Bortezomib Improves OS in Newly Diagnosed T-Cell Lymphoblastic Leukemia and Lymphoma

David T. Teachey, MD

The addition of bortezomib (Velcade) to chemotherapy improved survival rates in children and young adults with newly diagnosed T-cell lymphoblastic lymphoma (T-LL), according to data from the phase 3 AALL1231 trial (NCT02112916) published in the Journal of Clinical Oncology.¹

Results showed patients with T-LL and T-cell acute lymphoblastic leukemia (T-ALL) experienced a benefit in 4-year event-free survival (EFS) and overall survival (OS) with the addition of bortezomib vs chemotherapy alone. For all patients, the EFS rate for the bortezomib plus chemotherapy arm was 83.8% (± 2.1%), compared with 80.1% (± 2.3%) in the chemotherapy alone arm (HR, 0.833; P = .131). Additionally, the OS rate for the bortezomib group was 88.3% (± 1.8%), vs 85.7% (± 2.0%) for the chemotherapy group (HR, 0.772; P = .085).

Specifically, patients with T-LL achieved a 4-year EFS rate of 86.4% (± 4.0%) with bortezomib, vs 76.5% (± 5.1%) for chemotherapy (HR, 0.563; P = .041). Furthermore, this patient population experienced a 4-year OS rate of 89.5% (± 3.6%) with bortezomib and 78.3% (± 4.9%) with chemotherapy (HR, 0.421; P = .009).

“The results of this trial have the potential to change the standard of care for patients with T-LL and T-ALL,” lead study author David T. Teachey, MD, attending physician, director of clinical research, Center for Childhood Cancer Research at Children’s Hospital of Philadelphia, said in a press release.² “The data show that most patients with T-ALL no longer need cranial radiation for cure and also suggest bortezomib should be considered as part of the new standard of care for newly diagnosed patients with T-cell lymphoblastic lymphoma.”

The 5-year OS for children with relapsed T-ALL and T-LL is less than 35%, presenting a great unmet need to prevent recurrence.³ The AALL1231 trial aimed to test bortezomib in combination with chemotherapy based on compelling biological rationale, strong preclinical data, and encouraging efficacy and safety results from the phase 2 AALL07P1 trial (NCT00873093).⁴

AALL1231 examined patients between the ages of 1 and 30 years with newly diagnosed T-ALL or T-LL. Patients were randomly assigned 1:1 to receive a modified augmented Berlin-Frankfurt-Münster (BFM) chemotherapy regimen with or without bortezomib during induction and delayed intensification. Patients were also classified as standard risk, intermediate risk, and very high risk for treatment assignment based on disease characteristics.

In the bortezomib arm, patients received 4 doses at 1.3 mg/m² per block. During induction, bortezomib was given on Days 1, 4, 8, and 11. During delayed intensification, bortezomib was given on Days 1, 4, 15, and 18. Asparaginase intensification improves T-ALL outcomes, so patients received 2 additional doses of pegaspargase, 1 at day 18 of induction and 1 at delayed intensification.

Additionally, investigators adjusted the BFM backbone used in the predecessor phase 3 AALL0434 trial (NCT00408005) to enhance central nervous system (CNS)­–directed systemic therapy and limit the need for cranial radiation therapy. Investigators used dexamethasone during induction and maintenance rather than prednisone based on decreased relapse rate in the phase 4 UKALL2003 trial (NCT00222612) and the phase 3 AIEOP-BFM-ALL-2000 trial (NCT00430118). Notably, 90.8% of patients with T-ALL in AALL0434 received cranial radiation therapy while just 9.5% of patients with T-ALL in AALL1231 were scheduled for cranial radiation therapy.

Patients with standard-risk disease received a single interim maintenance phase of methotrexate plus pegaspargase, followed by delayed intensification and maintenance. Additionally, patients with intermediate-risk disease received first interim maintenance with high-dose methotrexate, followed by delayed intensification, then second interim maintenance with methotrexate plus pegaspargase and maintenance.

Notably, very high-risk patients with T-ALL who experienced induction failure received 3 BFM-based intensification blocks after consolidation. Following these blocks, patients with minimal residual disease (MRD) positivity were removed from protocol therapy as treatment failures. Patients with MRD negativity continued on therapy, receiving delayed intensification followed by methotrexate plus pegaspargase.

Patients with T-LL who had stable disease on day 29 imaging were considered very high-risk and received the same chemotherapy as patients with very high-risk T-ALL, followed by reimaging at the end of intensification. Patients with persistent residual T-ALL were also removed from protocol therapy, and the remainder continued on chemotherapy.

Furthermore, cranial radiation was only given to patients with very high-risk T-ALL and CNS3 T-ALL or T-LL during maintenance. Patients with persistent testicular leukemia at the end of induction were administered 24 Gy testicular radiation during consolidation.

Female patients with T-ALL or T-LL, plus male patients with T-LL, received treatment for 2 years from the start of first interim maintenance (standard- or intermediate-risk disease) or the first intensification block (very high-risk disease). Male patients with T-ALL were treated for 3 years.

The trial investigated overall EFS, OS, and safety in all patients, plus efficacy and safety specifically within patients with T-LL and T-ALL.

Among patients in the bortezomib arm (n = 408), 43.4 were less than 10 years old, 38.2% were between the ages of 10 and 16, and 18.4% were 16 years or older. Additionally, 72.3% were male. The majority of patients had a white blood cell count of higher than 50 x 1,000/µL (58.1%), CNS1 (77.4%), were White (70.8%), and had less than 5% bone marrow blasts on day 29 (95%).

In patients with T-ALL in the bortezomib arm, 65.1% had less than 0.01 bone marrow MRD on day 29, and that rate increased to 94.4% at the end of consolidation. Additionally, 55.5% patients with very high-risk T-ALL in the bortezomibarm had detectable MRD at the end of treatment blocks (n = 5). Furthermore, 71.7% of patients with T-ALL in the bortezomib arm were classified as not having early T-cell precursor.

Among patients with T-LL in the bortezomib group (n = 97), 44.3% had a complete response and compared with 42.9% and 57.1%, respectively, in the control arm (n = 105). Patients in the bortezomib arm had significantly better 4-year EFS (86.4% ± 4.0% vs 76.5% ± 5.1%; HR = 0.563; P = .041)and OS (89.5% ± 3.6% vs 78.3% ± 4.9%; HR = 0.421; P = .009).

Notably, 94.3% of patients with T-ALL achieved complete remission, and rates were similar across the treatment arms. The bortezomib arm had a MRD rate of at least 0.01% in 34.9% of patients with T-LL, compared with 38.8% in the chemotherapy arm. Additionally, only 13 patients in the bortezomib arm and 12 patients in the chemotherapy arm had an MRD rate of 0.1% or higher at the end of induction (P = .931).

Rates of grade 3 or higher adverse effects (AEs) were 80.0% and 76.5% in the bortezomib and chemotherapy arms, respectively (P = .234). Rates of grade 3 or higher peripheral neuropathy, an AE linked to bortezomib, were similar in both arms.

Overall, 20 infection-related deaths occurred, including 5 during induction, 4 during consolidation, 8 during delayed intensification, and 3 during maintenance. Additionally, 11 deaths stemmed from invasive fungal disease, including 9 in the chemotherapy arm.

References

1. Teachey DT, Devidas M, Wood BL, et al. Children’s Oncology Group trial AALL1231: a phase III clinical trial testing bortezomib in newly diagnosed T-cell acute lymphoblastic leukemia and lymphoma. J Clin Oncol. Publish online: March 10, 2022. Accessed March 21, 2022. doi:10.1200/JCO.21.02678
2. CHOP-led study finds bortezomib improves survival in children with newly diagnosed T-cell lymphoblastic lymphoma. News release. Children’s Hospital of Philadelphia. March 10, 2022. https://bit.ly/3Iy3Sl7
3. Burkhardt B, Mueller S, Khanam T, et al. Current status and future directions of T-lymphoblastic lymphoma in children and adolescents. Br J Haematol. 2016;173(4):545-59. doi:10.1111/bjh.14017
4. Horton TM, Whitlock JA, Lu X, et al. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: A report from the Children’s Oncology Group. Br J Haematol. 2019;186(2):274-285. doi:10.1111/bjh.15919