PMID- 31196847
OWN - NLM
STAT- MEDLINE
DCOM- 20200615
LR  - 20231012
IS  - 2473-9537 (Electronic)
IS  - 2473-9529 (Print)
IS  - 2473-9529 (Linking)
VI  - 3
IP  - 12
DP  - 2019 Jun 25
TI  - Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic 
      leukemia in 3 pivotal studies.
PG  - 1799-1807
LID - 10.1182/bloodadvances.2018028761 [doi]
AB  - 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.
CI  - (c) 2019 by The American Society of Hematology.
FAU - Coutre, Steven E
AU  - Coutre SE
AD  - Stanford University School of Medicine, Stanford, CA.
FAU - Byrd, John C
AU  - Byrd JC
AD  - The Ohio State University Comprehensive Cancer Center, Columbus, OH.
FAU - Hillmen, Peter
AU  - Hillmen P
AD  - Leeds Cancer Centre, St. James's Institute of Oncology, Leeds, United Kingdom.
FAU - Barrientos, Jacqueline C
AU  - Barrientos JC
AD  - Hofstra Northwell School of Medicine, Hempstead, NY.
FAU - Barr, Paul M
AU  - Barr PM
AD  - Wilmot Cancer Institute, University of Rochester Cancer Center, Rochester, NY.
FAU - Devereux, Stephen
AU  - Devereux S
AD  - King's College Hospital, National Health Service Foundation Trust, London, United 
      Kingdom.
FAU - Robak, Tadeusz
AU  - Robak T
AD  - Medical University of Lodz, Lodz, Poland.
FAU - Kipps, Thomas J
AU  - Kipps TJ
AD  - Moores Cancer Center, University of California San Diego, La Jolla, CA.
FAU - Schuh, Anna
AU  - Schuh A
AD  - Oxford National Institute for Health Research Biomedical Research Centre, 
      University of Oxford, Oxford, United Kingdom.
FAU - Moreno, Carol
AU  - Moreno C
AD  - Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 
      Barcelona, Spain.
FAU - Furman, Richard R
AU  - Furman RR
AD  - Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY.
FAU - Burger, Jan A
AU  - Burger JA
AUID- ORCID: 0000-0002-6177-7572
AD  - The University of Texas MD Anderson Cancer Center, Houston, TX.
FAU - O'Dwyer, Michael
AU  - O'Dwyer M
AUID- ORCID: 0000-0002-6173-7140
AD  - University College Hospital Galway, Galway, Ireland.
FAU - Ghia, Paolo
AU  - Ghia P
AUID- ORCID: 0000-0003-3750-7342
AD  - Universita Vita-Salute San Raffaele and Istituto di Ricovero e Cura a Carattere 
      Scientifico Ospedale San Raffaele, Milan, Italy.
FAU - Valentino, Rudolph
AU  - Valentino R
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
FAU - Chang, Stephen
AU  - Chang S
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
FAU - Dean, James P
AU  - Dean JP
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
FAU - James, Danelle F
AU  - James DF
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; and.
FAU - O'Brien, Susan M
AU  - O'Brien SM
AD  - Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, 
      CA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01578707
SI  - ClinicalTrials.gov/NCT01105247
SI  - ClinicalTrials.gov/NCT01722487
SI  - ClinicalTrials.gov/NCT01724346
SI  - ClinicalTrials.gov/NCT01109069
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R35 CA197734/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood Adv
JT  - Blood advances
JID - 101698425
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 1X70OSD4VX (ibrutinib)
RN  - JAC85A2161 (Adenine)
SB  - IM
MH  - Adenine/analogs & derivatives
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Anemia/chemically induced/epidemiology
MH  - Atrial Fibrillation/chemically induced/epidemiology
MH  - Diarrhea/chemically induced/epidemiology
MH  - Drug Tolerance/physiology
MH  - Fatigue/chemically induced/epidemiology
MH  - Female
MH  - Follow-Up Studies
MH  - Hemorrhage/chemically induced/epidemiology
MH  - Humans
MH  - Hypertension/chemically induced/epidemiology
MH  - Infections/chemically induced/epidemiology
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy
MH  - Male
MH  - Middle Aged
MH  - Neutropenia/chemically induced/epidemiology
MH  - Piperidines
MH  - Pneumonia/chemically induced/epidemiology
MH  - Prevalence
MH  - Protein Kinase Inhibitors/administration & dosage/*adverse effects/*therapeutic 
      use
MH  - Pyrazoles/administration & dosage/*adverse effects/*therapeutic use
MH  - Pyrimidines/administration & dosage/*adverse effects/*therapeutic use
MH  - Safety
PMC - PMC6595265
COIS- 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.
EDAT- 2019/06/15 06:00
MHDA- 2020/06/17 06:00
PMCR- 2019/06/13
CRDT- 2019/06/15 06:00
PHST- 2018/11/19 00:00 [received]
PHST- 2019/04/01 00:00 [accepted]
PHST- 2019/06/15 06:00 [entrez]
PHST- 2019/06/15 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2019/06/13 00:00 [pmc-release]
AID - bloodadvances.2018028761 [pii]
AID - 2018/028761 [pii]
AID - 10.1182/bloodadvances.2018028761 [doi]
PST - ppublish
SO  - Blood Adv. 2019 Jun 25;3(12):1799-1807. doi: 10.1182/bloodadvances.2018028761.