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.

Table 1: Reported CT among CLL/ mantle cell lymphoma pts
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 2: Possible mechanisms of Ibr-related CT
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 3: Penn recommendations for management of Ibr treated patients with 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