Children’s oncology group trial AALL1231: a phase III clinical trial of bortezomib in newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma

A previous Children’s Oncology Group (COG) trial AALL07P1 (NCT00873093[MM1] ) demonstrated the efficacy of bortezomib in treating patients with T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LL).¹ The objectives of the phase III COG AALL1231 trial (NCT02112916) reported by Teachey, et al., in the Journal of Clinical Oncology, were to further investigate the use of bortezomib in treating children and young adults with T-ALL/T-LL and evaluate reduced use of prophylactic cranial radiation therapy (CRT) in newly diagnosed T-ALL.² Use of CRT, which is current standard of care, causes significant long-term problems, including secondary cancers, irreversible endocrinopathies, neurocognitive decline, and neurotoxic effects. Patients were randomly assigned to a modified Berlin-Frankfurt-Münster (BFM) chemotherapy regimen with/without bortezomib during induction and delayed intensification. Modifications to the BFM backbone, used in the predecessor COG AALL0434 trial (NCT00408005)³, included a substitution of dexamethasone instead of prednisone and the addition of two extra doses of pegaspargase.

Objectives

• The primary objective was to compare event-free survival (EFS) in children and young adults with T-ALL/T-LL who were randomly assigned to a modified BFM backbone, in the presence/absence of bortezomib.
• A secondary objective was to determine if prophylactic CRT use can be eliminated in standard- and intermediate-risk patients with T-ALL.

Study design

• In total, 847 patients were enrolled in the study, with 824 passing eligibility criteria.
• Patients aged 1–30 years of age with newly diagnosed T-ALL or T-LL were eligible.
• Central nervous system (CNS) status was defined using cerebrospinal fluid obtained prior to starting systemic chemotherapy or based on clinical signs of CNS leukemia.
• Upon enrolment, patients were randomly assigned 1:1 to either receive bortezomib (Arm B, n = 408) or a placebo (Arm A, n = 416). Bortezomib treatment was split into four dosage blocks of 1.3 mg/m2/dose.[MM2] 
• Patients with T-ALL and T-LL were separately classified as standard risk, intermediate risk, and very high risk according to disease characteristics and treatment response.
• Several changes were made to the previously reported BFM backbone to enhance CNS-directed systemic therapy and limit CRT.^1,3
• A subset analysis was performed to assess the impact of eliminating CRT for patients with T-ALL.
  • Patients who received CRT in AALL0434 were compared with similar patients who did not receive CRT in AALL1231.
  • The cohort excluded patients who received nelarabine in AALL0434 and those who received bortezomib in AALL1231.

Key findings

• Overall, 4-year EFS and OS were 81.9% ± 1.5% and 87.0 ± 1.3%, respectively.
• For patients with T-ALL
  • At end of induction, 94.3% were in complete remission, and rates were similar between arms.
  • EFS and OS rates were similar with or without bortezomib treatment.
• For patients with T-LL
  • Either complete or partial remission was achieved in 99.9% of patients. Those treated with bortezomib had a significantly better 4-year EFS (86.4% ± 4.0% vs 76.5% ± 5.1%; Hazard ratio [HR], 0.563; p = 0.041) and OS (89.5% ± 3.6% vs 78.3% ± 4.9%; HR, 0.421; p = 0.009) than those treated with BFM alone.
• Overall Grade ≥3 toxicity rates were similar between patients who received bortezomib and those who did not (with bortezomib: 80.0%, without bortezomib: 76.5%; p = 0.234).
• Patients classified as very high risk had poor outcomes and bortezomib treatment was not effective in this population.
• The overall 4-year EFS rate was similar between patients in AALL1231 and the predecessor AALL0434 trial (81.9% ± 1.5% vs 84.4% ± 0.9%; p = 0.131); however, 4-year OS was lower for patients in AALL1231 compared with AALL0434 (87.0% ± 1.3% vs 90.0% ± 0.7%; p = 0.006).
• The number of patients with T-ALL who received CRT was just 9.5% in AALL1231, compared with 90.8% in AALL0434.
• When excluding patients from these trials who had received either nelarabine or bortezomib, there was no statistical difference in OS or EFS between similar patients who received CRT in AALL0434 and those who did not receive CRT in AALL1232 (OS, 91.6% ± 1.1% vs 91.5% ± 2.1%; p = 0.600; EFS, 88.0% ± 1.3% vs 86.1% ± 2.6%; p = 0.412).

Conclusion

AALL1231 demonstrated that the proteosome inhibitor bortezomib improved EFS and OS in patients with T-LL, but not T-ALL, when combined with modified augmented BFM chemotherapy. In addition, it was shown that CRT can be safely and effectively eliminated in ≥90% of patients with T-ALL, without intensifying systemic chemotherapy. These data indicate that incorporating bortezomib into standard of care therapy for newly diagnosed T-LL appears to be advantageous. It is hoped that future trials will build on these positive findings to enable high cure rates without routine CRT.