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Exploring Revumenib for KMT2-Rearranged Acute Leukemias in the AUGMENT Trial With Ibrahim Aldoss, MD

Recently, at the American Society of Hematology (ASH) Annual Meeting, Oncology Data Advisor sat down with Ibrahim Aldoss, MD, an Associate Professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope, to further discuss his presentation investigating revumenib for patients with relapsed/refractory histone-lysine N-methyltransferase 2A (KMT2A)-rearranged acute leukemias, as well as the results he presented and future steps in this area.  

Oncology Data Advisor: Welcome to Oncology Data Advisor, I'm Keira Smith. Today, we're here live at the ASH Annual Meeting, and I'm joined by Dr. Ibrahim Aldoss. Thank you so much for coming on the show today.

Ibrahim Aldoss, MD: Thank you for having me.

Oncology Data Advisor: To start off, would you like to introduce yourself and share what your work and your research focus on?

Dr. Aldoss: I'm Dr. Ibrahim Aldoss from City of Hope in the Department of Leukemia Hematopoietic Stem Cell Transplant, in Duarte, California. My interest is acute leukemia, and my research includes optimizing frontline therapy and treatment for relapsed/refractory acute leukemia, including cellular therapy and bone marrow transplant.

Oncology Data Advisor: Great. Today, we're talking about your presentation on revumenib monotherapy in patients with relapsed/refractory KMT2A-rearranged acute leukemias. For background, would you like to tell us a little bit about revumenib, its mechanism of action, and how it's been used in hematology so far?

Dr. Aldoss: Revumenib is a small molecule inhibitor of the KMT2A-menin interaction, and this is what drives the KMT2A-rearranged leukemias and inducing the leukemogenesis as well as for other genetic subtypes including the nucleophosmin 1 (NPM1)–mutated acute myeloid leukemia (AML). KMT2A-rearranged acute leukemia is a disease with unmet therapeutic need. It can present as AML, as an acute lymphoblastic leukemia (ALL), as an acute leukemia, or as ambiguous lineage in children, and adults account for 10% of all acute leukemias. KMT2A disease frequently relapses after transplant and chemotherapy, and when they relapse, the adults' outcomes are poor with low response rates and low median overall survival. Currently, there is no targeted therapy for KMT2A-rearranged leukemia.

Oncology Data Advisor: How are these leukemias treated currently?

Dr. Aldoss: So, currently for the relapsed/refractory setting, the only treatment available is combination chemotherapy, but the outcomes of combination chemotherapy when you give it in adults in their second salvage, or beyond the response rate, is less than 10%, and the median overall survival is less than three months.

Oncology Data Advisor: What is the AUGMENT-101 trial investigating?

Dr. Aldoss: This is a phase 2 study using single-agent revumenib in patients with KMT2A-rearranged acute leukemias. It has three cohorts, two cohorts for KMT2A-rearranged acute leukemia and one cohort that continues to enroll for NPM1-mutated AML. It is age-agnostic, which includes children as young as 30 days and there is no age limit above that. The study uses the recommended phase 2 dosing of revumenib, which is 163 mg given twice a day in combination with strong cytochrome P450 (CYP) 3A4 inhibitor. The primary end point is efficacy, and the secondary end point is composite complete response (CRc) rate. The study included prespecified interim analysis after the first 57 patients with centrally confirmed mutation followed adequately for six months or they discontinued treatment.

Oncology Data Advisor: Great, and what were the results of the trial that you presented yesterday?

Dr. Aldoss: The results of the study—the study included 57 patients treated on the efficacy cohort, this is including almost quarter of the patients who were children. The majority are AML heavily pretreated, where almost half of them had three or more prior lines of therapy. A quarter of them had induction failure and never achieved remission. Half of them had prior transplant, and the majority had venetoclax. And with median follow-up of 6.1 months, the overall response rate was 63%. The study made the primary efficacy end point, as there were 23% of patients achieving complete response (CR) with partial hematologic recovery (CRh), and the duration of remission in these patients was 6.4 months.

The majority of responders achieved a minimal residual disease (MRD)–negative CR, and close to 40% of responders were able to proceed with consolidation with allogeneic stem cell transplant. Half of those transplanted patients were able to continue revumenib after transplant as a maintenance therapy. Treatment was well-tolerated, and adverse events were manageable. The rate of drug discontinuation because of treatment-related adverse events was low, as well as dose reduction with only 6%. They discontinued the drug because of the treatment-related adverse events.

Oncology Data Advisor: Those are very impressive results. What are the next steps for investigating revumenib? I know this is a phase 1/2 trial. How is it going forward?

Dr. Aldoss: This phase 2 study was actually stopped early as we made the efficacy primary end points, and the company is going to the FDA with the hope of approval as a single agent in relapsed/refractory KMT2- rearranged acute leukemia based on these results. If you compare it to the historic control, outcomes are much better in terms of response, the depth of response, and also the overall survival for these patients who are heavily pretreated and have very limited options at this time. Now with the safety and the encouraging efficacy of the drug, the next step is, are we able to bring revumenib early in the treatment of these patients to improve their outcomes, and maybe spare more patients from being high-risk and having to go to allogeneic stem cell transplant early in the treatment course? So, there are different studies being proposed and studied at this time where they use it in combination therapy for these patients.

Oncology Data Advisor: Great. So, as the research progresses and revumenib is potentially FDA-approved in the future, how do you think it'll fit into the treatment landscape for KMT2a-rearranged acute leukemias?

Dr. Aldoss: I think the approval is going to be for relapsed/refractory disease, and I think this is very important as we don't have effective options at this time. I think it depends on patient fitness and age—it's a well-tolerated treatment and you can use it earlier in someone who's older and unfit to receive salvage chemotherapy. But even for younger patients, we're seeing excellent outcomes comparable to more intensive chemotherapy when it is used early, if not better, and better safety profiles. So, I imagine it will be used more frequently earlier in relapsed or refractory disease in patients with KMT2A-rearranged leukemias.

Oncology Data Advisor: It's very exciting. Is there anything else that clinicians or audience should know about revumenib or this research?

Dr. Aldoss: So, revumenib is also active for other leukemias with genetics that depends on the KMT2A-menin interaction. One of the common ones is the NPM1-mutated AML. So, there is still an ongoing cohort on the AUGMENT-101 study. They're testing single-agent revumenib in these patients, and it's a more common disease, almost 30% of all AML, the NPM1-mutated AML. Hopefully as the results become available, it will broaden the indication of revumenib for these patients.

Oncology Data Advisor: Great. Thank you so much for stopping by to talk about this research today. It was wonderful to hear about the trial.

Dr. Aldoss: Thank you.

About Dr. Aldoss

Ibrahim Aldoss, MD, is an Associate Professor in the Department of Hematology and Hematopoietic Cell Transplantation at City of Hope. As well, he is an active member at the Gehr Family Center for Leukemia Research. Dr. Aldoss' research interest surround acute lymphoblastic leukemias and acute myeloid leukemias, in which he is an active participant of clinical trials and studies.

For More Information

Aldoss I, Issa G, Thirman M, et al (2023). Revumenib monotherapy in patients with relapsed/refractory KMT2Ar acute leukemia: topline efficacy and safety results from the pivotal Augment-101 phase 2 study. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract LBA-5. Available at:

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor. 

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