title: 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.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, WA, USA. arezvani@fhcrc.org
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Rezvani
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.forename: Ami
authors.initials: A
authors.lastname: Batchelder
authors.forename: Aiko
authors.initials: A
authors.lastname: Kida
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.forename: George B
authors.initials: GB
authors.lastname: McDonald
mesh_terms: D000328:Adult; D000368:Aged; D002066:Busulfan / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016022:Case-Control Studies; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006504:Hepatic Veno-Occlusive Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D006801:Humans; D007275:Injections, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009190:Myelodysplastic Syndromes / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D002066:Busulfan