Clinical pharmacodynamic studies of high-dose methotrexate in acute lymphocytic leukemia.
As the intensity of cancer chemotherapy has been reported to influence clinical response for several drug-sensitive cancers, we have investigated the relation between systemic exposure to high-dose methotrexate (HDMTX) and clinical response in childhood acute lymphocytic leukemia (ALL). A total of 108 consecutive, previously untreated children with "standard-intermediate risk" ALL were randomized to receive postinduction therapy with HDMTX (1000 mg/m2 iv over 24 hours weekly for 3 weeks, then every 6 weeks for 72 weeks), superimposed on conventional therapy with low-dose 6-mercaptopurine (6MP; 50 mg/m2 orally per day) and methotrexate (MTX; 25 mg/m2 orally per week). The systemic clearance of HDMTX ranged from 40 to 131 ml/minute/m2 among these patients, yielding MTX steady-state plasma concentrations (Cpss) ranging from 9.3 to 25.4 microM during the infusion. The group of patients (n = 59) with median MTX Cpss less than 16 microM during the HDMTX infusion had a higher probability of having any relapse than patients (n = 49) with MTX Cpss greater than 16 microM (P less than 0.05). In a previously reported univariate analysis, patients with MTX Cpss less than or equal to 16 microM were 3.2 times more likely to relapse on therapy (P = 0.01) and 6.9 times more likely to have a hematologic relapse on therapy (P = 0.001). Multivariate and stepwise Cox's regression analyses indicated that MTX Cpss retains its prognostic importance even when other prognostic variables (i.e., DNA Index, WBC, hemoglobin) are considered.(ABSTRACT TRUNCATED AT 250 WORDS)
D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D006801:Humans; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics
D008727:Methotrexate