Hepatic failure after bone marrow transplantation.

The article by Beelen et al’ led us to report a case in which the busulfan plus cyclophosphamide preparative regimen for allogeneic bone marrow transplantation terminated in fatal hepatotoxicity. A 31-year-old man with chronic myelogenous leukemia in first chronic phase was bone marrow transplanted from a one DR mismatched donor. Based on encouraging results obtained by Santos et a12 and Tutschka et al,’ busulfan plus cyclophosphamide regimen was used as conditioning instead of regular cyclophosphamide plus total body irradiation. The protocol was used as described previously.2,’ Cyclosporin-A (with blood level monitorization) and methotrexate were administered for immunosuppression. The patient had an uneventful course during conditioning and infusion of the allogeneic marrow. At day +2 the patient began to experience severe fatigue and right upper abdominal discomfort accompanied by jaundice. Laboratory findings at that time were as follows: total bilirubin, 5 mg/dL; conjugated bilirubin, 2.1 mg/dL; nonconjugated bilirubin, 2.9 mg/dL; alkalen phosphatase, 52 U/L; ALT, 53 U/L; AST, 41 U/L; GGT, 114 U/L; BUN, 24 mg/dL; creatinine, 1.2 mg/dL. He was on ketoconasole prophylaxis 200 mg orally twice per day. All acute viral hepatitis markers, Epstein-Barr virus, cytomegalovirus IgG and IgM antibodies were negative. Methotrexate was discontinued. No evidence of graft-versus-host disease was observed except for high fever with negative cultures. The patient’s bilirubin levels continued to rise with normal levels of ALT and AST, and at day +9 his conjugated bilirubin was as follows: 7 mg/dL; nonconjugated bilirubin: 13.5 mg/dL; ALT, 18 U/L; AST, 26 U/L, alkalen phosphatase, 32 U/L; GGT, 33 U/L; and a steady rise in BUN and creatinine was observed. Cyclosporine was discontinued at day +7 because of the increase in blood levels due to hepatic and renal toxicity. No hepatomegaly was detected. Despite all efforts the patient died at day + 10 with massive bleeding. Antemortem biopsy showed degenerative and regenerative changes and biliary pigment accumulation in hepatocytes. Portal areas had no findings related to leukemia or viral hepatitis. The findings were accepted to be consistent with reactive hepatitis. We conclude that although very satisfying results are obtained by this preparative regimen, such fatal toxicities can be experienced.