypomethylating-agent failure. Leuk Lymphoma, 2019; 60(9):2207-2213. https://pubmed.ncbi.nlm.nih.gov/30773968/)

• Eltrombopag was given at a starting dose of 200mg orally per day either as monotherapy (n=7) or was added to HMA (n=22) after the failure of initial HMA therapy of high risk MDS. There was one early death (<30 days) due to infection/sepsis, an overall 11% (3/28) platelet improvement rate and a med survival of 12 mo. Addition of eltrombopag to HMA did not show additive toxicity.

Hutzschenreuter F et al. Granulocyte and granulocyte-macrophage colony stimulating factors for newly diagnosed patients with myelodysplastic syndromes. Cochrane Database Syst Rev2016, Feb 16 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26880256)

• A meta-analysis of five randomized controlled (RCT) trials for G-CSF (N=337) and two RCTs for GM-CSF (N=149) demonstrated no benefit in overall survival, progression free survival, progression to AML or in incidence of infections and PRBC transfusions. Larger data is needed to ascertain these observations.

Latagliata R et al. Erythropoietin treatment in patients with myelodysplastic syndromes and type 2 diabetes. Diabetes 2014: Jul 25 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/25060764

• A high dose erythropoietin alfa treatment (2 x 40,000 IU s.c./week) was administered to 140 low risk MDS patients, of which 27 had concomitant type-2 diabetes. The erythroid response rates were comparable between diabetic (17/27 or 62.9%) and non-diabetic patients (62/113 or 54.8%, p=0.446). Neither did the two groups differ with respect to response duration, relapse rate or overall survival.

Hematopoietic Stem Cell Transplantation

Shimoni A, et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT. Br J Haematology, 2021; Sept 12 [Online ahead of print] (DOI: 1111/bjh.17817 )

• Reduced intensity conditioning (RIC) is known for lower non-relapse mortality and higher relapse rates as compared to myeloablative conditioning (MAC). The assessment of post-allogeneic transplant outcomes, compared a type of RIC with Fludarabine/treosulfan (FT, n=367), with traditional RIC (n=687) and MAC(n=668). Besides the older age in FT and RIC compared to MAC, there were no other differences in baseline characteristics among the three groups. After a median f/u of over 5 years (64mo), FT matched RIC in lower NRM (30% and 27% respectively) vs MAC (34%, p=0.008), while it showed lower 5-year relapse comparable to MAC (25% for both) vs RIC (38%). In a multivariate analysis, FT was associated with lower risk of relapse (HR=0.55, p<0.001) and better OS (HR=0.72, p<0.01). Authors concluded that FT may a preferred regimen for allogeneic-hematopoietic cell transplant in MDS.

Kurosawa S et al, Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis. Bone Marrow Transplant, 2021; Sept 7 [Online ahead of print] (DOI: 1038/s41409-021-01447-y)

• While Fludarabine/busulfan (Flu/Bu4) is effective in myeloablation prior to allo-HSCT in AML, it is not established in MDS. The nationwide registry data from Japan between 2006 and 2018 was reviewed (N=2482) for comparison of allo-HSCT outcomes with Flu/Bu4 (n=153) versus Busulfan/Cyclophosphamide (Bu4/Cy, n=153) conditioning in MDS patients. The cumulative non-relapse mortality, cumulative incidence of relapse, the 3-year progression free survival or the 3-year OS were not significantly different with the two conditioning regimens.

Wei Y, et al. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci, 2021; 112(9): 3636-3644. (DOI: 1111/cas.15048)

• A combination of Low dose decitabine (LDEC, 15mg/m² day 1-3) with venetoclax (VEN, 200mg day 1-21) in a 2 mo cycle x 10 cycles, was tested in a prospective study of 20 AML/high-risk MDS patients starting approximately on day 100 post-transplantation. The median follow up was approximately 20 mo. For primary end points, the median 2-year event-free survival (EFS) was 17.5mo (525 days) with 17 patients event free. The most common adverse events (AEs) were neutropenia, anemia, thrombocytopenia, neutropenic fever and fatigue. No >3 grade AEs were observed. GVHD of any grade was observed in 55% patients.

Modi D, et al. Post-transplant cyclophosphamide versus thymoglobulin in HLA-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transplant Cell Ther, 2021;27(9): 760-767. (DOI: 1016/j.jtct.2021.06.018)

• This retrospective study of 76 patients with AML or MDS assessed (2006-2019) the efficacy and safety of two GVHD prophylaxis regimens post-transplant with HLA mismatched unrelated donor. Cyclophosphamide (50mg/kg on day 3 and 4) treatment was compared with thymoglobulin (total dose 4.5 mg/kg). Although, the grade 3-4 acute GVHD at day 100 did not show significant difference (12% vs 19,6%, p=0.38), chronic GVHD at 1 year was significantly lower with cyclophosphamide (16% vs 49%, p=0.006). Also with cyclophosphamide, the median time to engraftment was shorter for both neutrophils (15 vs 11days, p<0.001) and platelets (21 vs 15 days, p=0.002). No difference in OS, relapse rate, relapse free survival or GVHD-free relapse-free survival were noted with the two agents tested. In a propensity-score-based multivariate analysis, besides higher acute and chronic GVHD incidence, higher non-relapse mortality was demonstrated with thymoglobulin compared to cyclophosphamide.

Shimoni A, et al. Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT. Br J Haematology, 2021; Sept 12 [Online ahead of print] (DOI: 1111/bjh.17817 )

• Reduced intensity conditioning (RIC) is known for lower non-relapse mortality and higher relapse rates as compared to myeloablative conditioning (MAC). The assessment of post-allogeneic transplant outcomes, compared a type of RIC with Fludarabine/treosulfan (FT, n=367), with traditional RIC (n=687) and MAC(n=668). Besides the older age in FT and RIC compared to MAC, there were no other differences in baseline characteristics among the three groups. After a median f/u of over 5 years (64mo), FT matched RIC in lower NRM (30% and 27% respectively) vs MAC (34%, p=0.008), while it showed lower 5-year relapse comparable to MAC (25% for both) vs RIC (38%). In a multivariate analysis, FT was associated with lower risk of relapse (HR=0.55, p<0.001) and better OS (HR=0.72, p<0.01). Authors concluded that FT may a preferred regimen for allogeneic-hematopoietic cell transplant in MDS.

Kurosawa S et al, Fludarabine/busulfan versus busulfan/cyclophosphamide as myeloablative conditioning for myelodysplastic syndrome: a propensity score-matched analysis. Bone Marrow Transplant, 2021; Sept 7 [Online ahead of print] (DOI: 1038/s41409-021-01447-y)

• While Fludarabine/busulfan (Flu/Bu4) is effective in myeloablation prior to allo-HSCT in AML, it is not established in MDS. The nationwide registry data from Japan between 2006 and 2018 was reviewed (N=2482) for comparison of allo-HSCT outcomes with Flu/Bu4 (n=153) versus Busulfan/Cyclophosphamide (Bu4/Cy, n=153) conditioning in MDS patients. The cumulative non-relapse mortality, cumulative incidence of relapse, the 3-year progression free survival or the 3-year OS were not significantly different with the two conditioning regimens.

Wei Y, et al. Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome. Cancer Sci, 2021; 112(9): 3636-3644. (DOI: 1111/cas.15048)

• A combination of Low dose decitabine (LDEC, 15mg/m² day 1-3) with venetoclax (VEN, 200mg day 1-21) in a 2 mo cycle x 10 cycles, was tested in a prospective study of 20 AML/high-risk MDS patients starting approximately on day 100 post-transplantation. The median follow up was approximately 20 mo. For primary end points, the median 2-year event-free survival (EFS) was 17.5mo (525 days) with 17 patients event free. The most common adverse events (AEs) were neutropenia, anemia, thrombocytopenia, neutropenic fever and fatigue. No >3 grade AEs were observed. GVHD of any grade was observed in 55% patients.

Modi D, et al. Post-transplant cyclophosphamide versus thymoglobulin in HLA-mismatched unrelated donor transplant for acute myelogenous leukemia and myelodysplastic syndrome. Transplant Cell Ther, 2021;27(9): 760-767. (DOI: 1016/j.jtct.2021.06.018)

• This retrospective study of 76 patients with AML or MDS assessed (2006-2019) the efficacy and safety of two GVHD prophylaxis regimens post-transplant with HLA mismatched unrelated donor. Cyclophosphamide (50mg/kg on day 3 and 4) treatment was compared with thymoglobulin (total dose 4.5 mg/kg). Although, the grade 3-4 acute GVHD at day 100 did not show significant difference (12% vs 19,6%, p=0.38), chronic GVHD at 1 year was significantly lower with cyclophosphamide (16% vs 49%, p=0.006). Also with cyclophosphamide, the median time to engraftment was shorter for both neutrophils (15 vs 11days, p<0.001) and platelets (21 vs 15 days, p=0.002). No difference in OS, relapse rate, relapse free survival or GVHD-free relapse-free survival were noted with the two agents tested. In a propensity-score-based multivariate analysis, besides higher acute and chronic GVHD incidence, higher non-relapse mortality was demonstrated with thymoglobulin compared to cyclophosphamide.

Scott BL, et al. Myeloablative versus reduced-intensity conditioning for hematopoietic cell transplantation in acute myelogenous leukemia and myelodysplastic syndromes-long-term follow-up of the BMT CTN 0901 clinical trial. Transplant Cell Ther, 2021; Feb 26 [Online ahead of print] (https://doi.org/10.1016/j.jtct.2021.02.031)

• AML/MDS patients (18-65 yr age) with <5% marrow myeloblasts were randomized between myeloablative conditioning (MAC, n=135) and reduced-intensity conditioning (RIC, n=137) prior to receiving hematopoietic cell transplant (HCT) from HLA-matched donor. Median f/u was 51mo. At four years, treatment related mortality was higher in MAC (approx. 25%) compared to RIC (approx. 10%, p<0.001). On the other hand, relapse rate was significantly higher in RIC vs MAC (HR-4.06, p<0.001). At 3 years, the post-relapse survival rate was comparable between MAC and RIC (approx. 25%). The OS upon long term f/u though, was superior with MAC versus RIC (HR-1.54, p=0.03).

Brierley C and Steensma D. Allogeneic stem cell transplantation in myelodysplastic syndromes: does pretreatment clonal burden matter?. Curr Opin Hematol 2016; 23(2): 167-174 (http://www.ncbi.nlm.nih.gov/pubmed/26717194)

• This review surmises that patients with more than 10% marrow blasts should be considered for cytoreduction with therapies like hypomethylating agents prior to allogeneic SCT transplant whereas those with less than 10% blasts could proceed to transplant directly.

Sandhu KS et al. Umbilical cord blood transplantation outcomes in acute myelogenous leukemia/myelodysplastic syndromes patients ≥ 70 years old. Biol Blood Marrow Transplant 2015 Sept. 25 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26415559

• In a four year period within single institute, of the 70 total transplant patients with ≥ 70 years of age, 10 patients received umbilical cord blood (UCB) transplant. In these UCB patients, at 2 years, non-relapse mortality (20%), relapse (30%), disease free survival (50%) and overall survival (60%), were similar to those in another series of 60-69 years old patients indicating the feasibility of UCB transplant in ≥ 70 years old.

Guièze R et al. Management of myelodysplastic syndrome relapsing after allogeneic hematopoietic stem cell transplantation: A study by the French Scociety of Bone Marrow Transplantation and Cell Therapies. Biol Blood Marrow Transplant 2015 Aug 6. [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26256942

• One hundred forty seven consecutive patients relapsing after allogeneic HSCT for MDS were studied. The post-transplant treatments included immunotherapy (2^nd transplant or donor lymphocyte infusion, n=62) or cytoreductive treatment (n=39) or palliative/supportive care (n=46) with 2 year survival rates of 32%, 6% and 2% respectively in these three groups (p<0.001 for immunotherapy).

Robin M et al. Comparison of unrelated cord blood and peripheral blood stem cell transplantation in adults with myelodysplastic syndrome after reduced-intensity conditioning regimen: a collaborative study from Eurocord (Cord blood Committee of Cellular Therapy & Immunobiology Working Party of EBMT) and Chronic Malignancies Working Party. Biol Blood Marrow Transplant 2015; 21(3):489-495 http://www.ncbi.nlm.nih.gov/pubmed/25529382

• In a large series of high risk MDS patients (n=631), post reduced-intensity conditioning, mobilized peripheral blood stem cells (n=502) from unrelated donor as compared to umbilical cord blood transplant (n= 129) showed superior neutrophil engraftment (98% vs. 78%, p<0.001), lower 2 year non-relapse mortality (31% vs. 42%, p=0.03), better overall survival (49% vs. 30%, p<0.001) and Disease free survival (44% vs. 28%, p<0.001). The report suggested 10/10 HLA matched unrelated donor as an alternative when matched sibling is unavailable.

Hypomethylating Agents

Kantarjian H, et al. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer, 2021; Aug 23 [Online ahead of print] (DOI: 1002/cncr.33828)

• An oral nucleoside analogue, Sapacitabine was tested in an alternating cycles with decitabine. In a phase 3 randomized multicenter international study, elderly patients of ≥ 70 years age who were not candidates for standard induction chemotherapy were randomized 1:1 to receive decitabine (20 mg/m² 1-hr iv qd x 5 d every 8wk) in alternating cycles with sapacitabine in the test arm or decitabine alone in the control arm with same dosing in a every 4 week cycle. Patients with prior hypomethylating agent exposure were excluded. The primary endpoint was OS. A total of 482 patients were randomized to decitabine-sapacitabine vs decitabine monotherapy (n=241 each). The OS and CR rates were comparable between arms (OS: 5.9 mo vs 5.7 mo respectively, p=0.8902; CR: 16.6% vs 10.8% respectively, p=0.1468). However, in patients with low baseline WBC <10×10⁹/L, OS and CR were higher with sequential therapy than control monotherapy (n=321) (OS: 8.0mo vs 5.8mo respectively, p=0.145 and CR: 21.5% vs 8.6% respectively, p=0.0017).

Swaminathan M, et al. A phase I/II study of the combination of quizartinib with azacytidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome. Haematologica, 2021; 106(8):2121-2130. (DOI: 3324/haematol.2020.263392)

• AML patients FLT3-like tyrosine kinase-3-internal tandem duplication (FLT3-ITD) mutations receiving first salvage therapy (n=39) or previously untreated MDS/AML patients with >60 years age (n=34) were treated with quizartinib plus azacytidine (AZA) or low dose cytarabine (LDAC). The composite response rate among previously untreated patients was 87% (13/15; CR-8) with quizartinib+AZA and 74% (14/19; CR=1) in quizartinib+LDAC with median OS/relapse free survival (RFS) of 19.2/10.5 mo and 8.5/6.4 mo respectively. Among previously treated patients the composite response rate and median OS with two treatments were, 64%/12.8mo vs 29%/4mo respectively.

Kantarjian H, et al. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer, 2021; Aug 23 [Online ahead of print] (DOI: 1002/cncr.33828)

• An oral nucleoside analogue, Sapacitabine was tested in an alternating cycles with decitabine. In a phase 3 randomized multicenter international study, elderly patients of ≥ 70 years age who were not candidates for standard induction chemotherapy were randomized 1:1 to receive decitabine (20 mg/m² 1-hr iv qd x 5 d every 8wk) in alternating cycles with sapacitabine in the test arm or decitabine alone in the control arm with same dosing in a every 4 week cycle. Patients with prior hypomethylating agent exposure were excluded. The primary endpoint was OS. A total of 482 patients were randomized to decitabine-sapacitabine vs decitabine monotherapy (n=241 each). The OS and CR rates were comparable between arms (OS: 5.9 mo vs 5.7 mo respectively, p=0.8902; CR: 16.6% vs 10.8% respectively, p=0.1468). However, in patients with low baseline WBC <10×10⁹/L, OS and CR were higher with sequential therapy than control monotherapy (n=321) (OS: 8.0mo vs 5.8mo respectively, p=0.145 and CR: 21.5% vs 8.6% respectively, p=0.0017).

Swaminathan M, et al. A phase I/II study of the combination of quizartinib with azacytidine or low-dose cytarabine for the treatment of patients with acute myeloid leukemia and myelodysplastic syndrome. Haematologica, 2021; 106(8):2121-2130. (DOI: 3324/haematol.2020.263392)

• AML patients FLT3-like tyrosine kinase-3-internal tandem duplication (FLT3-ITD) mutations receiving first salvage therapy (n=39) or previously untreated MDS/AML patients with >60 years age (n=34) were treated with quizartinib plus azacytidine (AZA) or low dose cytarabine (LDAC). The composite response rate among previously untreated patients was 87% (13/15; CR-8) with quizartinib+AZA and 74% (14/19; CR=1) in quizartinib+LDAC with median OS/relapse free survival (RFS) of 19.2/10.5 mo and 8.5/6.4 mo respectively. Among previously treated patients the composite response rate and median OS with two treatments were, 64%/12.8mo vs 29%/4mo respectively.

Wan Z, and Han B. High-dose regimens of hypomethylating agents promote transfusion independence in IPSS lower-risk myelodysplastic syndromes: a meta-analysis of prospective studies. Ageing, 2021; Mar 26 [Online ahead of print] (https://doi.org/10.18632/aging.202767)

• A literature meta-analysis of prospective studies published between Jan 1990 and Jul 2020 compared different dosing regimens of two hypomethylating agents, azacytidine and decitabine in lower-risk MDS. No differences were noted between regimens of individual agents or between two agents with respect to response rates and OS. Safety profile too did not have significant differences besides decitabine (20mg/m2/day x 3days) showing higher rates of Grade 3/4 anemia and lower rates of diarrhea/constipation. The transfusion independence rate was higher with AZA (75mg/m2/day x 7day; p<0.025).

Garcia-Manero G, et al. Phase III randomized, placebo-controlled trial of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. J Clin Oncol, 2021; Mar 25 [Online ahead of print] (https://doi.org/10.1200/jco.20.02619)

• Lower risk MDS patients were randomized to receive CC-486 300mg/day for 21 days in a 28 day cycle (n=216) or placebo. The RBC transfusion-independence (TI) rate, and median duration of TI were higher in CC-486 treated patients (31%, and approx. 11mo) versus the placebo group (11%, p=0.0002, approx. 5mo). The rate of patients with >1.5mg increase in HB and the rate of platelet improvement were higher in CC-486 treated patients (23.4% vs 4.6% and 24.3% vs 6.5%). Furthermore, although overall death rate was similar in the two arms, the number of deaths in the first 56 days were higher in the treatment arm primarily due to infections in patients with notable pretreatment neutropenia (n=16 ) vs placebo (n=6).

Clavio M, et al. Overall survival of myelodysplastic syndrome patients after azacitidine discontinuation and applicability of the North American MDS Consortium Scoring System in clinical practice. Cancer, 2021; Mar 19 [Online ahead of print] (https://doi.org/10.1002/cncr.33472)

• This Italian registry study of 402 consecutively enrolled MDS patients showed that while 80% patients discontinued due to primary or adaptive resistance, 20% were responsive to AZA at treatment discontinuation. Among the latter, those who subsequently received hematopoietic stem cell transplant, had significantly improved survival. Furthermore, when assessed with North American MDS Consortium scoring system (n=278), the low-risk patients showed better survival vs high-risk patients (p<0.001) regardless of whether they received best supportive care (5mo vs 2mo respectively) or active treatment including transplant (16mo vs 8mo).

Feld J et al. Safety and Efficacy: Clinical experience of venetoclax in combination with hypomethylating agents in both newly diagnosed and relapsed/refractory advanced myeloid malignancies. Hemasphere, 2021; 5(4):e549 (https://doi.org/10.1097/hs9.0000000000000549)

• This retrospective analysis of a total of 72 patients (AML, n=65 and MDS, n=7), treated with a combination of venetoclax and hypomethylating agent showed CR/CRi in 53.8% newly diagnosed AML, and in 38.5% relapsed/recurrent AML. The responders to combination were enriched for TET2, IDH1 and IDH2 mutations, while non-responders showed enrichment for FLT3 and RAS mutations. Approx. 59% patients developed infections, and approx. 47% had neutropenic fever.

Garcia JS, et al. A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival. Leuk Res, 2021; Mar 2 [Online ahead of print] (https://doi.org/10.1016/j.leukres.2021.106555)

• This study level systematic review of literature included 237 clinical studies to assess outcomes with azacitidine in higher-risk MDS. The pooled marrow CR was 9%, overall CR-17%, and median overall survival of 18.6 mo. While the CR rate showed a weak correlation with median OS (Pearson’s r=0.315), it correlated strongly with median progression free survival (r=0.88) across studies.

Yalniz FF, et al. A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy. Br J Haematol, 2020;188(3): 404-412. (https://doi.org/10.1111/bjh.16173)

• This phase II study assessed the addition of pracinostat to hypomethylating agent (HMA) in MDS patients who showed primary or secondary failure on HMA or had stable disease without a clinical response. Forty five patients receiving a median 3 cycles showed one CR and 7 marrow CR with a median overall survival of 5.7 mo in previous HMA failure or 5.6mo in previous stable disease on HMA. Grade ≥3 adverse events were seen in 84% patients with 33% discontinuing treatment. The study concluded with the need to optimize the dose of pracinostat.

Cai L, et al. Role of TP53 mutations in predicting the clinical efficacy of hypomethylating therapy in patients with myelodysplastic syndrome and related neoplasms: a systematic review and meta-analysis. Clin Exp Med, 2020; 20(3): 361-371 (1007/s10238-020-00641-4 )   

• This systematic review and meta-analysis report on 22 original studies demonstrates that while MDS patients with TP53 mutations respond to hypomethylating agents well, their overall survival may still be poor regardless of their response.

Mozessohn L, et al. Healthcare utilization in patients with higher-risk MDS/low-blast count AML treated with azacytidine in the real-world. Leuk Lymphoma, 2020; Feb 8 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/32036719/)

• The Ontario AZA-MDS registry linked to population based administrative databases showed approx. 80% patients (705/877) had at least one emergency clinic visit; 33% in their first cycle. Also, approx. 77% had at least one hospitalization with a mean length approx. 18 days. A greater comorbidity, non-response to AZA and transfusion dependence were associated with both emergency room visits and hospitalizations. Also, among patients with ≥ 3 cycles of treatment hospitalization during first cycle was associated with an increased risk of death.

Chandhok N, et al. Hypomethylating agent- based combinations in higher risk myelodysplastic syndrome. Leuk Lymphoma, 2019; Dec 9 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31814484/)

• The authors argue that there continues to exist an unmet need to improve upfront treatment of higher risk MDS patients as only a proportion of patients respond to hypomethylating agents and the responses are less durable. Authors propose upfront combinations with other agents as a way to improve outcomes of HMA and list venetoclax and rigosertinib as promising agents for such combination.

Ren Y, et al. Decitabine for myelodysplastic syndromes: Dose comparison in a real world clinical setting. Leuk Lymphoma, 2019; 60(7): 1731-1739. (https://pubmed.ncbi.nlm.nih.gov/30616472/)

• This was a retrospective study with 133 MDS patients. The study demonstrated that in real world patients 15 mg/m2/day dose vs. 20mg/m2/day dose resulted in a comparable response rates (ORR-51.8% vs 52%, CR-15.7% vs 22% respectively), longer survival (21.6 mo vs 15.2 mo respectively), and lower hematologic toxicity (Gr3/4 neutropenia- 60% vs 88%; thrombocytopenia- 65% vs 88% respectively). Additionally, the report also found that the overall survival benefit with 15 mg/m2/day was primarily associated with lower risk patients.

Ades L, et al. A phase II study of efficacy and safety of an intensified schedule of azacytidine in intermediate-2 and high-risk patients with myelodysplastic synromes: A study by the Groupe Francophone Des Myelodysplasies (GFM). Heamatologica, 2019; 104(4):e131-e133. (https://pubmed.ncbi.nlm.nih.gov/30381302/)

• A azacytidine treatment intensification tested using a schedule leading to 20% higher number of days with azacytidine (75mg/m2/day x5 days in 14-day cycle) administration during first 8 weeks of treatment. Patients who achieved CR/PR received additional aza at 21-day cycles x 4 followed by std 7-day dosing in a 28-day cycle until progression. For patient not achieving CR or PR after first 8 weeks, additional 8 weeks of intensified treatment was given. The primary end point was response by IWG 2006 criteria after first 4 and 8 dose intensified cycles (15-day cycles). The int-2- and high-risk proportions were 65:35 among the 26 evaluable patients. The overall marrow response after 4- or 8-weeks intensified treatment was 22% (6/27). The marrow CR+ hematologic improvement (HI) was 65% after week 4 and 62% after week 8. With a f/u of approx. 42 mo, median duration of CR/PR was 10.5 mo, duration of overall response was 14 mo, and overall survival was 21.5 mo. Treatment intensification was not associated with increased toxicity.

Zeidan A, et al. Treatment sequence of lenalidomide and hypomethylating agents and the impact on clinical outcomes for patients with myelodysplastic syndromes. Leuk Lymphoma 2019;60(8):2050-2055. (https://pubmed.ncbi.nlm.nih.gov/30636526/)

• A US claims database study (Inovalon MORE2 registry) comparing outcomes of treatment sequence Len- HMA vs HMA-Len demonstrated longer time to discontinue second treatment (HR-0.52, p=0.023), and to disenroll from insurance used as proxy for survival (HR-0.64, p=0.017).

Qin Y et al. Hypomethylating agents for patients with myelodysplastic syndromes prior to hematopoietic stem cell transplantation: a systematic review and meta-analysis. Ann Hematol, 2019; Oct 22 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31637485)

• A meta-analysis of 6 cohort studies with MDS patients demonstrated that overall survival and relapse free survival were comparable regardless of the use of hypomethylating agents compared to chemotherapy or best supportive care prior to HSCT (OS- HR=0.81, p-0.104 and RFS- HR=0.96, p-0.749).

Reilly B et al. DNA methylation identifies genetically and prognostically distinct subtypes of myelodysplastic syndromes. Blood Adv, 2019; 3(19): 2845-2858. (https://www.ncbi.nlm.nih.gov/pubmed/31582393)

• Bone marrow DNA samples from 141 MDS patients showed 5 distinct CG methylation clusters which demonstrated distinct subtypes of patients otherwise not distinguished by mutations or clinical features. Patients with diverse genetic lesions converge into single methylation group who may share pathogenic mechanisms and clinical outcomes.

Vij R et al. A phase II multicenter study of the addition of azacitidine to reduced-intensity conditioning allogeneic transplant for high-risk myelodysplasia (and older patients with acute myeloid leukemia): Results of CALGB 100801 (Alliance). Biol Blood marrow Transplant, 2019; 25(10):1984-1992. (https://www.ncbi.nlm.nih.gov/pubmed/31212080)

• A total of 63 patients (40 unrelated and 23 matched related donors) received Fludarabine iv d -7 to d-3, busulfan daily to AUC 4000 µM/min d -6 to d -3 (after a prior test dose) and ATG d -6 to d -4. All patients also received up to 6 cycles of Azacitidine starting between d +42 to d +90. In total 41patients received AZA starting on median day 61 post-transplant of whom 17 completed 6 cycles. The 2-year cumulative rates of non-relapse mortality was 33.4%, and relapse of 25%. At med f/u of approx. 59 mo, the estimated PFS was approx. 41% at 2 year and 27% at 5 year. For the entire group of patients, the overall median PFS was 15.8mo and median overall survival was 19.2mo.

Garcia-Manero G et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicenter, open-label, randomized phase 1/2 trial. Lancet Haematol 2019;6(6):e317-e327. (https://www.ncbi.nlm.nih.gov/pubmed/31060979)

• Int-1, Int-2 or High risk MDS patients with or without prior exposure to hypomethylating agents were randomized to sc guadecitabine 60 mg/m2 (n=55) or 90 mg/m2 (n=50) on d1-5 in 28 d cycle. With median 3.2 yr f/u, the overall response (a composite of CR, PR, Marrow CR and HI) did not differ between the two dose levels (40% vs 55% respectively). For patients who were treatment naïve and those who were relapsing after previous exposure to hypomethylating agents, the overall response rates were 51% vs 43% respectively. The grade ≥3 adverse events included thrombocytopenia, neutropenia, febrile neutropenia, anemia and infections. The deaths due to adverse event were 7%. The recommended dose for future studies thus is 60 mg/m2.

Qin T et al. Risk of disease progression in low-risk MDS is linked to distinct epigenetic subtypes. Leukemia 2019; Jul 22 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Qin+T+and+Nimer+SD)

• A set of paired diagnostic and f/u samples were assessed in a cohort of 20 patients (13 with stable MDS and 7 with progressive MDS). Targeted sequencing was carried out with a panel of 59 genes frequently mutated in myeloid malignancies. The progressive disease patients had higher frequency of mutations/patient (3.2) vs stable disease patients (1.2, p=0.01). Furthermore, the study identified 356 differentially methylated regions (DMRs) between progressive and stable low-risk MDS. Whereas the methylation pattern of stable disease patients was closer to normal, that for progressive disease patients was significantly divergent. Supervised analysis showed that the number of DMRs nearly doubled (681) with progressive disease.

Sekeres MA et al. Randomized phase II study of azacitidine alone or in combination with lenalidomide or with vorinostat in higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia: North American Intergroup Study SWOG S1117. J Clin Oncol, 2017; 35(24):2745-2753.( https://www.ncbi.nlm.nih.gov/pubmed/28486043)

• In the phase II part of this phase II/III study, 277 high risk MDS/CMML patients were randomized to receive azacitidine alone (75 mg/m2/d 1-7 of 28 d cycle, n=92), or in combination with lenalidomide (10mg/d1-21, n=93)or with vorinostat (300mg bid d3-9, n=92). At a median follow up of 23 months, the ORR was 38% with azacitidine alone as compared to 49% with azacitidine+lenalidomide (p=0.14) and 27% with azacitidine+vorinostat (p=0.16). CMML patients showed higher ORR with lenalidomide combination than azacitidine alone (68% vs 28%, p=0.02).

Shapiro RM and Lazo-Langner A. Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia. BMC Hematol, 2018; Jan 31 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29435331)

• A metaanalysis of RCTs showed higher pooled proportion of overall response rate (ORR) with two 7-day schedules, 44.8% for 7-0-0 and 45.8% for 5-2-2, as compared to 41.2% on 5-day schedule (5-0-0).

Sohn SK et al. No benefit of hypomethylating agents compared to supportive care for higher risk myelodysplastic syndrome. Korean J Intern Med, 2017; Dec 15 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/29232940)

• A retrospective analysis of 279 high/very high MDS patients from the Korean MDS working party database estimated 3-yr survival rate of 53.1% with allogeneic HCT + HMA, 75% with allogeneic HCT without HMA, 17.3% with HMA alone and 20.8% with best supportive care. The multivariate analysis demonstrated association of OS with only allogeneic HCT alone (HR=0.36, p=0.002).

Komrokji R et al. Azacitidine in lower-risk myelodysplastic syndromes: a meta-analysis of data from prospective studies. Oncologist, 2018; 23(2):159-170. (https://www.ncbi.nlm.nih.gov/pubmed/29118268)

• A 15-yr retrospective search for ph 2/3 studies with azacitidine and patient level data from identified relevant studies led to analysis of 233 selected patients; approx. 90% non-del(5q) low risk MDS. The pooled estimates of RBC-transfusion independence and overall clinical benefit were approx. 39% and 42% respectively. Also, in a multivariate analysis, a planned use of ≥6 cycles was predictive of a response.

Medeiros BC et al. Randomized study of continuous high dose lenalidomide, sequential azacytidine and lenalidomide, or azacitidine in persons 65 years and over with newly diagnosed acute myeloid leukemia. Haematologica, 2018; 103(1):101-106. (https://www.ncbi.nlm.nih.gov/pubmed/29097499)

• A randomized open-label ph 2 study compared three therapeutic strategies in patients newly diagnosed with AML and ≥ 65 yrs of age; continuous high dose lenalidomide (n=15), sequential azacytidine and lenalidomide (n=39), or azacitidine (n=34) and demonstrated 1-yr survival rates of 21%, 44% and 52% respectively. Also, the hazard of death was greatest with continuous high dose lenalidomide.

Kantarjian HM et al. Guadecitabine (SGI-110) in treatment-naïve patients with acute myeloid leukemia: phase 2 results from a multicenter, randomized, phase 1/2 study. Lancet Oncol, 2017; 18(10): 1317-1326. (https://www.ncbi.nlm.nih.gov/pubmed/28844816)

• This cohort report focuses on outcomes in treatment naïve AML patients from a large randomized phase 1/2 study with AML and MDS patients. The patients were ≥65 yrs old and were not eligible to receive intensive chemotherapy. A total of 107 patients received Guadecitabine in a 28-day cycle on three schedules; 60mg/m² d1-5 (n=26), 90mg/m² d1-5 (n=28), or 60mg/m² d1-10 (n=53). Efficacy seemed comparable across the three schedules, with a composite complete response attained in approximately half the patients. The most frequent grade 3 AEs were febrile neutropenia, thrombocytopenia, neutropenia, pneumonia, anemia and sepsis. The 5-day vs 10-day schedule remained comparable. 22% deaths were related to AEs, were mainly due to sepsis. The recommended dose for future studies is 60mg/m² d1-5 in a 28-day cycle.

Sanchez-Garcia J et al. Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia. Leuk Lymphoma, 2017; Aug 24 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28836866)

• The efficacy of azacitidine was tested against the best supportive care in a prospective study with 36 lower-risk non-del (5q), transfusion dependent MDS patients subsequent to ESAs. The HI-E rate in azacitidine group after nine cycles was 44.4% vs 5.5% in the control group (p<0.01). Transfusion independence was noted with extended azacitidine treatment (median duration of 50 weeks).

Jabbour E et al. Randomized phase 2 study of low-dose decitabine vs Low-dose azacitidine in lower-risk MDS and MDS/MPN. Blood, 2017; 130(13):1514-1522. (https://www.ncbi.nlm.nih.gov/pubmed/28774880)

• Low/Int-1 risk MDS and MDS/MPN patients (n=113) were randomly assigned to receive decitabine 20mg/m² IV daily (n=73) or azacitidine 75mg/m² IV or SC daily (n=40) for 3 consecutive days in a 28-day cycle for a median of 9 cycles. When decitabine was compared with azacitidine, the ORR was 70% vs 49% (p=0.03), transfusion independence rates were 32% vs 16% (p=0.2), cytogenetic response was 61% vs 25% (p=0.02), overall event-free survival at a follow up of 20 months was 20 mo. vs 13 mo. (p=0.1), respectively. Both treatments were well tolerated.

Daver N et al. Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia and high-risk myelodysplastic syndrome. Haematologica, 2017; 102(10):1709-1717. (https://www.ncbi.nlm.nih.gov/pubmed/28729302)

• Vosaroxin and decitabine combination was tested in ≥60 yr. old patients with newly diagnosed AML (n=58) or high risk MDS (n=7). Decitabine was given at 20mg/m² d1-5 every 4-6 weeks up to 7 cycles. In combination, the initial dose of Vosaroxin 90mg/m² d1 and d4 in first 22 patients showed high incidence of Mucositis and was reduced in latter 43 patients to 70mg/m² d1 and d4. The ORR with combination was 74% including CR in 48%, and CRi Platelet in 17%. The 70mg/m² dose of Vosaroxin showed comparable ORR (74% vs 73%), better CR (51% vs 41%), better survival (14.6 mo. vs 5.5 mo., p=0.007) and significantly reduced the incidence of Mucositis (30% vs 59%, p=0.02) as well as lowered 8 week-mortality (9% vs 23%, p=0.14) when compared to 90mg/m² dose respectively. The multiparametric MRD negative status achieved in 54% subjects was correlated to improved survival (34 mo. in MRD neg. vs 8.3 mo. MRD pos., p=0.023)

Zhang Z et al. Decitabine treatment sensitizes tumor cells to T-cell mediated cytotoxicity in patients with myelodysplastic syndromes. Am J Transl Res 2017; 9(2): 454-465. (https://www.ncbi.nlm.nih.gov/pubmed/28337274)

• Decitabine treatment of MDS-derived cell lines significantly improved surface expression of cancer-testis antigens (CTAs) and also led to incremental recognition of CTA expressing MDS derived cells by cytotoxic T cells. There was increased HLA and ICAM-1expression specific to cytotoxic T cells. These data may support a role of decitabine in active adaptive immunity in MDS.

Apuri S et al. Evidence for selective benefit of sequential treatment with hypomethylating agents in patients with myelodysplastic syndrome. Clin Lymphoma Myeloma Leuk 2017 Jan 10 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28185797)

• A single institution study evaluated effectiveness of sequencing the two hypomethylating agents with each other. In the first line HI rates were comparable with both agents 63% with Azacytidine and 50% with decitabine. In the second line though, decitabine post azacitidine showed 19% HI as the best response compared to 40% with azacitidine post-decitabine. In line with these results, AML transformation was lower with the latter (29% vs 20% respectively). The median survival from the initiation of second line however was comparable (17.8 mo vs 22 mo).

Garcia-Manero G et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher risk myelodysplastic syndromes. Cancer 2017; 123(6):994-1002. (https://www.ncbi.nlm.nih.gov/pubmed/28094841)

• Int-2/high-risk MDS patients (n=102) were randomized 1:1 between azacitidine + pracinostat vs azacitidine + placebo. Respectively in the two groups, the CR rate by cycle 6 was 18% vs 33% (p=0.07), median overall survival of 16 and 19 months, and progression free survival of 11 and 9 months.

Welch JS et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016; 375(21):2023-2036. (https://www.ncbi.nlm.nih.gov/pubmed/27959731)

• This single institution trial enrolled a total of 116 subjects with AML or MDS with 46% patients clearing marrow blasts to <5% level. The unfavorable cytogenetic profile patients had better response (67%) with 20 mg/ m2 x 10 days administration of decitabine than those with intermediate or favorable cytogenetics (34%, p<0.001). Moreover, specifically in patients with TP53 mutations the response was 100% (21/21 patients) vs. 41% in wild type TP53 patients (p<0.001).

Pappa V et al. A retrospective study of azacitidine treatment in patients with intermediate-2 or high risk myelodysplastic syndromes in a real-world clinical setting in Greece. Int J Hematol 2017; 105(2):184-195. (https://www.ncbi.nlm.nih.gov/pubmed/27815858)

• A single country, multicenter, retrospective chart review study (RETRO-AZA-MDS-001) conducted between Feb-Nov 2012 assessed clinical benefit/risk profile of azacitidine in routine practice in int-2/high risk MDS. A total of 88 patients with a median of 6.6 month treatment duration showed ORR- approx. 38%, HI rate of 33%, AML transformation in 6.8%, transfusion independence in 7.3% among transfusion-dependent patients, and serious adverse events in 42%. Patients with no prior ESA were nearly 8 times more likely to achieve a clinical response with azacitidine (p=0.012).

Thépot S et al. A randomized phase II trial of azacitidine +/- epoetin-β in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica 2016; 101(8): 918-925. (https://www.ncbi.nlm.nih.gov/pubmed/27229713)

• The study prospectively compared outcomes of lower risk MDS relapsing after or refractory to ESA, if they were randomly treated with azacitidine or azacitidine + epoietin-β. Among the 98 patients randomized 1:1, transfusion independence was achieved after 6 cycles in comparable number of patients in both groups (approx. 16% with azacitidine alone or 14% with combination). So was the overall erythroid response similar in the two cohorts studied.

Zhang Z et al. increased PD-1/STAT1 ratio may account for the survival benefit in decitabine therapy for lower risk myelodysplastic syndrome. Leuk Lymphoma 2016 Aug 11 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27686004)

• Among the 44 lower risk MDS patients treated with decitabine, 59.1% achieved overall response, and 53.8% achieved reduction in PRBC/Platelet transfusion burden with a median overall survival of 19 mo for the group. An increase in type1 CD8+ population was noted and amplification of PD-1/STAT1 ratio of 2-4 was associated with longer survival.

Zeidan A et al. Comparative clinical effectiveness of azacitidine versus decitabine in older patients with myelodysplastic syndromes. Br J Haematol 2016 Sept 21 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/27650975)

• The study identified patients diagnosed with MDS between 2004-2011 in the US based SEER registry, who received ≥10 doses of either azacitidine or decitabine. With a median survival estimate of 15 mo (RAEB subset -12 mo), the study did not find significant difference with respect to the hypomethylating agent used (HR=1.06, p=0.37). A significantly shorter survival was noted in the present study with azacitidine treated RAEB patients as compared to previously reported survival for the same MDS subset in AZA-001 clinical study (11mo vs. 24.5mo, respectively).

Mittleman M et al. Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndrome (MDS)-ViLen-01 protocol. Ann Hematol 2016; 95(11)-1811-1818 (https://www.ncbi.nlm.nih.gov/pubmed/27546027)

• ViLen-01, a phase IIa study included treatment of high risk MDS with 6 month induction regimen of Azacitidine +lenalidomide followed by consolidation using azacitidine and maintenance with lenalidomide. A total of 25 subjects with significant co-morbidities in 88% were treated on the study (13 completing induction, 7 entered consolidation and 2 went into maintenance). Using IWG criteria, the authors reported 72% (18/25) ORR, 24% (6/25) CR, 12% (3/25) marrow CR, 36% (9/25) HI, PFS and OS both 12 mo. The safety profile was acceptable without any new signal for the combination over the expected AEs for individual agents.

Takahashi K et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.Oncotarget2016 Feb 9 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26871476)

• One hundred sixty eight MDS patients treated with hypomethylating agents were screened for TP53 mutations. Although the overall response rate did not vary, the response duration and overall survival were significantly shorter in patients with TP53 mutations as compared to those with wild type gene (DOR- 5.7 mo vs 28.5 mo, p=0.003; OS- 9.4 mo vs 20.7 mo, p<0.001 respectively). Additionally, at leukemic progression post hypomethylating agent treatment, TP53 mutations persisted.

Nazha A et al. Outcomes of patients with myelodysplastic syndromes who achieve stable disease after treatment with hypomethylating agents. Leuk Res2016; 41:43-47 (http://www.ncbi.nlm.nih.gov/pubmed/26777537)

• Within a MDS clinical research consortium database, stable disease (SD) was defined as no evidence of progression and without achievement of any other response. While 55% patients demonstrated best response to Azacytidine or Decitabine (AZA/DAC) at 4-6 mo, additional 20% achieved response at a later time point. Patients with SD at 4-6 mo who eventually achieved CR also had a superior survival vs. those who never improved beyond SD (28.1 mo vs 14.4 mo, p=0.04)

IMiDs

List A, et al. Lenalidomide-epoetin alfa versus lenalidomide monotherapy in myelodysplastic syndromes refractory to recombinant erythropoietin. J Clin Oncol, 2021; 39(9): 1001-1009. (https://doi.org/10.1200/jco.20.01691)

• A total of 195 non-del(5q) low risk patients with low probability of response to erythropoietin therapy (based on sEPO levels and/or prior erythropoietin treatment), were randomized to receive a combination of LEN+EPO alfa (n=99) or LEN alone (n=96). After 4 cycles, Major erythroid response (MER) was higher with the combination (28.3%, p=0.004) vs LEN alone (11.5%). At 16 wks too, the MER and overall erythroid response were higher with combination (38.9%/46.5% respectively) vs LEN monotherapy (15.5%/32.3% respectively). Lastly, the MER observed with the combination was also more durable versus LEN monotherapy (23.8 mo vs 13mo).

Almeida A et al. Safety profile of lenalidomide in patients with lower-risk myelodysplastic syndromes without del (5q): results of a phase 3 trial. Leuk Lymphoma, 2018; Jan 11, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29322849)

• This report presents the safety profile of lenalidomide treatment of low risk non-del(5q) ESA refractory/ineligible MDS patients (n=239) from a phase 3 study. Compared to the placebo, lenalidomide had higher incidence of grade 3/4 treatment emergent AEs (TEAE-44% vs 86% respectively). The risk of infection or hemorrhagic events, however, were not increased. Grade 3/4 non-hematologic events were rare. The report also provides guidance on managing lenalidomide related TEAEs.

Talati C, Sallman D and List A. Lenalidomide: myelodysplastic syndromes with del (5q) and beyond. Semin Heamtol, 2017; 54(3):159-166. (https://www.ncbi.nlm.nih.gov/pubmed/28958290)

• The article describes the differential mechanism of action for lenalidomide in del (5q) MDS vs non-del (5q) MDS. While lenalidomide may lead to elimination of the involved clone in patients with del (5q), it may enhance EPO receptor signaling in non-del(5q) patients. In the latter case, therefore, lenalidomide therapy may work better in combination with EPO-alfa.

Prebet T et al. Outcome of patients treated for myelodysplastic syndromes without deletion 5q after failure of lenalidomide therapy. Oncotarget 2017, Feb 8 [Epub ahead of print] (https://www.ncbi.nlm.nih.gov/pubmed/28184031)

• An international retrospective study assessed lenalidomide treated lower risk non-del(5q) MDS patients (n=384). Among these patients, 55% were treated with ESAs and 23% with hypomethylating agents (HMA) before lenalidomide treatment. The response to lenalidomide was seen in 17% patients with amedian lenalidomide treatment duration of 15 mo. Conversely, for the 64% who did not respond to lenalidomide, the median duration of treatment was only 4 mo . When HMA were used after lenalidomide, the overall survival was 51 mo vs. 31 mo with the best supportive care after lenalidomide (p=0.01).

Santini V et al. Randomized phase III study of lenalidomide versus placebo in RBC transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents J Clin Oncol 2016; 34(25): 2988-2996 (https://www.ncbi.nlm.nih.gov/pubmed/27354480)

• A phase III randomized placebo controlled double blind study with 239 ESA refractory or ineligible lower risk patients assessed efficacy and safety of lenalidomide in non-del(5q) MDS. The primary end point of ≥ 8 wk transfusion independence was achieved with lenalidomide treatment in 26.9% patients vs. 2.5% on the placebo arm (p<0.001). The median duration of TI with lenalidomide was 30.9 wks. Additionally ≥4 units reduction in PRBC transfusion at 112 days assessment time point was seen in 22% with lenalidomide, compared to none on the placebo arm. Neutropenia and thrombocytopenia were the most common adverse events.

McGraw KL et al. Lenalidomide Induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors. PLoS One 2014; 9(12): e114249 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25469886

• Localization of erythropoietin receptor (EpoR) within lipid raft microdomains is essential for its signaling. The present report demonstrated that the lipid raft assembly was significantly diminished in number and size in MDS erythroid progenitors as compared to normal controls. Lenalidomide rapidly induced raft assembly, recruitment of EpoR and its signaling upon EPO stimulation with JAK2/STAT5 phosphorylation in UT7 cell line and primary MDS erythroid progenitors. The raft assembly was also associated with F-actin polymerization.

Jonasova A et al. High level of full length cereblon mRNA in lower risk myelodysplastic syndrome with isolated 5q deletion is implicated in the efficacy of lenalidomide. J. Haematol. 2014: Oct 4 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25284710

• Previously down-regulation of cereblon (CRBN) gene expression was associated with resistance to lenalidomide treatment in myeloma. The present study demonstrated that del 5q low risk MDS patients had significantly higher levels of CRBN mRNA as compared to other low risk MDS patients or healthy controls. Furthermore, the CRBN expression was especially higher in responders to lenalidomide, which dropped coincidentally with MDS progression.

Zeidan AM et al. Lenalidomide treatment for lower risk nondeletion 5q myelodysplastic syndromes patients yields higher response rates when used before azacitidine Clin Lymphoma Myeloma Leuk 2015 Sept 2 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26440749

• In a study of 63 low risk MDS patients without 5q deletion, subsequent to ESA failure, a significantly higher Hematopoietic Improvement in Erythroid lineage (HI-E) was found when lenalidomide was administered before vs. after azacytidine (38% vs. 12 %, p = 0.04). No additional benefit in terms of leukemic transformation or overall survival was noted with a specific sequence of the two agents.

Beier F et al. Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide. Leuk Res 2015 Sept 21 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26427727

• Telomere length (TL) dynamics were assessed in 5q del MDS patients enrolled in the LEMON-5 study. Compared to age-matched healthy controls, the peripheral blood and/or bone marrow hematopoietic cells from patients showed significant loss of TL, which correlated with the duration of disease from diagnosis and extent of cytopenias. With respect to a corresponding baseline TL, following 6 months of lenalidomide treatment and attaining cytogenetic response, a significant recovery of TL was noted indicative of a shift toward normalization of hematopoiesis.

Weiss L et al. Real-world analysis of the Celgene Global Drug Safety database: Early discontinuation of lenalidomide in patients with myelodysplastic syndromes due to non-serious rash. Ther Clin Risk Manag 2015; 11:1355-1360. http://www.ncbi.nlm.nih.gov/pubmed/26379438

• The study examined rash in MDS patients treated with lenalidomide in real-world as documented in the Celgene Global Drug Safety database in comparison with MDS-003/004 clinical trials. Most rash adverse events were nonserious (CGDSD, 91%) or grade 1/2 (MDS-003/004, 87%-93%). Rash occurring at a median of 9 days after treatment initiation was the leading cause of permanent discontinuation of lenalidomide within 2 two cycles in 72% patients in the real world. In contrast, only 2-3% rash adverse events led to treatment discontinuation in MDS-003/004 trials.

Tinsley SM, Kurtin SE and Ridgeway JA. Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma, Leuk 2015 June 15 Suppl: S64-S69. http://www.ncbi.nlm.nih.gov/pubmed/26297281

• The registration clinical trial toxicity profile of lenalidomide across all indications noted most common adverse events of hematologic nature with grade 3 or more events as a reason for drug discontinuation. However, in the postmarketing setting an analysis of the Celgene Global Drug Safety database brought to light a nonserious rash as the leading cause of permanent drug discontinuation. The rarity of ≥grade 3 rash in registration trial may highlight differences in the management of rash in the real world. The rash observed was mild to moderate presenting as patchy, raised, macular skin lesions or sometimes as localized urticaria, which might be associated with pruritus.

Iron Chelation

Hoeks M et al. Impact of treatment with iron chelation therapy in patients with lower-risk myelodysplastic syndromes participating in the European MDS registry. Haematologica, 2019; Jul 5 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31278207)

• Low risk MDS patients with iron chelation therapy (224/2200 or approx. 10.2%) within European MDS registry were compared to contemporary non-chelated patients. After adjustment for demographic and disease characteristics the chelated patient showed 50% risk reduction in overall survival (HR=0.50), which improved further in propensity-score analysis of matched cases (HR=0.42). Approximately 39% chelated patients had erythroid response.

Immunosuppressive Therapies

Stahl M, et al. Use of immunosuppressive therapy for management of myelodysplastic syndromes: a systematic review and meta-analysis. Haematologica, 2020; 105(1):102-111. (3324/haematol.2019.219345 )

• A systematic literature review identified nine prospective cohort studies and 12 clinical trials using immunosuppressive therapy, mostly anti-thymocyte globulin ± cyclosporin A. The overall response rate was 42.5% with 12.5% CR and RBC transfusion independence rate of 33.4%. The leukemic transformation rate was 8.6% per patient year. The review highlights the immunosuppressive therapy as a therapeutic option to low-risk MDS patients. 

Novel Agents

Borthakur G et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in Ras-mutant relapsed or refractory myeloid malignancies. Cancer 2016 March 18 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26990290)

• This phase 1/2 study evaluated relapsed/ refractory AML, high risk-MDS and CMML patients with or without N-RAS or K-RAS mutations. The most common treatment related adverse events were diarrhea, rash, nausea and increased aminotransferase levels. The phase 2 recommended dose was 2 mg PO daily. Patients with N-RAS or K-RAS mutations showed response- 20% in AML/high risk MDS and 27% in CMML as compared to 3% in patients without N-RAS/K-RAS mutations. These results thus validated targeted activity of trametinib in RAS mutated patients.

Garcia-Manero G et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomized controlled phase 3 trial. Lancet Oncol 2016, March 8 [Epub ahead of print] (http://www.ncbi.nlm.nih.gov/pubmed/26968357)

• A total of 299 RAEB1, RAEB 2, RAEB-t and CMML patients were randomized 2:1 (199 treated with Rigosertib vs. 100 on best supportive care). With a median follow up of 19.5 months, rigosertib treatment resulted in an overall survival of 8.2 months vs. 5.9 months on control arm (HR=0.87, p=0.33). The most common adverse events with rigosertib were anemia, thrombocytopenia, neutropenia, febrile neutropenia, and pneumonia. With the lack of survival benefit in this trial, the future studies will focus on individual high risk subgroups

Brayer J et al. WT1 vaccination in AML and MDS: A pilot trial with synthetic analog peptides. Am. J. Hematol 2015: Mar 19 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/25802083

• The present study assessed safety, tolerability and immunogenicity of a polyvalent WT1 peptide vaccine. Previously treated high risk MDS patients and AML patients in remission were treated with a mixture of peptides from WT1 protein along with GMCSF. Six biweekly vaccinations followed by a maximum of 12 monthly doses were administered. Vaccinations were well tolerated with no discontinuation due to toxicity. One of the two MDS patients showed sustained transfusion independence and 2 of the 14 AML patients showed >1 year relapse free survival.

Di Stasi A et al. Review of the results of WT1 peptide vaccination strategies for myelodysplastic syndromes and acute myeloid leukemia from nine different studies. Front Immunol 2015; 6: 36 http://www.ncbi.nlm.nih.gov/pubmed/25699052

• A total of 51 eligible MDS/AML patients from 9 studies reported between 2004-2012 showed clinical benefit with WT1 peptide vaccination demonstrating its safety and clinical benefit including some patients who achieved and maintained remission long term over 8 years. The emergence of WT-1 specific T cells, and normalization/reduction of WT-1 mRNA levels were both associated with progression free survival.

Garcia-Manero G et al. A phase I study of oral ARRY-614, a p38 MAPK/Tie2 dual inhibitor, in patients with low or intermediate-1 risk myelodysplastic syndromes. Clin Cancer Res 2015; 21(5): 985-994 http://www.ncbi.nlm.nih.gov/pubmed/25480830

• A dose finding study with 45 patients receiving oral study medication at 400 to 1200 mg once daily or 200 or 300 mg twice daily. MTD was not reached with once daily dosing, but 300 mg twice daily was not tolerated. The most common side effects were primarily grade 1-2 including rash, diarrhea, dry skin, fatigue and anorexia. Disease response was seen in 14 evaluable cases (32%), all but one of whom were previously treated with hypomethylating agents. Five had bilineage response and 3 of the 25 RBC- and 5 of 7 platelet- transfusion dependent patients achieved transfusion independence.

Thepot S et al. A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure. Leuk Res 2014; 38(12): 1430-1434 http://www.ncbi.nlm.nih.gov/pubmed/25449687

• In this study, 18 patients with higher risk MDS and 12 with AML received 100 mg/day or 150 mg/day PO dose of erlotinib. Generally the treatment was well-tolerated with limited non-hematologic toxicities (common grade III/IV events being skin reactions or diarrhea). The 20% overall response rate was comprised of, 1 CR, 1 marrow CR and 4 hematologic improvement. The median duration of response was 5 months.

Jabbour EJ et al. Outcome of patients with low-risk and intermediate-1 risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS clinical research consortium. Cancer 2015; 121(6): 876-882 (http://www.ncbi.nlm.nih.gov/pubmed/25410759)

• The overall response to hypomethylating agents (HMA) was 35% with average 6 cycles and median duration of response being 7 months. Only 7% patient showed leukemic transformation while on therapy. Of the total 290 evaluable patients failing HMA, 77% remained low-risk MDS. With a 16 month follow up, median transformation-free survival and overall survival after HMA failure were 15 and 17 months respectively.

Santini V et al. Minimizing risk of hypomethylating agent failure in patients with higher risk MDS and practical management recommendations. Leuk Res 2014; 38(12): 1381-1391 http://www.ncbi.nlm.nih.gov/pubmed/25444075

• A perspective is provided specifically on optimizing the benefits of first-line hypomethylating agent use and on the management of azacitidine failure.

Jilg S et al. Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high risk myelodysplastic syndromes patients. Leukemia 2015 Jul 8 [Epub ahead of print] http://www.ncbi.nlm.nih.gov/pubmed/26153654

• Bone marrow mononuclear cells from primary samples of 124 MDS or secondary AML patients and 57 age-matched healthy volunteers were subjected to a treatment with anti-BCL2 agents ABT-737 or ABT-199. The drug sensitivity read as reduction in CD34+ cell number or colony forming capacity, could be demonstrated in high-risk/sAML samples, whereas the low-risk MDS or healthy donor samples remained unaffected.

Novel Therapies

Uckun FM, et al. A clinical phase 1B study of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancers (Basel), 2021; 13(16): 4113. (DOI: 3390/cancers13164113)

• A total of 46 RR AML/MDS patients who had failed multiple lines of prior therapy received APVO436 weekly as iv infusion at 10 dose levels between 0.3mcg to 60mcg. Maximum tolerable dose (MTD) was not reached at 60mcg weekly. Infusion related reaction was the most common AE seen in 28.3% patients, along with cytokine release syndrome (CRS) in 21.7% patients. The recommended phase 2 dose was determined at 0.2mcg/kg which showed appreciable clinical response including a CR.

Uckun FM, et al. A clinical phase 1B study of the CD3xCD123 bispecific antibody APVO436 in patients with relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome. Cancers (Basel), 2021; 13(16): 4113. (DOI: 3390/cancers13164113)

• A total of 46 RR AML/MDS patients who had failed multiple lines of prior therapy received APVO436 weekly as iv infusion at 10 dose levels between 0.3mcg to 60mcg. Maximum tolerable dose (MTD) was not reached at 60mcg weekly. Infusion related reaction was the most common AE seen in 28.3% patients, along with cytokine release syndrome (CRS) in 21.7% patients. The recommended phase 2 dose was determined at 0.2mcg/kg which showed appreciable clinical response including a CR.  

Sallman DA, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol, 2021; Jan 15 [Online ahead of print] (https://doi.org/10.1200/jco.20.02341)

• This phase Ib/II study assessed a small molecule APR-246 which restores wild-type p53 function. This novel compound was used in combination with azacitidine in 55 patients with at least one TP53 mutation (40MDS, 11AML, 4 MDS/MPN). The response among all patients/MDS/AML patients included, ORR-71%/73%/64%, CR-44%/50%/36% respectively. The responding patients showed lowered p53 expression with 38% achieving molecular remission and OS of 14.6 mo compared to 7.5 mo in non-responding patients (p=0.0005). Common adverse events for the combination were febrile neutropenia (33%), leukopenia (29%) and neutropenia (29%).

Fenaux P et al. Luspatercept in patients with lower risk myelodysplastic syndrome. N Engl J Med, 2020;382(2):140-151. (https://doi.org/10.1056/nejmoa1908892)      

• This double blind placebo controlled ph 3 study assessed luspaterept (1mg up to 1.75 mg per Kg body weight sc every 3 weeks) vs placebo in patients with very-low, low or intermediated risk MDS patients with ringed sideroblasts and who were transfusion dependent (N=229; 2:1:: luspatercept: placebo).Primary end-point was transfusion independence for ≥8 weeks in first 24 weeks of treatment which was seen in 38% on luspatercept versus 13% with placebo (p<0.001). The most common adverse events were fatigue, diarrhea, asthenia, nausea, and dizziness.

Stein EM et al. Enasidenib in patients with IDH2 myelodysplastic syndromes: a phase 1 subgroup analysis of the multicenter, AG221-C-001 trial. Lancet Haematol, 2020;7(4):e309-e319. (https://doi.org/10.1016/s2352-3026(19)30284-4)

• Seventeen previously treated patients with IDH2 mutation received a median 3 cycles of Enasidenib, an IDH2 inhibitor; 5 with ≥12 cycles (60-300 mg QD PO in 28 day cycle). After median follow up of 11mo no dose limiting toxicities were observed. The most common grade 3-4 treatment emergent adverse events were indirect hyperbilirubinaemia (35%), pneumonia (29%) and thrombocytopenia (24%), and no treatment related deaths. The overall response was seen in 9/17 (53%) patients with median duration of response of 9.2mo and median overall survival was 16.9mo.

Navada SC, et al. Rigosertib in combination with azacytidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study. Leuk Res, 2020;94: 106369 (1016/j.leukres.2020.106369 )

1. The phase 1 part of this phase 1/2 study involved 9MDS, 1CMML and 8AML patients. An oral Ras-inhibitor, rigosertib was given twice daily at 140mg or 280 mg or 560mg morning+280mg evening doses for 3 weeks of the 4week cycle. A standard dose azacytidine was given in the second week of the cycle. No dose limiting toxicities were noted and hence no maximum tolerated dose could be determined. The most frequent adverse events were diarrhea, constipation, fatigue, nausea, pneumonia and back pain. The majority of responses were in MDS/CMML patients (7/9) with only 2/7 responses in AML.

Taylor J, et al. Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukemia refractory to hypomethylating agents: a single-center, single arm, phase 2 trial. Lancet Haematol, 2020; 7(8):e566-e574. ( 1016/S2352-3026(20)30209-X )

• There is no current therapy for MDS refractory to hypomethylating agents under 6 months. This study aimed safety and activity of selinexor in MDS patients or oligoblastic acute myeloid leukemia (OAML). A phase 2 trial (18 y/o or older up to 30% MDS/OAML) received a 3-week long cycle of selinexor (60mg twice/week for 2 weeks, 1 week off). From the 23 patients evaluated, overall response rate was 26% (95% Cl 10-48) in 6 patients with marrow complete remission and 12 patients (52%, 95% Cl 31-73) had stable disease.

Kubasch AS, et al. Single agent talacotuzumab demonstrates limited efficacy but considerable toxicity in elderly high-risk MDS or AML patients failing hypomethylating agents. Leukemia, 2020; 34(4): 1182-1186. (1038/s41375-019-0645-z )

• SAMBA study assessing anti-CD123 therapeutic monoclonal called talacotuzumab in 19AML and 5 High-Risk MDS patients was terminated as a part of discontinuation of the drug development program by the manufacturer. 16/24 patients were resistant including 8/24 patients who relapsed after initial response to prior HMA therapy. The treatment related toxicity was significant including 2 deaths with pneumonia possibly related to treatment. The eight-week mortality was 25% and overall response rate was 8.3% including one complete remission. The benefit/risk ratio for talacotuzumab was determined to be unfavorable and hence the study was terminated.

Barot SV, Patel BJ, and Gerds AT. Patient-reported outcomes in myelodysplastic syndromes: the move from life span to health span (MDS). Current Hematol Malig Rep, 2020; Feb 11 [Online ahead of print] (https://pubmed.ncbi.nlm.nih.gov/32048198/)

• Although PRO measurement is less common in clinical studies in MDS, when conducted have demonstrated positive results with growth factors, HMS and IMiDs. Many new clinical studies have begun to incorporate a prospective PRO assessment using broad metrics such as EORTC-QLQ-C30, the previously reported FACT-An and MDS specific tools like QUALMS (Quality of life in Myelodysplasia Scale).

Sekeres M and Steensma D. Rethinking clinical trial end points in myelodysplastic syndrome. Leukemia, 2019;33(3):570-575. (https://pubmed.ncbi.nlm.nih.gov/30700839/)

• The review evaluates challenges to drug development and emphasizes the meaningfulness of study end points relevant to patients. The report also underscores the importance of assessing longer term end points such as response duration, quality of life and overall survival in addition to the currently common end points of hematologic and bone marrow response rates.

Faraoni I et al. Cytotoxicity and differentiating effect of the poly (ADP-Ribose) polymerase inhibitor Olaparib in myelodysplastic syndrome. Cancer, 2019; 11(9):E1373. (https://www.ncbi.nlm.nih.gov/pubmed/31527467)

• In primary cultures of bone marrow mononuclear cells from 28 MDS patients, olaparib showed cytotoxic effects with a median IC50 of 5.4µM, which is lower than the peak in vivo concentration reached with standard olaparib dose. Moreover, the cytotoxicity appeared specific to myeloid blasts and simultaneously an increase in metamyelocytes and mature granulocytes was noted while sparing the uninvolved lymphoid cells. These cytotoxic and differentiation effects were further augmented in combination with decitabine.

Santini V et al. Phase 2 study of the ALK5 inhibitor Galunisertib in very low-, low- and intermediate-risk myelodysplastic syndromes. Clin Cancer Res, 2019; Sept 3 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31481511)

• Galunisertib, an oral inhibitor of TGF beta receptor type I kinase (ALK5), was evaluated in a phase 3 study at twice daily 150 mg dose in 14 days on/14 days off schedule in VLR, LR and IR MDS patients (n=41). The hematologic improvement- erythroid was seen in 24.4% patients per IWG 2006. Among transfusion dependent patients HI-E was seen in 32.1%. Overall median duration of response in all patients was 90 days. The adverse events were grade 1/2 in 49% patients (fatigue, diarrhea, pyrexia, and vomiting).

Sallman DA et al. A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS). Leuk Res, 2019; 81:56-61 (https://www.ncbi.nlm.nih.gov/pubmed/31030089)

• Glasdegib was assessed in higher risk MDS patients (n=35) with hypomethylating agent. The overall response was seen in 2 patients (6%) with marrow CR with HI as the best response. The median overall survival was 10.4 mo. ≥3 infections occurred in 11% with non-hematologic toxicities generally being rare.

Savona MR et al. Phase 1b study of Glasdegib, a hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high risk MDS. Clin Cancer Res, 2018; Feb 20, [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/29463550)

• An open label dose finding phase 1b study in newly diagnosed high risk MDS/AML (N=52) assessed Glasdegib at 100 or 200 mg daily po in 28-day cycle in combination with low-dose cytarabine or decitabine in patients not suitable for induction chemotherapy or in combination with cytarabine/daunorubicin in fit patients. Whereas no dose limiting toxicities (DLT) were observed with combination treatments in unfit patients, there was one DLT of grade 4 neuropathy noted for combination in fit patients. Overall 16/52 (31%) patients achieved CR/CR-with incomplete hematopoietic recovery. The RP2D of 100mg was selected for combination with standard chemotherapy.

Komrokji R et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol, 2018; 5(2):e63-e72. (https://www.ncbi.nlm.nih.gov/pubmed/29331635)

• RBC-transfusion dependent low/int-1 risk MDS patients refractory or ineligible to ESAs who were either non-del(5q) or were del(5q) but refractory to lenalidomide, were randomly assigned to receive sotatercept subcutaneously at 0.1 mg/kg (n=7) or 0.3 mg/kg (n=6) or non-randomly assigned to 0.5mg/kg(n=21), 1mg/kg (n=35) or 2mg/kg (n=5). HI-E, the primary end-point was achieved in 29/62 patients (47%) with high baseline transfusion burden and 7/12 (58%) patients with low transfusion burden. The most commonly reported AEs were fatigue (26%) and peripheral edema (24%). Among the grade 3/4 treatment emergent AEs reported (5%), most common were lipase increase and anemia. One death was noted due to treatment emergent hematoma and fall.

Ueda Y et al. A phase 1/2 study of the WT1 peptide cancer vaccine WT4869 in patients with myelodysplastic syndrome.  Cancer Sci, 2017; Sept 26 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/28949050)

• In a dose finding study transfusion dependent MDS patients were administered with a synthetic peptide vaccine WT4869 derived from WT1 gene at 5-1200 μg/dose intradermally every 2 weeks. Among the 25 enrolled patients, dose limiting toxicity was observed in one patient at 50 μg/dose level and in another patient at 400 μg/dose level. With overall response rate of approximately 18% and median survival of 65 weeks, the MTD remained undetermined.  WT1-specific cytotoxic T cells were detectable in 11/25 evaluable patients.

Platzbecker U et al. Luspatercept for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicenter, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol, 2017; 18(10):1338-1347. (https://www.ncbi.nlm.nih.gov/pubmed/28870615)

• Luspatercept is postulated to relieve the TGFβ protein superfamily imposed inhibition of erythropoiesis and hence may have a therapeutic role in treating MDS related anemia. PACE-MDS is a phase 2 study in low/int-1 MDS patients or non-proliferative CMML who had persistent anemia with or without RBC transfusion support at the time of enrollment. In this dose-finding study, Luspatercept was administered subcutaneously every 3 weeks (dose range- 0.125 mg/kg to 1.75 mg/kg for first 5 doses and then in extension study starting at 1 mg/kg titrated up to 1.75 mg/kg). The base study with 27 patients receiving a range of doses, safety and responses were assessed at week 12. Further, 31 patients were enrolled in the extension study cohort. 32/51 (63%) total patients receiving higher doses (0.75- 1.75 mg/kg) achieved HI-E per IWG criteria vs. only 2/9 responders among patients receiving lower doses. With three treatment-related Gr 3 AEs, the treatment was overall well-tolerated.

Wermke M et al. Mammalian-target of rapamycin inhibition with temsirolimus in myelodysplastic syndromes (MDS) patients is associated with considerable toxicity: results of the temsirolimus pilot trial by the german MDS study group (D-MDS). Br J Haematol 2016; 175(5):917-924. (https://www.ncbi.nlm.nih.gov/pubmed/27714772)

• A prospective study enrolled lower risk MDS patients with transfusion dependent anemia and/or neutropenia and higher risk patients relapsed/refractory to 5-azacitidine. A total of 20 patients (9 lower- and 11 higher-risk) were treated with a weekly 25mg dose of Temsirolimus. Only four patients showed stable disease without HI after four months. The remaining patients discontinued early due to adverse events. A significant decline in marrow vascularization was seen with treatment without impact on the balance of peripheral blood T-cell populations.

Swords RT et al. KB004, a first-in-class monoclonal antibody targeting the receptor tyrosine kinase EphA3 in patients with advanced hematologic malignancies: results from a phase 1 study. Leuk Res 2016; 50:123-131. (https://www.ncbi.nlm.nih.gov/pubmed/?term=Sword+RT+and+EphA3)

• An anti-Ephrin receptor tyrosine kinase monoclonal antibody was tested in a phase 1 study with multiple hematologic malignancies including MDS and AML. The most common toxicities were grade 1/2 infusion reactions in approx. 80% treated patients becoming dose limiting beyond 250 mg. The weekly schedule of the drug was found to be well tolerated with clinical responses noted in all the hematologic conditions tested.

Schuler MK et al. Effects of a home-based exercise program on physical capacity and fatigue in patients with low to intermediate risk myelodysplastic syndrome- pilot study. Leuk Res 2016; 47:128-135 (https://www.ncbi.nlm.nih.gov/pubmed/27326698)

• A prospective non-randomized feasibility study assessed evaluating safety and efficacy of home-based exercise intervention to overcome fatigue and build physical capacity was a subject of the present report. In a strength and endurance building training, of 21 total MDS patients, 15 (71%) continued on study till week 12 with 11 completing the program. Significant improvement in 6 min-walking distance exercise was seen. However no improvement was noted in fatigue scores.

Transplantation

Beelan DW et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic hematopoietic stem cell transplantation for older patients with acute myeloid leukemia or myelodysplastic syndrome (MC-FludT.14/L): a randomized, non-inferiority, phase 3 trial. Lancet Haematol, 2019; Oct 9 [Epub ahead of print]. (https://www.ncbi.nlm.nih.gov/pubmed/31606445)

• This report is based on the final analysis of the study with a median f/u of 15.4mo for treosulfan and 17.4mo for busulfan. AML patients in first or consecutive complete remission (marrow blasts <5%) or MDS with marrow blasts <20% were randomized in this open label study to receive Treosulfan (iv 10g/m2 daily x 3d) or busulfan (0.8 mg/kg). Both groups received iv fludarabine 30mg/m2 daily x5d. The treosulfan arm had higher 2-year event-free survival rate (64%) compared to the busulfan arm (50.4%, HR=0.65, p=0.0051 for superiority). The safety profiles were similar in the two groups. Treosulfan -fludarabine may therefore hold the promise of standard preparative regimen for allogeneic HSCT in AML.

Patient-Reported Outcomes

Stojikov I, et al. Core set of patient-reported outcomes for myelodysplastic syndromes- EUMDS Delphi study in patients and hematologists. Blood Adv, 2021; Sept 7 [Online ahead of print] (DOI: 1182/bloodadvances.2021004568)

• As a part of the prospective European LeukemiaNet MDS (EUMDS) registry, a 2-round survey was conducted with MDS patients and hematologists for the selection of preferred PRO measures out of 40 well selected instruments based on a systematic MDS literature search. Per the agreement between patients and hematologists, and based on predefined inclusion criteria, “general quality of life” was chosen by both patients and hematologists. Whereas, hematologists also selected two additional measures, “transfusion-dependency burden” and “ability to work/activities of daily living.”

Abel GA, et al. Peri-transfusion quality of life assessment for patients with myelodysplastic syndromes. Transfusion, 2021; July 12 [Online ahead of print] (DOI: 1111/trf.16584)

• A total of 62 MDS patients were enrolled in the study, of which 37 completed 1-day- pre- and 7-day-post- RBC transfusion questionnaires (QOL in myelodysplasia scale (QUALMS)). Among these 37 patients, 35% reported increased QUALMS score, 46% had no change and 19% reported a decrease post transfusion. Also, 23% reported that their physician discussed the results before next transfusion.

Amitai I, et al. Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study. Br J Haemaol, 2021; 194(2): 319-324. (DOI: 1111/bjh.17537)

• This analysis of Canadian MDS registry attempted to validate the Fatigue-international prognostic scoring system among higher risk MDS patients. The use of EORTC Quality of life-core 30 (QLQ-C-30) instrument with threshold of ≥45 points, in higher IPSS risk group stratified patients into distinct groups with different survival outcomes. These findings were further validated with Revised IPSS and other fatigue scales.

Stojikov I, et al. Core set of patient-reported outcomes for myelodysplastic syndromes- EUMDS Delphi study in patients and hematologists. Blood Adv, 2021; Sept 7 [Online ahead of print] (DOI: 1182/bloodadvances.2021004568)

• As a part of the prospective European LeukemiaNet MDS (EUMDS) registry, a 2-round survey was conducted with MDS patients and hematologists for the selection of preferred PRO measures out of 40 well selected instruments based on a systematic MDS literature search. Per the agreement between patients and hematologists, and based on predefined inclusion criteria, “general quality of life” was chosen by both patients and hematologists. Whereas, hematologists also selected two additional measures, “transfusion-dependency burden” and “ability to work/activities of daily living.”

Abel GA, et al. Peri-transfusion quality of life assessment for patients with myelodysplastic syndromes. Transfusion, 2021; July 12 [Online ahead of print] (DOI: 1111/trf.16584)

• A total of 62 MDS patients were enrolled in the study, of which 37 completed 1-day- pre- and 7-day-post- RBC transfusion questionnaires (QOL in myelodysplasia scale (QUALMS)). Among these 37 patients, 35% reported increased QUALMS score, 46% had no change and 19% reported a decrease post transfusion. Also, 23% reported that their physician discussed the results before next transfusion.

Amitai I, et al. Patient-reported fatigue refines prognosis in higher-risk myelodysplastic syndromes (MDS): a MDS-CAN study. Br J Haemaol, 2021; 194(2): 319-324. (DOI: 1111/bjh.17537)

• This analysis of Canadian MDS registry attempted to validate the Fatigue-international prognostic scoring system among higher risk MDS patients. The use of EORTC Quality of life-core 30 (QLQ-C-30) instrument with threshold of ≥45 points, in higher IPSS risk group stratified patients into distinct groups with different survival outcomes. These findings were further validated with Revised IPSS and other fatigue scales.

Stauder R, et al. Patient-reported outcome measures in studies of myelodysplastic syndromes and acute myeloid leukemia: Literature review and landscape analysis. Eur J Haematol, 2020; 104(5): 476-487. (1111/ejh.13389 )

• This extensive review noted that across studies in MDS and AML, the most frequently used patient reported outcome measures (PROMs) were generic like SF-36 or EQ-5D or cancer specific like EORTC QLQ-C30, and FACT-An. However, MDS specific PROMS like QUALMS or QOL-E and AML specific PROMS like FACT-Leu or EORTC QLQ-Leu were used only in a minority of studies. The review underscores the need to use MDS/AML specific PROMS in future studies.

Troy JD et al. Patient-reported distress in myelodysplastic syndromes and its association with clinical outcomes: A retrospective cohort study. J Natl Compr Cancer Netw, 2018; 16(3):267-273. (https://www.ncbi.nlm.nih.gov/pubmed/29523665)

• NCCN defines distress as a multifunctional unpleasant emotional experience of a psychologic nature that may interfere with patient’s ability to cope with cancer symptoms and treatment. A single center retrospective 2-yr study on patient-reported distress demonstrated increased risk for death with even a single point increase on the distress scale used (HR=1.18) suggesting a need for further exploration of this topic.

Santini V et al. The effect of lenalidomide on health-related quality of life in patients with lower-risk non-del (5q) myelodysplastic syndromes: results from the MDS-005 Study. Clin Lymphoma Myeloma Leuk, 2018; 18(2):136-144. (https://www.ncbi.nlm.nih.gov/pubmed/29429612)

• MDS-005 study in RBC-transfusion dependent low risk non-del(5q) MDS had previously shown effectiveness of lenalidomide in achieving RBC-transfusion independence (TI ≥8wks) in approx. 27% patients (p<0.001) vs placebo (2.5%). EORTC QOL questionnaire-core 30 tool was used in the current investigation to assess HRQOL. At week 24, after adjusting for baseline score, emotional functioning showed benefit with lenalidomide treatment. Also, a positive correlation with all 5 preselected scales (fatigue, dyspnea, global QOL, physical functioning and emotional functioning) was observed with achieving TI ≥8wks (p<0.01) and with all except emotional functioning in case of increased Hb (p<0.05).

Efficace F et al. Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes. Cancer 2018; 124(6):1251-1259. (https://www.ncbi.nlm.nih.gov/pubmed/29231969)

• A new prognostic index adding patient-reported fatigue severity to IPSS [FA-IPSS(h)- Fatigue-IPSS (high risk)] was developed based on previously untreated MDS patients who completed EORTC QOL questionnaire-core 30 at baseline. The index estimated median overall survival in FA-IPSS-risk-1 or -2 or -3 as 23,16, and 10 months respectively. The predictive accuracy of this new index was higher than conventional IPSS alone in development cohort as well as in a subsequent validation cohort that in addition included previously treated patients

RBC Transfusion and Growth Factors

Rozema J, et al. Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study. Transfusion, 2021; Sept 3 [Online ahead of print] (DOI: 1111/trf.16631)

• An observational, retrospective, population-based study of MDS patients (n=292) from the HemoBase registry in a Friesland province of the Netherlands (2005-2017), showed high RBC transfusion burden (HTB >8units/16wk) in 46.6% patients and low transfusion burden (LTB) in 5.8% patients. Once univariate and multivariable regression analyses were performed, the odds ratio for HTB was particularly high in patients aged 75-84 years, or those with high risk MDS or MDS-EB-2.

Komrokji R, et al. Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Leuk Lymphoma, 2021; Aug 27 [Online ahead of print] (DOI: 1080/10428194.2021.1971217)

• MDS/MPN-RS-T is characterized by anemia, ring sideroblasts, and persistent thrombocytosis. 167 MDS/MPN-RS-T patients at a single institute (Moffitt, USA) were evaluated to compare the hematological improvement (HI) response rates among different therapies, including lenalidomide. 84% patients had SF3B1 mutations and 43% had JAK2 V617F mutations. Overall, 46% patients received erythropoiesis stimulating agents (ESA), 28% had lenalidomide and 27% got hypomethylating agents (HMA). The HI rate with the three treatments were 58%, 53% and 24% respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMA.

Rozema J, et al. Patterns of transfusion burden in an unselected population of patients with myelodysplastic syndromes: A population-based study. Transfusion, 2021; Sept 3 [Online ahead of print] (DOI: 1111/trf.16631)

• • An observational, retrospective, population-based study of MDS patients (n=292) from the HemoBase registry in a Friesland province of the Netherlands (2005-2017), showed high RBC transfusion burden (HTB >8units/16wk) in 46.6% patients and low transfusion burden (LTB) in 5.8% patients. Once univariate and multivariable regression analyses were performed, the odds ratio for HTB was particularly high in patients aged 75-84 years, or those with high risk MDS or MDS-EB-2.

Komrokji R, et al. Treatment outcomes for patients with myelodysplastic syndrome/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Leuk Lymphoma, 2021; Aug 27 [Online ahead of print] (DOI: 1080/10428194.2021.1971217)

• • MDS/MPN-RS-T is characterized by anemia, ring sideroblasts, and persistent thrombocytosis. 167 MDS/MPN-RS-T patients at a single institute (Moffitt, USA) were evaluated to compare the hematological improvement (HI) response rates among different therapies, including lenalidomide. 84% patients had SF3B1 mutations and 43% had JAK2 V617F mutations. Overall, 46% patients received erythropoiesis stimulating agents (ESA), 28% had lenalidomide and 27% got hypomethylating agents (HMA). The HI rate with the three treatments were 58%, 53% and 24% respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMA.

Boyko O, et al. Erythropoietin as an independent prognostic factor in myelodysplastic syndromes. Exp Oncol, 2021; 43(1): 41-45. (https://doi.org/10.32471/exp-oncology.2312-8852.vol-43-no-1.15914)

• Elevated serum EPO levels were observed in MDS patients as compared to healthy individuals (p<0.01). However, the difference in sEPO between low versus high-risk patients was not significant. sEPO levels correlated negatively with Hb levels and bone marrow blast counts in high risk patients. Also, an inverse correlation was seen between sEPO and sTNFα in low-risk patients.

Vicente A, et al. Eltrombopag monotherapy can improve hematopoiesis in patients with low to intermediate risk-1 myelodysplastic syndromes. Haematologica, 2020; May 21 [Online ahead of print]. (3324/haematol.2020.249995 )

• A phase 2 dose escalation study in Low/int-1 risk MDS patients assessed eltrombopag (EPAG) at 50 mg/day to a maximum of 150mg/day over 16 weeks. Eleven of twenty five patients (44%) had hematologic response; 5 had uni-lineage and 6 bi-lineage. Presence of PNH clone, marrow hypocellularity, thrombocytopenia ± other cytopenia and elevated plasma thrombopoietin predicted response. The safety profile was consistent with previous experience of EPAG. Ten patients discontinued after med time on treatment of 16 months and having a response. Four of them restarted EPAG later and had a robust second response.

Duong Vu H, et al. A sequential two-stage dose escalation study of eltrombopag in patients with myelodysplastic syndrome and thrombocytopenia after hypomethylating agent failure. Leuk Lymphoma, 2020; 61(8): 1901-1907. ( 1080/10428194.2020.1751841 )

• Thrombocytopenia is seen often in MDS patients and this study conducted a trial of eltrombopag in MDS and MPN or AML patients after hypomethylating agent failure. They had a mean baseline platelet count <50 x 10⁹ /L. The dose was upped from 50 mg to 200 mg daily. The maximally tolerated dose was determined with 37 patients, but it was not reached. In 9 patients (24%), 2 achieved marrow CR with hematologic improvement, 1 marrow CR without HI, and 6 HI. The median overall survival for these patients was 7.5 months and eltrombopag yielded modest results for mostly high-risk MDS patients post HMA failure.

Targeted Therapies

Bewersdorf JP, et al. Venetoclax-based combination in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant. Leuk Lymphoma, 2021; Sept 3 [Online ahead of print] (DOI: 1080/10428194.2021.1966788)

• A retrospective study of AML/High-risk MDS patients from Memorial Sloan Kettering Cancer Center and Yale University, who received venetoclax either prior to or after allo-HCT between 2016 and 2020 showed 1-year OS rate of 79% in those receiving venetoclax before and 43.4% in those receiving after allo-HCT. These results demonstrate the feasibility of venetoclax therapy as a salvage regimen.

Bewersdorf JP, et al. Venetoclax-based combination in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant. Leuk Lymphoma, 2021; Sept 3 [Online ahead of print] (DOI: 1080/10428194.2021.1966788)

• A retrospective study of AML/High-risk MDS patients from Memorial Sloan Kettering Cancer Center and Yale University, who received venetoclax either prior to or after allo-HCT between 2016 and 2020 showed 1-year OS rate of 79% in those receiving venetoclax before and 43.4% in those receiving after allo-HCT. These results demonstrate the feasibility of venetoclax therapy as a salvage regimen.

RBC Transfusions

Stanworth SJ, et al. Red cell transfusion in outpatients with myelodysplastic syndromes: A feasibility and exploratory randomized trial. Br J Haematol, 2020; Jan 20 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31960409/)

• This multinational study randomized 38 patients in outpatient clinic to initiate RBC transfusion at standard threshold of Hb ≤8.0 g/dL (n=20) vs a liberal threshold of Hb≤10.5 g/dL (n=18). The compliance for transfusion threshold was 86% vs 99% in the standard vs liberal groups and the mean pre-transfusion Hb was 8.0 g/dL and 9.7 g/dL respectively. Using EORTC QLQ-C30 and EQ-5D-5L tools, the quality of life was found to be better in patients on liberal Hb threshold arm.

de Swart L, et al. Impact of red blood cell transfusion dose density on progression free survival in lower-risk myelodysplastic syndromes patients. Haematologica, 2020; 105(3): 632-639. (https://pubmed.ncbi.nlm.nih.gov/31171638/)

• The analysis based on European MDS registry included 1267 lower risk MDS patients: 317 had died without progression and 162 had disease progression. When assessed for the impact of blood transfusions on overall progression-free survival (PFS), the transfusion density as low as 3 units/16 weeks was associated with poorer PFS that continued to increase beyond 8 units/16 weeks.

Kaphan E, et al. Impact of transfusion on survival in patients with myelodysplastic syndromes: current knowledge, new insights and transfusion clinical practice. Blood Rev, 2019; Dec 18 [Online ahead of print]. (https://pubmed.ncbi.nlm.nih.gov/31918886/)

• Patients treated with red blood cell (RBC) transfusions experience shorter survival as compared to those treated with erythropoiesis stimulating agents (ESAs). The report has attempted to list the physiologic impacts of chronic RBC transfusion strategy highlighting iron toxicity, cardiac event rate, oxidative stress and RBC storage lesions due to physicochemical changes in RBCs.

Lin Y et al. Prophylactic RhCE and Kell antigen matching; impact on alloimmunization in transfusion-dependent patients with myelodysplastic syndromes. Vox Sang 2017; 112(1):79-86. (https://www.ncbi.nlm.nih.gov/pubmed/28097704)

• A study of 176 transfusion dependent MDS patients reveals importance of an institutional policy for prophylactic antigen matching for RhCE and Kell antigens. Overall, 17% of the patients developed alloantibodies, with the majority showing at least one anti-RhCE or Kell antigens. When assessed for the prophylactic matching policy before transfusion, the rate was significantly lower (11%) vs. when no policy was applied (23%).