clinical topic updates

Hypomethylating Agent Resistance in High-Risk MDS

by Rami S. Komrokji, MD

Overview

The standard of care for patients with higher-risk myelodysplastic syndrome (MDS) includes treatment with the hypomethylating agents (HMAs) azacitidine and decitabine; however, responses are usually transient as resistance typically emerges. Additional strategies are needed.

Expert Commentary

Rami S. Komrokji, MD

Senior Member
Section Head, Leukemia and MDS
Vice Chair, Department of Malignant Hematology
Moffitt Cancer Center
Professor of Medicine & Oncologic Sciences
University of South Florida Health Morsani College of Medicine
Tampa, FL

Although there are many predictors of HMA failure, we currently have very few treatments for high-risk MDS, and we often must use a treatment that we know is not going to be as effective as we would hope because we lack other options."

Rami S. Komrokji, MD

Resistance to HMAs is a major issue. Outcomes after HMA failure are poor, with studies showing a median survival of 4 to 6 months in patients with high-risk MDS. HMA failure can be categorized into primary or secondary failure. Patients who experience primary HMA failure do not respond to HMA therapy from the outset, while those who experience secondary failure do respond initially but then lose their response over time. Some data from clinical trials suggest differences in survival based on the form of failure; however, resistance is almost inevitable with the use of HMAs, whether the patient has primary or secondary failure. Although there are many predictors of HMA failure, we currently have very few treatments for high-risk MDS, and we often must use a treatment that we know is not going to be as effective as we would hope because we lack other options. 

Several factors are associated with HMA resistance, including the complexity of the cytogenetics and the presence of circulating blasts. In addition, there are several patient-related factors that are linked to HMA resistance, such as functional status and adherence to the regimen itself. Molecular biology is also involved in resistance to therapy. For instance, TP53 mutations are present in approximately 20% of the high-risk MDS population, and we see that patients with these mutations respond to HMA therapy, but the responses are very short lived. Even with newer therapies such as venetoclax, the adverse impact of TP53 mutations has not been overcome. 

Recent work by Rahmani et al linked ASXL1 mutations to enhanced sensitivity to venetoclax and azacitidine via epigenetic upregulation of BCL2 expression, suggesting that venetoclax may perhaps be able to overcome resistance in this setting. Indeed, at the 63rd American Society of Hematology Annual Meeting and Exposition, we presented some real-world data exploring the addition of venetoclax to HMA therapy in patients with higher-risk MDS. The combination did appear to improve the complete response rates, including in ASXL1-mutant MDS. Clearly, an overall survival benefit for this combination can only be evaluated in a randomized clinical trial, but our data suggest promising activity.

I think that TP53 mutations, in particular, continue to be a real challenge. We are hopeful that several drugs that are currently in development may be combined with HMAs to be effective in a manner that is agonistic with respect to somatic mutations. Initial signals from some studies of magrolimab (an anti-CD47 monoclonal antibody that targets the innate immunity) and sabatolimab (a TIM-3 inhibitor that targets the stem cells and engages the T cells) have been encouraging; work is ongoing in this area.

References

Adès L. High-risk MDS after HMAs. Hemasphere. 2019;3(suppl):138-140. doi:10.1097/HS9.0000000000000219

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.

Jabbour E, Garcia-Manero G, Batty N, et al. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010;116(16):3830-3834. doi:10.1002/cncr.25247

Komrokji RS, Al Ali N, Chan O, et al. Assessing the role of venetoclax in combination with hypomethylating agents in higher risk myelodysplastic syndromes [abstract 536]. Abstract presented at: 63rd American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021.

Rahmani NE, Ramachandra N, Sahu S, et al. ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine. Blood Cancer J. 2021;11(9):157. doi:10.1038/s41408-021-00541-0

Sallman DA, Asch AS, Kambhampati S, et al. The first-in-class anti-CD47 antibody magrolimab combined with azacitidine is well-tolerated and effective in AML patients: phase 1b results [abstract 330]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Takahashi K, Patel K, Bueso-Ramos C, et al. Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents. Oncotarget. 2016;7(12):14172-14187. doi:10.18632/oncotarget.7290

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