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Advancing Therapies for Myelodysplastic Syndromes

Kumar Das, Dibash PhD

doi: 10.1097/01.COT.0000831296.38963.a8
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Myelodysplastic Syndromes:
Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of closely related clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia (AML) (N Engl J Med 2020; doi: 10.1056/NEJMra1904794).

The treatment goals for patients with MDS focuses on changing the natural progression of the disease, as well as improving the peripheral blood values. The treatment modalities for newly diagnosed and relapsed/refractory MDS depend on the individual patient's risk classification, fitness, goals and preferences, and suitability for hematopoietic cell transplantation.

Unfortunately, there is a tremendous unmet need for new, more effective but tolerable strategies to manage MDS. Historically, challenges relating to the treatment of MDS include the extreme genetic and clinical heterogeneity of MDS disease subsets, high relapse rates, variable disease course, comorbidities of this patient population, and advanced age (Leukemia 2021; doi: 10.1038/s41375-021-01265-7). The 2020 Surveillance, Epidemiology, and End Results data shows the incidence rate of MDS rises with age, particularly in those ≥70 years of age (Clin Lymphoma Myeloma Leuk 2022;

Recent advances in molecular genetic diagnostics have improved our understanding of the pathogenesis of MDS, and a personalized approach to therapy in MDS has ensued. Here, we discuss several agents with unique mechanisms of action that can potentially advance the treatment of MDS after years of stagnancy.


A recent FDA-approved agent for MDS is the first-in-class erythroid maturation agent, luspatercept, which was approved in 2020. It is for the treatment of anemia failing an erythropoiesis-stimulating agent and requiring at least two red blood cell units over 8 weeks in adult patients with very low-risk to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis. Luspatercept boosts late-stage erythropoiesis by binding a number of endogenous transforming growth factor-β superfamily ligands, thus reducing SMAD2/3 signaling (N Engl J Med 2020; doi: 10.1056/NEJMoa1908892).


Venetoclax is a first-in-class agent that selectively binds to and blocks the activity of the pro-survival B-cell lymphoma-2 (BCL-2) protein, which precludes some hematologic cancers from experiencing apoptosis (Hematol Oncol Clin North Am 2020; doi: 10.1016/j.hoc.2019.10.005). This may lead to improved response to hypomethylating agents (HMA), including in cells previously resistant to HMA treatment.

Previously, venetoclax had been approved in combination with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed AML in adults 75 years or older or with comorbidities that preclude use of intensive induction chemotherapy. Recently, the FDA has granted breakthrough therapy designation to the combination of venetoclax plus azacitidine as a potential systemic therapy for patients with newly diagnosed, higher-risk MDS. The approval was based on the data from the Phase Ib M15-531 trial.

Venetoclax is currently being assessed in several clinical trials. The Phase Ib M15-522 trial is investigating venetoclax either alone or in combination with azacitidine for the treatment of patients with relapsed or refractory MDS. The Phase III VERONA study is recruiting patients and investigating oral venetoclax in combination with intravenous or subcutaneous azacitidine to study change in disease in adults with newly diagnosed higher-risk MDS.


Magrolimab is a first-in-class macrophage immune checkpoint inhibitor that targets CD47. Studies have suggested that CD47 is an essential mediator by which cancer cells and cancer stem cells evade the intrinsic expression of the prophagocytic “eat me” signal.

Results of a single-arm Phase Ib study by Sallman and colleagues demonstrated that the combination of magrolimab and azacitidine in untreated intermediate-risk to very high-risk MDS resulted in an overall response rate of 92 percent and a CR rate of 50 percent in 24 patients with an acceptable safety profile (The Hematologist 2021; Also, the combination demonstrated use of magrolimab may be promising for patients with MDS who have TP53-mutated myeloid disease, another underserved population with poor outcomes.

Another study—the ENHANCE trial—is investigating magrolimab in combination with azacitidine versus azacitidine plus placebo in treatment-naïve patients with intermediate-risk, high-risk, or very high-risk MDS. The study aims to determine if the addition of magrolimab will improve clinical efficacy without added toxicity.

However, the FDA has placed a hold on all clinical trials investigating the combination of magrolimab and azacitidine in MDS and AML due to an imbalance of investigator-reported unexpected adverse reactions.

Guillermo Garcia-Manero, MD, chatted with Oncology Times to share his perspectives on the challenges, hopes, and new agents that have entered the MDS treatment armamentarium. He is a physician-scientist at The University of Texas MD Anderson Cancer Center and his research focuses on MDS and AML with the aims to understand, treat, and eventually cure these deadly diseases.

Oncology Times: What are the current challenges in the standard of care for patients with MDS?

Garcia-Manero: “The myelodysplastic syndromes are a very complex and heterogeneous group of myeloid disorders. In addition, we now understand that likely the cell origin of MDS is a primitive hematopoietic stem cell that is difficult, if not impossible, to eradicate. Therefore, current therapies provide suboptimal outcomes. Right now, the best we can do is understand, at the cytogenetic and molecular levels, subsets of patients that would benefit, or not, from specific type of therapies and use them in the most appropriate context. We need better compounds to improve cytopenia for patients with so-called lower-risk disease and better approaches for those with higher-risk disease. Finally, we need to be able to incorporate stem cell transplant better.”

Oncology Times: What are the treatment goals for patients with MDS, and how do treatment goals differ between patients with low-risk MDS and high-risk MDS?

Garcia-Manero: “In my opinion, the main treatment goal should be to improve survival. This is particularly important for patients with higher-risk disease and fundamentally for patients with so-called ‘hypomethylating agent failure’ MDS that have very poor prognosis, but survival should also be a goal for patients with lower-risk disease. It should be noted that a significant fraction of patients with lower-risk disease have a relatively poor prognosis. Of course, improvement of cytopenia, transfusion needs, and transformation are important goals as is improvement of quality of life.

“In the future, we may be able to delay or prevent MDS in patients in clonal hematopoiesis of indeterminate potential/clonal cytopenia of undetermined significance (CHIP/CCUS). We need also to understand better the interplay between comorbidities and therapy that could be somehow molecularly linked. This is an important point that we have never measured in a prospective fashion.”

Oncology Times: Are there any investigational agents in development that you are particularly excited about for patients with MDS?

Garcia-Manero: “There are multiple agents being studied for both lower- and higher-risk patients. The COMMANDS study with luspatercept in frontline lower-risk MDS patients is very important. Also, we are awaiting the results of telomerase inhibitor, imetelstat, in lower-risk disease. Other targets in lower-risk disease include molecules involved in innate immunity pathways that are upregulated in this disease. These include Toll-like receptor inhibitors; IL-1 inhibitors, such as canakinumab; IRAK inhibitors, and other targets/agents in this pathway.

“In higher-risk disease, there are three large, randomized studies comparing single-agent azacitidine versus combinations, including the VERONA trial (combining the BCL-2 inhibitor venetoclax with azacitidine); immunotherapy combinations with anti-CD47 antibodies such as magrolimab (the ENHANCE trial) and others; and TIM-3 inhibitors such as sabatolimab (the STIMULUS studies).

“There is also an interest in studying more intense forms of therapy in selected younger patients with AML-like therapy, [along with] a large list of other new agents being explored in combinations. Another important area is the study of oral hypomethylating agents, such as decitabine/cedazuridine and potentially oral azacitidine (CC-486). Finally, there are important studies evaluating targeted approaches such as blocking isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2).

“That said, we also have significant needs. Examples include patients with HMA failure where there is a paucity of specific studies, with eltanexor being one, and for patients with p53 mutated disease. Finally, we also need better studies incorporating therapy post SCT in patients at risk of relapse.”

Dibash Kumar Das is a contributing writer.

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