Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group

Abstract

Children's Cancer Group-1991 selected 2 components from the Children's Cancer Group studies shown to be effective in high-risk acute lymphoblastic leukemia and examined them in children with National Cancer Institute standard-risk acute B-precursor lymphoblastic leukemia. These were (1) vincristine and escalating IV methotrexate (MTX) without leucovorin rescue during the interim maintenance (IM) phases and (2) addition of a second delayed intensification (DI) phase. Eligible patients (n = 2078) were randomly assigned to regimens containing either oral (PO) MTX, PO mercaptopurine, dexamethasone, and vincristine or IV MTX during IM phases, and regimens with either single DI or double DI. Five-year event-free survival (EFS) and overall survival for patients on the PO MTX arms were 88.7% ± 1.4% and 96% ± 0.9% versus 92.6% ± 1.2% and 96.5% ± 0.8% for those on the IV MTX arms (P = .009, P = .66). Five-year EFS and overall survival for patients who received single DI were 90.9% ± 1.3% and 97.1% ± 0.8% versus 90.5% ± 1.3% and 95.4% ± 3.8% for those who received double DI (P = .71, P = .12). No advantage was found for a second DI; however, replacement of PO MTX, PO mercaptopurine, vincristine, and dexamethasone during IM with vincristine and escalating IV MTX improved EFS.

Figures

Figure 1

Protocol schema. OS, included regimen of oral (PO) methotrexate (MTX), mercaptopurine, vincristine, and dexamethasone (during the interim maintenance [IM] phases) and single delayed intensification; OD, included regimen of PO MTX, mercaptopurine, vincristine, and dexamethasone (during the IM phases) and double delayed intensification; IS, included regimen of IV MTX and vincristine (during the IM phases) and single delayed intensification; ID, included regimen of IV MTX and vincristine (during the IM phases) and double delayed intensification. *t(4;11)(q21;q23)(q34;q11), t(9;22), balanced t(1;19)(q23;p13), and hypodiploidy with < 45 chromosomes.

Figure 2

Event-free survival (EVS) and overall survival (OS) in randomly assigned patients with B-precursor acute lymphoblastic leukemia.

Figure 3

Event-free survival (EFS) and overall survival (OS) by route of methotrexate (MTX) administration. (A) EFS by route of MTX administration in the interim phases. (B) OS by route of MTX administration in the interim maintenance phases. PO indicates oral.

Figure 4

Event-free survival (EFS) and overall survival by number of delayed intensification (DI) phases. EFS (A) and overall survival (B) by number of DI phases.

Figure 5

Five-year cumulative incidence of isolated relapse by route of methotrexate (MTX) administration during the interim maintenance phases. Five-year cumulative incidence of isolated CNS relapse (A), isolated testicular relapse (B), and isolated non-CNS nontesticular extramedullary relapse (C) by route of MTX administration during the interim maintenance phases. PO indicates oral; RHR, relative hazard ratio.