CHANGES IN RED-BLOOD-CELL METHOTREXATE PHARMACOLOGY AND THEIR IMPACT ON OUTCOME WHEN CYTARABINE IS INFUSED WITH METHOTREXATE IN THE TREATMENT OF ACUTE LYMPHOCYTIC-LEUKEMIA IN CHILDREN - A PEDIATRIC-ONCOLOGY-GROUP STUDY

Since it is unclear whether methotrexate and cytarabine are synergisti c or antagonistic in the treatment of acute lymphoblastic leukemia, th e Pediatric Oncology Group studied the prognostic significance of a po tential interaction between these agents. RBC methotrexate concentrati ons were compared from 140 patients at lower risk of relapse randomize d to two treatment groups: one receiving six methotrexate infusions wi th overlapping cytarabine; the other, six methotrexate infusions alone , Samples from 248 patients from all risk groups were studied to deter mine whether patients with extremely low RBC methotrexate concentratio ns had infection outcomes. Among low-risk patients studied 3 weeks aft er the sixth infusion, median RBC methotrexate concentrations were 0.1 3 nmol/ml RBCs (n = 71) for the methotrexate-only group and 0.02 nmol/ ml RBCs (n = 69) for the methotrexate/cytarabine-treated low-risk pati ents, P < 0.001 by the two-sided Wilcoxon test, For low- and high-risk patients receiving methotrexate/cytarabine infusions, event-free surv ival at 1 and 3 Sears after RBC sampling was 97 +/- 2% and 90 +/- 3% f or patients with concentrations greater than the median, and 88 +/- 3% and 78 +/- 4% for those with concentrations at or below the median, L og rank comparisons of event-free survival in the first year and overa ll yielded P = 0.005 and P = 0.04, respectively. Cytarabine altered me thotrexate pharmacology when the drugs were infused together, Patients whose levels were extremely low had an adverse prognosis, Although th is study could not assess efficacy of the methotrexate/cytarabine comb ination, it appears that concurrent administration is not optimal.