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J Clin Oncol. 2018 Oct 10;36(29):2926-2934. doi: 10.1200/JCO.2018.77.7250. Epub 2018 Aug 23.

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

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Stuart S. Winter, Children's Minnesota Cancer and Blood Disorders Program, Minneapolis, MN; Kimberly P. Dunsmore, Carilion Clinic, Roanoke, VA; Meenakshi Devidas and Zhiguo Chen, University of Florida, Gainesville, FL; Brent L. Wood, Seattle Children's Hospital, Seattle, WA; Natia Esiashvili, Emory University, Atlanta, GA; Nancy Eisenberg, University of New Mexico Health Sciences Center, Albuquerque, NM; Nikki Briegel, Princess Margaret Hospital for Children, Perth, Western Australia, Australia; Robert J. Hayashi, St Louis Children's Hospital, St Louis, MO; Julie M. Gastier-Foster, Nationwide Children's Hospital; Julie M. Gastier-Foster and Nyla A. Heerema, Ohio State University, Columbus, OH; Andrew J. Carroll, University of Alabama at Birmingham, Birmingham, AL; Barbara L. Asselin, University of Rochester Medical Center and Wilmot Cancer Institute, Rochester; Elizabeth A. Raetz and William L. Carroll, Perlmutter Cancer Center at NYU Langone Health, New York, NY; Paul S. Gaynon, Children's Hospital of Los Angeles, Los Angeles; Mignon L. Loh, University of California, San Francisco, San Francisco, CA; Michael J. Borowitz, Johns Hopkins University, Baltimore, MD; Karen R. Rabin, Baylor College of Medicine, Houston; Naomi J. Winick, University of Texas Southwestern, Dallas, TX; Patrick A. Zweidler-Mckay, ImmunoGen, Waltham, MA; and Stephen P. Hunger, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA.

Erratum in



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.


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.


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.


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.

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