Addition of Nelarabine to Standard Therapy Improves Disease-Free Survival in Newly Diagnosed T-Cell ALL

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As reported in the Journal of Clinical Oncology by Kimberly P. Dunsmore, MD, of the Virginia Tech Carilion School of Medicine and Carilion Clinic, Roanoke, and colleagues, 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.1

As noted by the investigators: “Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia but has not been fully evaluated in those with newly diagnosed disease.”

Kimberly P. Dunsmore, MD

Kimberly P. Dunsmore, MD

Study Details

In the trial, 1,562 evaluable patients (aged 1 to 31 ) 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 without leucovorin rescue plus pegaspargase (C-MTX) or high-dose methotrexate 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 at 650 mg/m2/d, incorporated into the ABFM regimen. Patients with induction failure were nonrandomly assigned to high-dose methotrexate plus nelarabine. Patients with overt central nervous system (CNS) disease received high-dose methotrexate 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 (n = 323) or not receive (n = 326) nelarabine with backbone therapy, 151 received C-MTX alone (including 97 with intermediate-risk and 54 with high-risk disease) and 147 received C-MTX plus nelarabine (95 with intermediate-risk and 52 with high-risk disease), and 185 received high-dose methotrexate alone (123 with intermediate-risk and 62 with high-risk disease) and 176 received high-dose methotrexate plus nelarabine (118 with intermediate-risk and 58 with high-risk disease). Among the four randomized groups, a total of 214 patients not receiving nelarabine had intermediate-risk and 116 had high-risk disease, and a total of 213 patients receiving nelarabine had intermediate-risk and 110 had high-risk disease. The primary endpoint for the randomized comparison of nelarabine vs no nelarabine was disease-free survival.

Treatment Outcomes

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

Among 659 patients randomly assigned to receive (n = 323) vs not receive nelarabine (n = 336) with backbone therapy, the 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 methotrexate 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%), high-dose methotrexate with nelarabine (85.5%), and high-dose methotrexate without nelarabine (78.1%). Disease-free survival with high-dose methotrexate without nelarabine was significantly lower than that within the other groups, with this group having no significant increase in the rates of higher-risk patient characteristics or higher day 29 minimal residual disease (MRD) vs the other groups.

Among the randomly assigned patients with overt CNS disease, the 5-year disease-free survival was 93.1% among 29 patients receiving high-dose methotrexate plus nelarabine vs 67.9% in 28 receiving high-dose methotrexate without nelarabine (P = .014).

The 5-year disease-free survival and overall survival rates for patients randomly assigned to receive vs not receive nelarabine were 90.8% vs 86.3% (P = .077) and 91.3% vs 92.4% (P = .617), respectively, among patients with intermediate-risk disease and 83.5% vs 74.1% (P = .106) and 88.5% vs 79.2% (P = .051), respectively, among patients with high-risk disease. Among the 43 patients with induction failure who were nonrandomly assigned to receive high-dose methotrexate plus nelarabine, the 5-year event-free survival was 53.1%.

For patients who received nelarabine vs those who did not receive nelarabine, the 5-year disease-free survival was 92.3% vs 89.0% (P = .01) among patients with day 29 MRD < 0.1% and 83.5% vs 73.4% (P = .0003) among those with day 29 MRD ≥ 0.1%.

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).


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


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% vs 8% (P = .664).

Second malignant neoplasms occurred in three patients receiving C-MTX vs five receiving C-MTX plus nelarabine and in two receiving high-dose methotrexate vs two receiving high-dose methotrexate plus nelarabine.

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

DISCLOSURE: The study was supported by grants from the National Institutes of Health and by St Baldrick’s Foundation. Dr. Dunsmore has an immediate family member who has been employed by, holds stock or other ownership interests in, and has been reimbursed for travel, accommodations, or other expenses by Dexcom.


1. Dunsmore KP, Winter SS, Devidas M, et al: Children’s Oncology Group AALL0434: A phase III randomized clinical trial testing nelarabine in newly diagnosed T-cell acute lymphoblastic leukemia. J Clin Oncol. August 19, 2020 (early release online).