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.