A Report of the Event Free Survival (EFS) for Children with Newly Diagnosed Standard Risk Acute Lymphoblastic Leukemia (ALL) Treated on Pediatric Oncology Group (POG) Protocol 9605.

POG 9605 opened in 1996, as a randomized 2x2 factorial design for children with standard risk ALL to determine: 1) whether the addition of 6 months of delayed intensification with divided dose oral methotrexate (ddMTX) improves the event free survival (EFS) and 2) the effect on EFS of delivering oral 6-mercaptopurine (MP) on a divided (twice daily) vs. once daily schedule, during delayed intensification and continuation. A total of 1063 eligible patients were randomized to the post induction therapy. Following remission induction, consolidation was defined as weeks (wk) 5–24 from diagnosis, and all patient received MTX 1 g/m² IV over 24 hours q3 wks x 6 courses, with leucovorin rescue 10 mg/m² p.o./IV q6h for 5 doses beginning 42 hours after the start of MTX infusion, oral MP 50 mg/m²/day, prednisone/vincristine (VCR) pulses, (prednisone 40 mg/m²/day x 7 days, with VCR 1.5mg/m²/dose (max 2 mg) IV days 1 and 8, on wks 8.17 and 25. Late intensification was defined as wks 25–52. Patients were randomized to the following regimens: 1) MTX 20 mg/m² IM q wk, MP 75 mg/m² p.o. qhs, 2)ddMTX 25 mg/m² p.o. q6h x 4 doses q2wks, leucovorin 5 mg/m² p.o. q12h x 2 doses, (beginning 48 h after the start of ddMTX), MP 75 mg/m² po qhs, 3)MTX 20 mg/m² IM q wk, MP 37.5mg/m² p.o. BID 4)ddMTX (as in regimen 2) MP 37.5 mg/m² p.o. BID. All regimens received prednisone/VCR pulses wks 25, 41, 57, 73 89 and 105. Continuation therapy was defined as wks 53 to 130. All patients received MTX 20mg/m² IM weekly. Reg 1&2: MP 75 mg/m² qhs; Reg 3&4: MP 37.5 mg/m²/dose BID. CNS prophylaxis was age adjusted, initially with triple intrathecal chemotherapy (TIT), amended in 1999 to deliver IT MTX alone, and leucovorin rescue was subsequently added because of projected excessive neurotoxicity. The overall EFS for this study is 77%±1.6 %(s.e.) at 6 years. This study had a 2x2 factorial design to answer the two questions related to MTX and MP delivery, respectively. However, the results showed statistically significant interaction between the MTX and MP questions (P=0.0081). There were significant differences in EFS between the four arms (stdMTX-stdMP 70.7%±3.6%, ddMTX-stdMP 82.7%±2.9%, stdMTX-ddMP 80.7%±3.2%, ddMTX-ddMP 76.4%±3.2%), P=0.0141. Although ddMTX-stdMP and stdMTX-ddMP had significantly better EFS compared to the stdMTX-stdMP arm (P=0.005 and P=0.01, respectively), this was not designed as a four arm study and has insufficient power to determine which arm was superior.