Impact of Baseline Comorbidities and Treatment on Cardiovascular (CV) Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL): Results of a Systematic Literature Review (SLR) of Interventional Trials and a Targeted Literature Review (TLR) of Real-World Observational Studies in CLL
Authors: Chen Yen-Chou , Palhares De Miranda Paulo Andre P. , Sile Bersabeh , Fox Grace , Chukwu Chinenye , Moslehi Javid J. , O'Quinn Rupal 
Published: December 2023

Background: Ibrutinib, the first Bruton tyrosine kinase inhibitor (BTKi) indicated for CLL, has been associated with a higher risk of CV events, including atrial fibrillation (AF) and hypertension, vs non-BTKi active comparators and placebo. In a phase 3 clinical trial of patients (pts) with CLL comparing ibrutinib with acalabrutinib-a more selective, second-generation BTKi-CV event incidence was numerically higher with ibrutinib and the incidence and cumulative risk of AF were significantly higher with ibrutinib (Byrd JC et al. J Clin Oncol. 2021;39:3441-52). Ibrutinib's toxicity profile prompted changes to its prescribing information and lowered its recommendation status in current CLL guidelines. We conducted an SLR of interventional trials in CLL followed by a supplemental TLR of observational studies in CLL to explore the extent to which CV outcomes of pts with CLL are driven by their baseline comorbidities or treatments.

Methods: Embase and MEDLINE were searched to identify evidence in peer-reviewed journals (cutoff date: June 23, 2023). For the SLR, limits were English articles published in 2012 or later, and inclusion criteria specified phase 2/3 interventional trials in adults aged ≥18 y with treatment-naive or relapsed/refractory CLL. Treatments included BTKis, BCL-2 inhibitors, and chemoimmunotherapy. CV outcomes were arrhythmia, heart failure, major adverse CV events, major bleeding, myocardial infarction, stroke, sudden cardiac death, and venous thromboembolism. For the TLR, language and time limits were analogous to the SLR. Additional limits were observational studies with &gt;70% CLL pts receiving any or no treatment. The TLR assessed baseline CV events/risk, including arrhythmia, heart failure, major adverse CV events, major bleeding, myocardial infarction, stroke, sudden cardiac death, and venous thromboembolism.

Results: The SLR yielded 55 studies. Among the phase 3 randomized controlled trials, incidence ranges were 0%-16% for AF/atrial flutter, 0%-6.9% for heart failure, and 0%-11% for major bleeding; rates were generally higher with BTKis, among which ibrutinib appeared to be associated with the highest rates ( Figure 1). CV data from the SLR were sparse and heterogeneous, primarily due to limited baseline CV risk reporting and substantial variability in CV adverse event reporting. To clarify relationships of CV risk with treatment, we performed the TLR, which yielded 24 studies. Analysis of baseline CV risk reported in the observational studies yielded several key findings ( Figure 2): 1) in pts with CLL, the risk of CV events, including AF, increased with age; in pts aged 65−74 y and ≥65 y, the reported risk of AF was 2.4-fold and 2.8-fold higher, respectively, than that of pts aged &lt;65 y (Shanafelt TD et al. Leuk Lymphoma. 2017;58:1630-9; Visentin A et al. Hematol Oncol. 2019;37:508-12); 2) baseline CV risk was similarly high in pts with CLL and matched non-CLL comparators (Larsson K et al. Am J Hematol. 2022;97:E255-7); 3) ibrutinib was associated with a higher risk of CV disease relative to chemotherapy, even when prior AF, age, and anticoagulant exposure were controlled for (Abdel-Qadir H et al. J Clin Oncol. 2021;39:3453-62). In ibrutinib-treated pts with a B-cell malignancy followed in cardio-oncology clinics (N=53; n=38 CLL), median time to new onset of ibrutinib-related AF was 5.5 mo; AF incidence was 15-fold higher in ibrutinib-treated pts overall vs that expected in an age- and sex-comparable general population and in ibrutinib-treated pts with CLL vs that expected in pts with CLL and no ibrutinib treatment (Baptiste F et al. Open Heart. 2019;6:e001049).

Conclusions: CLL primarily affects the elderly, who are at higher risk of CV events vs a younger demographic. Results suggest that some pts with CLL have an increased risk of adverse CV outcomes; thus, it would be inaccurate to attribute the higher rates of CV events observed in pts with CLL solely to their treatment as it is plausible that pts with CLL already have an elevated CV risk contributing to such outcomes. However, our findings suggest that the first-generation BTKi (ibrutinib) may impact CV outcomes in these pts; data examining the CV risk of second-generation BTKis and other novel therapies (eg, venetoclax) are limited. Future research that consistently estimates baseline CV risk and closely monitors CV parameters in pts with CLL is required to ascertain the true risk of CV disease due to CLL treatment.