Evaluation of the Incidence and Risk Factors Associated with Major Cardiovascular Events in Patients Receiving Acalabrutinib Therapy
Authors: Azali Leylah , Hazelden Lindsay , Wiczer Tracy , Palettas Marilly , Thomas Rebekah , Aossey Connor , Blachly James S. , Grever Michael R. , Kittai Adam S. , Rogers Kerry A. , Byrd John C. , Woyach Jennifer A. , Addison Daniel , Bhat Seema A 
Published: November 2020

Background
Acalabrutinib is a highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Ibrutinib, the first-generation nonselective BTK inhibitor, has been associated with cardiovascular (CV) complications including atrial fibrillation and ventricular arrhythmias, potentially related to off-target effects. In prior studies, the incidence of major adverse cardiovascular effects (MACE) with ibrutinib was 16.5-38%. With acalabrutinib being more selective, we postulate that less of these off-target effects would be seen. Although early experience with acalabrutinib suggests improved tolerability compared to ibrutinib, the long-term CV risks are unknown. Therefore, we sought to characterize the incidence, risk factors, and management of CV complications associated with acalabrutinib across long-term follow-up.
Methods
We performed a retrospective single-center cohort study of adult patients treated with acalabrutinib for a hematologic malignancy from January 2010 to August 2019. Patient demographics, CV and cancer variables, and CV complications were collected throughout the duration of acalabrutinib therapy. MACE was defined as cardiac arrhythmias (including atrial and ventricular arrhythmias), myocardial infarction, stroke, heart failure, and CV death. CV events, including arrhythmias, were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), and adjudicated with an independent cardiologist. Descriptive statistics were used to summarize patient characteristics, using the mean ± standard deviation (SD) or median (interquartile range) for continuous variables and frequency counts with percentages for categorical variables. Time-to-event analysis methods were used to summarize MACE outcomes and evaluate associations with these outcomes.
Results
Overall, 290 patients treated with acalabrutinib were identified, majority had CLL (89%), and were male (72%) with a median age of 64 years. Seventy-seven (27%) patients were previously treated with ibrutinib. Sixty-seven percent of patients had a prior cardiac history, including 49% with baseline hypertension (HTN). MACE occurred in 18 patients (6%). Atrial fibrillation was the most common event occurring in 12 patients, followed by diastolic heart failure in 3 patients. There was one ventricular arrhythmic event (0.3%). Forty-four percent of patients temporarily held acalabrutinib during the MACE event, while 50% had no change to their acalabrutinib therapy. After the event, 6% of patients discontinued acalabrutinib and 11% of patients had dose reduced to 100mg daily. Age, gender, diabetes, kidney disease, and smoking status were found to be significantly associated with MACE. The odds of MACE were 1.8 times higher for every 7-year increase in age; when looking at just atrial fibrillation, the odds were 1.58 times higher for every 7-year increase in age. The effect of current smokers compared to never smokers was not significantly associated with MACE, however the odds of MACE were 3.4 higher in former smokers compared to never smokers. In comparison to ibrutinib (Dickerson, et al. Blood, 2019), the rate of MACE was lower- 66 vs 21 events per 1,000 person-years (P&lt;0.05). Of the patients who developed MACE during acalabrutinib treatment, 7 (39%) died. Causes of death were related to infection, respiratory failure, or progression to hospice care. For survival outcomes, 79% of patients were expected to be alive at 3 years post acalabrutinib therapy, and 75% at 5 years. Among patients who experienced a MACE event, survival outcomes were worse (P = 0.046), with 71% of patients expected to be alive at 3 years compared to 50% at 5 years (Figure).
Conclusion
In summary, acalabrutinib was associated with a lower, but significant risk of MACE compared to ibrutinib. The occurrence of these cardiac events appears to associate with worse survival outcomes. Further research into the mechanism(s) of these events, their implications, and the optimal preventative strategies for adverse CV complications after BTK inhibitor initiation is needed.
Figure 1

Disclosures
Blachly: AbbVie, AstraZeneca, KITE Pharma: Consultancy. Rogers:Genentech: Research Funding; Acerta Pharma: Consultancy; Pharmacyclics: Consultancy; AstraZeneca: Consultancy, Other: Travel Funding; Janssen: Research Funding; AbbVie: Consultancy, Research Funding. Byrd:Kartos Therapeutics: Research Funding; Trillium: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Acerta Pharma: Research Funding; Syndax: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. Woyach:AbbVie: Research Funding; Janssen: Consultancy, Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Pharmacyclics: Consultancy, Research Funding; Verastem: Research Funding.