Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes

Targeted busulfan ((BU)-B-T) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (BU)-B-T/CY to CY/(BU)-B-T) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/(BU)-B-T conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. Compared with (BU)-B-T/CY-conditioned patients, CY/TBU-conditioned patients had greater exposure to CY (P < .0001) and less exposure to 4-hydroxycyclophosphamide (P < .0001). Clinical outcomes were compared between cases and controls (n = 271) conditioned with (BU)-B-T/CY for the same indications. In patients with myelofibrosis, CY/(BU)-B-T conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (BU)-B-T/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/(BU)-B-T cohort (2% versus 13%; P = .01). CY/(BU)-B-T conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/(BU)-B-T is superior to (BU)-B-T/CY as conditioning for patients with myelofibrosis. (C) 2013 American Society for Blood and Marrow Transplantation.