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ASH 2025 | The role and future of BCL2 inhibitors in HR-MDS
In this video, Sangeetha Venugopal, MD, MS, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, discusses the current role of BCL2 inhibitors in high-risk myelodysplastic syndromes (HR-MDS). She notes that she believes venetoclax still has a role in some patients, despite the negative results of the Phase III VERONA trial (NCT04401748) and briefly mentions the GLORA-4 trial (NCT06641414), a Phase III study evaluating lisaftoclax plus the hypomethylating agent (HMA) azacitidine for first-line treatment of newly diagnosed HR-MDS. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
So this is a very interesting question because the VERONA trial has been a disappointment for many of us in the myeloid malignancy community, but I do think that it’s not so cut and dry as the trial results and especially because the trial also enrolled patients with less than five percent blasts and especially yesterday when in the MDS meeting and in the MDS oral presentation, we also saw cedazuridine with Decitabine and Venetoclax, which has shown better response rate and more patients going into stem cell transplant...
So this is a very interesting question because the VERONA trial has been a disappointment for many of us in the myeloid malignancy community, but I do think that it’s not so cut and dry as the trial results and especially because the trial also enrolled patients with less than five percent blasts and especially yesterday when in the MDS meeting and in the MDS oral presentation, we also saw cedazuridine with Decitabine and Venetoclax, which has shown better response rate and more patients going into stem cell transplant. And the median blast count in that patient population was 12%. So I do think Venetoclax still has a role to play. The combination still has a role to play in this population. In unfit AML, so Azacitidine has not shown to be specifically sensitive to any mutations. However, Venetoclax has shown to be, at least in the AML population. So it’s across the board. It is in some of the mutations that are quite sensitive to Venetoclax. So, for example, splicing factor mutations or IDH mutations. So these are quite common in high-risk MDS, so I do think that population will benefit by using this HMA with Venetoclax combination.
Now, newer BCL2 inhibitors are also coming up, especially lisaftoclax. And the trial is already up and enrolling, which is a GLORIA4 trial. And the responses are evaluated by IWG 2023 criteria. And they have dual primary endpoints of complete remission rate and overall survival. We are very excited about that study. Hopefully this will be a great option for our patients. So BCL-2 inhibitor is still not out, we just need to tease out which patients benefit with the combination of hypomethylating agent and BCL-2 inhibitor.
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