ASH 2024 | A Phase II trial of venetoclax and cytarabine with or without midostaurin in older patients with AML

I would like to share with you results of our Phase II Intervene study, which is actually an investigator-initiated clinical trial as part of the Australasian Leukemia Lymphoma Collaborative Group. This is a randomized prospective study comparing venetoclax and low-dose cytarabine with or without midostaurin in older patients with newly diagnosed non-adverse cytogenetic risk AML. And the concept of this study is can we deliver a novel triplet venetoclax-based regimen in a safe manner and see efficacious outcomes in these fit older patients with AML. And the reason we chose to add in a FLT3 inhibitor is because we know that FLT3 mutations, especially FLT3 ITD, is a recurrent mechanism of resistance to venetoclax-based therapies. We also see emergence of these mutations at time of relapse. At present, patients getting venetoclax-based therapies, actually like VEN-AZA or VEN-low-dose cytarabine, actually do not benefit from the addition of venetoclax alone. When we designed our regimen, we had a number of key considerations. We are targeting an older patient population, unfit for intensive chemotherapy, so age 60 plus. So it has to be tolerable. It has to not cause excess myelosuppression. and so we chose midostaurin which is a shorter acting FLT3 inhibitor and then we delivered all three drugs as a sequential doublet manner. So what I mean by that is we start off with the venetoclax low-dose cytarabine first and the low-dose cytarabine goes to day 10 and we bring in the midostaurin from day 11 onwards. So that sort of prevents throwing all three drugs at the patient at once and then you have this really nice optimal overlap between venetoclax and the FLT3 inhibitor for about 18 days. We conducted this study across 21 different hospitals in Australia and New Zealand and we enrolled 120 patients. It was randomized in a two-to-one manner so we ended up with 79 in the triplet midostaurin arm and then the control arm which is low-dose cytarabine venetoclax had about 41 patients. It was quite an older cohort as mentioned median age was 74 years. So the key findings in terms of toxicity was it’s really quite well tolerated. The adverse events were quite comparable between both arms though we did see more low-grade gastrointestinal adverse events in the midostaurin arm as expected. The cardiac related toxicity rates were really low and comparable between both arms. We also saw that our regimen was very well tolerated so the median time to next cycle was 35 days and that really didn’t increase over time and really allowed you know patients from regional rural areas of Australia and New Zealand to be able to have this treatment without very very close monitoring of blood counts which can be an issue with the azacitidine venetoclax-based triplet therapies. From an efficacy perspective, in the overall population of non-adverse cytogenetic risk, we actually did not see a significant improvement. So the overall response rate was 72% in the triplet group and then 68% in the doublet group and there were no significant improvement in the overall leukemia-free survival. However, when we zoomed into those with FLT3 ITD mutations, we actually saw a really significant difference in the overall response rate. With overrall response rate in the FLT3 ITD group over 80% and only about 56% in the control group. And that translated into a significant improvement in overall survival as well. So ITD patients had a median survival of 16.6 months versus 8.8 months in the control group. We also saw really deep molecular response. So the measurable residual disease of the FLT3 ITD was actually undetectable in 67% of the triplet group compared to none in the control group. And interestingly at time of relapse about 44% of the triplet group had a FLT3 ITD negative relapse. So overall we thought this this regimen is really tolerated, very deliverable, and really resulted in significant improvement in efficacy in the FLT3 ITD mutant patients. In terms of other molecular subgroups, we’re still looking into it. At the moment, there doesn’t seem to be any clear signal of benefit with the addition of midostaurin, but that’s something that we’ll be working on as we continue to look through the data. Thank you.

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