Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients

Abstract

Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced intensity transplants can also achieve cure, and result in less treatment related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a Phase I/II trial to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24 hour area under the curve (AUC) of approximately 7095 uMmin which represents a 43% increase over the standard total daily AUC dose of 4800 uMmin given by intermittent schedules. DLTs at doses over 8000 uMmin were identified as a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary or other organ toxicies were seen while efficacy appeared to be improved at higher dose levels. Continuous infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy.

Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee

“…† When the AUC is expressed in micromolar (micromoles/L) units, then the BU molecular weight (246.3 g/mol) must be used to calculate the AUC in mg/L units. BU dosing frequency has ranged from the traditional Q6H to Q24H [62,82] or as a continuous infusion [86]. For the first 20 years, BU was only available as 2-mg tablet that was administered Q6H.…”

Handling Incomplete or Late-Onset Toxicities in Early-Phase Dose-Finding Clinical Trials: Current Practice and Future Prospects

“…Two trials implementing TITE-CCD were identified, and both were in an adult-only population. 11 , 12 One trial was a phase I trial, 12 and the other one was a phase I/II trial. 11 Both trials used TITE-CCD with a run-in period, that is, initial escalation was in cohorts of three patients until at least one patient developed a DLT.…”

Chimerism in Myeloid Malignancies following Stem Cell Transplantation Using FluBu4 with and without Busulfan Pharmacokinetics versus BuCy

“…However that was not feasible because of the lack of the necessary controlled studies and the published literature was too heterogeneous regarding patient population, conditioning regimen, Bu dosing, and Bu PK data [ 10 ]. Several studies provided recommendation of a maximally tolerated daily exposure of Bu of less than 6,000 mMxmin for 4 days [ 13 ], while others evaluated the maximally tolerated systemic exposure of intravenous Bu in combination with fludarabine and they showed that Bu can be safely escalated to an AUC of 7000 mMxmin or more without an appreciable difference in nonrelapse mortality [ 14 , 15 ] although with need of more patients and longer follow-up in those studies. In our patients, the median AUC targeted was 6000 uMolxMin and the median actual target given was 5354 uMolxMin.…”