Ibrutinib (Ibr) dose modification for management of early cardiac adverse events in patients with chronic lymphocytic leukemia: Pooled analysis of 7 clinical trials

Introduction: Sustained progression-free survival (PFS) has been demonstrated with continuous Ibr-based therapy and with time-limited treatment (tx) with the Ibr + venetoclax (Ven) combination in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Adverse events (AEs), including cardiac AEs, have been observed with all BTK inhibitors; for Ibr, they are more frequent in the first year of tx. Active management of AEs with dose reductions may facilitate continuation of Ibr tx and optimize outcomes. Methods: Pooled data from 1210 evaluable patients from the primary analyses of 7 clinical studies evaluating continuous single-agent Ibr (PCYC-1102 [n = 48]; PCYC-1112 [n = 195]; RESONATE-2 [n = 136]), continuous Ibr-based combination therapy (iLLUMINATE [n = 113]; HELIOS [n = 289]), or time-limited tx with Ibr + Ven (CAPTIVATE [n = 323]; GLOW [n = 106]) were analyzed to evaluate incidence of early cardiac AEs and outcomes of subsequent Ibr dose reductions (for any AE), both occurring within 12 months of Ibr-based tx initiation in patients with CLL/SLL. Cardiac AEs were identified using terms under the system organ class for cardiac disorders. AE recurrence (same or worse grade) was evaluated by preferred term and measured up to 30 days after last dose of Ibr or start of next-line therapy, whichever occurred first. Results: 212 patients had a cardiac AE; the majority were grade 1–2, with only 72 patients having a grade 3–4 cardiac AE. Of those, 52 (25%), 75 (35%), and 85 (40%) patients received single-agent Ibr, Ibr + anti-CD20, and Ibr + Ven, respectively. In total, 17/212 (8%) patients had dose reductions of Ibr (to 280 mg, n = 8; to 140 mg, n = 9); only 4 patients had a dose reduction specifically following a cardiac AE. Among these 17 patients, 3 (18%) received single-agent Ibr, 5 (29%) received Ibr + anti-CD20, and 9 (53%) received Ibr + Ven. Eight of 9 patients (89%) who received Ibr + Ven and had a dose reduction went on to complete tx. Patients with cardiac AEs with versus without dose reductions tended to be older (≥75 y: 29% vs. 19%), were less heavily pretreated (≥1 prior line of tx: 12% vs. 41%), had less bulky disease (29% vs. 42%), and had fewer cytogenetic abnormalities (del[17p]: 6% vs. 12%; del[11q]: 12% vs. 26%; mutated TP53: 0% vs. 9%; Table). Median follow-up was 21.8 and 16.0 months for patients with and without dose reductions, respectively. No patient with a dose reduction had recurrence of the same cardiac AE at the same or worse severity, both overall and as a serious AE (vs 22% and 11% in patients without dose reduction, respectively). No patient died due to recurrence of the same cardiac AE, regardless of dose reduction. PFS was not negatively impacted by dose reduction (n = 17; median PFS not reached, 24-month PFS: 94%). Conclusions: Dose reduction following early cardiac AEs may enable patients to continue benefiting from Ibr tx while mitigating risks for recurrence or worsening of cardiac AEs. The research was funded by: This research was funded by Pharmacyclics LLC, and AbbVie Company. Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. A. Tedeschi Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Janssen Other remuneration: Speakers bureau: AbbVie, AstraZeneca, BeiGene, Janssen G. A. M. Fraser Consultant or advisory role: AbbVie, Janssen Honoraria: AbbVie, Janssen Research funding: Celgene, Janssen Other remuneration: Speakers bureau: Janssen, Lundbeck R. Greil Consultant or advisory role: AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead Sciences, Janssen, Merck, Merck Sharpe & Dohme, Novartis, Roche, and Takeda Stock ownership: Eli Lilly Honoraria: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Gilead Sciences, Merck Sharpe & Dohme, Novartis, and Sandor Research funding: Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Gilead Sciences, Merck, Merck Sharpe & Dohme, Novartis, Roche, Sandor, and Takeda Other remuneration: travel/accommodations/expenses from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, Gilead Sciences, Janssen, Merck Sharpe & Dohme, Novartis, and Roche T. Munir Consultant or advisory role: MorphoSys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead Sciences, Janssen, and Novartis Other remuneration: travel/accommodations/expenses from AbbVie, Gilead Sciences, and Janssen N. E. Kay Research funding: AbbVie, AstraZeneca, MEI, and Pharmacyclics, an AbbVie company I. W. Flinn Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Century Therapeutics, Genentech, Genmab, Gilead Sciences, Great Point Partners, Hutchison MediPharma, Iksuda Therapeutics, InnoCare Pharma, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Novartis, Nurix Therapeutics, Pharmacyclics, Roche, Seattle Genetics, Servier Pharmaceuticals, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, Vincerx Pharma, Yingli Pharmaceuticals Research funding: AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Curis, Forma Therapeutics, Forty Seven, Genentech, Gilead Sciences, IGM Biosciences, Incyte, Infinity Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, Novartis, Pfizer, Pharmacyclics, Portola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium Therapeutics, Triphase Research & Development Corp., Unum Therapeutics, Verastem S. Lee Employment or leadership position: AbbVie, Pharmacyclics LLC, an AbbVie company, and Regeneron Stock ownership: AbbVie C. Saifan Employment or leadership position: AbbVie Stock ownership: AbbVie J. Kearbey Employment or leadership position: AbbVie, Bayer Healthcare Stock ownership: AbbVie, Merck, Eli Lilly Other remuneration: Patents/royalties: The Ohio State University S. Patel Employment or leadership position: AbbVie Stock ownership: AbbVie J. C. Barrientos Consultant or advisory role: BeiGene, AbbVie, AstraZeneca, MEI Honoraria: Janssen Research funding: Merck, Oncternal, Pharmacyclics LLC, an AbbVie company, and Velosbio

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