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

Abstract

Targeted busulfan ((T)BU) 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 (T)BU/CY to CY/(T)BU) 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/(T)BU 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 (T)BU/CY-conditioned patients, CY/(T)BU-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 (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (T)BU/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/(T)BU cohort (2% versus 13%; P = .01). CY/(T)BU 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/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.

View details for DOI 10.1016/j.bbmt.2013.04.005

View details for Web of Science ID 000321093500008

View details for PubMedID 23583825