Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults With Low-Risk B-Cell ALL in First Relapse

Abstract

Purpose: Blinatumomab, a bispecific T-cell engager immunotherapy, is efficacious in relapsed/refractory B-cell ALL (B-ALL) and has a favorable toxicity profile. One aim of the Children's Oncology Group AALL1331 study was to compare survival of patients with low-risk (LR) first relapse of B-ALL treated with chemotherapy alone or chemotherapy plus blinatumomab.

Patients and methods: After block 1 reinduction, patients age 1-30 years with LR first relapse of B-ALL were randomly assigned to block 2/block 3/two continuation chemotherapy cycles/maintenance (arm C) or block 2/two cycles of continuation chemotherapy intercalated with three blinatumomab blocks/maintenance (arm D). Patients with CNS leukemia received 18 Gy cranial radiation during maintenance and intensified intrathecal chemotherapy. The primary and secondary end points were disease-free survival (DFS) and overall survival (OS).

Results: The 4-year DFS/OS for the 255 LR patients accrued between December 2014 and September 2019 were 61.2% ± 5.0%/90.4% ± 3.0% for blinatumomab versus 49.5% ± 5.2%/79.6% ± 4.3% for chemotherapy (P = .089/P = .11). For bone marrow (BM) ± extramedullary (EM) (BM ± EM; n = 174) relapses, 4-year DFS/OS were 72.7% ± 5.8%/97.1% ± 2.1% for blinatumomab versus 53.7% ± 6.7%/84.8% ± 4.8% for chemotherapy (P = .015/P = .020). For isolated EM (IEM; n = 81) relapses, 4-year DFS/OS were 36.6% ± 8.2%/76.5% ± 7.5% for blinatumomab versus 38.8% ± 8.0%/68.8% ± 8.6% for chemotherapy (P = .62/P = .53). Blinatumomab was well tolerated and patients had low adverse event rates.

Conclusion: For children, adolescents, and young adults with B-ALL in LR first relapse, there was no statistically significant difference in DFS or OS between the blinatumomab and standard chemotherapy arms overall. However, blinatumomab significantly improved DFS and OS for the two thirds of patients with BM ± EM relapse, establishing a new standard of care for this population. By contrast, similar outcomes and poor DFS for both arms were observed in the one third of patients with IEM; new treatment approaches are needed for these patients (ClinicalTrials.gov identifier: NCT02101853).

FIG 1.

CONSORT diagram. ^aPatients were censored at the time of withdrawal of consent in the analyses. ^bRisk group definitions: (1) early treatment failure: >25% marrow blasts or failure to clear CNS leukemia; (2) high risk: bone marrow relapse <36 months after diagnosis, or isolated extramedullary relapse <18 months from diagnosis; (3) intermediate risk: bone marrow relapse ≥36 months after diagnosis, or isolated extramedullary relapse ≥18 months after diagnosis; and MRD ≥ 0.1%; (4) low risk: same as intermediate risk, except MRD < 0.1%. ^c1:1 random assignment, stratified by risk group, site of relapse, first remission duration, and postreinduction MRD. ^dOne proceeded to continuation 2 after continuation 1. ^eOne proceeded to maintenance after blinatumomab cycle 1. One proceeded to maintenance after blinatumomab cycle 2. MRD, minimal residual disease.

FIG 2.

(A) Disease-free survival and (B) overall survival of all LR patients. (C) Disease-free survival and (D) overall survival of LR patients with BM ± EM relapse. (E) Disease-free survival and (F) overall survival of LR patients with IEM relapse. P values were based on stratified log-rank tests, and HR and 95% CI were based on stratified Cox regression models. BM, bone marrow; DFS, disease-free survival; EM, extramedullary; HR, hazard ratio; IEM, isolated EM; LR, low risk; OS, overall survival.

FIG 3.

Cox regression of disease-free survival among patients with iBM or BM + EM disease. ^aP value for comparison of blinatumomab arm versus chemotherapy arm was one-sided. ^bP value for comparison of patient/disease characteristics was two-sided. ^cTime from initial diagnosis to relapse. BM, bone marrow; EM, extramedullary; HR, hazard ratio; iBM, isolated marrow; MRD, minimal residual disease.

FIG 4.

Sites of first versus second relapses by treatment arm in patients with initial BM ± EM relapse (A) and patients with initial IEM relapse (B). BM, bone marrow; EM, extramedullary; iBM, isolated marrow; IEM, isolated EM.

FIG A1.

(A) DFS and (B) OS of LR patients with isolated marrow relapse. (C) DFS and (D) OS of low-risk patients with marrow plus EM. DFS, disease-free survival; EM, extramedullary; OS, overall survival.

FIG A2.

(A) DFS and (B) OS of low-risk patients with iCNS relapse. (C) DFS and (D) OS of low-risk patients with iTesticular relapse. DFS, disease-free survival; iCNS, isolated CNS; IEM, isolated extramedullary; iTesticular, isolated testicular; OS, overall survival.