{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:50:09Z","timestamp":1790686209388,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,12,2]],"date-time":"2018-12-02T00:00:00Z","timestamp":1543708800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Pharmacyclics LLC, an AbbVie Company"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for treatment of various B\u2010cell malignancies. In ibrutinib clinical studies, low\u2010grade haemorrhage was common, whereas major haemorrhage (MH) was infrequent. We analysed the incidence of and risk factors for MH from 15 ibrutinib clinical studies (<jats:italic>N<\/jats:italic>\u00a0=\u00a01768), including 4 randomised controlled trials (RCTs). Rates of any\u2010grade bleeding were similar for single\u2010agent ibrutinib and ibrutinib combinations (39% and 40%). Low\u2010grade bleeding was more common in ibrutinib\u2010treated than comparator\u2010treated patients (35% and 15%), and early low\u2010grade bleeding was not associated with MH. The proportion of MH in RCTs was higher with ibrutinib than comparators (4.4% vs. 2.8%), but after adjusting for longer exposure with ibrutinib (median 13\u00a0months vs. 6\u00a0months), the incidence of MH was similar (3.2 vs. 3.1 per 1000 person\u2010months). MH led to treatment discontinuation in 1% of all ibrutinib\u2010treated patients. Use of anticoagulants and\/or antiplatelets (AC\/AP) during the study was common (~50% of patients) and had an increased exposure\u2010adjusted relative risk for MH in both the total ibrutinib\u2010treated population (1.9; 95% confidence interval, 1.2\u20133.0) and RCT comparator\u2010treated patients (2.4; 95% confidence interval, 1.0\u20135.6), indicating that ibrutinib may not alter the effect of AC\/AP on the risk of MH in B\u2010cell malignancies.<\/jats:p>","DOI":"10.1111\/bjh.15690","type":"journal-article","created":{"date-parts":[[2018,12,3]],"date-time":"2018-12-03T02:25:01Z","timestamp":1543803901000},"page":"558-569","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Incidence of and risk factors for major haemorrhage in patients treated with ibrutinib: An integrated analysis"],"prefix":"10.1111","volume":"184","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-4961","authenticated-orcid":false,"given":"Jennifer R.","family":"Brown","sequence":"first","affiliation":[{"name":"Chronic Lymphocytic Leukemia Center Dana\u2010Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javid","family":"Moslehi","sequence":"additional","affiliation":[{"name":"Vanderbilt\u2010Ingram Cancer Center Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Ewer","sequence":"additional","affiliation":[{"name":"The University of Texas MD Anderson Cancer Center Houston TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Chao Family Comprehensive Cancer Center University of California Irvine Orange CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Ghia","sequence":"additional","affiliation":[{"name":"Strategic Research Program on CLL Universit\u00e0 Vita\u2010Salute San Raffaele Milano and IRCCS Istituto Scientifico San Raffaele Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Cymbalista","sequence":"additional","affiliation":[{"name":"H\u00f4pital Avicenne Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tait D.","family":"Shanafelt","sequence":"additional","affiliation":[{"name":"Mayo Clinic Rochester MN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graeme","family":"Fraser","sequence":"additional","affiliation":[{"name":"Juravinski Cancer Centre McMaster University Hamilton ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8937-6351","authenticated-orcid":false,"given":"Simon","family":"Rule","sequence":"additional","affiliation":[{"name":"Plymouth University Peninsula Schools of Medicine and Dentistry Plymouth UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven E.","family":"Coutre","sequence":"additional","affiliation":[{"name":"Stanford University School of Medicine Stanford CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Sarah","family":"Dilhuydy","sequence":"additional","affiliation":[{"name":"CHU Hopitaux de Bordeaux Pessac France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Cramer","sequence":"additional","affiliation":[{"name":"German CLL Study Group University of Cologne Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Jaeger","sequence":"additional","affiliation":[{"name":"Medical University of Vienna Wien Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Dreyling","sequence":"additional","affiliation":[{"name":"University Hospital LMU Munich Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"The Ohio State University Comprehensive Cancer Center Columbus OH USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6393-6154","authenticated-orcid":false,"given":"Steven","family":"Treon","sequence":"additional","affiliation":[{"name":"Dana\u2010Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily Y.","family":"Liu","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Chang","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amulya","family":"Bista","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama","family":"Vempati","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Boornazian","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph","family":"Valentino","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Reddy","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Mahler","sequence":"additional","affiliation":[{"name":"Janssen Research &amp; Development LLC Raritan NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Yang","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Graef","sequence":"additional","affiliation":[{"name":"Pharmacyclics LLC, an AbbVie Company Sunnyvale CA USA"}],"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 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,12,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(16)30187-6"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-04-1142"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-08-764712"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.171041"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509388"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.306130"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215637"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1400376"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-10-606038"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1509981"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.35.15_suppl.7510"},{"key":"e_1_2_8_13_1","first-page":"4326","article-title":"Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in hematologic malignancies","volume":"130","author":"Byrd J.C.","year":"2017","journal-title":"Blood"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2016001883"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00465-9"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1431"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00667-4"},{"key":"e_1_2_8_18_1","doi-asserted-by":"crossref","first-page":"3268","DOI":"10.1182\/blood.V126.23.3268.3268","article-title":"Incidence of major hemorrhage among CLL and MCL patients compared to the general elderly population: an analysis of the US SEER\u2010medicare linked database","volume":"126","author":"Gifkins D.M.","year":"2015","journal-title":"Blood"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14660"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.247"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.316"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V128.22.3229.3229"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-06-583294"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2015.126672"},{"key":"e_1_2_8_25_1","doi-asserted-by":"crossref","first-page":"4387","DOI":"10.1182\/blood.V128.22.4387.4387","article-title":"Major bleeding complications among patients treated with ibrutinib and concomitant antiplatelet, anticoagulant, or supplemental therapy","volume":"128","author":"Pavlik A.","year":"2016","journal-title":"Blood"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.10-0134"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2005.01204.x"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2438_97"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13651"},{"key":"e_1_2_8_30_1","first-page":"152","article-title":"Safety and activity of the highly specific BTK inhibitor BGB\u20103111 in patients with indolent and aggressive non Hodgkin's lymphoma","volume":"130","author":"Tam C.S.","year":"2017","journal-title":"Blood"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1501548"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-08-664086"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1306220"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-03-635326"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017009720"},{"key":"e_1_2_8_36_1","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.1182\/blood.V124.21.3296.3296","article-title":"Elucidation of mild bleeding disorders reported under ibrutinib (Imbruvica(R)) therapy: implications for optimal clinical management","volume":"124","author":"Ysebaert L.","year":"2014","journal-title":"Blood"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2016.09.010"}],"container-title":["British Journal of Haematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjh.15690","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.15690","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bjh.15690","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bjh.15690","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,9]],"date-time":"2023-09-09T22:03:28Z","timestamp":1694297008000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bjh.15690"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,12,2]]},"references-count":36,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1111\/bjh.15690"],"URL":"https:\/\/doi.org\/10.1111\/bjh.15690","archive":["Portico"],"relation":{},"ISSN":["0007-1048","1365-2141"],"issn-type":[{"value":"0007-1048","type":"print"},{"value":"1365-2141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,12,2]]},"assertion":[{"value":"2018-08-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-12-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}