H. Seidel et al., ON THE PROGNOSTIC VALUE OF SYSTEMIC METHOTREXATE CLEARANCE IN CHILDHOOD ACUTE LYMPHOCYTIC-LEUKEMIA, Leukemia research, 21(5), 1997, pp. 429-434
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.