MDS 2023: Challenges in Diagnosis and Treatment – Abstract
Moshe Mittelman, Tel-Aviv Sourasky Medical Center, Tel-Aviv University, IsraelThe myelodysplastic syndromes (MDS) are clonal bone marrow (BM) stem cell disease(s), characterized by abnormal hematopoiesis, with anemia (95%) and/or other cytopenias. The basic pathogenesis is based on genetics and inflammation of aging (inflammaging). The median age of onset is 74 yr and the incidence increases with age. Patients are classified as having a lower (LR-MDS) or higher risk disease (HR-MDS), and leukemic transformation occurs in 20%-60%.The challenges in 2023 are: a) Diagnosis: new tools – less invasive and more accurate; earlier diagnosis; identify individuals at risks. b) Better understanding of the pathogenesis; genetics and inflammaging. c) Harmonize the various classifications. d) Treatment of LR-MDS: improve the quality of life; more effective agents for anemia, especially after failure of erythropoietin and luspatercept; effective and safe agents for thrombocytopenia. e) Treatment of HR-MDS: Hypomethylating agents (HMA) are (still) the standard 1st line treatment, but how can we improve the limit of 50% response rate lasting 2 years?We will focus in this symposium on some of these issues. Genetic and AI tools may help in identifying pre-MDS states, and individuals at risk, as well as establish early diagnosis, non-invasively and perhaps more accurately. Future may allow diagnostic procedures in which marrow examination can be avoided, at least in some of the suspected patients.

RBC transfusions and erythropoietin (EPO) remain the 1^st line treatment for anemia. EPO is safe and might delay the need for RBC transfusions. A recent EUMDS study suggests a prolonged survival with EPO. Lenalidomide remains effective for MDS with del(5q) (50% response), but also somewhat effective (27%) in non-del(5q) patients. Luspatercept appears as an effective second-line (maybe 1st ?) agent. We will discuss it here. Several experimental agents are investigated, including oral azacytidine, imetelstat, a pyruvate-kinase activator and roxadustat. For thrombocytopenia two agents, romiplostim and eltrombopag, were shown to be effective. However, due to safety concerns their development has been stopped.

Patients with HR-MDS are offered HMA as the standard 1st line treatment. Younger patients may respond to antileukemic treatment with or without transplant. Ways to improve the HMA effect include treating the HMA-related complications; modified HMA formulation; combinations of HMA with other agents (venetoclax appears to be the frontrunner), novel agents and targeted molecules.

Mario Cazzola, MD Fondazione IRCCS Policlinico San Matteo and University of Pavia, 27100 Pavia, Italy

Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by ineffective erythropoiesis, peripheral cytopenia, and a variable risk of progression to acute myeloid leukemia (AML). In the last 15 years, our understanding of these disorders has advanced substantially with the use of massively parallel DNA sequencing methods in translational studies. This has enabled the development of novel diagnostic and prognostic approaches and has also promoted innovative clinical trials aimed at defining precision treatments. An abundance of clinical and biological data is currently being collected on individual patients. Interpreting these data and navigating the genomic complexity of MDS represents an increasing challenge for clinicians. Current classifications of MDS and related disorders account for only a minor portion of genomic data. Exploiting artificial intelligence and machine learning to take advantage of genomic characterization becomes mandatory: the final objective of a mechanistic classification is to best inform clinical decision-making. This requires international collaboration, the creation of knowledge banks, the preparation of web portal tools, and the conduction of clinician-driven clinical trials.

Michael R. Savona, MD

Clonal hematopoiesis (CH) is an over-representation of mature blood cells derived from a single, genetically identical clone.¹ CH is genetically heterogeneous, with most cases resulting from somatically-derived mutations in leukemogenic driver genes within hematopoietic stem cells.² Variants have been reported from >70 CH driver genes, though more than two-thirds of CH mutations are found in one of three genes: DNMT3A, TET2, and ASXL1 (‘DTA’ mutations).^1-5 While CH-associated genes span a diverse set of cellular functions and processes, including epigenetic regulation, transcription, and RNA splicing,6 the resulting effect of a CH driver mutation is enhanced cellular fitness leading to a selective advantage for the clone and subsequent clonal expansion.⁶

Most commonly, CH presents as clonal hematopoiesis of indeterminate potential (CHIP), an asymptomatic state with normal blood counts. CHIP is highly correlated with increasing age, with 15% of patients over the age of 65 estimated to have CH with a variant allele fraction (VAF) of at least 2%.^1-3 Clonal cytopenia of uncertain significance (CCUS) occurs in the presence of a clone and one or more associated cytopenias without a clear identifiable cause and a bone marrow biopsy without myelodysplasia, and clonal monocytosis of undetermined significance (CMUS) represents a phenotype of monocytosis without marrow changes classifiable as CMML.⁷ Numerous studies have demonstrated that CH increases potential to progress to hematologic malignancy, thus, CH is considered a premalignant state, and it is estimated that 0.5-1% of CHIP cases transform into an overt hematologic malignancy per year after acquiring additional somatic mutations. By definition, CCUS and CMUS are accompanied with hematologic phenotypes and thus can be more pervasive, particularly in patients with multiple mutations, high VAFs, and/or those with non-DTA, myeloid-neoplasm type clones.8 A more recent analysis of over 400,000 UK biobank participants added red blood cell indices to these features to yield a CH risk score (CHRS) now available online: www.CHRSapp.com.⁹

Existing research points toward aberrant inflammatory signaling as a putative mechanism for CH pathology.^10-13 Given the diversity of genes involved in CH, it is unlikely that a single mechanism exists for all downstream pathologies. As such, the prevailing immune dysregulation hypothesis as it currently exists does not completely reflect the complexity of CH across disease manifestations, and future work should focus on articulating mutation-specific effects on inflammation and secondary inflammatory consequences. In addition to malignancy risk, CH is associated with a high burden of organ dysfunction, and confers a 40% increase in all-cause mortality.^1-2 Recent reports of CH-associated organ dysfunction include increased risk of stroke and atherosclerotic vascular disease (ASCVD),^11-14 inflammation and autoimmune disease,^15-17 chronic obstructive pulmonary disease,18 and chronic kidney disease,^19-20 among others.²¹

The CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE) Registry and Repository was established with the goal of relating genotype-phenotype relations and understanding the natural history of CH. Patients who are at risk for CH, or with known CH, provide serial access to blood and tissue collected at normally scheduled visits. CHIVE aims to maximize vascular risk reduction, and understanding the genotype-phenotype relationships of CH to develop new clinical trials in CH. Using guidance from the patterns established from retrospective data, CHIVE investigators monitor patients as ‘low risk’ or ‘high risk’ every 6, or 12 months, respectively. CHIP clinics managing these patients will use the CHRS, and validation and refinement of this tool will enhance risk stratification for myeloid neoplasia; but should not miss the opportunity for patient education around vascular risk reduction. Serial sampling in the CHIVE repository, aggressive attempts to modify vascular disease, and iterative application of lessons learned for new guidance will shape care for higher risk patients with CH, and ultimately lead to guidance for clinical trials in this arena.References

1. Jaiswal S, Fontanillas P, Flannick J, et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. N Engl J Med. 2014;371(26):2488-2498. doi:10.1056/NEJMoa1408617
2. Xie M, Lu C, Wang J, et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med. 2014;20(12):1472-1478. doi:10.1038/nm.3733
3. Genovese G, Kähler AK, Handsaker RE, et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferred from Blood DNA Sequence. N Engl J Med. 2014;371(26):2477-2487. doi:10.1056/NEJMoa1409405
4. Buscarlet M, Provost S, Zada YF, et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood. 2017;130(6):753-762. doi:10.1182/blood-2017-04-777029
5. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126(1):9-16. doi:10.1182/blood-2015-03-631747
6. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer. 2017;17(1):5-19. doi:10.1038/nrc.2016.112
7. DeZern AE, Malcovati L, Ebert BL. CHIP, CCUS, and Other Acronyms: Definition, Implications, and Impact on Practice. Am Soc Clin Oncol Educ Book. 2019;(39):400-410. doi:10.1200/EDBK_239083
8. Gallì A, Todisco G, Catamo E, et al. Relationship between clone metrics and clinical outcome in clonal cytopenia. Blood. 2021;138(11):965-976. doi:10.1182/blood.2021011323
9. Weeks R, niruola A, Neuberg D, et al. Prediction of risk for Myeloid Malignancy in Clonal Hematopoiesis. NEJM Evid. 2023;2(5): doi: 10.1056/EVIDoa2200310
10. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. N Engl J Med. 2017;377(2):111-121. doi:10.1056/NEJMoa1701719
11. Fuster JJ, MacLauchlan S, Zuriaga MA, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355(6327):842-847. doi:10.1126/science.aag1381
12. Bick AG, Pirruccello JP, Griffin GK, et al. Genetic Interleukin 6 Signaling Deficiency Attenuates Cardiovascular Risk in Clonal Hematopoiesis. Circulation. 2020;141(2):124-131. doi:10.1161/CIRCULATIONAHA.119.044362
13. Abplanalp WT, Cremer S, John D, et al. Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure. Circ Res. 2021;128(2):216-228. doi:10.1161/CIRCRESAHA.120.317104
14. Heimlich, J. B. et al. Mutated cells mediate distinct inflammatory responses in clonal hematopoiesis. bioRxiv, 2022.2012.2001.518580 (2022). https://doi.org:10.1101/2022.12.01.518580
15. Bekele DI, Patnaik MM. Autoimmunity, Clonal Hematopoiesis, and Myeloid Neoplasms. Rheum Dis Clin N Am. 2020;46(3):429-444. doi:10.1016/j.rdc.2020.03.001
16. Cumbo C, Tarantini F, Zagaria A, et al. Clonal Hematopoiesis at the Crossroads of Inflammatory Bowel Diseases and Hematological Malignancies: A Biological Link? Front Oncol. 2022;12:873896. doi:10.3389/fonc.2022.873896
17. Bolton KL, Koh Y, Foote MB, et al. Clonal hematopoiesis is associated with risk of severe Covid-19. Nat Commun. 2021;12(1):5975. doi:10.1038/s41467-021-26138-6
18. Miller PG, Qiao D, Rojas-Quintero J, et al. Association of clonal hematopoiesis with chronic obstructive pulmonary disease. Blood. 2022;139(3):357-368. doi:10.1182/blood.2021013531
19. Huang Z, Vlasschaert C, Robinson-Cohen C, et al. Emerging evidence on the role of clonal hematopoiesis of indeterminate potential in chronic kidney disease. Transl Res. Published online December 2022:S1931524422003176. doi:10.1016/j.trsl.2022.12.009
20. Vlasschaert C, Moran SM, Rauh MJ. The Myeloid-Kidney Interface in Health and Disease. Clin J Am Soc Nephrol. 2022;17(2):323-331. doi:10.2215/CJN.04120321
21. Evans MA, Walsh K. Clonal hematopoiesis, somatic mosaicism, and age-associated disease. Physiol Rev. 2023;103(1):649-716. doi:10.1152/physrev.00004.2022
22. Abdel-Wahab, O., Tefferi, A. & Levine, R. L. Role of TET2 and ASXL1 mutations in the pathogenesis of myeloproliferative neoplasms. Hematol Oncol Clin North Am 26, 1053-1064 (2012). https://doi.org:10.1016/j.hoc.2012.07.006
23. Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer cell 20, 11-24 (2011). https://doi.org:10.1016/j.ccr.2011.06.001
24. Christen, F. et al. Modeling clonal hematopoiesis in umbilical cord blood cells by CRISPR/Cas9. Leukemia 36, 1102-1110 (2022). https://doi.org:10.1038/s41375-021-01469-x
25. Bick, A. G. et al. Inherited causes of clonal haematopoiesis in 97,691 whole genomes. Nature 586, 763-768 (2020). https://doi.org:10.1038/s41586-020-2819-2
26. Trowbridge, J. J. & Starczynowski, D. T. Innate immune pathways and inflammation in hematopoietic aging, clonal hematopoiesis, and MDS. The Journal of experimental medicine 218 (2021). https://doi.org:10.1084/jem.20201544
27. Ferrone, C. K., Blydt-Hansen, M. & Rauh, M. J. Age-Associated TET2 Mutations: Common Drivers of Myeloid Dysfunction, Cancer and Cardiovascular Disease. Int J Mol Sci 21 (2020). https://doi.org:10.3390/ijms21020626
28. Miller, T. E. et al. Mitochondrial variant enrichment from high-throughput single-cell RNA-seq resolves clonal populations. bioRxiv, 2021.2003.2008.434450 (2021). https://doi.org:10.1101/2021.03.08.434450
29. Miller, T. E. et al. Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations. Nat Biotechnol (2022). https://doi.org:10.1038/s41587-022-01210-8
30. Nam, A. S. et al. Single-cell multi-omics of human clonal hematopoiesis reveals that <em>DNMT3A</em> R882 mutations perturb early progenitor states through selective hypomethylation. bioRxiv, 2022.2001.2014.476225 (2022). https://doi.org:10.1101/2022.01.14.476225
31. Guess, T. et al. Distinct patterns of clonal evolution drive myelodysplastic syndrome progression to secondary acute myeloid leukemia. Blood Cancer Discov (2022). https://doi.org:10.1158/2643-3230.BCD-21-0128
32. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. The New England journal of medicine 371, 2488-2498 (2014). https://doi.org:10.1056/NEJMoa1408617
33. Jaiswal, S. et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease. The New England journal of medicine 377, 111-121 (2017). https://doi.org:10.1056/NEJMoa1701719
34. Stoeckius, M. et al. Cell Hashing with barcoded antibodies enables multiplexing and doublet detection for single cell genomics. Genome Biol 19, 224 (2018). https://doi.org:10.1186/s13059-018-1603-1
35. Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nature Communications 12, 1088 (2021). https://doi.org:10.1038/s41467-021-21246-9
36. Hafemeister, C. & Satija, R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol 20, 296 (2019). https://doi.org:10.1186/s13059-019-1874-1
37. Stuart, T. et al. Comprehensive Integration of Single-Cell Data. Cell 177, 1888-1902 e1821 (2019). https://doi.org:10.1016/j.cell.2019.05.031
38. Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573-3587 e3529 (2021). https://doi.org:10.1016/j.cell.2021.04.048
39. Valent, P. et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica 104, 1935-1949 (2019). https://doi.org:10.3324/haematol.2019.222059
40. Zeng, A. G. X. et al. A cellular hierarchy framework for understanding heterogeneity and predicting drug response in acute myeloid leukemia. Nat Med 28, 1212-1223 (2022). https://doi.org:10.1038/s41591-022-01819-x
41. Schmid, K. T. et al. scPower accelerates and optimizes the design of multi-sample single cell transcriptomic studies. Nature Communications 12, 6625 (2021). https://doi.org:10.1038/s41467-021-26779-7
42. Loberg, M. A. et al. Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis. Leukemia 33, 1635-1649 (2019). https://doi.org:10.1038/s41375-018-0368-6
43. Yan, X. J. et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43, 309-315 (2011). https://doi.org:10.1038/ng.788
44. Xu, J. J. et al. Srsf2(P95H/+) co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia-like disease in mice. Leukemia 36, 2883-2893 (2022). https://doi.org:10.1038/s41375-022-01727-6

Matteo G Della Porta Center for Accelerating Leukemia/Lymphoma Research (CALR) Cancer Center & AI Center Humanitas Research Hospital – Humanitas University, Milan, Italy

matteo.della_porta@hunimed.eu
Fatigue due to anaemia is one of the most common symptoms that brings patients diagnosed with lower-risk myelodysplastic syndromes (MDS) to medical attention. As a result, the goals in treating patients with lower-risk myelodysplastic syndromes are often focused on improving cytopenias and quality of life. Erythropoiesis-stimulating agents (ESAs), such as recombinant erythropoietin, are used for transfusion-dependent anaemia, particularly in patients with low serum erythropoietin (<500 U/L) and a red blood cell transfusion requirement of less than 2 red blood cell units per month. Response to ESA-based therapy can be as high as 70%,1 but if serum erythropoietin is higher than 500 U/L, the expected response rate is lower than 10%. In April, 2020, luspatercept—an erythroid maturation agent with a mechanism of action distinct from ESA therapy—was approved by the US Food and Drug Administration for patients with lower-risk myelodysplastic syndromes (with the presence of ring sideroblasts and or SF3B1 mutation) who were transfusion dependent with disease refractory to or unlikely to respond to ESA-based therapy. Luspatercept binds to select transforming growth factor-β superfamily ligands and decreases Smad-2/3 signalling. It is this inhibitory effect on Smad-2/3 signalling that enables late stage erythroblast differentiation.

Due to the favourable responses seen with luspatercept, a possible role for its use as initial therapy for transfusion-dependent patients with lower-risk MDS has emerged. The COMMANDS study is an open-label investigation of luspatercept versus epoetin alfa in ESA-naive patients with lower-risk MDS. The trial enrolled 356 patients and is ongoing for follow-up. In the interim analysis 301 patients were randomly assigned to receive either luspatercept (n=147) or epoetin alfa (n=154). 73% of the study population had MDS that was positive for ring sideroblasts. The primary endpoint was defined as red blood cell transfusion independence for at least 12 weeks with a concurrent increase in mean haemoglobin of at least 1·5 g/dL (weeks 1–24) and was reached in 86 (59%) of 147 patients assigned to luspatercept versus 48 (31%) of 154 patients assigned to erythropoietin alfa therapy (p<0·0001). Furthermore, the median duration of red blood cell transfusion independence lasting at least 12 weeks was longer with luspatercept than with epoetin alfa (127 vs 77 weeks). Overall, luspatercept showed an acceptable safety profile consistent with previous observations. A better response rate with luspatercept was observed in all patient’s subgroups stratified according endogenous EPO levels, and the severity of transfusion dependency. In patients without ring sideroblasts the response rate of the two treatment arms was comparable, the exposure to luspatercept being associated with longer response duration.

These findings show that ESA-naive patients with lower-risk myelodysplastic syndromes benefit from upfront luspatercept-based therapy, particularly those with ring sideroblast-positive status or SF3B1 mutated profiles.

Abstract – Yes
Aristoteles Giagounidis, MDErythroid stimulating agents (ESA) have been the linchpin of therapy in early myelodysplastic syndromes (MDS), and for good reason. Decades of experience with ESA have shown their safety, tolerability and effectiveness in alleviating myelodysplastic syndrome induced anemia. It has been repeatedly shown that ESA do not increase the likelihood of AML transformation and that side effects are well manageable. A recent study (the COMMANDS trial [1]) implies that luspatercept is superior to ESA in improving anemia in MDS patients with or without ring sideroblasts. However, this study is based on assumptions that do not reflect the clinical reality: The vast majority of patients with lower risk myelodysplastic syndromes will be diagnosed before they become transfusion dependent. Hence, the treating physician will most often be confronted with a patient suffering from anemia, but not necessarily from transfusion dependent anemia. In a seminal study published by Fenaux et al. it was shown that ESA work best in patients with non-transfusion dependent anemia and an endogenous erythropoietin level of <200 U/L [2]. However, it was precisely this patient population that did not feature in the COMMANDS trial. The inclusion criteria of that trial stipulated transfusion dependence of 2-6 U per 8 weeks prior to baseline. Still, ESA were more effective in achieving the primary endpoint of red blood cell transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1,5 g/dL during weeks 1–24 in the non-ring sideroblastic subgroup (46% for ESA vs 41% for luspatercept, respectively). Given that it is anticipated that patients with EPO levels of >200 U/L do not respond well to treatment (only 12% primary response rate in the COMMANDS trial) and that transfusion dependent patients also have a low response rate to ESA, the target population for ESA treatment should consist of non-transfusion dependent patients with an EPO level of <200 U/L. In this population, response rates close to 70% can be achieved which reflects the efficacy of ESA if the patient selection is sensible. Therefore, ESA remain my favorite drug in the first line treatment of MDS patients that are not transfusion dependent and display an EPO level of <200 U/L.Literature

1. Platzbecker U, Della Porta MG, Santini V, et al. . Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet 2023;402:373-385.
2. Fenaux P, Santini V, Spiriti MAA, et al. . A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-alpha in anemic patients with low-risk MDS. Leukemia 2018;32:2648-2658.

Dr. Nazha

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic disorders, characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a substantial risk of progression to acute myeloid leukemia (AML). Timely diagnosis, accurate prognosis, and optimized treatment are crucial for the management of patients with MDS. With the rapid advancements in technology, Artificial Intelligence (AI) offers a transformative approach in reshaping our understanding and management of MDS.

In this presentation, Dr. Nazha will delve into the transformative role of AI in the management of MDS. He’ll explore how AI-powered models enhance the diagnostic precision by analyzing intricate genetic and clinical data and advanced imaging, refine prognostic capabilities by predicting disease progression and transformation to AML, and optimize treatment selection, pinpointing specific therapies tailored to individual patient needs. Moreover, He will venture into the promising frontier of generative AI, which opens an opportunity to use multimodel approach to improve MDS diagnosis and treatment, heralding a new era in MDS and cancer research.

Guillermo Garcia-Manero, MD
Section of MDS, Department of Leukemia, MD Anderson Cancer Center, University of Texas.Treatment options for patients with higher-risk MDS (HR-MDS) include hypomethylating agents, AML-like therapy and stem cell transplantation (SCT). At the time of writing this abstract, no therapy has been shown to be superior to single agent azacitidine in a randomized clinical trial and SCT is still restricted to fit patients with a suitable donor. In this presentation, I will: discuss what constitutes HR-MDS in 2023; update on the development of oral hypomethylating agents; data of combinations with hypomethylating agents; a role for targeted interventions against IDH1, IDH2 and Flt-3 and a model for incorporation of SCT. Finally, I will also discuss re-emerging data with AML-like therapy and the limited options for HMA-failure MDS. In 2024, we expect the results of the Verona trial that could change our approach to the treatment of this group of patients. At the conclusion of this presentation hopefully I would have share our a modern treatment approach to HR-MDS.

Uwe Platzbecker^1,2,3

¹Medical Clinic and Policlinic 1, Hematology and Cellular Therapy, Leipzig University Hospital, Leipzig, Germany, ²German MDS Study Group (G-MDS) and ³European Myelodysplastic Syndromes Cooperative Group (EMSCO group, www.emsco.eu)

Abstract
The heterogeneous nature of myelodysplastic neoplasms (MDS) implies a complex and personalized variety of therapeutic approaches. Among them, the only potentially curative option, still, remains an allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is anyway accessible to only a small number of fit patients. Considering the potential treatment-related complications associated with allo-HSCT in MDS patients, a serious selection process of patients is inevitable. Therefore, identification of patient and disease-related factors, predicting outcome after allo-HSCT, is mandatory. While the IPSS/R/M have been developed mainly to determine the prognostic risk in newly diagnosed MDS patients, their predictive value concerning the post transplantation outcome was confirmed in several studies. Should patients be treated with an HMA or chemotherapy before allo-HSCT? Retrospective analyses have demonstrated that i.e. with HMA the outcome was improved for patients in complete remission compared to those with active disease at the time of allo-HSCT. Importantly, these studies underlie a certain selection bias for patients with chemo-sensitive disease and excluded patients who did not undergo allo-HSCT because of therapy-related toxicity. Therefore, the value of prior therapy is still not clear because of the absence of randomized trials. This is also because HMA and induction chemotherapy can be associated with a considerably short-term toxicity and many patients with MDS tend to have a delayed recovery of their counts. This leaves the question of when and how to “bridge” to transplant often an individual decision e.g. based on the time of identification of a compatible donor. Novel combination therapies may however pave the way for novel, effective and safe approaches prior to allo-HSCT.

Christopher J. Gibson, MD Dana-Farber Cancer Institute/Harvard Medical School

MDS patients who are candidates for allogeneic transplantation are frequently offered cytoreductive therapies prior to transplant. In this talk, I will argue that routine cytoreduction prior to transplant is not supported by available evidence and can in some cases be counterproductive.
Definitions: “Cytoreduction” in the context of MDS can either refer to the administration of a hypomethylating agent, with or without venetoclax, or to conventional induction chemotherapy. The term is most commonly used to refer to patients with excess blasts, in whom the goal of cytoreduction is to reduce the blast count to less than 5% of bone marrow cellularity. In some cases, however, the term is used less precisely to refer to any administration of cytotoxic drugs, irrespective of blast count.

The use of pre-transplant cytoreduction can be considered in two distinct scenarios:

1. Cytoreduction should not generally be employed in MDS patients without excess blasts. The primary benefit of cytoreduction in MDS is the prevention of progression to acute myeloid leukemia.

1. Patients without excess blasts are generally at low risk of imminent transformation, especially when transplant is planned in the near future, and thus do not derive this benefit.
2. In such patients, cytoreduction can lead to cytopenias and associated complications (infections, bleeding) that delay transplant (Kröger et al, JCO 2021).

2. In patients with excess blasts, the use of cytoreduction depends on the trajectory of disease

1. Blast percentage should be interpreted in the context of MDS dynamics, and not as a static number.
2. In some patients, > 5% blasts does not connote imminent transformation to acute leukemia.
   1. This is frequently the case in MDS/MPN overlap cases in whom blasts are part of a spectrum of increased immature myeloid cells.
   2. It may also be the case in slowly progressive MDS in which the blast count is gradually increasing.
   3. In some older or frail patients with MDS, there is a limited window for administration of cytotoxic therapy, and it may be more productive to respond to an increasing blast count in these patients by moving quickly to transplant rather than spending time on cytoreduction.
3. On the other hand, patients with rapidly increasing blasts counts, or patients found to have blast counts > 10% at the time of MDS diagnosis, are likely in the process of AML transformation. In these cases, cytoreduction may help control disease and improve the likelihood of successful transplant, particularly in patients receiving reduced intensity conditioning regimens.
4. Of note, the American Society for Transplantation and Cellular Therapy’s guidelines for transplant in MDS patients do not recommend routine administration of cytotoxic therapy prior to transplant and rate the evidence supporting this practice a “C” (Defilipp et al, TCT 2023).

References:

1. DeFilipp Z, Ciurea SO, Cutler C, et al. Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines. Transplant Cell Ther. 2023;29(2):71-81.
2. Kröger N, Sockel K, Wolschke C, et al. Comparison between 5-azacytidine treatment and allogeneic stem cell transplantation in elderly patients with advanced MDS according to donor availability (VidazaAllo Study). J Clin Oncol 2021;39(30):3318-3328.