Favorable outcomes of front-line risk-adapted therapy in young patients with diffuse large B-cell lymphoma with clinically or biologically high-risk features.
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ABSTRACT:
SUBMITTER: Zou H
PROVIDER: S-EPMC11230830 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Favorable outcomes of front-line risk-adapted therapy in young patients with diffuse large B-cell lymphoma with clinically or biologically high-risk features.
Zou Hesong H Liu Wei W Wang Yi Y Shan Dandan D Xie Ting T Li Ru R Liu Huimin H Huang Wenyang W Fu Mingwei M Wang Tingyu T Lyu Rui R Deng Shuhui S Sui Weiwei W Xu Yan Y Yi Shuhua S An Gang G Qiu Lugui L Zou Dehui D
Chinese medical journal 20231207 13
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Project description:Background: TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We report results of a phase I single-institution escalation study of front-line treatment with R-CHOP and TAK-659 in treatment-naïve high-risk DLBCL. Methods: Patients with high-risk DLBCL were treated with R-CHOP for 1 cycle, followed by combined R-CHOP and TAK-659 for an additional five cycles, with TAK-659 dosing escalated from 60 mg, to 80 mg, to 100 mg daily, based on a 3 + 3 design. The primary objective was to determine the safety and establish the maximum tolerated dose (MTD) of TAK-659 in this setting. Results: Twelve patients were enrolled. Dose level 3 (100 mg) was established as the MTD. Dose level 1 (60 mg) maintained a similar area under the curve (AUC) to the MTD. With a median follow-up of 21 months, 92% of patients achieved complete response (CR). The most common treatment-emergent adverse events were lymphopenia (100%), infection (50%, n = 3 opportunistic), aspartate aminotransferase elevation (100%), and alanine aminotransferase elevation (83%). Conclusion: A TAK-659 dose of 60 mg was well tolerated, did not require dose modifications, and maintained a similar AUC to the MTD. The combination of R-CHOP and TAK-659 in patients with newly diagnosed high-risk DLBCL produces promising CR rates.
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Project description:BackgroundOutcomes for patients with high-risk diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP chemotherapy are suboptimal but, to date, no alternative regimen has been shown to improve survival rates. This phase 2 trial aimed to assess the efficacy of a Burkitt-like approach for high-risk DLBCL using the dose-intense R-CODOX-M/R-IVAC regimen.Patients and methodsEligible patients were aged 18-65 years with stage II-IV untreated DLBCL and an International Prognostic Index (IPI) score of 3-5. Patients received alternating cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin and high-dose methotrexate) alternating with IVAC chemotherapy (ifosfamide, etoposide and high-dose cytarabine) plus eight doses of rituximab. Response was assessed by computed tomography after completing all four cycles of chemotherapy. The primary end point was 2-year progression-free survival (PFS).ResultsA total of 111 eligible patients were registered; median age was 50 years, IPI score was 3 (60.4%) or 4/5 (39.6%), 54% had a performance status ≥2 and 9% had central nervous system involvement. A total of 85 patients (76.6%) completed all four cycles of chemotherapy. There were five treatment-related deaths (4.3%), all in patients with performance status of 3 and aged >50 years. Two-year PFS for the whole cohort was 67.9% [90% confidence interval (CI) 59.9-74.6] and 2-year overall survival was 76.0% (90% CI 68.5-82.0). The ability to tolerate and complete treatment was lower in patients with performance status ≥2 who were aged >50 years, where 2-year PFS was 43.5% (90% CI 27.9-58.0).ConclusionsThis trial demonstrates that R-CODOX-M/R-IVAC is a feasible and effective regimen for the treatment of younger and/or fit patients with high-risk DLBCL. These encouraging survival rates demonstrate that this regimen warrants further investigation against standard of care.Trial registrationClinicalTrials.gov (NCT00974792) and EudraCT (2005-003479-19).
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