134 | EFFICACY AND SAFETY OF FIRST‐LINE IBRUTINIB PLUS VENETOCLAX IN PATIENTS WITH MANTLE CELL LYMPHOMA (MCL) WHO WERE OLDER OR HAD TP53 MUTATIONS IN THE SYMPATICO STUDY

Clinical Trial Information: NCT03112174 Introduction: The phase 3 SYMPATICO study evaluated ibrutinib (Ibr) combined with venetoclax (Ven) in 3 cohorts of patients with MCL: an open-label safety run-in phase to evaluate concurrent initiation of Ibr+Ven in relapsed/refractory (R/R) MCL; a randomized phase to evaluate Ibr+Ven versus Ibr+placebo (Pbo) in R/R MCL; and an open-label cohort to evaluate first-line Ibr+Ven in treatment-naive (TN) MCL. Primary analysis of the randomized phase showed superior progression-free survival (PFS) with Ibr+Ven versus Ibr+Pbo in patients with R/R MCL (Wang M et al. Lancet Oncol. 2025). Here, we report efficacy and safety of Ibr+Ven in patients with TN MCL in older patients (≥ 65 years) or younger patients with a TP53 mutation (TP53mut) (≥ 18 years) who are in need of novel and better tolerated treatment options. Methods: Older patients (≥ 65 years) or patients with a TP53mut with TN MCL received oral Ibr 560 mg once daily and Ven (5-week ramp-up to 400 mg once daily) for 2 years, then single-agent Ibr 560 mg until progressive disease (PD) or unacceptable toxicity. The primary endpoint was complete response (CR) rate assessed by investigator per Lugano criteria. Key secondary endpoints included overall response rate (ORR), duration of response (DOR), PFS, overall survival (OS), and time to next treatment. Subgroup analyses were performed according to TP53mut status and age. Results: In total, 78 patients with TN MCL were enrolled. At baseline, 83% of patients were ≥ 65 years, 97% had Eastern Cooperative Oncology Group performance status of 0–1, 45% had high-risk simplified MCL International Prognostic Index score, 31% had bulky disease (≥ 5 cm), 78% had bone marrow involvement, 46% had splenomegaly, and 37% had TP53mut. Median time on study was 40.5 months (range, 0.6+–46.9). The CR rate was 69% (95% CI: 58–79), and the ORR was 95% (95% CI: 87–99). Median DOR was 37.1 months (95% CI: 30.3–NE). Median PFS was 40.2 months, and 3-year OS was 79%. The CR rate was 76% in patients ≥ 65 years without TP53mut, 44% in patients ≥ 65 years with TP53mut, and 73% in patients < 65 years with TP53mut; median PFS was 40.2, 22.0, and 15.4 months, and 3-year OS was 85%, 66%, and 73%, respectively (Table). Median duration of treatment was 24.0 months (range, 0.3–46.9). Most common adverse events (AEs) were diarrhea (49%), fatigue (37%), neutropenia (35%), and COVID-19 (32%). The most common grade ≥ 3 AE was neutropenia (29%). Conclusions: First-line Ibr+Ven showed promising efficacy with high CR rates and durable remissions in patients with TN MCL with and without TP53mut. Safety was acceptable and trended better in younger patients. Ibr+Ven may be an option for older patients with TN MCL or patients of any age with TP53mut. Research funding declaration: This study was funded by Pharmacyclics LLC, an AbbVie Company Encore Abstract: ASCO 2025; EHA 2025 Keywords: combination therapies Potential sources of conflict of interest: M. Wang Consultant or advisory role: AstraZeneca, Bayer Healthcare, BeiGene, BioInvent, CSTone, DTRM Biopharma (Cayman) Limited, Epizyme, Genentech, InnoCare, Janssen, Juno Therapeutics, Kite Pharma, Loxo Oncology, Miltenyi Biomedicine GmbH, Oncternal, Pharmacyclics LLC, an AbbVie Company, and VelosBio Honoraria: Acerta Pharma, Anticancer Association, AstraZeneca, BeiGene, BGICS, BioInvent, CAHON, Chinese Medical Association, Clinical Care Options, Dava Oncology, Eastern Virginia Medical School, Epizyme, Hebei Cancer Prevention Federation, Imedex, Janssen, Kite Pharma LLC, Miltenyi Biomedicine GmbH, Moffit Cancer Center, Mumbai Hematology Group, Newbridge Pharmaceuticals, OMI, OncLive, Pharmacyclics LLC, an AbbVie Company, Physicians Education Resources (PER), Practice Point Communications (PPC), Scripps, The First Afflicted Hospital of Zhejiang University, and TS Oncology Educational grants: Acerta Pharma, AstraZeneca, BioInvent, Celgene, Janssen, Juno Therapeutics, Kite, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics LLC, an AbbVie Company, Physician Education Resources (PER), VelosBio, and Verastem Other remuneration: Acerta Pharma, AstraZeneca, BeiGene, BioInvent, Celgene, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Oncternal, Pharmacyclics LLC, an AbbVie Company, and VelosBio M. Hoffmann Consultant or advisory role: AstraZeneca, BeiGene, Janssen, Kite, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics Honoraria: AstraZeneca, BeiGene, Janssen, Kite, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics T. Wrobel Consultant or advisory role: BeiGene, Bristol Myers Squibb, Celgene, Gilead, GSK, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda Honoraria: BeiGene, Bristol Myers Squibb, Celgene, Gilead, Janssen-Cilag, Novartis, Roche, Sanofi, and Takeda Other remuneration: Roche M. Trneny Consultant or advisory role: AbbVie, Amgen, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, MorphoSys, Novartis, Roche, and Takeda Honoraria: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, F. Hoffmann-La Roche, Gilead Sciences, Incyte, Janssen, MorphoSys, Novartis, Portola, and Takeda Educational grants: AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen, Roche, and Takeda D. Belada Consultant or advisory role: Gilead Sciences, Janssen-Cilag, Novartis, Roche, and Takeda Educational grants: Gilead Science, Roche, and Takeda Other remuneration: Genmab, Janssen-Cilag, MorphoSys, and Roche P. Panayiotidis Honoraria: AbbVie, Genesis Pharma, Gilead Sciences, Janssen, and Novartis Educational grants: AbbVie, Genesis Pharma, Novartis, and Roche W. Jurczak Consultant or advisory role: AstraZeneca, BeiGene, Janssen, Loxo Oncology, Roche, and Sandoz Other remuneration: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, MorphoSys, Novo Nordisk, Roche, Sandoz, Takeda, and TG Therapeutics P. L. Zinzani Consultant or advisory role: ADC Therapeutics, AstraZeneca, BeiGene, BMS, Incyte, Janssen, Kite/Gilead, Kyowa Kirin, MSD, Novartis, Recordati, Roche, Sandoz, Secura Bio, SERVIER, SOBI, and Takeda Other remuneration: AstraZeneca, BeiGene, BMS, Incyte, Janssen, Kite/Gilead, Kyowa Kirin, MSD, Novartis, Recordati, Roche, SERVIER, SOBI, and Takeda M. Keating Consultant or advisory role: Janssen and Roche S. Yoon Consultant or advisory role: Amgen, Antengene, Janssen, Novartis, Regeneron, Sanofi, and Takeda Honoraria: Celgene, Janssen, and Novartis Other remuneration: Chong Kun Dang Pharmaceutical Corp, JW Pharmaceutical Corporation, Kyowa Kirin, Roche/Genentech, and Yuhan C. S. Tam Honoraria: AbbVie, BeiGene, Janssen, and LOXO Other remuneration: AbbVie, BeiGene, and Janssen N. A. Johnson Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Gilead Sciences, Incyte, Lilly, and Roche/Genentech Honoraria: AbbVie, AstraZeneca, and Incyte Other remuneration: Gilead Sciences, Incyte, and Roche E. Szafer-Glusman Employment or leadership position: AbbVie Stock ownership: AbbVie J. Lin Employment or leadership position: AbbVie Stock ownership: AbbVie J. P. Dean Employment or leadership position: AbbVie Stock ownership: AbbVie J. Neuenburg Employment or leadership position: AbbVie Stock ownership: AbbVie G. von Keudell Consultant or advisory role: AbbVie, Incyte, Merck, and Pharmacyclics LLC, an AbbVie Company Honoraria: AbbVie, Incyte, Merck, and Pharmacyclics LLC, an AbbVie Company Other remuneration: AbbVie, Janssen, Merck, Syndax, and TG Therapeutics

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