ASCO 2025 | A myeloablative fractionated busulfan conditioning regimen with sorafenib for alloSCT in AML

First of all, thank you for inviting me and giving me an opportunity to discuss our results. Let me set the stage for this study. So currently, the treatment or the transplant fails in patients with acute myeloid leukemia because of either patients relapse or they die because of treatment or develop what we call non-relapse mortality. And in typical studies, you know, which involve older patients, we would say that treatment-related mortality is somewhere between 20% and 30%, and relapse rate is above 30%. So essentially, we are curing about 40% to 50% patients, particularly older patients, who get a reduced intensity regimen. 

So our goal in this study, and this follows our previous studies, where what we have been trying to do is to increase the intensity of conditioning. It is very well known that myeloablative conditioning reduces relapse rate. However, the challenge is it also increases the non-relapse mortality. So patients, older patients particularly, who are at higher risk of treatment-related mortality, do get reduced intensity regimen. And what we attempted to do was to reduce the treatment-related mortality and offer myeloablative conditioning. So instead of delivering myeloablative conditioning over a four-day period, which is what typically is done – you give fludarabine and busulfan over a four-day period -we gave it over a three-week period, wherein we gave a dose of busulfan, 80 mg per meter square on day minus 20, and another dose on day minus 13, and the rest of the fludarabine and busulfan on day minus 6 to minus 3. The advantage of this regimen, as we have shown in other studies, it reduces the toxicity of the regimen and reduces the non-relapse mortality. 

So we could get non-relapse mortality down to 10% at one year. We then said, how do you increase the efficacy of this regimen? And therefore, we added a targeted agent like sorafenib, which is a multi-kinase, but one of the effects is against FLT3 kinase. And patients were eligible for this study if they were 18 to 70 years old with a fully matched donor, and they had to have AML. Another important point to note in this study is that these patients were FLT3-ITD positive, about a third of the patient, but the rest of the patients were FLT3-ITD negative. 

And we proceeded with the dose-finding study in the Phase I part of this trial. So we gave sorafenib from day minus 24 to day minus 5 before transplant, day 0 being day of cell infusion. So this coincided with part of our outpatient busulfan regimen and part of our inpatient fludarabine and busulfan regimen. We were hoping to get synergy with this combination. Patients were also eligible to receive post-transplant sorafenib maintenance therapy for up to one year. Now, this regimen, patients were eligible if they were between 18 to 70, and in the Phase I part of the trial, the first three patient got a dose of 200 milligrams per day. We escalated it in a cohorts of three ultimately reaching 800 milligrams per day and the dose limiting toxicity was grade three or higher regimen related toxicity. 

800 milligrams, which was the highest dose, was the safe dose tolerated in the Phase I trial. And therefore, we first enrolled nine patients at three lower doses, and all subsequent 50 patients were enrolled on the Phase II dose of 400 milligrams twice a day. And the primary objective here was to see the progression-free survival of this regimen. And to cut to the chase, the bottom line is at one year, the progression-free survival was 77.8%, and at two years, it was 68%, and the curve flattens thereafter, and it remains 68% at that point. 

What is important to note over here is the risk profile of the patients enrolled in this trial. So the median age was 53. 42 patients, or 70% of the patients, were in CR1, 6 or 10% in CRi, and 11% had more advanced disease. ELN adverse cytogenetics was seen in 57% of the patients. 31 patients or half of the patients were MRD positive, which is quite important. And the donor was sibling in third and matched unrelated in two-thirds of the patients. Our one-year and two-year overall survival was over 75%, and progression-free survival was, as I already mentioned, 68% at three years. The relapse rate at two years was 21%, and non-relapse mortality was 10%. 

So we feel that these are very encouraging results. We did a multivariate analysis, and the only factor predictive of overall and progression-free survival was presence of MRD. So we feel that this approach may improve outcome, as we saw in our Phase II study, in patients with acute myeloid leukemia.

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