Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

• Published in: Journal of clinical oncology Vol. 38; no. 28; pp. 3282 - 3293
• Main Authors: Dunsmore, Kimberly P, Winter, Stuart S, Devidas, Meenakshi, Wood, Brent L, Esiashvili, Natia, Chen, Zhiguo, Eisenberg, Nancy, Briegel, Nikki, Hayashi, Robert J, Gastier-Foster, Julie M, Carroll, Andrew J, Heerema, Nyla A, Asselin, Barbara L, Rabin, Karen R, Zweidler-Mckay, Patrick A, Raetz, Elizabeth A, Loh, Mignon L, Schultz, Kirk R, Winick, Naomi J, Carroll, William L, Hunger, Stephen P
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 01.10.2020
• Subjects: Adolescent; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Arabinonucleosides - administration & dosage; Arabinonucleosides - adverse effects; Asparaginase - administration & dosage; Asparaginase - adverse effects; Child; Cohort Studies; Disease-Free Survival; Female; Humans; Leucovorin - administration & dosage; Leucovorin - adverse effects; Male; Methotrexate - administration & dosage; Methotrexate - adverse effects; ORIGINAL REPORTS; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - adverse effects; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Prednisone - administration & dosage; Prednisone - adverse effects; Treatment Outcome
• DOI: 10.1200/JCO.20.00256
• ISSN: 0732-183X

Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively ( = .029). Differences between DFS in a four-arm comparison were significant ( = .01), with no interactions between the MTX and nelarabine randomizations ( = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% 6.9% ± 1.4%, respectively; = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.