Myelodysplastic syndromes (MDS) affect an estimated 3.3 per 100,000 people in the United States, with increased incidence among men (mainly White and non-Hispanic), older adults, and individuals who have been exposed to cytotoxic therapy.1 In a paper published in the American Journal of Hematology, the authors provide an overview of the diagnosis and management of MDS, including recent treatment updates.2

Some new treatments that were recently approved by the U.S. Food and Drug Administration include luspatercept (approved April 3, 2020), and the oral combination of decitabine/cedazuridine (approved July 7, 2020).3,4 Additionally, there are “multiple ongoing advanced clinical trials that may results in newer treatments for patients in the near future,” said lead author Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Selected recommendations outlined in the paper are highlighted below.2

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Patients with idiopathic cytopenia of undetermined significance (ICUS) may be followed in the community, while those with clonal hematopoiesis of undetermined potential (CHIP) or clonal cytopenia of undetermined significance (CCUS) should be followed more closely in a “CHIP” clinic.

Newly Diagnosed Lower-Risk MDS

In most low-risk patients with significant anemia and no additional cytopenia, the authors believe that erythroid stimulating agents (ESA) with or without granulocyte colony-stimulating factor are not contraindicated. They maintain therapy for at least 3 months, with continuation in responding patients “until transfusion effect is lost.” The authors also noted that they do not recommend the use of thrombomimetic agents.

Lenalidomide is the standard of care for patients with lower-risk MDS with anemia, good platelets, and del5q but should not be used in those with thrombocytopenia. In patients who are transfusion-dependent, 5-azacitidine and decitabine may be considered.

While not generally recommended for those with lower-risk disease at initial presentation, allogeneic stem cell transplantation (alloSCT) should be considered up front for young patients with hypoplastic MDS.

Luspatercept is an approved therapy for patients with refractory anemia with ring sideroblasts (RARS) who have received an ESA but is not recommended for other MDS subtypes.

Relapsed or Refractory Lower-Risk MDS

AlloSCT remains the only active option for lower-risk patients with HMA failure, as there are no approved agents for this group. 

Newly Diagnosed Higher-Risk MDS

Azanucleosides represent the standard of care for most higher-risk patients. As 5-azacitidine was associated with improved survival in a randomized trial, it is considered the standard front-line treatment for this group.5

While alloSCT should be considered for higher-risk patients, this may not apply to those with high-risk mutations, such as TP53, where transplant may be considered only in specific circumstances.6

All patients with MDS should be considered for enrollment in an investigational clinical trial.

Precision Medicine in MDS

The authors recommend the use of NGS assays at baseline and each time therapeutic decisions are considered for MDS patients.

“We still have multiple challenges — we need better options than single agent HMA in the front line for higher-risk patients, as well as options for patients experiencing HMA failure and better approaches to incorporate alloSCT in our patients,” according to Dr Garcia-Manero.

To further explore updates regarding MDS updates, we interviewed James M. Rossetti, DO, hematologist at the MDS Center of Excellence at the UPMC Hillman Cancer Center in Pittsburgh, Pennsylvania.

What are your thoughts about the updates described by Garcia-Manero, et al?

Dr Rossetti: This update is well-written, comprehensive, and clinician-friendly. As Garcia-Manero, et al note, this group of disorders is exceedingly heterogeneous in presentation, disease progression, and treatment responsiveness. Further, they identify some of the diagnostic challenges and outline newer entities that, while failing to meet diagnostic criteria for MDS, may have substantial implications relating to evolution to MDS as well as potential risk associated with comorbid conditions or the use of cytotoxic therapy for other disease states.

The authors also note potential shortcomings of the commonly utilized risk-stratification models while highlighting the need for continued validation of incorporating molecular data into the prognostic landscape. They very nicely lay out a practical approach to the patient with MDS, not only based on risk level and prior treatment with HMA, but interweaving other important factors such as comorbidity, cytogenetics, and molecular data.

What are some of the most notable recent updates regarding MDS?

Dr Rossetti: Recently, there is much encouragement and hope for patients with MDS, as new therapies have either been approved or are showing promise in clinical trials. In addition to providing practical recommendations for the appropriate use of traditional therapies, Dr Garcia-Manero describes the clinical utility of recently approved therapies, as well as that of supportive care measures such as the benefit of iron chelation in lower-risk patients.

Importantly, it is noted that lower-risk patients with RARS have traditionally had few effective therapies available for reducing red-cell transfusion needs. The recent approval of luspatercept for this subset of patients is quite encouraging, though further data is needed regarding improvement in quality of life and survival. Ongoing studies are also looking at the utility of this promising agent in other types of MDS.

The newly approved decitabine/cedazuridine adds a needed level of convenience for patients and may well enhance the evolution of combination therapy trials in the future.

What are remaining challenges, and how are these currently approached in practice?

Dr Rossetti: Patients with very high-risk cytogenetic or molecular profiles and those who have failed HMA therapy continue to do relatively poorly both in transplant and nontransplant settings. In this regard, Garcia-Manero, et al rightly stress the importance of trials looking at epigenetic modifiers in combination with targeted therapies. Encouragingly, APR-246 has shown promise in patients with p53 mutated MDS, carrying expanding designations from the [U.S. Food and Drug Administration].6 Clinicians anxiously await phase 3 data assessing the impact of this agent in combination with azacitidine.

Clinical trials are needed for nearly all MDS subtypes. As such, many MDS physicians would agree that enrollment in clinical trials remains the primary challenge facing continued progress in the field.

What should be the focus of future investigation in MDS?      

Dr Rossetti: While transplant remains the only curative option for MDS, the morbidity, mortality, and survival statistics associated with such treatment all remain areas of great need. Though it is true that more patients than ever are now considered transplant-eligible, continued improvement in identifying patients with particularly high-risk for post-transplant relapse is crucial. Moreover, the evolving understanding of the biology behind these disorders will hopefully allow for the development of combination strategies that will favorably modify this risk in pre- and posttransplant settings.


  1. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112(1):45-52. doi:10.1182/blood-2008-01-134858
  2. Garcia-Manero G, Chien K, Montalban-Bravo G. Myelodysplastic syndromes: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. Published online August 3, 2020. doi:10.1002/ajh.25950
  3. US Food and Drug Administration. FDA approves luspatercept-aamt for anemia in adults with MDS. Accessed online September 15, 2020.
  4. US Food and Drug Administration. FDA approves oral combination of decitabine and cedazuridine for myelodysplastic syndromes. Accessed online September 15, 2020.
  5. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232. doi:10.1016/S1470-2045(09)70003-8
  6. Sallman DA, DeZern AE, Garcia-Manero G, et al. Phase 2 results of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia (AML). Blood. 2019;134(Suppl1): 676. doi:10.1182/blood-2019-131055

This article originally appeared on Hematology Advisor