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Addition of Bortezomib to Chemotherapy in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma


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As reported in the Journal of Clinical Oncology by Teachey et al, the phase III Children’s Oncology Group AALL1231 trial has shown that the addition of bortezomib to a modified augmented Berlin-Frankfurt-Münster (BFM) backbone improved survival outcomes in patients with newly diagnosed T-cell lymphoblastic lymphoma (T-LL). It was also found that BFM modification allowed avoidance of prophylactic cranial radiation in patients with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL).

Study Details

In the trial, 824 children and young adults (aged 1 to 30 years) with T-ALL (n = 615) or T-LL (n = 209) were randomly assigned between 2014 and 2017 to receive a modified augmented BFM backbone with (n = 408; 307 with T-ALL, 101 with T-LL) vs without (n = 416; 308 with T-ALL, 108 with T-LL) bortezomib during induction and delayed intensification. Modifications to augmented BFM (daunorubicin, vincristine, prednisone, dexamethasone, pegaspargase, and methotrexate) included use of dexamethasone instead of prednisone and the addition of two extra doses of pegaspargase in an attempt to avoid use of prophylactic cranial radiation; the modifications were changes from the BFM regimen used in the predecessor COG AALL0434 trial evaluating nelarabine as the experimental agent in the same setting, in which most patients with T-ALL received prophylactic cranial radiation. Bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11 during induction and days 1, 4, 15, and 18 during delayed intensification. The primary outcome measure was event-free survival.

Event-Free and Overall Survival

Among all patients, 4-year event-free survival was 81.9% ± 1.5% and 4-year overall survival was 87.0% ± 1.3%. Event-free survival at 4 years was 83.8% ± 2.1% in the bortezomib group vs 80.1% ± 2.3% in the control group (hazard ratio [HR] = 0.833, P = .131); 4-year overall survival was 88.3% ± 1.8% vs 85.7% ± 2.0% (HR = 0.772, P = .085).

KEY POINTS

  • The addition of bortezomib to chemotherapy significantly improved event-free and overall survival in patients with T-LL.
  • No significant benefit was observed with the addition of bortezomib in patients with T-ALL.

Among patients with T-ALL, 4-year event-free survival was 82.9% ± 2.4% with bortezomib vs 81.5% ± 2.5% without bortezomib (P = .396) and 4-year overall survival was 87.9% ± 2.1% vs 88.3% ± 2.1% (P = .469). Among patients with T-LL, 4-year event-free survival was 86.4% ± 4.0% with bortezomib vs 76.5% ± 5.1% without bortezomib (HR = 0.563, P = .041) and 4-year overall survival was 89.5% ± 3.6% vs 78.3% ± 4.9% (HR = 0.421, P = .009).

In the predecessor COG AALL0434 trial, 90.8% of patients with T-ALL received prophylactic cranial radiation; in the current trial, 9.5% of patients were scheduled to receive prophylactic cranial radiation. Evaluation of comparable AALL0434 patients with T-ALL who received prophylactic cranial radiation (n = 634 who did not receive nelarabine)  and AALL1231 patients with T-ALL who did not receive prophylactic cranial radiation (n = 229 who did not receive bortezomib) showed no significant differences in 4-year event-free survival  (88.0% ± 1.3% vs  86.1% ± 2.6%, P = .412), 4-year overall survival (91.6% ± 1.1% vs 91.5% ± 2.1%, P = .600), or cumulative incidence of central nervous system relapse (4.5% ± 0.8% vs 5.4% ± 1.5%, P = .456) or any relapse (9.1% ± 1.2% vs 8.1% ± 1.8%, P = .836).

Toxicity

No excess toxicity was observed in patients receiving bortezomib. Grade ≥ 3 adverse events occurred in 80.0% of patients in the bortezomib group vs 76.5% of the control group (P = .234). Infection-related deaths occurred in 10 patients in each group. Overall rates of peripheral neuropathy were as expected and similar in the two groups. Grade ≥ 4 pulmonary toxicity occurred in 15 patients in the bortezomib group vs 11 in the control group (P = .393).

The investigators concluded, “Patients with T-LL had significantly improved event-free survival and overall survival with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of [prophylactic cranial radiation] in more than 90% of patients with T-ALL without excess relapse.”

David T. Teachey, MD, of the Division of Oncology, The Children’s Hospital of Philadelphia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Institutes of Health, Leukemia and Lymphoma Society, and St. Baldrick’s Foundation. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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