Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia

Abstract

Summary In a population-based study of 115 children with non-B-cell acute lymphoblastic leukaemia, we analysed the relation of the degree of leukopenia and risk of relapse to the degree of hepatotoxicity (as measured by serum aminotransferase (AT)) during oral methotrexate (MTX) and 6-mercaptopurine (6MP) maintenance chemotherapy (MT). Hepatotoxicity was calculated as a mean of all AT-measurements (mATMT). Lack of hepatotoxicity was defined as a mATMT < 40 IU I -. A highly significant correlation was demonstrated between the mean AT during the first, second, and third year of MT (r > 0.70, P < 0.00001). mATMT was not related to the mean WBC during MT (r = -0.03, P = 0.36), but was related to the rise in WBC following cessation of therapy (r = 0.24, P = 0.06). Patients with recurrent disease had significantly lower mATMT than patients staying in remission (P = 0.03 for both over-all and haematological relapse risk (Figure 1). One hundred and twenty-eight patients completed induction and consolidation therapy. Of these, 13 were excluded from this study due to major protocol violation during induction or consolidation therapy, refusal of MT by parents, AT not measured during MT, or lack of data (3, 1, 7 and 2 patients). Thus, 115 patients (67 boys and 48 girls) were eligible for analyses, with 56 cases of standard risk (SR), 39 cases of daily for 4 days); 6MP = oral 6-mercaptopurine (75 mg m-2 day-'); MTX = oral methotrexate (20 mg m-2 week-'); M = intrathecal methotrexate (12 mg m 2); pred/p = oral prednisone (60 mg m-2 day-'); -= 6-thioguanine (60 mg m 2 day-'); | / M = 500/1,000 mg MTX 24 h infusion with leucovorin rescue; V = vincristine (2 mg m2, max. 2 mg dose-'); XXXX = CNSirradiation (2,400 cGy).

Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia

“…The majority of MTX is bound to albumin in the blood and, when HDM is administered, approximately one-third of MTX is metabolized in the liver. It is well known that MTX/6MP maintenance therapy causes hepatotoxicity 28 and this may in part be because of methylated metabolites of 6MP. 29 It is possible that a reduced degree of hepatotoxicity second to the reduced 6MP doses could have caused an improvement in the hepatic clearance of MTX and explain the moderate decrease in 42 h MTX concentrations observed in the present study.…”

Genetic polymorphisms associated with adverse events and elimination of methotrexate in childhood acute lymphoblastic leukemia and malignant lymphoma

“…ML is also treated by chemotherapy, with a high cure rate (Murphy et al 1989;Anderson et al 1993). Treatment is, however, often limited by severe toxicity, including hepatotoxicity and myeloid suppression (Schmiegelow et al 1989;Schmiegelow and Pulczynska 1990). It is therefore important to predict the occurrence of adverse events.…”

“…High-dose treatment with methotrexate often causes hepatotoxicity and bone marrow suppression, however (Schmiegelow et al 1989;Schmiegelow and Pulczynska 1990), necessitating dose reduction or cessation of treatment, one reason for a relapse of ALL and ML. For appropriate use of methotrexate it would therefore be useful to identify a predictor and/or the mechanism of the adverse effects of methotrexate.…”

Pharmacokinetics of intravenous busulfan and evaluation of the bioavailability of the oral formulation in conditioning for haematopoietic stem cell transplantation

“…9 Hepatotoxicity, as a marker of high exposure to an anticancer drug, may even be associated with a more favourable outcome in some settings. 10 Therefore we do not regard individual dose adjustments justified outside clinical studies. With these low intravenous doses, we were not able to show a marked reduction of interpatient variability of BU-AUCs.…”