Marked Increase in Veno-Occlusive Disease of the Liver Associated With Methotrexate Use for Graft-Versus-Host Disease Prophylaxis in Patients Receiving Busulfan/Cyclophosphamide

• Published in: Blood 1992-05, Vol.79 (10), p.2784-2788
• Main Authors: Essell, James H., Thompson, James M., Harman, Glenn S., Halvorson, Ronald D., Snyder, Michael J., Johnson, Robert A., Rubinsak, James R.
• Format: Article
• Language: English
• Subjects: Actuarial Analysis; Adult; Biological and medical sciences; Bone Marrow Transplantation - immunology; Bone Marrow Transplantation - methods; Busulfan - adverse effects; Busulfan - therapeutic use; Cyclophosphamide - therapeutic use; Drug toxicity and drugs side effects treatment; Female; Follow-Up Studies; Graft vs Host Disease - prevention & control; Hepatic Veno-Occlusive Disease - chemically induced; Humans; Leukemia - surgery; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - surgery; Leukemia, Myeloid, Acute - surgery; Male; Medical sciences; Methotrexate - adverse effects; Methotrexate - therapeutic use; Methylprednisolone - adverse effects; Methylprednisolone - therapeutic use; Pharmacology. Drug treatments; Precursor Cell Lymphoblastic Leukemia-Lymphoma - surgery; Time Factors; Toxicity: digestive system; Whole-Body Irradiation
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V79.10.2784.2784

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.