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ASH 2025 | A Phase II trial of busulfan, fludarabine, cladribine, thiotepa, and venetoclax conditioning for AML
Uday Popat, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, discusses findings from a Phase II trial (NCT04708054) of myeloablative fractionated busulfan, fludarabine, cladribine, thiotepa, and venetoclax conditioning for high-risk acute myeloid leukemia (AML). Prof. Popat highlights that the regimen demonstrated a three-year progression-free survival of 58% and a relapse rate of 24%, with particularly encouraging results in TP53-negative patients. This interview took place at the 67th ASH Annual Meeting and Exposition, held in Orlando, FL.
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Transcript
This is the conditioning regimen pre-transplant that is more than a decade in the making. So the idea here simply was to design a myeloablative conditioning regimen and to it add all the agents that are active in AML and to see if we could reduce the relapse rate. So the trick here was to do it safely. So the first thing we did was instead of giving it over a four-day period, we gave it over a three-week period...
This is the conditioning regimen pre-transplant that is more than a decade in the making. So the idea here simply was to design a myeloablative conditioning regimen and to it add all the agents that are active in AML and to see if we could reduce the relapse rate. So the trick here was to do it safely. So the first thing we did was instead of giving it over a four-day period, we gave it over a three-week period. So we start on day minus 20, give a dose of busulfan, and continue venetoclax along with it, and then come in later with cladribine, fludarabine, thiotepa, and the rest of the busulfan. So what we found is that if you do it this way, you can give a very aggressive regimen very safely. So our idea here was, in this particular trial, was to test it in the patients who are at the highest risk of relapse. So patients were eligible if they had relapsed or refractory disease. And if they were in remission, they had to be having MRD positive or ELN adverse risk AML. And we allowed for any donor, including haploidentical and mismatched unrelated donor, and about a quarter of the patients had those. Our age limit was up to 70 years of age, and the median age was 75. Because this was a high-risk population, we had almost a quarter of the patients with TP53 mutation. 75% of the patients were MRD positive. And a third of the patients had active leukemia. And two-thirds of the patients had ELN adverse risk disease. Next, what we observed was the primary endpoint here was progression-free survival at one year. And our goal was to beat the historic progression-free survival of 30% in this population of patients. And what we found was three-year progression-free survival was 58% with a relapse rate of 24% and non-relapse mortality of 15%. So we were very encouraged. The study met its primary endpoint. And we now have a regimen, which is myeloablative, which combines all the agents that are active in AML, and we are now going to carry it through to a Phase III study. What was very exciting about this was in TP53 negative patients, despite the high-risk disease, three-year survival was 74% with the relapse rate of just 13%. So we are very excited and we’ll see what we see in the Phase III study.
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