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

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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 (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .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% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms.

Conclusion: The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.

FIG 1.

CONSORT diagram for study. (*) Includes patients who were not eligible to receive nelarabine (randomized to arms A and C only) either during the safety phase (intermediate risk [IR]) or efficacy phase (seizure disorder or preexisting peripheral neuropathy). (†) IR patients with CNS3 and testicular disease were assigned to arm C during the safety phase. The most commons reasons why patients came off study between the first and second stages of randomization were because the physician determined it was in the best interests of the patient and the participant declined to participate in the randomization. AlloHSCT, allogeneic hematopoietic stem-cell transplantation; C-MTX, escalating-dose methotrexate without leucovorin rescue plus pegaspargase; CRT, cranial radiation therapy; EOI, end of induction; HDMTX, high-dose methotrexate with leucovorin rescue; HR, high risk; IF, induction failure; LR, low risk; T-ALL, T-cell acute lymphoblastic leukemia; T-LLy, T-Cell lymphoblastic lymphoma.

FIG 2.

(A) Event-free survival (EFS) and overall survival (OS) curves for all patients with T-cell acute lymphoblastic leukemia; 5-year EFS and OS rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. (B) EFS by race and ethnicity; 5-year EFS rates were 83.7% ± 1.3% for White patients, 81.8% ± 3.4% for Black patients, and 85.1% ± 2.7% for other patients (P = .702). (C) EFS by sex; 5-year EFS rates were 82.6% ± 2.3% for females and 84.1% ± 1.3% for males (P = .289).

FIG 3.

Disease-free survival (DFS) and overall survival (OS) comparisons for nelarabine versus no nelarabine in the randomized cohorts. (A) Five-year DFS rates were 88.2% ± 2.4% with nelarabine compared with 82.1% ± 2.7% without nelarabine (P = .029). (B) Five-year OS rates were 90.3% ± 2.2% with nelarabine compared with 87.9% ±without nelarabine (P = .168). (C) Five-year DFS rates for the 4 randomized arms were as follows: escalating-dose methotrexate without leucovorin rescue plus pegaspargase (C-MTX) with nelarabine, 91.4% ± 3.1% (n = 147); C-MTX without nelarabine, 87.2% ± 3.5% (n = 151); high-dose methotrexate with leucovorin rescue (HDMTX) with nelarabine, 85.5% ± 3.6% (n = 176); and HDMTX without nelarabine, 78.1% ± 4.0% (n = 185; P = .01). (D) DFS by age group in patients randomly assigned to nelarabine; 5-year DFS rates were as follows: age < 10 years, 87.1% ± 3.5%; age 10-15 years, 91.3% ± 3.7%; and age ≥ 16 years, 84.8% ± 7.1% (P = .77). (E) DFS by age group in patients not randomly assigned to nelarabine; 5-year DFS rates were as follows: age < 10 years, 80.3% ± 3.8%; age 10-15 years, 81.9% ± 4.9%; and age ≥ 16 years, 88.6% ± 5.5% (P = .441).

FIG 4.

The 5-year cumulative incidence rates of CNS relapse (isolated and combined) in the nelarabine versus no nelarabine arms were 1.3% ± 0.63% and 6.9% ± 1.4%, respectively (P = .0001).

FIG A1.

Disease-free survival (DFS) for patients with CNS3 randomly assigned to high-dose methotrexate with leucovorin rescue (HDMTX) with or without nelarabine; 5-year DFS rates were 93.1% ± 6.5% for HDMTX with nelarabine and 67.9% ± 12.2% for HDMTX without nelarabine (P = .014).

FIG A2.

Disease-free survival (DFS) by day 29 minimal residual disease (MRD) status. (A) Five-year DFS rates in the nelarabine group were 92.3% ± 2.9% in those with MRD < 0.1% and 83.5% ± 3.9% for those with MRD ≥ 0.1% (P = .0102). (B) Five-year DFS rates in the no nelarabine group were 89.0% ± 3.1% in those with MRD < 0.1% and 73.4% ± 4.3% in those with MRD ≥ 0.1% (P = .0003).