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Highlights of Latest Literature in MDS

 
Epidemiology, Diagnosis and Prognosis

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.

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

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.

  • 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)

  • 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)

  • 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)

  • 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)

  • 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

  • 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

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

  • 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

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:

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.

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.

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 (2nd 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:

Allogeneic Bone Marrow Transplant

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

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

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

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 (2nd 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 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

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.

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

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.

RBC Transfusions

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%).

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