Dose intensification of methotrexate and cytarabine during intensified continuation chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: POG 9406: a report from the Children's Oncology Group.

Purpose: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL). Patients and Methods: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2 x 2 factorial design to receive MTX 1 g/m(2) versus 2.5 g/m(2) and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy. Results: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8 +/- 2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7 +/- 2.4% (P = 0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4 +/- 2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1 +/- 2.3%) (P = 0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase. Conclusions: Increasing MTX dosing to 2.5 g/m(2) did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.