Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials
Harvard University1, Vanderbilt University2, University of California, Irvine3, Vita-Salute San Raffaele University4, French Institute of Health and Medical Research5, Mayo Clinic6, McMaster University7, University of Plymouth8, University of California, San Diego9, Stanford University10, University of Cologne11, Medical University of Vienna12, Ludwig Maximilian University of Munich13, Ohio State University14, Janssen Pharmaceutica15, University of Texas MD Anderson Cancer Center16
TL;DR: The results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation, and the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset.
Abstract: The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).
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TL;DR: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL.
Abstract: Background Data regarding the efficacy of treatment with ibrutinib–rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients wi...
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339 citations
Memorial Sloan Kettering Cancer Center1, BC Cancer Agency2, University of Southampton3, University of Bologna4, Fudan University5, Peking University6, Charles University in Prague7, University of Ulsan8, University of Helsinki9, Kindai University10, Ondokuz Mayıs University11, Jagiellonian University12, Rabin Medical Center13, Tel Aviv University14, China Medical University (Taiwan)15, Hebron University16, Sorbonne17, Janssen Pharmaceutica18, National Institutes of Health19
TL;DR: The study did not meet its primary end point in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup, but in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety.
Abstract: PURPOSEIbrutinib has shown activity in non–germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, d...
320 citations
Cites background from "Characterization of atrial fibrilla..."
...2%).(20) Aspergillus infection was reported only in patients age 60 years or older....
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TL;DR: Sustained efficacy and acceptable tolerability of ibrutinib over an extended time is demonstrated, providing the longest experience for Bruton tyrosine kinase inhibitor treatment in patients with CLL/SLL.
316 citations
University of Texas MD Anderson Cancer Center1, University of Rochester Medical Center2, Medical University of Łódź3, Tom Baker Cancer Centre4, Vita-Salute San Raffaele University5, Rabin Medical Center6, University of Leeds7, Stanford University8, King's College9, North Shore Hospital10, Ghent University Hospital11, Autonomous University of Barcelona12, University of California, San Diego13
TL;DR: Ibrutinib benefit was consistent in patients with high prognostic risk ( TP53 mutation, 11q deletion, and/or unmutated IGHV ) and increased depth of response over time and sustained PFS and OS benefit versus chlorambucil.
Abstract: RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time.
279 citations
References
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TL;DR: This article proposes methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation, but these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function.
Abstract: With explanatory covariates, the standard analysis for competing risks data involves modeling the cause-specific hazard functions via a proportional hazards assumption Unfortunately, the cause-specific hazard function does not have a direct interpretation in terms of survival probabilities for the particular failure type In recent years many clinicians have begun using the cumulative incidence function, the marginal failure probabilities for a particular cause, which is intuitively appealing and more easily explained to the nonstatistician The cumulative incidence is especially relevant in cost-effectiveness analyses in which the survival probabilities are needed to determine treatment utility Previously, authors have considered methods for combining estimates of the cause-specific hazard functions under the proportional hazards formulation However, these methods do not allow the analyst to directly assess the effect of a covariate on the marginal probability function In this article we pro
11,109 citations
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...sion model accounting for deaths and disease progression without prior AF as competing risk events.(5,16) The AF risk score for each...
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TL;DR: This document summarizes current research, plans, and recommendations for future research, as well as providing a history of the field and some of the techniques used, currently in use, at the National Institutes of Health.
Abstract: Jeffrey L. Anderson, MD, FACC, FAHA, Chair
Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect
Nancy M. Albert, PhD, RN, FAHA
Biykem Bozkurt, MD, PhD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC
Mark A. Creager, MD, FACC, FAHA[#][1]
Lesley H. Curtis, PhD, FAHA
David DeMets, PhD[#][1]
Robert A
6,967 citations
TL;DR: In this article, a simple stroke risk stratifi cation schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS 2 schema, with low event rates in low-risk subjects and only a small proportion of subjects into the intermediate-risk category.
5,499 citations
TL;DR: Estimates of expected health outcomes for larger societies are included, where data exist, and the level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales.
Abstract: Guidelines summarize and evaluate all currently available evidence on a particular issue with the aim of assisting physicians in selecting the best management strategy for an individual patient suffering from a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes for textbooks. The legal implications of medical guidelines have been discussed previously.
A large number of Guidelines have been issued in recent years by the European Society of Cardiology (ESC) as well as by other societies and organizations. Because of the impact on clinical practice, quality criteria for development of guidelines have been established in order to make all decisions transparent to the user. The recommendations for formulating and issuing ESC Guidelines can be found on the ESC Web Site (http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx).
In brief, experts in the field are selected and undertake a comprehensive review of the published evidence for management and/or prevention of a given condition. A critical evaluation of diagnostic and therapeutic procedures is performed, including assessment of the risk–benefit ratio. Estimates of expected health outcomes for larger societies are included, where data exist. The level of evidence and the strength of recommendation of particular treatment options are weighed and graded according to pre-defined scales, as outlined in Tables 1 and 2 .
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Table 1
Classes of recommendations
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Table 2
Levels of evidence
The experts of the writing panels have provided disclosure statements of all relationships they may have that might be perceived as real or potential sources of conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. Any changes in conflict of interest that arise during the writing period must be notified to the ESC. The Task Force report received its entire financial support from …
5,329 citations
TL;DR: There was a significant AF-sex interaction: AF diminished the female advantage in survival and AF remained significantly associated with excess mortality, with about a doubling of mortality in both sexes in subjects free of valvular heart disease and preexisting cardiovascular disease.
Abstract: Background—Atrial fibrillation (AF) causes substantial morbidity. It is uncertain whether AF is associated with excess mortality independent of associated cardiac conditions and risk factors. Methods and Results—We examined the mortality of subjects 55 to 94 years of age who developed AF during 40 years of follow-up of the original Framingham Heart Study cohort. Of the original 5209 subjects, 296 men and 325 women (mean ages, 74 and 76 years, respectively) developed AF and met eligibility criteria. By pooled logistic regression, after adjustment for age, hypertension, smoking, diabetes, left ventricular hypertrophy, myocardial infarction, congestive heart failure, valvular heart disease, and stroke or transient ischemic attack, AF was associated with an OR for death of 1.5 (95% CI, 1.2 to 1.8) in men and 1.9 (95% CI, 1.5 to 2.2) in women. The risk of mortality conferred by AF did not significantly vary by age. However, there was a significant AF-sex interaction: AF diminished the female advantage in survi...
4,390 citations