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Blood, Vol. 93 No. 9 (May 1), 1999:
pp. 2817-2823
Prognostic Importance of 6-Mercaptopurine Dose Intensity in Acute
Lymphoblastic Leukemia
Mary V. Relling,
Michael L. Hancock,
James M. Boyett,
Ching-Hon Pui, and
William E. Evans
From the Departments of Pharmaceutical Sciences, Hematology/Oncology,
and Biostatistics and Epidemiology, St Jude Children's Research
Hospital, Memphis; and the Colleges of Medicine and Pharmacy, The
University of Tennessee, Memphis.
6-Mercaptopurine (6MP) and methotrexate are the
backbone of continuation therapy for childhood acute lymphoblastic
leukemia (ALL). In studies of oral 6MP and methotrexate, indices of
chronic systemic exposure to active metabolites of these agents,
namely, red blood cell (RBC) concentrations of methotrexate
polyglutamates (MTXPGs) and thioguanine nucleotides (TGNs) have
positively correlated with event-free survival (EFS). Our objective was
to evaluate whether MTXPGs, TGNs, and the dose intensity of
administered methotrexate and 6MP were prognostic in the setting of a
treatment protocol in which all treatment was coordinated through a
single center, and the weekly doses of methotrexate were given
parenterally. On protocol Total XII, 182 children achieved remission
and received weekly methotrexate 40 mg/m2 parenterally and
daily oral 6MP, interrupted every 6 weeks during the first year by
pulse chemotherapy. A total of 709 TGN, 418 MTX-PG, and 267 thiopurine
methyltransferase (TPMT) measurements, along with complete dose
intensity information (dose received divided by protocol dose per week)
for 19,046 weeks of 6MP and methotrexate, were analyzed. In univariate
analyses, only higher dose intensity of 6MP and of weekly methotrexate
were significant predictors of overall EFS (P = .006 and
.039, respectively). The occurrence of neutropenia was associated with
worse outcome (P = .040). In a multivariate analysis, only
higher dose intensity of 6MP (P = .020) was a significant
predictor of EFS, with lower TPMT activity (P = .096) tending
to associate with better outcome. 6MP dose intensity was also
associated (P = .007) with EFS among patients with homozygous
wild-type TPMT phenotype. Lower 6MP dose intensity was primarily due to
missed weeks of therapy and not to reductions in daily dose. We
conclude that increased dose-intensity of oral 6MP is an important
determinant of EFS in ALL, particularly among those children with a
homozygous wild-type TPMT phenotype. However, increasing intensity of
therapy such that neutropenia precludes chemotherapy administration may
be counterproductive.
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