Systemic methotrexate exposure is greater after intrathecal than after oral administration.

PURPOSE: To compare systemic exposure after intrathecal and oral methotrexate administration. PATIENTS AND METHODS: We analyzed red cell methotrexate polyglutamate concentrations with a sensitive radioligand-binding assay in 80 patients enrolled in the Children's Cancer Group (CCG) trial 1922 for acute lymphoblastic leukemia. Methotrexate concentrations were measured 7 days after the last doses of intrathecal and oral routes, using patients as their own controls. Intrathecal methotrexate was given on an age-adjusted schedule. Data was normalized to the actual dose received per body surface area. RESULTS: The mean red cell methotrexate concentration 7 days after the last of four weekly intrathecal doses of methotrexate was 178 pmol/mL red blood cells, which was significantly greater than the result 7 days after subsequent weekly oral methotrexate of 122 pmol/mL (P = 0.00001). Intrathecal dosing resulted in an average systemic exposure ratio of 1.7 to 1 compared with oral administration. CONCLUSION: Intrathecal methotrexate administration results in significantly greater systemic exposure than oral administration. Our data support the hypothesis that the systemic effect of intrathecal methotrexate affects ALL therapy.

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.