EHA 2025 | Efficacy and safety of combining venetoclax with cytarabine and actinomycin D in R/R AML

Relapsed/refractory AML patients still remain a very big challenge to salvage them and to bridge them to an allotransplant. So the regimen we are working on in Vilnius is actually based on the three drug combination with venetoclax, actinomycin D and low-dose cytarabine. The main scientific interest in this is that actinomycin D might inhibit the MCL1 protein which is a major resistance mechanism of venetoclax. So this investigational triplet was evaluated prospectively in our single center study in which we have enrolled 107 patients already. The regimen consisted of low-dose cytarabine for 10 days, 20 milligrams per square meter sub-q, actinomycin D, three doses, and venetoclax capped at 600 milligrams of a total of 28 days, but in the majority of cases we do a bone marrow evaluation at day 14 and if the marrow is in aplasia we stop the venetoclax. So the median venetoclax exposure is actually 14 days in this regimen. So those 107 patients had a median age of 64 years old. Their median ECOG evaluation was one. For the majority of patients this was a first salvage regimen but one-third of the patients actually were previously treated with two or even more prior therapy lines. 30% had adverse cytogenetics, 10% had TP53 mutations. What we actually saw that the overall response rate to this regimen was 78%. So that’s cumulative complete remission rates plus morphological leukemia-free state. So the true CR, cumulative CR rate was 62%. Importantly for some patients who had targetable mutations such as FLT3 or IDH1/2 mutations, we did add a fourth drug to the regimen, which was gilteritinib in FLT3-mutated patients and IDH1 or 2 inhibitors such as ivosidenib or enasidenib. With this high overall response rates, we had the possibility to bridge a proportion of patients. So that’s 42% of all patients were allowed to go to an allotransplant in remission. So that is a high bridge to transplant rate. The median overall survival was 14 months and the median relapse-free survival was 10 months. The best outcomes were of course seen in patients who had been bridged to an allotransplant, had NPM1 or IDH1-2 mutations. On the other hand, the multivariable analysis also showed some negative factors impacting overall survival such as PTPN11 mutations, adverse cytogenetics and a poor ECOG status of two. The toxicity was manageable and this was something we had expected in an elderly relapsed/refractory male patient population. So the early mortality rate at day 30 was 6%. So that’s not that high.

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