A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acutelymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial

A prospective, randomized multicenter study was performed to evaluate the r elative efficacy of two different concepts for early intensive therapy in a randomized trial of children with B-precursor acute lymphoblastic leukemia (ALL) at high risk (HR) for relapse. Four hundred and ninety eligible chil dren with HR-ALL were randomized on the Pediatric Oncology Group (POG) 9006 phase III trial between 7 January 1991 and 12 January 1994. After predniso ne (PDN), vincristine (VCR), asparaginase (ASP) and daunorubicin (DNR) indu ction, 470 patients received either 12 intensive parenteral treatments of i ntermediate dose (1 g/m(2) each) methotrexate (MTX) and mercaptopurine (NIP ) over 24 weeks (regimen A) or 12 intensive course of alternating myelosupp ressive drug combinations given over 30 weeks (regimen B). These drug combi nations included MTX/MP, teniposide (VM-26)/cytosine arabinoside (AC) and V CR/PDN/DNR/AC/ASP. Central nervous system (CNS) prophylaxis was age-adjuste d triple intrathecal chemotherapy. Patients with CNS disease at diagnosis w ere treated with craniospinal irradiation after the intensive phase. Contin uation was standard doses of MTX and NIP for 2 years. This trial was closed early because of an apparent early difference favoring regimen B. Results show that 470 patients achieved remission (97%). Two hundred and thirty two were randomized to regimen A and 238 to regimen B. The estimated 4-year ev ent-free survival (EFS) for patients treated with regimen A is 61.6 % (s.e. = 3.3%) and with regimen B is 69.4% (s.e; = 3.1%), P = 0.091. Toxicities w ere more frequent on regimen B. In conclusion, for children with B-precurso r ALL at high risk to relapse, early intensification with myelosuppressive combination chemotherapy was more toxic but produced no significant differe nce in EFS when compared to those treated with parenteral methotrexate and mercaptopurine.