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Updates in High-Risk Myelodysplastic Syndrome

Presentation by Dr Aditi Shastri, Montefiore Medical Center

At the Total Health 2023 Best of Heme Conference held in Vail, Colorado, Dr Aditi Shastri from Montefiore Medical Center presented updates in treatment for high-risk myelodysplastic syndrome (MDS).

Current Treatment for High-Risk MDS

Dr Shastri began with a general overview of the treatment approach for the high-risk MDS patient, which starts with an assessment of whether the patient is a candidate for allogeneic stem cell transplant (ASCT), because this remains the only curative therapy. For patients who are not candidates for ASCT, the “Aza-nucleotide” therapies are generally the standard of care for high-risk MDS. Non-ASCT patients are also candidates for inclusion in clinical trials, of which, as Dr Shastri noted, there are many available.


Dr Shastri noted that DNA methyltransferase inhibitors, or DNMTi, have been shown to improve survival in MDS patients, and agents such as azacytidine and decitabine, remain a cornerstone of therapy for high-risk patients. She noted that more recently, efforts have been made to improve the delivery of DNMTi (“bioavailability”) and to create oral formulations of these drugs which are less burdensome to administer to patients as compared to their original intravenous (IV) formulations. In this regard, she reviewed data for ASTX 727, an oral DNMTi consisting of decitabine and a cytidine deaminase inhibitor that serves to prevent the degradation of the drug in the digestive tract. Dr Shastri noted that response rates in clinical studies with the oral formulation are similar to those seen with the IV formulation, and this is now an approved option for treatment of high-risk MDS patients. For patients who fail treatment with DNMTi, however, Dr Shastri noted that the prognosis is very poor, with an overall survival (OS) of only about 3 to 4 months, and this continues to be a problem for clinicians treating patients with high-risk MDS. She noted that some studies have suggested a role for “salvage therapy” using ASCT, and that investigational agents may also be beneficial to improve survival for some patients, so ASCT and a clinical trial should be discussed with the patient as options to consider after DNMTi failure.

Magrolimab and Other Immune-Directed Therapies

Dr Shastri then reviewed data for magrolimab, an antibody that blocks a molecule called CD47, a “checkpoint” mechanism that lies on the surface of immune cells. Cancer cells can evade detection and destruction by the immune system by upregulating their expression of CD47, and by blocking this molecule, magrolimab causes the immune cells to recognize and “eat” the cancer cells, a process called phagocytosis. In addition, Dr Shastri explained that magrolimab also works synergistically with azacytidine in this manner, to further enhance the phagocytosis and killing of the tumor cells.

In a phase I study of patients with high-risk MDS, Dr Shastri noted that magrolimab + azacytidine treatment resulted in an overall response rate (ORR) of 74.4%, and efficacy was also seen in the more difficult to treat subpopulation of patients having a mutation in the gene TP53, with an ORR of 68%. She also highlighted that 35% of the high-risk MDS patients who were transfusion dependent at the start of the study became transfusion independent after treatment. Another measure of efficacy, the allele frequency of TP53 mutation was also reduced early in the course of treatment, and Dr Shastri noted this could indicate that this combination therapy might be beneficial to alter the overall course and trajectory of disease in this harder to treat subgroup of TP53-mutated patients.

With respect to adverse events (AEs) associated with the magrolimab + azacytidine therapy, Dr Shastri noted that the regimen was overall quite tolerable, however, because CD47 is also expressed on the surface of red blood cells, there is an “on-target” AE of anemia that can occur, and because of this, patients need to be monitored closely early in the course of treatment. She highlighted an ongoing, randomized, phase III trial of this combination therapy, ENHANCE, which will compare therapy with magrolimab + azacytidine versus placebo+ azacytidine in MDS patients who are designated as very high-risk. She also mentioned two additional immune-directed therapies which have shown promise for high-risk MDS, sabatolimab, an antibody therapy directed against a molecule known as TIM-3, and Evorpacept, another anti-CD47 antibody therapy, both of which are currently under investigation in clinical trials in high-risk MDS.

Other Options for High-Risk MDS: Venetoclax and IRAK-4 Inhibitors

Venetoclax is an inhibitor of BCL2, a protein that promotes cellular survival by inhibiting the process of programmed cell death, or apoptosis, and is another treatment option that has shown promise in high-risk MDS. Dr Shastri noted that treatment with venetoclax in combination with azacytidine showed an ORR of 84% in high-risk MDS patients, and the median time to response was very short (0.9 months), so clinicians can tell early on if patients are responding to treatment or not. In addition, the median duration of response was over one year (12.4 months), and responses have been observed across patients with a wide range of mutations. She highlighted the ongoing phase III VERONA trial which will assess the efficacy of venetoclax (or placebo) in combination with azacytidine in patients with high-risk MDS. Another potential target for treatment in high-risk MDS is a molecule known as IRAK-4, the long isoform of which is overexpressed in MDS, and is correlated with a poor prognosis. Dr Shastri noted that emavusertib, which selectively targets IRAK-4, has shown efficacy as a single agent, both in patients with acute myeloid leukemia (AML) as well as in patients with high-risk MDS. Studies with emavusertib and other IRAK-4 inhibitors are therefore ongoing in high-risk MDS.


Quick Summary

  • DNMTi like azacytidine and decitabine are the current standard of care for patients with high-risk MDS, but outcomes are dismal for patients failing these therapies.

  • Options for patients failing DNMTi include allogeneic stem cell transplant and clinical trials.

  • Magrolimab is an inhibitor of CD47 that has shown efficacy, in combination with azacytidine for patients with high-risk MDS.

  • Magrolimab is generally well tolerated but patients need to be carefully monitored for the on-target adverse event of anemia.

  • Other promising strategies for high risk MDS include immune modulating therapies like sabatolimab, BCL2 inhibitors like venetoclax, and IRAK-4 inhibitors which are currently under investigation.


See more from the 2023 Best of Hematology Conference here.

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