ASH 2025 | HMA with venetoclax versus HMA alone in the frontline management of HR-MDS: a real-world analysis

This was an abstract that we had as an oral presentation at the ASH 2025 annual meeting. So the background about this study is currently we know that hypermethylating agent monotherapy has remained as a standard of care for patients with higher risk MDS. Even though they have been long available, the response rates with these agents are low and the long-term outcomes are poor, and there is a high area of unmet need for getting newer drugs for high-risk myelodysplastic syndrome. BCL-2 is an anti-apoptotic protein that we know that’s overexpressed in myeloid cells, and preclinical studies have also shown that there is a synergistic effect by combining azacitidine along with BCL-2 inhibitors such as venetoclax that would really lead to a synergistic effect. In fact, there were a lot of phase one clinical trials, at least a few of them that are already presented, where the combination of hypomethylating agent with venetoclax had shown encouraging efficacy, primarily leading to high response rates and higher ability to bridge patients to allogeneic stem cell transplant. And this was basically followed by adoption of this regimen in clinical practice at several centers while awaiting the results of the phase three clinical trial. 

So what we aim to do here is actually analyze the real world outcomes of hypomethylating agent venetoclax therapy in the frontline management of higher-risk MDS patients and compare that with a contemporary cohort of patients who received HMA monotherapy around the same time. So this was a retrospective analysis. We collected data from 19 academic U.S. medical centers. We included patients who were treated at those centers who were adults with treatment-naive myelodysplastic syndrome, intermediate, high or very high risk by IPSS-R scoring, who received either frontline management with hypomethylating agent and venetoclax or hypomethylating agent monotherapy between the period of 2015 to 2024. Our cohort included a large population of patients, 1,198 patients. 313 of them received upfront HMA venetoclax combination therapy, and 885 patients received HMA monotherapy during that time period. 

We did multiple different analyses comparing the outcomes between these two treatment groups, and what we found was the treatment was generally well tolerated, with an overall lower incidence of some of the expected side effects of BCL-2 inhibition, such as tumor lysis syndrome, and relatively similar incidences when compared to neutropenic fever and risk of clinically significant bleeding. The most important part we wanted to highlight is actually how the outcomes of the treatment were. Therapy with hypomethylating agent and venetoclax actually led to significantly improved response rate, event-free survival, and overall survival in our analysis as compared to patients who just received HMA monotherapy. And when we try to investigate more deeply into who are all the patient populations who benefit from a combination of venetoclax with hypomethylating agent, the most pronounced benefit was seen in patients who had de novo MDS, those who did not have a TP53 mutation, patients who had a baseline bone marrow blast between 10% to 19%, and who were subsequently bridged to an allogeneic stem cell transplant. 

So what we found was, while these treatments have been used in real-world practice, it is usually manageable in terms of how these agents are given and monitored. And most importantly, our study also highlights the specific patient subgroups who may particularly benefit by adding a BCL-2 inhibitor to a hypomethylating agent backbone. Again, there are hopefully other studies that will be looking into this approach, and we are also looking into some of the publications that would come up from the Phase III randomized clinical trial, the results of some of which were also presented at the ASH annual meeting. We were very excited to conduct the study and we are looking forward to having more analysis come out in the future as well.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.