Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma

Abstract

Purpose: To improve the outcomes of patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL), the proteasome inhibitor bortezomib was examined in the Children's Oncology Group phase III clinical trial AALL1231, which also attempted to reduce the use of prophylactic cranial radiation (CRT) in newly diagnosed T-ALL.

Patients and methods: Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients.

Results: AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600).

Conclusion: Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse.

Trial registration: ClinicalTrials.gov NCT02112916.

FIG 1.

CONSORT diagram for the study. ^aIneligible reasons: nine disease type or histology, one patient characteristics, six prior therapies, four stage extent of disease, one timing of start of protocol therapy, and two other (not enrolled in AALL08B1). ^bTwo induction death, 14 off protocol therapy in induction, one off study in consolidation, and three off protocol therapy in consolidation. ^cOne induction death, one off therapy in induction, and one off study in consolidation. ^dFive induction death, two consolidation death, five off protocol therapy in induction, and one off study in consolidation. ^eTwo off protocol therapy in induction and one off study in induction. Arm A, control arm; Arm B, bortezomib arm; IR, intermediate-risk; SR, standard-risk; T-ALL, T-cell acute lymphoblastic leukemia; T-LL, T-cell lymphoblastic lymphoma; VHR, very high-risk.

FIG 2.

EFS and OS curves for all eligible and evaluable patients. (A) Four-year EFS and OS rates for all patients were 81.9% ± 1.5% and 87.0% ± 1.3%, respectively. (B) Four-year EFS and OS for patients with T-ALL were 82.2% ± 1.7% and 88.1% ± 1.5%, respectively. (C) Four-year EFS and OS for patients with T-LL were 81.2% ± 3.3% and 83.6% ± 3.1%, respectively. EFS, event-free survival; OS, overall survival; T-ALL, T-cell acute lymphoblastic leukemia; T-LL, T-cell lymphoblastic lymphoma.

FIG 3.

EFS and OS for no bortezomib (arm A) and bortezomib (arm B) randomized cohorts. (A) 4-year EFS rates for all patients were 83.8 ± 2.1% with bortezomib compared with 80.1 ± 2.3% without bortezomib (P = .131). (B) 4-year OS rates for all patients were 88.3 ± 1.8% with bortezomib compared with 85.7 ± 2.0% without bortezomib (P = .085). (C) 4-year EFS rates for patients with T-ALL were 82.9% ± 2.4% with bortezomib compared with 81.5% ± 2.5% without bortezomib (P = .396). (D) 4-year OS rates for patients with T-ALL were 87.9% ± 2.1% with bortezomib compared with 88.3% ± 2.1% without bortezomib (P = .469). (E) 4-year EFS rates for patients with T-LL were 86.4% ± 4.0% with bortezomib compared with 76.5% ± 5.1% without bortezomib (P = .041). (F) 4-year OS rates for patients with T-LL were 89.5% ± 3.6% with bortezomib compared with 78.3% ± 4.9% without bortezomib (P = .009). T-ALL, T-cell acute lymphoblastic leukemia; T-LL, T-cell lymphoblastic lymphoma; EFS, event-free survival; OS, overall survival.

FIG 4.

Comparison of outcomes between all patients in AALL1231 and AALL0434, the predecessor trial to AALL1231. (A) Four-year EFS rates in AALL1231 versus AALL0434 were 81.9% ± 1.5% and 84.4% ± 0.9%, respectively (P = .131). (B) Four-year OS rates in AALL1231 versus AALL0434 were 87.0% ± 1.3% and 90.0% ± 0.7%, respectively (P = .006). (C) Four-year CI rates of relapse in AALL1231 versus AALL0434 were 8.4% ± 1.0% and 9.3% ± 0.8%, respectively (P = .562). (D) Four-year CI rates of remission death in AALL1231 versus AALL0434 were 3.9% ± 0.7% and 2.1% ± 0.4%, respectively (P = .008). CI, cumulative incidence; EFS, event-free survival; OS, overall survival.