High-Risk MDS and AML: Present Strategies and Future Directions
Treatment decisions for patients with high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML) are guided by the individual patient’s medical fitness level, which may be a limiting factor. With numerous clinical trials evaluating novel therapies in high-risk patients underway, there is hope that novel regimens will be US Food and Drug Administration approved in the near future.
What is the foundation of therapy for HR-MDS and AML, and how do you expect that this might be changing in the coming years?
Professor and Dr. Kenneth B. McCredie Chair in Clinical Leukemia Research
“We are beginning to see a higher proportion of patients—even older patients—responding to novel therapies and then proceeding to stem cell transplantation.”
The current strategies being developed for patients with HR-MDS depend on the type of mutation that may be present. With mutational profiling analysis, we can work toward targeting specific mutations for our patients. For example, mutations in IDH1/IDH2 are currently targeted by ivosidenib (IDH1 mutations) and enasidenib (IDH2 mutations) in patients with AML, and clinical trials with these agents are underway in MDS. Both IDH1 and IDH2 are mutated in MDS in approximately 5% to 15% of patients, respectively. There is also a small subset of patients with NPM1 mutations, which have been linked to favorable outcomes with intensive chemotherapy. FLT3 mutations, which are important in AML, can also occur in those with HR-MDS, particularly when they progress from low-risk MDS to HR-MDS or when they transform to AML. There are several FLT3 inhibitors that are currently under investigation for use in patients with FLT3 mutations.
There are also doublets that are under investigation for patients with AML who are ineligible for intensive therapy that have shown promising preliminary data. For example, the BCL-2 inhibitor venetoclax combined with azacitidine improved complete remission rates and durability of response, with an acceptable toxicity profile, in a phase 3 study of patients with AML. If the results for this doublet in patients with MDS are consistent with what we have seen in AML, this will be a significant advancement in MDS. Another combination that has shown promise in HR-MDS is pevonedistat with azacitidine. Preliminary data presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition by Sekeres and colleagues showed that this combination led to improved response rates, event-free survival, and overall survival (OS) in patients with HR-MDS, suggesting the possibility of it becoming a significant doublet in this population. Sabatolimab, an antibody that targets TIM-3, is an immune checkpoint inhibitor currently under evaluation for HR-MDS. It works differently than immunotherapy that targets PD-1 or CTLA-4. TIM-3 is expressed on leukemic stem cells, and the combination of sabatolimab with a hypomethylating agent is believed to have an antileukemic effect and to elicit an immune response. Data recently presented at ASH 2020 suggest that this doublet is associated with significant clinical activity.
Finally, 2 other compounds of interest include magrolimab and eprenetapopt (APR-246). Magrolimab targets CD47 and activates the phagocytic activity of the macrophage; it is considered an immune checkpoint for macrophages. Pilot studies performed in England and the United States have shown that the combination of magrolimab and azacitidine had significant clinical activity in both MDS and AML, particularly in patients with TP53-mutated disease. However, we still need more data to understand the potential role of eprenetapopt combined with azacitidine in HR-MDS with TP53 mutations.
In the future, I think that there will be a significant effort to develop effective triplet regimens. We are beginning to see a higher proportion of patients—even older patients—responding to novel therapies and then proceeding to stem cell transplantation. Overall, I believe that we are in a better therapeutic position today than we were a few years ago.
“Once we have a better understanding of disease biology, we can develop regimens that synergistically target the cancer cells and ultimately improve OS.”
While it is exciting to see that adding novel therapies to the backbone of hypomethylating agent therapy can improve outcomes, allogeneic stem cell transplantation remains the only curative option for patients with HR-MDS or AML. The median age of patients with MDS and AML is over 60 years, which has, historically, prevented many individuals from transplant eligibility. As patients age, they have more comorbidities, a decline in performance status and nutritional status, and less psychosocial support. However, transplant eligibility has now expanded with the availability of DNA-based typing, which allows for a better selection of donors. Furthermore, the preparative regimens are now less intensive and nonmyeloablative, minimizing mucosal and other organ toxicities that precluded transplants in older patients.
It is important to consider allogeneic transplantations in older patients without significant comorbidities, especially in those whose therapy goals are curative and not palliative, but only a minority of patients are eligible for transplant. So, I am excited about novel therapies that have the potential to improve response and survival outcomes in the majority of our patients who are not eligible for curative treatment. Once we have a better understanding of disease biology, we can develop regimens that synergistically target the cancer cells and ultimately improve OS.
Finally, we need to improve the availability of novel agents for HR-MDS and AML to the American population. Through the National Cancer Institute and the Cancer Therapy Evaluation Program, there is an effort to develop the MyeloMATCH program, where clinical trials will be available at community oncology centers across the country. A patient will have a thorough genomic analysis of their disease when they are enrolled in a study, helping to ensure that they are allocated the most appropriate therapy.
Assistant Member, Department of Malignant Hematology
“Advancements in frontline treatments for patients with HR-MDS and AML will result from the approval of novel therapies and from real-world experience with those therapies. We are optimistic that this will also lead to an improved standard of care for a broader range of patients.”
The future of HR-MDS treatment is somewhat bright for new doublet combinations, but we are still awaiting results from phase 3 studies to evaluate improvement in OS. I also hope that more of these trials with novel combinations will include post-transplant outcomes as a secondary analysis. By improving the depth of remission, we are better positioned to improve outcomes with transplantation. If we can also achieve hematologic improvements, we may be able to enhance the functional status of patients so that they can become eligible for a transplant. Therefore, a critical analysis of these studies can determine the percentage of patients who are transplanted, outcomes of a transplant, and minimal residual disease status before and potentially after transplant. The other part of the equation is to identify which novel therapies improve survival without transplant and, potentially, to identify early biomarkers that will predict long-term outcomes. Ideally, these investigations can be performed in tandem, moving novel therapies to the frontline setting to increase the number of patients who proceed to transplant and to improve outcomes with or without transplant.
For high-risk patients, we may be moving toward the direction of triplet regimens, assuming that they are well tolerated and that they improve patient outcomes. In fact, venetoclax, magrolimab, pevonedistat, and sabatolimab, which have shown high activity as doublets, are now under evaluation in triplet regimens. Advancements in frontline treatments for patients with HR-MDS and AML will result from the approval of novel therapies and from real-world experience with those therapies. We are optimistic that this will also lead to an improved standard of care for a broader range of patients.
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