patient care perspectives

Combination Strategies to Overcome Hypomethylating Agent Resistance

by Courtney D. DiNardo, MD, MSCE

Overview

Effective strategies for hypomethylating agent (HMA) resistance are needed in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Our featured expert reviews research on therapeutic combinations that hold promise.

Expert Commentary

Courtney D. DiNardo, MD, MSCE

Associate Professor
Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

Agents targeting TIM-3 and CD47 are immunotherapy options that do not seem to be associated with as many immune-mediated adverse events as the standard PD-1, PD-L1, and CTLA-4 ICIs, which has been a positive development.”

Courtney D. DiNardo, MD, MSCE

We still do not fully understand HMA resistance as well as we should. Unfortunately, most patients who receive an HMA as monotherapy will experience resistance, even if these patients initially respond to treatment. There are a whole host of HMA combinations, both in the MDS and the AML space, that are being studied to try to improve these outcomes. The combination with venetoclax has been very effective and has become a frontline HMA combination of choice, but there are other combinations that are under development as well.

When adding combinations, we have to be much more attuned to potential toxicity. We also must be especially careful when treating patients with MDS because their bone marrow already starts out a bit more disordered and dysfunctional. With venetoclax-based therapy, we have to be aware of the potential for cytopenias, and with immune checkpoint inhibitors (ICIs), we need to be more aware of some of the immune-related adverse events, such as pneumonitis, colitis, or rashes. Despite the varying toxicities, the rationale behind most of the combinations is similar and compelling when it comes to MDS, high-risk MDS, and AML (ie, the aim is to improve responses).

Some particularly exciting combinations in MDS and AML involve novel ICIs. Magrolimab is an antibody against CD47 that acts as a macrophage ICI to promote tumor cell phagocytosis. In both MDS and AML, combinations with azacitidine and magrolimab seem to be effective, even in patients with TP53 mutations. Individuals with TP53-mutated myeloid malignancies are among the most difficult to treat, so if this combination is truly effective in a TP53-agnostic way, that is going to be really important.

TIM-3 is a checkpoint that is particularly relevant for myeloid malignancies. Sabatolimab is the TIM-3 inhibitor that is furthest along in development, and there are several ongoing studies that are evaluating sabatolimab-based combinations. Agents targeting TIM-3 and CD47 are immunotherapy options that do not seem to be associated with as many immune-mediated adverse events as the standard PD-1, PD-L1, and CTLA-4 ICIs, which has been a positive development.

There are also combinations involving targeted therapies such as azacitidine with IDH1, IDH2, and FLT3 inhibitors. Data from the recently reported phase 3 AGILE study of azacitidine and the IDH1 inhibitor ivosidenib showed favorable results. I think that this may be another combination that we will be using in IDH1-mutated AML.

Triplet therapies are also under evaluation. There are currently more and more clinical trials examining azacitidine plus venetoclax and a third agent such as an IDH inhibitor, an FLT3 inhibitor, or a novel ICI. There is more potential myelosuppression and toxicity with a triplet approach, but the hope is to achieve even deeper remissions and more durable survivals once we establish the optimal dosing strategies for triplet regimens.

References

Bewersdorf JP, Carraway H, Prebet T. Emerging treatment options for patients with high-risk myelodysplastic syndrome. Ther Adv Hematol. 2020;11:2040620720955006. doi:10.1177/2040620720955006

Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (MBG453) in combination with hypomethylating agents (HMAs) in patients (pts) with very high/high-risk myelodysplastic syndrome (vHR/HR-MDS) and acute myeloid leukemia (AML): final analysis from a phase Ib study [abstract 244]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

ClinicalTrials.gov. A study of MBG453 in combination with azacitidine and venetoclax in AML patients unfit for chemotherapy (STIMULUS-AML1). Updated April 26, 2022. Accessed May 13, 2022. https://clinicaltrials.gov/ct2/show/NCT04150029

Daver N, Boddu P, Garcia-Manero G, et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. 2018;32(5):1094-1105. doi:10.1038/s41375-018-0070-8

Montesinos P, Recher C, Vives S, et al. AGILE: a global, randomized, double-blind, phase 3 study of ivosidenib + azacitidine versus placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation [abstract 697]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Stomper J, Rotondo JC, Greve G, Lübbert M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia. 2021;35(7):1873-1889. doi:10.1038/s41375-021-01218-0

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