BTK Inhibitor Discontinuation Outpaces CLL Trials in Community Care

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who began first-line covalent Bruton tyrosine kinase inhibitors (cBTKis) in US community oncology practices stopped treatment more often than patients in pivotal trials, and adverse events (AEs) were the most frequently documented reason, according to a retrospective cohort study published in eJHaem.¹ The estimated probability of discontinuation by 24 months was 51.2% across the 584-patient cohort, and 238 of 385 patients (61.8%) who stopped first-line treatment did not go on to receive a second-line regimen.

“In particular, older patients in this real‑world CLL/SLL cohort demonstrated consistently poorer outcomes across key clinical end points,” the authors wrote. “Across treatments, exposure‑adjusted adverse event patterns were broadly consistent with those observed in clinical trials, with mostly similar rates across cBTKis.”

Second-Generation BTK Inhibitors in CLL/SLL

The FDA approved acalabrutinib (Calquence; AstraZeneca) for adults with CLL or SLL in November 2019 on the basis of the ELEVATE-TN (NCT02475681) and ASCEND (NCT02970318) trials.² Zanubrutinib (Brukinsa; BeOne Medicines) followed in January 2023, supported by the SEQUOIA (NCT03336333) and ALPINE (NCT03734016) trials.^3,4 Both agents showed fewer cardiovascular AEs than ibrutinib (Imbruvica; Pharmacyclics/Johnson & Johnson) in trials, but evidence on their use and tolerability in routine practice remains sparse, the authors wrote.¹ A separate Medicare claims–based analysis linked first-line zanubrutinib with longer time on treatment among patients 65 years or older.⁵

Using electronic health records and chart abstraction from sites in The US Oncology Network, investigators identified adults who started first-line ibrutinib (n = 384), acalabrutinib (n = 150), or zanubrutinib (n = 50) from November 21, 2019, through July 31, 2023. The median age was 73 years (IQR, 65-80), and median follow-up was 35.6, 42.3, and 16.1 months in the 3 groups, respectively.

BTK Inhibitor Discontinuation and Gaps Before Next Treatment

By the end of follow-up, 65.9% of patients had discontinued first-line therapy, including 70.6% with ibrutinib, 62% with acalabrutinib, and 42% with zanubrutinib. AEs were behind 38.4% of all discontinuations, ranging from 45.4% with ibrutinib to 20.4% with acalabrutinib, whereas progression or death prompted 9.9%.

Median time to treatment discontinuation (TTD) was 23 months overall (95% CI, 19.7-26.2), including 18.7 months with ibrutinib and 35.6 months with acalabrutinib. In the multivariable model, acalabrutinib was associated with longer TTD vs ibrutinib (HR, 0.61; 95% CI, 0.47-0.79), but zanubrutinib was not (HR, 0.81; 95% CI, 0.51-1.29). Bleeding events (HR, 2.03; 95% CI, 1.31-3.14) and infections (HR, 1.44; 95% CI, 1.02-2.01) after treatment began, along with higher comorbidity burden and 17p deletion, were tied to shorter TTD. Median time to next treatment or death was 48.1 months, roughly 2 years longer than median TTD.

“This discrepancy suggests that patients who discontinue [first-line] cBTKi therapy, which was commonly attributed to adverse events, often do not advance immediately to [second-line] therapy and, instead, experience a reprieve from treatment,” the authors wrote.

AE Rates and Survival Outcomes in Community Practice

Per 1000 patient-months, the atrial fibrillation rate was 4.69 with zanubrutinib, 4.16 with ibrutinib, and 2.78 with acalabrutinib, a pattern the authors said runs counter to earlier studies and should be read cautiously given the small zanubrutinib subgroup.

“Although cBTKis have been linked to higher cardiovascular risk, the adverse events most strongly associated with treatment discontinuation were bleeding and infections,” they wrote.

At 24 months, 72.8% of the cohort remained progression-free, and 81.9% were alive, below the 2-year progression-free rates of 86% to 89% in the RESONATE-2, ELEVATE-TN, and SEQUOIA trials. The authors attributed this gap to older, more comorbid real-world patients compared with clinical trial participants. Age 70 years or older was associated with shorter real-world progression-free survival (HR, 2.20; 95% CI, 1.53-3.17).

The authors acknowledged that the retrospective design and potentially incomplete health records could bias results and that the zanubrutinib group was small with shorter follow-up. TP53 mutation status was also undocumented for 87.7% of patients.

“These findings highlight the unmet need for treatment strategies that improve tolerability and prolong time on therapy to achieve optimal outcomes for patients with CLL/SLL, particularly for older patients, in the real-world community oncology setting,” the authors concluded.

References

1. Burke JM, Zackon I, Wang Y, et al. Real-world treatment patterns, tolerability, and outcomes among patients with CLL/SLL treated with first-line ibrutinib, acalabrutinib, or zanubrutinib in the US community oncology setting: a retrospective cohort study. EJHaem. 2026;7(6):e70432. doi:10.1002/jha2.70432

2.Project Orbis: FDA approves acalabrutinib for CLL and SLL. News release. FDA. November 21, 2019. Accessed November 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/project-orbis-fda-approves-acalabrutinib-cll-and-sll

3. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. News release. FDA. January 19, 2023. Accessed November 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma

4. Caffrey M. FDA gives zanubrutinib approval for first-line, R/R CLL/SLL. AJMC®. January 19, 2023. Accessed November 5, 2026. https://www.ajmc.com/view/fda-gives-zanubrutinib-approval-for-first-line-r-r-cll-sll

5. Shaw ML. Zanubrutinib tops rivals in real-world CLL survival study. AJMC®. June 24, 2026. Accessed November 5, 2026. https://www.ajmc.com/view/zanubrutinib-tops-rivals-in-real-world-cll-survival-study