Cardiovascular Magnetic Resonance Imaging in Patients With Ibrutinib-Associated Cardiotoxicity
Authors: Buck Benjamin , Chum Aaron P. , Patel Mitkumar , Carter Rebecca , Nawaz Haseeb , Yildiz Vedat , Ruz Patrick , Wiczer Tracy , Rogers Kerry A. , Awan Farrukh T. , Bhat Seema , Guha Avirup , Kittai Adam S. , Simonetti Orlando P. , Raman Subha V. , Wallace Grant , Sanchez Reynaldo , Bonsu Janice M. , Gambril John , Haddad Devin , Mann James , Wei Lai , Kola-Kehinde Onaopepo , Byrd John C. , Woyach Jennifer A. , Addison Daniel 
Published: February 2023

Importance

Ibrutinib has been associated with serious cardiotoxic arrhythmias. In preclinical models, these events are paralleled or proceeded by diffuse myocardial injury (inflammation and fibrosis). Yet whether this is seen in patients or has implications for future cardiotoxic risk is unknown.

Objective

To assess the incidence and outcomes of myocardial injury among patients with ibrutinib-related cardiotoxicity.

Design, Setting, and Participants

This cohort study included consecutive patients treated with ibrutinib from 2012 to 2019, phenotyped using cardiovascular magnetic resonance (CMR) from a large US Comprehensive Cancer Center registry.

Exposures

Ibrutinib treatment for cancer control.

Main Outcomes and Measures

The primary outcome was the presence of late gadolinium enhancement (LGE) fibrosis. The secondary outcome was the occurrence of major adverse cardiac events (MACE), defined as atrial fibrillation, heart failure, symptomatic ventricular arrhythmias, and sudden death of probable or definite ibrutinib association after CMR. We also assessed parametric-mapping subclinical fibrosis (native-T1, extracellular volume fraction) and inflammation/edema (max-T2) measures. Cardiovascular magnetic resonance measures were compared with those obtained in similar consecutive patients with cancer without ibrutinib treatment (pretreatment controls). Observed measures were also compared with similar-aged broad population rates (general-population controls) and a broader pool of cardiovascular disease (CVD) risk–matched cancer controls. Multivariable regression was used to assess the association between CMR measures and MACE.

Results

Overall, 49 patients treated with ibrutinib were identified, including 33 imaged after treatment initiation (mean [SD] age, 65 [10] years, 9 [27%] with hypertension, and 23 [69.7%] with index-arrhythmias); median duration of ibrutinib-use was 14 months. The mean (SD) pretreatment native T1 was 977.0 (73.0) ms, max-T2 56.5 (4.0) ms, and 4 (13.3%) had LGE. Posttreatment initiation, mean (SD) native T1 was 1033.7 (48.2) ms, max-T2 61.5 (4.8) ms, and 17 (54.8%) had LGE (P &amp;lt; .001, P = .01, and P &amp;lt; .001, respectively, pre- vs post-ibrutinib treatment). Native T12SDs was elevated in 9 (28.6%), and max-T22SDs in 21 (63.0%), respectively. Cardiovascular magnetic resonance measures were highest in those with suspected toxic effects (P = .01 and P = .01, respectively). There was no association between traditional CVD-risk or cancer-treatment status and abnormal CMR measures. Among those without traditional CVD, 16 (58.6%) had LGE vs 38 (13.3%) in matched-controls (relative-risk, 4.8; P &amp;lt; .001). Over a median follow-up of 19 months, 13 (39.4%) experienced MACE. In multivariable models inclusive of traditional CVD risk factors, LGE (hazard ratio [HR], 4.9; P = .04), and native-T12SDs (HR, 3.3; P = .05) associated with higher risks of MACE.

Conclusions and Relevance

In this cohort study, myocardial injury was common in ibrutinib users, and its presence was associated with higher cardiotoxic risk.