Pharmacokinetic Dose Guidance of IV Busulfan with Fludarabine with Allogeneic Stem Cell Transplantation Improves Progression Free Survival in Patients with AML and MDS; Results of a Randomized Phase III Study
Authors: Andersson Borje S , de Lima Marcos J , Saliba Rima M , Shpall Elizabeth J , Popat Uday , Jones Roy , Nieto Yago , Hosing Chitra M , Kebriaei Partow , Alousi Amin M , Worth Laura L. , Madden Timothy , Gulbis Alison , Chen Julianne J , Rondon Gabriela , McAdams Patricia , McMullin Becky , Andreeff Michael , Champlin Richard 
Published: October 2019

Abstract
Abstract 892
The myeloablative, reduced toxicity regimen, IV Busulfan (Bu) and fludarabine (Flu), is effective conditioning for allogeneic stem cell transplantation for treatment of patients with AML and MDS. We performed a prospective randomized study to optimize the antileukemic cytoreduction of this regimen, testing the hypothesis that pharmacokinetically (PK-) guided IV Bu-dosing to an average daily AUC of 6,000 μMol-min yields improved leukemia-free survival compared with a fixed IV Bu dose of 130 mg/m2, which gives a median AUC of approximately 5000 μMol-min. The study was approved by the M.D. Anderson Cancer Center IRB and all patients provided informed consent.
139 patients were in a first or second complete remission (CR), 86 were not in remission, including patients with marrow remission but with incomplete hematologic recovery (CRi) or with active disease. Median age was 50 years (range 13–65). 51% received a transplant from a related donor and 49% had unrelated donors. 28% patients received bone marrow and 72% PBPC grafts. Disease characteristics are summarized in the following table. Median follow-up of surviving patients was 25 months (2–66).
The patients receiving PK guided busulfan dosing had significantly better progression free survival at 3 years than the fixed dose group, 56% (45–66%) vs. 42% (32–52%) P=0.03, as well as lower cumulative incidence of progression 23% (16–34%) vs. 35% (27–46%) p=0.03. Overall survival at 3 years for the two groups was 57% (46–68%) vs 47% (36–57%) p=0.2.
The greatest effect was seen in patients not in remission at the time of transplant. The cumulative incidence of disease progression for the PK Guided and Fixed dose groups was 20% and 25% in patients transplanted in remission (P=0.5), and 29% and 50% for patients transplanted not in remission (P=0.03). Major outcomes are summarized in the following table.
There was no significant difference in toxicity pattern, incidence of acute GVHD or treatment related mortality between the PK-guided/adjusted and fixed- dose groups. In multivariate analysis, poor risk cytogenetics and flt3 mutation was associated with inferior PFS.
In conclusion, administration of higher dose intravenous busulfan using pharmacokinetic dose guidance targeting an AUC of 6000 μMol-min combined with fludarabine improved progression free survival in patients undergoing allogeneic stem cell transplantation for treatment of AML and MDS, without increasing the risks for serious toxicity and treatment-related mortality.

Disclosures:
Andersson: Otsuka: Consultancy, MD Anderson Cancer holds a patent on busulfan. Off Label Use: Busulfan for conditioning for AML. Popat:Otsuka: Research Funding. Jones:Otsuka: Membership on an entity's Board of Directors or advisory committees. Nieto:Otsuka Corp: Research Funding. Kebriaei:Otsuka: Research Funding. Worth:Otsuka Corp: Research Funding. Champlin:Otsuka Corp: Research Funding; NCI CA55164: Research Funding.