At the 2023 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois, Uday Popat, MD, University of Texas MD Anderson Cancer Center, Houston, Texas, presented data from a randomized clinical trial that indicated the fractionation of busulfan reduced toxicities and may lower the non-relapse mortality among patients with acute myeloid leukemia (AML)  and myelodysplastic syndromes (MDS), without increasing relapse rate. 

Transcript: 

Hi, my name is Uday Popat and I'm a professor in [the] department of stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center in Houston. I'm here at [the] [American Society of Clinical Oncology] (ASCO) meeting presenting my data on a fractionated busulfan regimen, which is intended to reduce toxicity [and] improve [the] safety and efficacy of a bone marrow transplant preparatory regimen. 

This regimen is based on a very simple premise: if you give chemotherapy over a longer period, you reduce the toxicity. Traditionally, the conditioning regimen before allogeneic transplant is given over a 4-day period and results in significant morbidity and mortality. We were wondering how to reduce the toxicity, and therefore morbidity and mortality. Over the last 10 years or so, we have developed a longer fractionated regimen. 

Essentially, what we do is take a third of the busulfan dose and give it 1 or 2 weeks earlier, prior to the regular block of chemotherapy. The conditioning regimen now spans a 3-week period. What we see here is [a] reduction in toxicity. At this meeting, we are presenting a randomized trial, which confirms the proof of the principle that by extending the duration and the length of chemotherapy, you can reduce toxicity. This is a randomized trial comparing 2 schedules of chemotherapy over a 2-week period versus a 3-week period. The chemotherapy here is fludarabine, cladribine, and busulfan. 

We are comparing the chemotherapy regimen that is given over a 2-week period. That means a third of the busulfan dose is given on days minus-13 and minus-12 before [the] transplant, day 0 being the day the cells are infused. We just moved in the experimental alarm, 1 dose of chemotherapy, from day minus-12 to day minus-20. Essentially, this is comparing 2 schedules. Everything else is similar in these 2 cohorts of patients, just 1 dose of busulfan was moved 1 week earlier. What we find is [that] we significantly reduce toxicity. 

We enroll[ed] 59 patients in 1 arm and 57 patients in the longer arm. Patients had AML or MDS. Just by moving 1 dose of chemotherapy 1 week earlier, we significantly reduced toxicity from 93% to 73%, or [a] 20% reduction. This was mainly as a result of reduction in all toxicities, but mainly mucositis, which went down from 34% to 11%.

This translated into [an] improvement in non-relapse mortality. Non-relapse mortality went down from 19% in [the] shorter arm to 7% in the longer arm. By reducing the toxicity and improving safety, we were able to give this regimen to older and unfit patients. Half of the patients in this cohort were older than 60. What we also were able to do [was] add 2 additional drugs to the standard fludarabine and busulfan. We were able to add cladribine and venetoclax in a group of patients and in a multivariate analysis, [and] this translated into a beneficial effect in progression-free survival. 

We are carrying out this for the studies and our intention is to take this to a randomized trial and compare this 3-week regimen to the standard fludarabine and busulfan regimen. Thank you.

Source: 

Popat, U, Lontos K, Bassett R, et al. Myeloablative fractionated busulfan-based conditioning regimen in patients with AML and MDS: Results of a randomized clinical trial comparing 2 fractionation schedules. Presented at the ASCO Annual Meeting; June 2-6, 2023; Chicago, Illinois. Abstract 7051