title: Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT.
abstract: BU-CY is the established non-TBI-based myeloablative conditioning regimen for allogeneic hematopoietic SCT. However, liver toxicity and hepatic veno-occlusive disease (VOD) are frequent life-threatening complications. Pharmacological considerations suggest that BU can trigger toxicity of subsequent CY. Recent animal data confirmed this hypothesis. Less liver toxicity and better outcomes were observed when mice were treated with the reversed order of CY and BU. We analyzed in this study liver toxicity and outcome in patients receiving BU-CY (16 patients) or CY-BU (59 patients). Liver function differed significantly with higher levels of liver function tests between day +10 and +30, and a higher cumulative incidence of VOD in the BU-CY cohort (2/16 (12.5%) vs 0/59 (0%), P=0.006). TRM was significantly higher in patients receiving BU-CY (cumulative incidence BU-CY 45%, CY-BU 17%, P=0.02), without yet translating into a significant survival difference (incidence for survival: BU-CY 38%, CY-BU 63%; hazard ratio 1.19 for BU-CY, 95% confidence interval 0.29-4.82, P=0.80). Rates of engraftment and relapse were not different. These data support the concepts derived from animal models in favor of CY-BU compared with traditional BU-CY and form the basis for prospective controlled comparisons.
authors.affiliation: Division of Hematology, University Hospital Basel, Basel, Switzerland. ncantoni@uhbs.ch
authors.forename: N
authors.initials: N
authors.lastname: Cantoni
authors.forename: S
authors.initials: S
authors.lastname: Gerull
authors.forename: D
authors.initials: D
authors.lastname: Heim
authors.forename: J
authors.initials: J
authors.lastname: Halter
authors.forename: C
authors.initials: C
authors.lastname: Bucher
authors.forename: A
authors.initials: A
authors.lastname: Buser
authors.forename: D A
authors.initials: DA
authors.lastname: Tsakiris
authors.forename: J
authors.initials: J
authors.lastname: Passweg
authors.forename: A
authors.initials: A
authors.lastname: Tichelli
authors.forename: M
authors.initials: M
authors.lastname: Stern
authors.forename: A
authors.initials: A
authors.lastname: Gratwohl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002066:Busulfan / Q000008:administration & dosage / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D004334:Drug Administration Schedule; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced* / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D019172:Transplantation Conditioning / Q000009:adverse effects* / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan