Escalating Dose Intravenous Methotrexate without Leucovorin Rescue during Interim Maintenance Is Superior to Oral Methotrexate for Children with Standard Risk Acute Lymphoblastic Leukemia (SR-ALL): Children’s Oncology Group Study 1991
A substantial number of relapses derive from the NCI standard risk population. CCG-1991 tested two components of the successful COG augmented “BFM” regimen (N Engl J Med1998; 338:1663) in this subset in a 2 × 2 factorial design. Patients received a 3-drug Induction: vincristine (V), pegylated asparaginase, dexamethasone (D), and intrathecal (IT) cytarabine and methotrexate (M). Patients with an unfavorable early marrow response by morphology (> 25% blasts at day 14, or >25% blasts at day 7 and >5% blasts at day 14) were assigned rescue daunorubicin and “augmented BFM” therapy. Other patients, termed rapid early responders (RER), received Consolidation (daily oral mercaptopurine (MP) and weekly IT M) and were randomized to receive either single or double delayed intensification (DI) phases, and D pulses, oral daily MP, weekly M and monthly V (Reg O) or V and intravenous (IV) escalating dose M with no leukovorin every 10 days for two months preceding and following the DI phase (Reg I).
Induction Consolidation Interim Maintenance Delayed Intensification (DI #1) Interim Maintenance Reg O Oral MP/M/D Reg O Oral 6MP/M/D Maintenance DI #2 Maintenance Reg I V/IV M Reg I V/IV M Maintenance DI #2 Maintenance
CCG-1991 enrolled a total of 3026 patients between 6/1/00 and 1/31/05 with 2078 eligible randomized non-T ALL patients. The overall 5-year event free (EFS) and overall survival (OS) for the randomized patients was 90.5% (SE = 1.0 %), and 96.0% (SE = 1.0%). We previously reported the double DI randomization (Blood2006; 108: abstract #146). Events were 71/1042 patients in Regimen I, and 100/1036 patients in Regimen O. For Reg I and Reg O, 5-year EFS was 92.1% and 88.7% (p = 0.02; RHR = 0.69 respectively. Comparison by type of events: isolated and combined marrow relapse (55 and 54), isolated CNS relapse (10 and 25), testes relapse (0 and 5), death in remission (1 and 5), secondary neoplasm (2 and 6), and other (2 and 4). The benefit was shown in both sexes. The overall survival was 96% on either arm. We therefore conclude that Reg I was superior for children with B-precursor SR-ALL with RER. We saw decreases in CNS and testes relapse with no decrease in marrow relapse. At this time, we find no difference in OS between the two arms.
Matloub, Y; Bostrom, BC; Hunger, SP; Angiolillo, AL; Cole, C; Thomson, B; Devidas, M; Heerema, NA; La, MK; Buckley, PJ; Carroll, WL; Winick, N; Sather, H; Nachman, JB; Gaynon, PS
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