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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., Competing Interests: David T. TeacheyConsulting or Advisory Role: SobiResearch Funding: Novartis (Inst), Beam Therapeutics (Inst), NeoImmuneTech (Inst) Meenakshi DevidasHonoraria: Novartis Brent L. WoodHonoraria: Amgen, Seattle Genetics, AbbVie, Janssen, Amgen, Astellas Pharma, Roche Diagnostics, Beckman CoulterConsulting or Advisory Role: SysmexResearch Funding: Amgen (Inst), Seattle Genetics (Inst), Pfizer (Inst), Juno Therapeutics (Inst), BiolineRx (Inst), Biosight (Inst), Stemline Therapeutics (Inst), Janssen Oncology (Inst), Novartis, Kite, a Gilead company (Inst), Macrogenics (Inst)Travel, Accommodations, Expenses: Amgen, Amgen Robert J. HayashiConsulting or Advisory Role: Magenta Therapeutics Michelle HermistonStock and Other Ownership Interests: Gladiator Biosciences, Coagulant TherapeuticsConsulting or Advisory Role: Novartis, Sobi, Kalivir ImmunotherapeuticsPatents, Royalties, Other Intellectual Property: Spouse has patents pending for platform technology with application to oncology, diagnostics, anti-infections, and for antibleeding technology Michelle L. HermistonStock and Other Ownership Interests: Gladiator Biosciences, Coagulant TherapeuticsConsulting or Advisory Role: Novartis, Sobi, Kalivir ImmunotherapeuticsPatents, Royalties, Other Intellectual Property: Spouse has patents pending for platform technology with application to oncology, diagnostics, anti-infections, and for antibleeding technology J. Hunter ArcherStock and Other Ownership Interests: Johnson & Johnson/Janssen, AbbVie, Merck, Abbott Laboratories, Lilly, Zomedica, GlaxoSmithKline, Artelo Biosciences, Becton Dickinson, Bristol Myers Squibb Company, Tonix Pharmaceuticals, Cerebain Biotech Company, Gentech Keith J. AugustConsulting or Advisory Role: Jazz Pharmaceuticals, Beam TherapeuticsSpeakers' Bureau: Novartis Steve Y. ChoConsulting or Advisory Role: Progenics, Blue Earth Diagnostics, Bristol Myers Squibb, Radmetrix, Haymarket Medical EducationResearch Funding: Progenics (Inst), Advanced Accelerator Applications (Inst)Other Relationship: RadmetrixUncompensated Relationships: Focus-X Therapeutics Kimberly P. DunsmoreEmployment: DexcomStock and Other Ownership Interests: DexcomTravel, Accommodations, Expenses: Dexcom Brian T. FisherConsulting or Advisory Role: Astellas PharmaResearch Funding: Pfizer (Inst), Merck (Inst) Jason L. FreedmanStock and Other Ownership Interests: Massive BioConsulting or Advisory Role: Massive Bio Paul J. GalardyStock and Other Ownership Interests: AbbVie, Abbott Laboratories, Johnson & Johnson/Janssen Paul Harker-MurrayConsulting or Advisory Role: Consultancy for Regeneron Pharmaceuticals (2019) Terzah M. HortonResearch Funding: Takeda Alok I. JajuStock and Other Ownership Interests: Gilead Sciences Eric S. SchaferConsulting or Advisory Role: Beam Therapeutics Stuart S. WinterHonoraria: Jazz PharmaceuticalsConsulting or Advisory Role: Jazz PharmaceuticalsPatents, Royalties, Other Intellectual Property: Therapeutic use of the PreBCR to target B-cell acute leukemiasTravel, Accommodations, Expenses: Jazz Pharmaceuticals Patrick Zweidler-McKayEmployment: ImmunogenStock and Other Ownership Interests: ImmunogenPatents, Royalties, Other Intellectual Property: Patent applications submitted, no royalties Catherine M. BollardLeadership: Cabaletta BioConsulting or Advisory Role: Mana Therapeutics, Catamaran Bio Mignon L. LohConsulting or Advisory Role: MediSix Therapeutics Stephen P. HungerStock and Other Ownership Interests: Amgen, MerckHonoraria: Jazz Pharmaceuticals, Servier/Pfizer Elizabeth A. RaetzResearch Funding: Pfizer (Inst)Other Relationship: CelgeneNo other potential conflicts of interest were reported.