title: Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality.
abstract: Hepatic venoocclusive disease (HVOD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is a well-recognized dose-limiting toxicity of oral busulfan (Bu)-based preparative regimens. The unpredictable absorption of oral Bu from the gastrointestinal (GI) tract and hepatic first-pass effects have led to the development of an intravenous Bu preparation (i.v. Bu). The purpose of this retrospective comparison was to evaluate the incidence rate of HVOD and the 100-day mortality rate in patients treated with a busulfan/cyclophosphamide (BuCy2) regimen in which either oral Bu or i.v. Bu was administered. Data from 2 similar groups of patients treated between March 1995 and December 1997 were analyzed. Thirty patients were treated with oral Bu (1 mg/kg x 16 doses) at City of Hope and 61 patients were treated with i.v. Bu (0.8 mg/kg x 16 doses) in a multicenter trial involving 7 sites. Bu was followed by Cy (60 mg/kg x 2 days) and a histocompatible-sibling-donor HSCT. In the i.v. Bu treatment group, 48% of the patients were classified as heavily pretreated (> or = 3 prior chemotherapy regimens, prior radiation, or prior HSCT) with 13% having had a prior HSCT and 75% having active disease at the time of transplantation. According to the same classification criteria, 33% of the patients in the oral-Bu treatment group were considered heavily pretreated, with 23% having had a prior HSCT and 80% having active disease at the time of transplantation. The incidence rates of clinically diagnosed HVOD were 5/61 (8%) and 10/30 (33%) after i.v. and oral Bu, respectively. HVOD-related mortality occurred in 2 (3.3%) of 61 i.v. and 6 (20%) of 30 oral Bu patients. The (standardized) Jones criteria for HVOD were met by 4.9% of i.v. and 20% of oral Bu patients. Univariate logistic regression analysis identified oral versus i.v. Bu (P = .001) and a diagnosis of myelodysplastic syndrome (P = .04) as statistically significant factors in the development of HVOD, with prior extensive treatment identified as marginally significant (P = .25). No other demographic parameter was found to be significant. After adjustment for prior treatment, multivariate analyses showed that the use of oral versus i.v. Bu was the strongest predictor for development of HVOD (odds ratio, 7.5; 95% confidence interval, 2.1-27.2; P = .002). This study showed that the incidence rate of HVOD is significantly lower (P = .002) and the 100-day survival rate significantly higher (P = .002) in patients treated with i.v. Bu than in patients treated with oral Bu when Bu is used as part of a BuCy2 preparative regimen for allogeneic HSCT.
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, California 91010, USA. Ashwin_2_Kashyap@GSK.com
authors.forename: Ashwin
authors.initials: A
authors.lastname: Kashyap
authors.forename: John
authors.initials: J
authors.lastname: Wingard
authors.forename: Pablo
authors.initials: P
authors.lastname: Cagnoni
authors.forename: Jones
authors.initials: J
authors.lastname: Roy
authors.forename: Stephan
authors.initials: S
authors.lastname: Tarantolo
authors.forename: Wendy
authors.initials: W
authors.lastname: Hu
authors.forename: Karl
authors.initials: K
authors.lastname: Blume
authors.forename: Joyce
authors.initials: J
authors.lastname: Niland
authors.forename: Joycelynne M
authors.initials: JM
authors.lastname: Palmer
authors.forename: William
authors.initials: W
authors.lastname: Vaughan
authors.forename: Hugo
authors.initials: H
authors.lastname: Fernandez
authors.forename: Richard
authors.initials: R
authors.lastname: Champlin
authors.forename: Stephen
authors.initials: S
authors.lastname: Forman
authors.forename: Borje S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002066:Busulfan / Q000008:administration & dosage* / Q000633:toxicity*; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D019337:Hematologic Neoplasms / Q000150:complications / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods* / Q000401:mortality; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control; D006801:Humans; D015994:Incidence; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods; D014184:Transplantation, Homologous
chemical_list: D003520:Cyclophosphamide; D002066:Busulfan