Evaluation of the Incidence and Risk Factors Associated with Major Cardiovascular Events in Patients Receiving Acalabrutinib Therapy

Abstract

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<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.

Cardiovascular Toxicities of BTK Inhibitors in Chronic Lymphocytic Leukemia

“… 15 Similar observations were noted in a preliminary acalabrutinib report. 16 In cardiac-focused studies, the presence of left atrial remodeling, marked by atrial dilation, significantly increased the risk for ibrutinib-associated AF events. 11 , 17 The presence of pre-existing cardiovascular disease (CVD) also appears to confer an increased risk of AF events.…”

“…25 Notably, in an evaluation of acalabrutinib-treated hematologic malignancy patients, the development of incident AF and other cardiac events is associated with worse long-term survival. 16 …”

“…Based on the aforementioned and emerging studies and our multidisciplinary experience, we suggest a systematic approach to cardiac consideration before BTK inhibitor treatment initiation. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 This specifically includes obtaining a clear cardiovascular history, including screening for any evidence of baseline palpitations, dyspnea, exertional chest pain, edema, unexplained syncope, or overt arrhythmias. If there is a concern for arrhythmia or prior electrocardiographic evidence of AF, next-generation BTK inhibitor therapies can be considered.…”

“… a Patients who develop cardiotoxic events (ie, AF) higher risk of long-term mortality with BTK inhibitor (ibrutinib, acalabrutinib) therapies. 16 , 23 …”

Bruton’s tyrosine kinase inhibitor-related cardiotoxicity: The quest for predictive biomarkers and improved risk stratification

“…In one meta-analysis of 1,505 ibrutinib-treated patients, age (older than 65) and history of atrial fibrillation were associated with the risk of developing ibrutinib-related atrial fibrillation [ 9 ]. Another study found that history of atrial fibrillation and Framingham Heart Study AF risk score were significantly associated with the development of atrial fibrillation [ 10 ], whereas a similar study found that heart failure and left atrial abnormality on electrocardiogram were independent predictors of atrial fibrillation [ 11 ].…”