Improved Survival for Children and Young Adults With T-Lineage Acute Lymphoblastic Leukemia: Results From the Children's Oncology Group AALL0434 Methotrexate Randomization

Abstract

Purpose: Early intensification with methotrexate (MTX) is a key component of acute lymphoblastic leukemia (ALL) therapy. Two different approaches to MTX intensification exist but had not been compared in T-cell ALL (T-ALL): the Children's Oncology Group (COG) escalating dose intravenous MTX without leucovorin rescue plus pegaspargase escalating dose, Capizzi-style, intravenous MTX (C-MTX) regimen and the Berlin-Frankfurt-Muenster (BFM) high-dose intravenous MTX (HDMTX) plus leucovorin rescue regimen.

Patients and methods: COG AALL0434 included a 2 × 2 randomization that compared the COG-augmented BFM (ABFM) regimen with either C-MTX or HDMTX during the 8-week interim maintenance phase. All patients with T-ALL, except for those with low-risk features, received prophylactic (12 Gy) or therapeutic (18 Gy for CNS3) cranial irradiation during either the consolidation (C-MTX; second month of therapy) or delayed intensification (HDMTX; seventh month of therapy) phase.

Results: AALL0434 accrued 1,895 patients from 2007 to 2014. The 5-year event-free survival and overall survival rates for all eligible, evaluable patients with T-ALL were 83.8% (95% CI, 81.2% to 86.4%) and 89.5% (95% CI, 87.4% to 91.7%), respectively. The 1,031 patients with T-ALL but without CNS3 disease or testicular leukemia were randomly assigned to receive ABFM with C-MTX (n = 519) or HDMTX (n = 512). The estimated 5-year disease-free survival ( P = .005) and overall survival ( P = .04) rates were 91.5% (95% CI, 88.1% to 94.8%) and 93.7% (95% CI, 90.8% to 96.6%) for C-MTX and 85.3% (95% CI, 81.0%-89.5%) and 89.4% (95% CI, 85.7%-93.2%) for HDMTX. Patients assigned to C-MTX had 32 relapses, six with CNS involvement, whereas those assigned to HDMTX had 59 relapses, 23 with CNS involvement.

Conclusion: AALL0434 established that ABFM with C-MTX was superior to ABFM plus HDMTX for T-ALL in approximately 90% of patients who received CRT, with later timing for those receiving HDMTX.

Trial registration: ClinicalTrials.gov NCT00408005.

Fig 1.

CONSORT diagram for risk-stratified therapy. (*) Includes IR patients not randomly assigned to receive nelarabine during the safety phase (assigned to arms A and C only). EOI, end of induction; HR, high risk; IR, intermediate risk; LR, low risk; T-ALL, T-cell acute lymphoblastic leukemia; T-LLy, T-cell non-Hodgkin lymphoma.

Fig 2.

Event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) curves overall and by regimen. (A) EFS and OS curves for all patients with T-cell acute lymphoblastic leukemia; 5-year EFS and OS rates were 83.8% (81.2% to 86.4%) and 89.5% (87.4% to 91.7%), respectively. (B) DFS curves for Capizzi-style escalating intravenous methotrexate (C-MTX) versus high-dose methotrexate (HDMTX) randomly assigned cohorts; 5-year DFS rate was 91.5% (88.1% to 94.8%) for C-MTX and 85.3% (81.0% to 89.5%) for HDMTX. (C) OS curves for C-MTX versus HDMTX randomly assigned cohorts; 5-year OS was 93.7% (90.8% to 96.6%) for C-MTX and 89.4% (85.7% to 93.2%) for HDMTX.

Fig 3.

Disease-free survival (DFS) and overall survival (OS) for low-risk (LR), intermediate-risk (IR), and high-risk (HR) groups by regimen. (A) LR T-cell acute lymphoblastic leukemia (T-ALL): 5-year DFS rate was 92.6% (83.3% to 100%) for Capizzi-style escalating intravenous methotrexate (C-MTX) versus 96.2% (88.2% to 100%) for high-dose methotrexate (HDMTX), and the OS rate was 94.4% (86.2% to 100%) for C-MTX versus 98.1% (92.3% to 100%) for HDMTX. (B) IR T-ALL: 5-year DFS rate was 92.5% (88.7% to 96.3%) for C-MTX versus 88.3% (83.7% to 92.9%) for HDMTX, and the OS rate was 94.6% (91.2% to 97.9%) for C-MTX versus 91.3% (87.2% to 95.3%) for HDMTX. (C) HR T-ALL: 5-year DFS rate was 87.4% (78.8% to 96.0%) for C-MTX versus 70.0% (57.9% to 82.0%) for HDMTX, and the OS rate was 90.5% (82.8% to 98.2%) for C-MTX versus 79.1% (68.3% to 89.9%) for HDMTX.

Fig A1.

Randomization and assignment strategies. (*) Participants with CNS3 and testicular disease were nonrandomly assigned to high-dose methotrexate (HDMTX). C-MTX, Capizzi-style escalating intravenous methotrexate; DI, delayed intensification.

Fig A2.

Cumulative incidence rate of relapse by site for Capizzi-style escalating intravenous methotrexate (C-MTX) and high-dose methotrexate (HDMTX) randomly assigned cohorts. (A) Isolated bone marrow relapse. (B) Isolated CNS relapse. (C) Combined bone marrow and CNS relapse.

Fig A3.

Disease-free survival (DFS) and overall survival (OS) by early response status. (A) Rapid early responders: 5-year DFS was 93.3% (89.4% to 97.1%) for Capizzi-style escalating intravenous methotrexate (C-MTX) versus 90.0% (85.1% to 94.6%) for high-dose methotrexate (HDMTX; hazard ratio, 0.722 [0.421 to 1.238]; P = .23), and OS was 94.5% (91.0% to 98.0%) for C-MTX versus 92.1% (87.8% to 96.4%) for HDMTX (hazard ratio, 0.801 [0.429 to 1.493]; P = .48). (B) Slow early responders: 5-year DFS was 88.7% (82.7% to 94.7%) for C-MTX versus 78.1% (70.4% to 85.8%) for HDMTX (hazard ratio, 0.501 [0.305 to 0.824]; P = .001), and OS was 92.4% (87.3% to 97.5%) for C-MTX versus 85.2% (78.6% to 91.8%) with HDMTX (hazard ratio, 0.506 [0.276 to 0.928]; P = .03).