Rituximab, bendamustine, and cytarabine followed by venetoclax in older patients with high-risk mantle cell lymphoma (FIL_V-RBAC): a multicentre, single-arm, phase 2 study
- PMID: 40975105
- DOI: 10.1016/S2352-3026(25)00252-2
Rituximab, bendamustine, and cytarabine followed by venetoclax in older patients with high-risk mantle cell lymphoma (FIL_V-RBAC): a multicentre, single-arm, phase 2 study
Abstract
Background: Bendamustine and rituximab combined with intermediate-dose cytarabine (RBAC) is one of the standard initial treatments for older, fit patients with mantle cell lymphoma. We aimed to investigate whether the addition of venetoclax to RBAC would improve progression-free survival in patients with high-risk mantle cell lymphoma.
Methods: FIL_V-RBAC was a multicentre, single-arm, phase 2 study done in 35 institutions of the Fondazione Italiana Linfomi in Italy. Treatment-naive patients with a histological diagnosis of mantle cell lymphoma, aged 65 years or older and fit according to the Fondazione Italiana Linfomi modified comprehensive geriatric assessment (or younger than 65 years and ineligible for high-dose chemotherapy with Eastern Cooperative Oncology Group performance status of 2 or less), were classified after enrolment as having low-risk or high-risk disease, based on the presence of blastoid morphology, Ki67 30% or higher, TP53, or 17p deletion. Patients with a low-risk profile received RBAC intravenously (rituximab 375 mg/m2 and day 1; bendamustine 70 mg/m2 on days 1 and 2; and cytarabine 500 mg/m2 on days 1, 2, and 3) every 4 weeks for 6 cycles. Patients with a high-risk profile received four cycles of RBAC followed by fixed-duration oral venetoclax consolidation (4 months, 800 mg/day) and maintenance (20 months, 400 mg/day). The primary endpoint was 2-year progression-free survival for patients with a high-risk profile who received at least one dose of RBAC. This trial was registered with ClinicalTrials.gov, NCT03567876, and this is the final report.
Findings: Between Sept 10, 2018, and July 26, 2021, 155 patients were screened for inclusion, 140 of whom were enrolled and analysed for study endpoints. Median age was 72 (IQR 69-76), 107 (76%) patients were male, 33 (24%) were female, and all were White. 54 (39%) patients had a high-risk profile (28 [20%] with TP53 mutations, 19 [14%] with 17p deletions, 34 [24%] with Ki67 ≥30%, and 13 [9%] with a blastoid morphology) and 86 (61%) had a low-risk profile. After a median follow-up of 45 months (IQR 40-55), the 2-year progression-free survival in the high-risk group was 60% (95% CI 48-74) and the median progression-free survival was 37 months (95% CI 19-not reached). The most frequent grade 3 or worse adverse events during venetoclax consolidation were neutropenia (12 [28%] of 43 patients), followed by thrombocytopenia (three [7%]) and skin reactions (three [7%]). During venetoclax maintenance, the most frequent grade 3 or worse adverse events were neutropenia (seven [19%] of 37 patients), followed by thrombocytopenia (two [5%]) and anaemia (two [5%]). One (1%) of 140 patients had a treatment-related death (tumour lysis syndrome during first induction with RBAC in a patient with a high-risk profile).
Interpretation: To our knowledge, this is the first prospective study to stratify patients with mantle cell lymphoma to different treatments according to their risk profile. Our results suggest that the addition of fixed-duration venetoclax improves the performance of RBAC in patients with a high-risk disease profile. Our findings point to the importance of identifying patients with high-risk disease at initial diagnosis.
Funding: Fondazione Italiana Linfomi-Ente del Terzo Settore, Leukemia and Lymphoma Society, and Ministry of Health, Italy, and AbbVie.
Translation: For the Italian translation of the abstract see Supplementary Materials section.
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Conflict of interest statement
Declaration of interests CV reports support for the study from the Leukemia & Lymphoma Society (award number MCL7005–24); payment or honoraria for lectures or presentations from AbbVie, Bristol Myers Squibb, AstraZeneca, Servier, Incyte, Roche, Pfizer, Novartis, Gentili, Janssen, Kite-Gilead, BeiGene, Lilly, and Kyowa Kirin; support for attending meetings and/or travel from AbbVie, Bristol Myers Squibb, AstraZeneca, Servier, Incyte, Roche, Pfizer, Novartis, Gentili, Janssen, Kite-Gilead, BeiGene, Lilly, Kyowa Kirin, and Johnson & Johnson; and participation on a data safety monitoring board or advisory board from AbbVie, Bristol Myers Squibb, Incyte, Roche, Pfizer, and Johnson & Johnson. FMQ reports payment or honoraria for lectures or presentations from AstraZeneca and Kite-Gilead; support for attending meetings and/or travel from Novartis, Roche, and GSK; and consultant with no compensation for Sandoz. PC reports payment or honoraria for lectures, presentations, and educational events from AbbVie, Amgen, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, SOBI, and Takeda; support for attending meetings and/or travel from AbbVie, Amgen, Bristol Myers Squibb, Gilead/Kite, Janssen, Novartis, Roche, and Takeda; and participation on a data safety monitoring board or advisory board from AbbVie, Amgen, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Gilead/Kite, GSK, Incyte, Janssen, Jazz Pharma, Novartis, Pfizer, Roche, Sanofi, SOBI, and Takeda. LF reports payment or honoraria for lectures or presentations from BeiGene, AbbVie, and Janssen. AC reports payment or honoraria for lectures or presentations from Kite/Gilead, Roche, and Gentili; and support for attending meetings and/or travel from Roche and Kite/Gilead. VRZ reports support with grants or contracts from Kite/Gilead; consulting fees from Roche; payment or honoraria for lectures or presentations from Incyte, Janssen, Lilly, SOBI, and Takeda; support for attending meetings and/or travel from BeiGene, Janssen, Roche, and Takeda; and participation on a data safety monitoring board or advisory board from AbbVie, AstraZeneca, Kite/Gilead, Novartis, Roche, SOBI, and Takeda. FP reports payment or honoraria for lectures or presentations from Roche, Lilly, Kite/Gilead, Janssen, SOBI, and AbbVie; support for attending meetings and/or travel from Roche, Lilly, Kite/Gilead, Janssen, SOBI, and AbbVie; and participation on a data safety monitoring board or advisory board from Roche, AbbVie, SOBI, and Lilly. AR reports payment from AbbVie and participation on an advisory board from AbbVie. SH reports consulting fees from AbbVie, BeiGene, Bristol Myers Squibb, Incyte, Ipsen, Lilly, Roche, Takeda, Gilead, and Novartis; and support for attending meetings and/or travel from Roche, Gilead, and Takeda. FGR reports participation on a data safety monitoring board or advisory board from Takeda, Incyte, and Johnson & Johnson. ADR reports consulting fees from Roche, Incyte, Kite, Novartis, AbbVie, and SOBI; payment or honoraria for lectures or presentations from Roche, Incyte, Kite, Novartis, AbbVie, Ely Lilly, Johnson & Johnson, SOBI, and Bristol Myers Squibb; support for attending meetings and/or travel from Kite, BeiGene, and AbbVie. RS reports participation on a data safety monitoring board or advisory board from Incyte. AB reports payment or honoraria for lectures or presentations from Roche, Kyowa Kirin, and Takeda. GM reports consulting fees, payment or honoraria for lectures or presentations, payment for expert testimony, support for attending meetings and/or travel, participation on a data safety monitoring board or advisory board, and leadership or fiduciary role in other board, society, committee, or advocacy group from AbbVie. FM reports payment or honoraria for lectures or presentations from AstraZeneca, Roche, Sandoz, Incyte, Gilead, and Novartis; support for attending meetings and/or travel from Kite, Gilead, BeiGene, Takeda, and Sandoz; participation on a data safety monitoring board or advisory board from Takeda, Janssen, and Gilead; and leadership or fiduciary role in other board, society, committee, or advocacy group for Fondazione Italiana Linfomi, unpaid. GG reports consulting fees from Takeda, Roche, Lilly, Gilead, Incyte, AbbVie, SOBI, and BeiGene; payment or honoraria for lectures or presentations from Takeda, Roche, and Incyte; support for attending meetings and/or travel from Roche and Takeda; and participation on a data safety monitoring board or advisory board from Takeda, Roche, and AbbVie. RF reports payment or honoraria for lectures or presentations from Kite, SOBI, Incyte, and Novartis. ML reports payment or honoraria for lectures or presentations from AbbVie, Acerta, Amgen, ADC Therapeutics, BeiGene, Celgene/Bristol Myers Squibb, Eusapharma, GSKI, Gentili, Gilead/Kite, Novartis, Incyte, Johnson & Johnson, Jazz, Lilly, Regeneron, Roche, and Sandoz; and participation on a data safety monitoring board or advisory board from Regeneron. MB reports consulting fees from Roche and SOBI; payment or honoraria for lectures or presentations from Roche, SOBI, Eli Lilly, Gilead, BeiGene, AstraZeneca, and AbbVie; and support for attending meetings and/or travel from Roche and BeiGene. All other authors declare no competing interests.
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