Addition of Nelarabine to Standard Therapy in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia

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As reported in the Journal of Clinical Oncology by Dunsmore et al, the phase III Children’s Oncology Group AALL0434 trial has shown that the addition of nelarabine to standard therapy improved disease-free survival in children and young adults with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).

The investigators noted, “Nelarabine is effective in inducing remission in patients with relapsed and refractory … T-ALL but has not been fully evaluated in those with newly diagnosed disease.”

Study Details

In the trial, 1,562 evaluable patients aged 1 to 31 years were enrolled between 2007 and 2014. All patients received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2×2 pseudofactorial 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 650 mg/m2 per day incorporated into ABFM. Patients with induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients except those with low-risk disease received cranial irradiation.

Overall, among 659 patients randomly assigned to receive or not receive nelarabine with backbone therapy, 151 received C-MTX alone, 147 received C-MTX plus nelarabine, 185 received HDMTX alone, and 176 received HDMTX plus nelarabine. The primary endpoint for the randomized comparison of nelarabine vs no nelarabine was disease-free survival.

Treatment Outcomes


  • The addition of nelarabine to C-MTX and to HDMTX significantly improved disease-free survival.
  • Disease-free survival at 5 years was 88.2% with vs 82.1% without nelarabine.

Among all 1,562 patients, 5-year event-free survival was 83.7% and 5-year overall survival was 89.5%.

Among patients randomly assigned to receive (n = 323) vs not receive nelarabine (n = 336) with backbone therapy, 5-year disease-free survival was 88.2% vs 82.1% (P = .029). Overall survival at 5 years was 90.3% vs 87.9% (P = .168).

Differences in disease-free survival in a comparison of the four randomized groups were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Disease-free survival at 5 years was highest in the C-MTX plus nelarabine group (91.4%), followed by C-MTX without nelarabine (87.2%), HDMTX with nelarabine (85.5%), and HDMTX without nelarabine (78.1%). Disease-free survival in the HDMTX without nelarabine group was significantly lower than that of the other groups, with this group having no significant increase in rates of higher risk patient characteristics or higher day 29 minimal residual disease vs the other groups.

Among randomized patients with overt CNS disease, 5-year disease-free survival was 93.1% among 29 patients receiving HDMTX plus nelarabine vs 67.9% in 28 receiving HDMTX without nelarabine (P = .014).

Overall, patients who received nelarabine had significantly fewer isolated and combined CNS relapses vs patients who did not receive nelarabine, with a 5-year cumulative incidence of 1.3% vs 6.9% (P = .0001).


Among the 659 patients in the four randomized groups, grade ≥ 3 nontargeted toxicity occurred in 41.2% of patients receiving nelarabine vs 46.1% in those not receiving nelarabine (P = .2). Targeted central neurotoxicity of grade ≥ 3 occurred in 3.4% vs 2.1% of patients (P = .298). Among targeted peripheral neurotoxicities, grade ≥ 3 motor neuropathy occurred in 8.0% vs 5.7% (P = .223) and grade ≥ 3 sensory neuropathy occurred in 9.0% vs 8.0% (P = .664).

The investigators concluded: “The addition of nelarabine to ABFM therapy improved [disease-free survival] for children and young adults with newly diagnosed T-ALL without increased toxicity.”

Kimberly P. Dunsmore, MD, of Virginia Tech Carilion School of Medicine and Carilion Clinic, Roanoke, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. For full disclosures of the study authors, visit

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