ON THE PROGNOSTIC VALUE OF SYSTEMIC METHOTREXATE CLEARANCE IN CHILDHOOD ACUTE LYMPHOCYTIC-LEUKEMIA

The prognostic value of systemic methotrexate clearance (Cl-MTX) durin g high-dose therapy was evaluated in a cohort of 42 children with acut e lymphocytic leukemia (ALL). As part of an extensive chemotherapy pro tocol, they had received a total of 293 methotrexate (MTX) infusions i n the 6-8 g/m(2) dose range. At the termination of the study, when the y had all been followed up for 3.5 years or more, 26 of these patients were still in continuous complete remission, whereas 16 had suffered relapse. The intrapatient variability in Cl-MTX during the eight cours es was up to six-fold. In 67% of the patients, the maximum level of Cl -MTX reached at least twice the minimum value. The coefficients of var iation for the intra- and interindividual variability in Cl-MTX were 9 -57% and 26-41%, respectively. The cumulative probability of relapse, estimated by the Kaplan-Meier procedure, was increased for patients wi th a high Cl-MTX during the initial treatment course, but the differen ce was not significant on a 5% level. There was no significant relatio nship between high individual median Cl-MTX and subsequent relapse of ALL. However, Cl-MTX during the initial infusion, the time-dependent m ean for Cl-MTX and the individual patient's median Cl-MTX were signifi cant predictors for event-free survival in a Cox proportional hazards regression analysis. The present study demonstrates gross pharmacokine tic variability and unpredictable values of Cl-MTX in subsequent cours es after standardized administration of MTX to paediatric patients wit h ALL. In spite of the association between Cl-MTX and prognosis shown by some of the analyses, estimates of Cl-MTX rates may not necessarily be related to disease outcome in a way that can be exploited to the b enefit of the individual patient. (C) 1997 Elsevier Science Ltd.