Abstract
Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P < 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure). In conclusion: NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.
Highlights
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for malignancies such as leukemia, lymphomas and some solid tumors, as well as non-malignant diseases such as metabolic disorders and aplastic anemia[1]
In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT)
Alkaline phosphatase (ALP) were significantly (P < 0.0001, P = 0.016 and P = 0.0002 respectively, t-test) decreased after conditioning compared to their start values before the initiation of conditioning
Summary
Hematopoietic stem cell transplantation (HSCT) is a curative treatment for malignancies such as leukemia, lymphomas and some solid tumors, as well as non-malignant diseases such as metabolic disorders and aplastic anemia[1]. Busulphan is predominantly metabolized in the liver by conjugation with glutathione (GSH)[4,5,6,7]. GSTA1 is the most active glutathione transferase in catalyzing Bu-GSH conjugation, while GSTM1 and GSTP1 are less active[8,9]. This conjugation results in the formation of sulfonium ion that is an unstable intermediate and is degraded to tetrahydrothiophene (THT). Busulphan was previously reported to cause liver toxicity such as SOS in patients undergoing HSCT10–13. SOS was defined by McDonlad et al as the onset of two of the following occurring before day 30 post-HSCT: (1) jaundice (bilirubin > 27 μmol/L), (2) tender hepatomegaly and (3) ascites or weight gain. Endothelial cell damage due to the toxicity of conditioning regimen may lead to activation of several clotting factors[13,17]
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