title: Marked increase in veno-occlusive disease of the liver associated with methotrexate use for graft-versus-host disease prophylaxis in patients receiving busulfan/cyclophosphamide.
abstract: The use of cyclosporine-A/methotrexate (CyA/MTX) for graft-versus-host disease (GVHD) prophylaxis is safe and effective for patients undergoing allogeneic bone marrow transplantation after preparation with cyclophosphamide and total body irradiation. We report 87 patients prepared for allogeneic transplant with busulfan 4 mg/kg/d orally for 4 days, followed by cyclophosphamide 60 mg/kg/d intravenously for 2 days (Bu4Cy2). A marked increase in hepatotoxicity was observed in 20 patients administered CyA/MTX, compared with 67 historical control patients who received CyA/methylprednisolone (CyA/MP) for GVHD prophylaxis with all other treatment and support variables remaining constant. The incidence of hyperbilirubinemia (bilirubin greater than or equal to 2 mg/dL) increased from 48% to 80% (P = .02), and the mean maximal bilirubin increased from 4.67 +/- 7.27 to 8.72 +/- 8.73 mg/dL (P = .04), when CyA/MTX was used in place of CyA/MP for GVHD prophylaxis. In addition, the incidence of veno-occlusive disease (VOD) increased from 18% to 70% (P = .0001), and death caused by VOD increased from 4.5% to 25% (P = .02). Survival was not significantly different for the two groups because of a higher non-VOD death rate in patients receiving CyA/MP for GVHD prophylaxis (P = .77). We suggest caution when using Bu4Cy2 in combination with CyA/MTX for GVHD prophylaxis.
authors.affiliation: Department of Hematology/Medical Oncology, Wilford Hall USAF Medical Center, Lackland AFB, TX 78236-5300.
authors.forename: J H
authors.initials: JH
authors.lastname: Essell
authors.forename: J M
authors.initials: JM
authors.lastname: Thompson
authors.forename: G S
authors.initials: GS
authors.lastname: Harman
authors.forename: R D
authors.initials: RD
authors.lastname: Halvorson
authors.forename: M J
authors.initials: MJ
authors.lastname: Snyder
authors.forename: R A
authors.initials: RA
authors.lastname: Johnson
authors.forename: J R
authors.initials: JR
authors.lastname: Rubinsak
mesh_terms: D000206:Actuarial Analysis; D000328:Adult; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods; D002066:Busulfan / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000517:prevention & control*; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced*; D006801:Humans; D007938:Leukemia / Q000601:surgery*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000601:surgery; D015470:Leukemia, Myeloid, Acute / Q000601:surgery; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use*; D008775:Methylprednisolone / Q000009:adverse effects / Q000627:therapeutic use*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000601:surgery; D013997:Time Factors; D014916:Whole-Body Irradiation
chemical_list: D003520:Cyclophosphamide; D002066:Busulfan; D008775:Methylprednisolone; D008727:Methotrexate