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Clinical Trial
. 2019 Jun 25;3(12):1799-1807.
doi: 10.1182/bloodadvances.2018028761.

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

Steven E Coutre  1 , John C Byrd  2 , Peter Hillmen  3 , Jacqueline C Barrientos  4 , Paul M Barr  5 , Stephen Devereux  6 , Tadeusz Robak  7 , Thomas J Kipps  8 , Anna Schuh  9 , Carol Moreno  10 , Richard R Furman  11 , Jan A Burger  12 , Michael O'Dwyer  13 , Paolo Ghia  14 , Rudolph Valentino  15 , Stephen Chang  15 , James P Dean  15 , Danelle F James  15 , Susan M O'Brien  16
Affiliations
Clinical Trial

Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

Steven E Coutre et al. Blood Adv. .

Abstract

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

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Conflict of interest statement

Conflict-of-interest disclosure: S.E.C. has received honoraria from Janssen and Pharmacyclics LLC, an AbbVie company; consulted/advised for AbbVie, BeiGene, and Janssen; and received research funding from AbbVie, Pharmacyclics LLC, an AbbVie Company, Gilead, Janssen, and Acerta. J. C. Byrd has received research funding from Acerta, Genentech, Janssen, and Pharmacyclics LLC, an AbbVie Company. P.H. has consulted/advised for and received honoraria and research funding from AbbVie, Pharmacyclics LLC, an AbbVie Company, and Janssen and received travel expenses from AbbVie and Janssen. J. C. Barrientos has consulted/advised for AbbVie, Gilead, Pharmacyclics LLC, an AbbVie Company, and Janssen and received research funding from AbbVie, Gilead, and Pharmacyclics LLC, an AbbVie Company. P.M.B. has consulted/advised for and received research funding from Pharmacyclics LLC, an AbbVie Company. S.D. has consulted/advised for Janssen, AbbVie, GlaxoSmithKline, and Bristol-Myers Squibb and received travel expenses from and served on the speakers’ bureau for Janssen and Gilead. T.R. has received research funding from Pharmacyclics LLC, an AbbVie Company. T.J.K. has consulted/advised for AbbVie, Genentech-Roche, Gilead, Celgene, and Pharmacyclics LLC, an AbbVie Company, and received research funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an AbbVie Company, and Oncternal. A.S. has consulted/advised for Roche, Gilead, Janssen, AbbVie, Pharmacyclics LLC, an AbbVie Company, and Novartis and received research funding and travel expenses from Janssen, Gilead, and AbbVie. C.M. has consulted/advised for Janssen, AbbVie, and Pharmacyclics LLC, an AbbVie Company. R.R.F. has consulted/advised for AbbVie, Acerta, Genentech, Gilead, Incyte, Loxo Oncology, Janssen, Pharmacyclics LLC, an AbbVie Company, Sunesis, TG Therapeutics, and Verastem and served on a Data Safety and Monitoring Board for Incyte. J.A.B. has received honoraria and has consulted/advised for Janssen; received travel/accommodation expenses from and served on speakers’ bureau for Gilead, Janssen, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics; and received research funding from BeiGene, Gilead, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics. M.O. has stock ownership and holds patents, royalties, or other intellectual property with Onkimmune Ltd.; received honoraria from and consulted/advised for Janssen; received research funding from Janssen, Celgene, and GlycoMimetics; and received travel expenses from Celgene. P.G. has received honoraria from AbbVie, Acerta, BeiGene, Celgene, Gilead, Janssen, Roche, and Sunesis; consulted/advised for AbbVie, Acerta, BeiGene, Celgene, Gilead, Janssen, Pharmacyclics LLC, an AbbVie Company, and Sunesis; received research funding from AbbVie, Gilead, Janssen, and Novartis; and served on the speakers’ bureau for Gilead. R.V. is employed and serves in a leadership role with Pharmacyclics LLC, an AbbVie Company, and has stock ownership in AbbVie and Gilead. S.C. is employed by Pharmacyclics LLC, an AbbVie Company, and has stock ownership in AbbVie, Johnson & Johnson, Abbott, Ipsen, and Portola. J.P.D. is employed by Pharmacyclics LLC, an AbbVie Company, has been employed by CTI BioPharma Corp., and has stock ownership in AbbVie and CTI BioPharma Corp. D.F.J. is employed by Pharmacyclics LLC, an AbbVie Company; has stock ownership in and holds patents, royalties, or other intellectual property with AbbVie; and her husband is employed by and has stock ownership in AbbVie. S.M.O. has consulted/advised for AbbVie, Alexion, Amgen, Aptose Biosciences, Inc., Astellas, Celgene, Gilead, GlaxoSmithKline, Janssen Oncology, Pfizer, Pharmacyclics LLC, an AbbVie Company, Sunesis, TG Therapeutics, and Vaniam Group LLC and received research funding from Acerta, Gilead, Kite, Pfizer, Pharmacyclics LLC, an AbbVie Company, Regeneron, Sunesis, and TG Therapeutics.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Most common treatment-emergent AEs in the integrated safety analysis (N = 330). AEs of any grade occurring in >15% of patients or grade 3/4 AEs occurring in >3% of patients are shown. *Muscle spasm and constipation included 1 (<1%) grade 3/4 AE each, and febrile neutropenia included 1 (<1%) grade 1/2 (AEs not shown).
Figure 2.
Figure 2.
Most common grade 3/4 AEs in the PCYC-1102/1103 long-term cohort (n = 94). Grade 3/4 AEs occurring in >3% of patients are shown.
See this image and copyright information in PMC

References

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