EHA 2026 | Results of a Phase II study of venetoclax plus mini-hyper-CVD in older adults with Ph-negative ALL

Well, thank you so much for the opportunity to talk about my presentation at EHA 2026, where I, as you are alluding to, am presenting my work, a phase two study of venetoclax plus mini hyper-CVD for older adults with newly diagnosed or de novo Philadelphia-negative ALL. And so as you frame the question, you’re sort of acknowledging the longstanding challenge we’ve had treating older adults with Philadelphia-negative ALL, and that’s because the disease in this patient population typically has been associated with adverse disease biology, so features of disease that make it relatively insensitive to chemotherapy. And additionally, patients in this age group don’t tolerate well the chemotherapies that we’ve traditionally used to treat children and younger adults with ALL. And so we have sort of a two-pronged problem of a difficult disease and an inability of older patients to tolerate the established regimens that were really developed for younger patients. 

And so that was sort of the background for which we designed this study. And the concept here was to take an attenuated chemotherapy, dose-reduced chemotherapy, taking drugs that we use to treat ALL, but decreasing the doses and omitting some chemotherapies that are traditionally toxic, like anthracycline and asparaginase, and using dose-reduced cyclophosphamide, dexamethasone, and vincristine, a relatively less intense regimen that’s tolerable, and adding a drug called venetoclax, which is a BCL2 inhibitor that we know, based on preclinical findings as well as some other clinical trials done by colleagues of mine, that can increase its sensitivity to chemotherapy. And we know that lymphoblasts, or ALL in particular, can be sensitive to this drug. And so that was the concept behind the study. We had previously completed a phase one study in both frontline and relapse patients where we demonstrated safety and some encouraging efficacy in a small population of frontline patients. And so we decided to expand our work and do a phase two study of only newly diagnosed patients, and we treated 50 patients, and that’s what we’re presenting here. 

We enrolled a representative population the high-risk features that we talked about were well-represented, as you can see if you review the primary data, but we included patients who had high-risk genomics, including TP53, Philadelphia chromosome-like, KMT2A rearranged, were all included. And we included some also B and T, including some early T-cell precursor. We also included patients with prior multiple myeloma therapy-related ALL. So we had a diverse group of patients, but well-represented with high-risk features. And we treated these patients. And what we saw was that the regimen, we were encouraged to see that the regimen continues to demonstrate both a relatively favorable safety profile as well as efficacy. 

So in terms of safety, we did not see any tumor lysis syndrome. This is a concern with venetoclax. We did not see any tumor lysis-like syndrome. And we saw low rates of therapy-related mortality and serious morbidity. So we only had one patient that had an early death, which we believe was really related to the aggressive nature of that patient’s leukemia. And then we saw very low rates of deaths in remission during post-treatment phases, including with just five patients or 10%, with only three of those patients related to infectious complications or sepsis. Of course, any toxicity is too much, and so that’s an area that we’ll be continuing to work on, but the rates were low compared to historical controls. And so with that regard, we felt this was a really tolerable regimen. Notably, we did not see any liver toxicity, no VOD, and we did not see any other significant organ toxicities or really difficulty with poor count recovery. 

So we have a favorable toxicity regimen, and then we were encouraged by the efficacy as well. Again, I want to emphasize the really high-risk patient population and the inclusion of both B and T-cell patients, but the majority of patients achieved remission. We saw remission in close to 90% of patients. We saw that those remissions were predominantly MRD negative as measured by flow cytometry, where 85% of those remissions were MRD negative. And a good number of these patients were MRD negative also by NGS, by deep sequencing at deep levels. So we saw these remissions were frequent, and they were deep, and they extended across the range of patients, including we really noticed that one particular high-risk population, TP53 disease, hypodiploid, TP53 ALL, we saw a universal, all 11 of those patients achieve a flow MRD negative remission, which was really remarkable for a particular high-risk subgroup. We’ll also report long-term the durability of responses, which will continue to extend that follow-up for future publications, but two-year overall survival was 70%, and two-year disease-free survival was 60% or two-thirds of patients. 

So overall, we’re really excited to present this work and look forward to presenting details and discussing with my colleagues at EHA. But the conclusions are that this is a venetoclax-based regimens with mini hyper-CVD is effective and tolerable for older adults with Philadelphia-negative ALL. And this benefit extends to groups with high unmet need, including patients with hypodiploid TP53 ALL. And we look forward to further research to understand how to minimize even the relatively low rates of toxicity. We want to get that even lower and how to further extend and enhance the response rates. Again, excellent here, but a further improvement always needed, and we continue our efforts for this patient population.

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