Retrospective Study Shows Frontline Zanubrutinib Associated With Fewer Cardiac AEs vs Ibrutinib and Acalabrutinib in CLL/SLL

Simon Blanc, MD

Findings from a real-world analysis of frontline BTK inhibitor treatment patterns for United States (US) patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), showed that the incidence of cardiovascular adverse effects (AEs) 6 months after treatment initiation was higher among patients who received ibrutinib (Imbruvica) or acalabrutinib (Calquence) compared with those treated with zanubrutinib (Brukinsa).¹ These findings were presented during the 28th International Congress on Hematologic Malignancies.

A total of 2465 patients were included in the retrospective analysis who were previously treated with ibrutinib (n = 1314), acalabrutinib (n = 1068), or zanubrutinib (n = 83). Among patients who underwent a follow-up of at least 3 months after BTK inhibitor initiation, the incidence of cardiac AEs was highest in those treated with ibrutinib at 10.1% (n = 106/1048), followed by acalabrutinib and zanubrutinib at 7.3% each (acalabrutinib, n = 56/767; zanubrutinib, n = 5/69). In patients with at least 6 months of follow-up, the rates of cardiovascular AEs were 13.4% for ibrutinib (n = 123/921), 9.8% for acalabrutinib (n = 62/631), and 7.5% for zanubrutinib (n = 3/40).

Notably, given the FDA's approval of zanubrutinib for the treatment of patients with CLL/SLL in January 2023,² the sample size for zanubrutinib in this retrospective study was comparatively smaller with limited follow-up compared with ibrutinib and acalabrutinib, which study authors noted as a potential limitation for this study. Ibrutinib and acalabrutinib were approved by the regulatory agency for the frontline treatment of patients with CLL in March 2016 and November 2019, respectively.^3,4

In the current National Comprehensive Cancer Network Guidelines, the second-generation BTK inhibitors acalabrutinib (with or without obinutuzumab [Gazyva]) and zanubrutinib are listed as preferred frontline treatment options for patients with CLL/SLL, along with venetoclax (Venclexta) plus obinutuzumab.⁵ Ibrutinib, a first-generation BTK inhibitor, is listed under other recommended regimens.

In this real-world study, investigators examined the clinical characteristics, treatment patterns, and AEs associated for patients with CLL/SLL who were treated with 1 of the 3 BTK inhibitors in the frontline setting.¹

Investigators utilized the IntegraConnect-PrecisionQ database, which comprises de-identified electronic health records, practice management, and claims data sourced from 55 practices and over 1600 providers within the community oncology setting across the US.

Data were gathered for patients 18 years of age and older diagnosed with CLL or SLL who initiated treatment between January 1, 2020, and February 28, 2023, with follow-up data collected through May 31, 2023. Eligible patients were required to have at least 5 CLL/SLL visits or more vs non-CLL/SLL visits, and all patients needed to have undergone 2 or more evaluation and management visits.

The objectives of the analysis were to identify patient demographics and baseline characteristics; incidence of cardiac AEs; time to next treatment (TTNT); and time to treatment discontinuation or death (TTD).

Investigators identified 5911 patients who initiated first-line therapy; 2465 patients received a BTK inhibitor in the first line compared with 3,446 patients who were not administered a BTK inhibitor–containing regimen in the first line. Among those who did not receive BTK inhibitor in the first line, 185 patients went on to receive a BTK inhibitor in later lines.

The median age was 71 years (range, 35-89) for patients who received ibrutinib, 72 years (range, 37-89) for those given acalabrutinib, and 73 years (range, 40-88) for patients administered zanubrutinib. The majority of patients across all treatments were male and White. Furthermore, an ECOG performance status of 0 or 1 was seen in 90.2% of patients in the ibrutinib group, 88.6% of patients in the acalabrutinib group, and 85.2% of patients in the zanubrutinib group.

The 3-month follow-up rates were 79.7%, 71.8%, and 83.1% for ibrutinib, acalabrutinib, and zanubrutinib, respectively. The 6-month follow-up rates were 70.1%, 59.1%, and 48.1%, respectively, and the median duration of follow-up was 19.1 months (95% CI, 0.4-41.5), 13.1 months (95% CI, 0.1-40.4), and 7.4 months (95% CI, 1.4-26.6), respectively. The main comorbidities seen were chronic pulmonary disease (ibrutinib, 2.4%; acalabrutinib, 3.2%; zanubrutinib, 3.6%), diabetes without chronic complications (4.4%; 3.9%; 2.4%), diabetes with chronic complications (1.8%; 1.1%; 0%), gastroesophageal reflux disease (4.4%; 3.7%; 2.4%), gastrointestinal disease (7.8%; 8.1%; 6%), renal disease (3.9%; 5.1%, 0%), and iron-deficient anemia (4.6%; 5.8%; 1.2%).

Additionally, any cardiovascular comorbidities were observed in 16.1%, 16.7%, and 12% of patients treated with ibrutinib, acalabrutinib, and zanubrutinib, respectively. Cardiovascular comorbidities included acute ischemic heart disease (ibrutinib, 0.2%; acalabrutinib, 0.1%; zanubrutinib, 0%), atrial fibrillation (3.2%; 3.5%; 3.6%), bleeding (0.1%; 0,3%; 0%), cardiac arrest (0%; 0.1%; 0%), cardiac arrhythmia (0.8%; 0.2%; 0%), hypertension (14.5%; 14.7%; 9.6%), myocardial infarction (0.5%; 0.9%; 0%), stroke (0.5%; 0.5%; 0%), ventricular tachyarrhythmia (0.2%; 0.1%; 0%), atrial flutter (0.5%; 0.7%; 0%), congestive heart failure (0.3%; 0.7%; 0%), ischemic stroke (cerebral infarction; 0.2%; 0.5%; 0%), left ventricular dysfunction (0.1%; 0.2%; 0%), ventricular tachycardia (0.%; 0.1%; 0%), and angina pectoris (0.3%; 0%; 0%).

Regarding all patients who received BTK inhibitors in the frontline setting, the distribution of treatment regimens showed that 53.3% of patients were prescribed ibrutinib, 43.3% received acalabrutinib, and 3.4%, were administered zanubrutinib. In patients who received a BTK inhibitor in subsequent lines of treatment after undergoing a non–BTK inhibitor–based regimen in the front line, 45.9% were given ibrutinib, 42.7% received acalabrutinib, and 11.4% were administered zanubrutinib.

Additional data showed that patients treated with frontline zanubrutinib experienced a median TTNT that was not reached (NR; 95% CI, 12.6-NR) compared with 31.3 months (95% CI, 26.5-35.5) for patients in the ibrutinib group and 35.8 months (95% CI, 31.8-NR) for those in the acalabrutinib group.

In the frontline setting, the median time to TTD was 12.7 months (95% CI, 11.7-15.3) for ibrutinib, 15.7 months (95% CI, 12.0-20.4) for acalabrutinib, and 12.9 months (95% CI, 10.3-NR) for zanubrutinib. Additionally, the percentage of patients continuing treatment at the 6– and 12-month marks was highest with zanubrutinib at 72.3% and 61.4%, respectively, compared with 62.6% and 53.1% for acalabrutinib at 6 and 12 months, respectively, and 62.3% and 51.9% for ibrutinib at 6 and 12 months, respectively.

References

1. Blanc S, Hou JZ, JR, Maglinte GA, et al. Real-world bruton tyrosine kinase inhibitor (BTKi) treatment patterns among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in us community oncology practices. Presented at: 28th International Congress on Hematologic Malignancies; February 29 to March 3, 2024. Miami, FL.
2. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed April 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
3. Imbruvica (ibrutinib) approved by U.S. FDA for the first-line treatment of chronic lymphocytic leukemia. News release. AbbVie. March 4, 2016. Accessed April 11, 2024. https://news.abbvie.com/2016-03-04-IMBRUVICA-ibrutinib-Approved-by-U-S-FDA-for-the-First-line-Treatment-of-Chronic-Lymphocytic-Leukemia
4. Project Orbis: FDA approves acalabrutinib for CLL and SLL. FDA. November 21, 2019. Accessed April 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll
5. NCCN clinical practice guidelines in oncology (NCCN guidelines): chronic lymphocytic leukemia/small lymphocytic lymphoma. NCCN. March 26, 2024. Accessed April 11, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf