{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T16:21:02Z","timestamp":1794673262263,"version":"4.9.1"},"reference-count":31,"publisher":"American Society of Hematology","issue":"12","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,6,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 \u22653 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.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018028761","type":"journal-article","created":{"date-parts":[[2019,6,13]],"date-time":"2019-06-13T16:45:26Z","timestamp":1560444326000},"page":"1799-1807","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":128,"title":["Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies"],"prefix":"10.1182","volume":"3","author":[{"given":"Steven E.","family":"Coutre","sequence":"first","affiliation":[{"name":"Stanford University School of Medicine, Stanford, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center, Columbus, OH;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hillmen","sequence":"additional","affiliation":[{"name":"Leeds Cancer Centre, St. James\u2019s Institute of Oncology, Leeds, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline C.","family":"Barrientos","sequence":"additional","affiliation":[{"name":"Hofstra Northwell School of Medicine, Hempstead, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Barr","sequence":"additional","affiliation":[{"name":"Wilmot Cancer Institute, University of Rochester Cancer Center, Rochester, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Devereux","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospital, National Health Service Foundation Trust, London, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadeusz","family":"Robak","sequence":"additional","affiliation":[{"name":"Medical University of Lodz, Lodz, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Kipps","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego, La Jolla, CA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Schuh","sequence":"additional","affiliation":[{"name":"Oxford National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Moreno","sequence":"additional","affiliation":[{"name":"Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard R.","family":"Furman","sequence":"additional","affiliation":[{"name":"Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-7572","authenticated-orcid":false,"given":"Jan A.","family":"Burger","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center, Houston, TX;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6173-7140","authenticated-orcid":false,"given":"Michael","family":"O\u2019Dwyer","sequence":"additional","affiliation":[{"name":"University College Hospital Galway, Galway, Ireland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-7342","authenticated-orcid":false,"given":"Paolo","family":"Ghia","sequence":"additional","affiliation":[{"name":"Universit\u00e0 Vita-Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph","family":"Valentino","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; 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