Acalabrutinib, a next-generation Bruton's tyrosine kinase inhibitor (BTKi), associates with dramatic efficacy against B-cell malignancies. Recently, unexplained ventricular arrhythmias (VAs) with next-generation BTKi-therapy have been reported. Yet, whether acalabrutinib associates with VAs in long-term follow-up is unknown. Leveraging a large cohort of 290 consecutive B-cell malignancy patients treated with acalabrutinib from 2014-2020, we assessed the incidence of VAs. The primary endpoint was incident VA-development, including ventricular fibrillation, ventricular tachycardia, and symptomatic premature ventricular-contractions. Probability Scores were assessed to determine likelihood of acalabrutinib-association. Incident rates as a function of time-on-therapy were calculated. Weighted average observed incidence rates were compared to expected population rates using relative risks. Absolute excess risk (AER) for acalabrutinib-associated VAs was estimated. Over 1,063 person-years of follow-up, there were 8 cases of incident VAs, including 6 in those without coronary-disease (CAD) or heart-failure (HF), and 1 sudden death; median time-to-event was 14.9 months. Among those without prior ibrutinib-use, CAD, or HF, the weighted average incidence was 394 per 100,000 person-years compared to a reported incidence of 48.1 among similar-aged non-BTKi-treated subjects (RR 8.2, P<0.001; AER 346). Outside of age, no cardiac or electrocardiographic variables associated with VA-development. Collectively, these data suggest VAs may be a class-effect of BTKi-therapies.
Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. Conclusions Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.
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.
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