Bruton's Tyrosine Kinase Inhibition Is Associated with Manageable Cardiac Toxicity

Introduction: Ibrutinib (Ibr) is a small molecule that effectively targets B cell malignancies by inhibiting Bruton's tyrosine kinase activity (BTK). Clinical studies have shown a consistent increase in OS, PFS and response rate for relapsed-refractory CLL and mantle cell lymphoma (MCL) with variable cardiac toxicity (CT) (Table 1). Methods: Retrospective analysis of pts treated at The Abramson Cancer Center at the University of Pennsylvania to identify the incidence and characteristics of Ibr related CT. Results: We identified 32 pts treated with Ibr (87.6% CLL, 6.2 MCL, 6.2% other). The median age was 65 yrs (47-83). 53% of patients had a prior history of cardiovascular (CV) comorbidities: 16% hypertension (HTN), 3 % arrhythmia, 9% CAD, 0% with heart failure. During the course of therapy, we identified 11 pts (mean age 69.6 yrs; range 51-83) with presumed Ibr-induced CT: 5 with AF (16%), 4 patients with aggravation of pre-existing HTN (13%), 1 with sinus bradycardia (3%), and 1 with unexplained syncope (3%). 88% were male and all had at least one cardiac co-morbidity. The median time to onset of AF was 197 days (63-358) and acceleration of HTN 42 days (27-57). All of the HTN patients had pre-existing HTN and of the 5 pts with AF, 2 had a history of HTN, 2 PAF, and 3 CAD. All patients were co-managed by the treating oncologist and cardiologist. Successful management of CT did not require Ibr discontinuation in all pts. We observed no arrhythmia or treatment related embolic/bleeding events; AF pts were all anticoagulated (3% warfarin, 87% novel antithrombotic drug). In 2/5 AF pts, Ibr dose was reduced. BTK inhibition may induce unique CT by affecting the regulation of off target kinases with BTK selectivity (Table 2). Table 3 provides recommendations for management of Ibr related CT for the practicing oncologist. Conclusions: We identified a 34% incidence of Ibr related CT. These results are unique in that we provide long-term follow up of such events and demonstrate that in practice, Ibr related CT can successfully be managed by the medical oncologist / cardio-oncology team. No pts discontinued Ibr in this series due to CT events. Pre-existing CV disease is a major risk factor for Ibr-related AF and HTN. The absence of cardiac co-morbidity may have negative predictive value. In conclusion, there is a potential for CT in elderly patients with pre-existing cardiac disease and HTN treated with Ibr. This suggests the need for proactive co-management of these patients with cardiologists trained in cardio-oncology. | Cardiac Event | CLL (Byrd, 2013) | MCL (Wang, 2014) | RESONATE (Byrd, 2014) | Follow-up analysis (Byrd, 2015) | | ---------------------------- | ------------------------ | ------------------------ | ----------------------------- | --------------------------------------- | | AF | 3 (4%) | 5 (4.5%) | 6 (3%) | 8 (6%) | | Peripheral edema | 18 (21%) | 3 (2.7%) | 22 (11%) | NA | | Hypertension | 5 (11%) | NA | NA | 27 (20%) | | Dyspnea | NA | 30 (27%) | 23 (12%) | NA | | Supraventricular tachycardia | 1 (1%) | NA | NA | NA | Table 1. Reported CT among CLL/ mantle cell lymphoma pts | Protein | Relation to BCR signaling | Proposed mechanism | Clinical CT | || | Phosphatidylinositol 3-kinase (PI3K) | Upstream activator and downstream substrate of BTK | Alter gene expression in ventricular tissue; Compromised regulation of autonomic calcium oscillations in cardiac cells to alter automaticity | AF, Hemodynamic compromise, Bradycardia | | Heat shock protein 70 | Decreased HSP 70 levels in response to attenuated PI3K activity | Compromised role in cardiac remodeling under pressure overload or stress | AF, hypertension | | Phospholipase C gamma 2 (PLCγ-2) | Downstream protein activated by BTK in BCR signaling | Attenuated activation of PLCγ-2 compromises calcium signaling | AF, cardiac arrhythmia | Table 2. Possible mechanisms of Ibr-related CT | AF | Exclude hyperthyroidism Consider Ibr dose reduction Rate control beta or calcium channel blocker. Start at low dose, uptitrate to HR < 100. If limited by hypotension, consider digoxin CVA Prevention with anticoagulation based on CHA2DS2-VASC score | || | HTN | ACE inhibitors and/or calcium channel blockers as first line | | Bradycardia | Differentiate whether pt is symptomatic If asymptomatic and HR increases appropriately with exertion, no further evaluation or treatment necessary Avoid negative chronotropic medications | Table 3. Penn recommendations for management of Ibr treated patients with CT Disclosures Schuster: Novartis: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Hoffman-LaRoche: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees. Svoboda: Seattle Genetics: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Celldex: Research Funding. Rago: Gilead Sciences: Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees. Mato: Genentech: Consultancy; Gilead: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pronai Pharmaceuticals: Research Funding; Pharmacyclics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding.