Frontline Treatment Discontinuation Is Higher in the Real World vs Clinical Trials in CLL/SLL

Treatment discontinuation with frontline covalent BTK inhibitors was higher in the real-world setting compared with clinical trials among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to data from a retrospective study presented during the 2025 ASH Annual Meeting.¹

Findings from the study revealed that patients who were treated with ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa) during the study observation period (n = 584) discontinued treatment at a rate of 65.9%. Reasons for discontinuation included toxicity (38%), disease progression or death (10%), physician preference (7%), completed treatment plan (6%), other reasons (7%), or reasons not documented (34%).

“These results highlight the unmet need for treatment strategies that improve tolerability and prolong time on therapy for patients with CLL/SLL in the real-world community oncology setting,” John M. Burke, MD, a hematologist and medical oncologist at Rocky Mountain Cancer Centers in Aurora, Colorado, and his coauthors wrote in a poster presentation of the data.

The study authors noted that the second-generation BTK inhibitors acalabrutinib and zanubrutinib are more selective compared with ibrutinib and have shown reduced cardiotoxicity in clinical trials.²

What was the design of the retrospective study of BTK inhibitor treatment patterns in CLL/SLL?

The retrospective, observational cohort study included adult patients with CLL/SLL who initiated a first-line regimen including ibrutinib, acalabrutinib, or zanubrutinib between November 2019 and July 2023 in US community oncology practices.¹ Eligible patients were required to have had at least 1 subsequent clinic visit and data accessible for research purposes during the observation period. Patients who received treatment for another primary cancer, experienced a prior Richter transformation, or who participated in an interventional clinical trial were excluded.

Data for the study was gathered using the structured and unstructured fields of The US Oncology Network’s electronic health record and supplemental external mortality data from claims, obituary, and government datasets.

The study objective was to assess real-world treatment patterns, discontinuation factors, and toxicity associated with first-line covalent BTK inhibitors among patients with CLL/SLL treated in the US community oncology setting.

At baseline, patients in the overall population had a median age of 73 years (IQR, 65-80). Most patients were White (76.5%), not Hispanic or Latino (81.7%), and initiated frontline treatment in 2020 (54.6%).

What were the additional findings from the real-world study of BTK inhibitor use in CLL/SLL?

Additional findings from the study showed that patients who received ibrutinib (n = 384), acalabrutinib (n = 150), and zanubrutinib (n = 50) experienced median times to treatment discontinuation (TTD) of 18.7 months (95% CI, 16.1-23.0), 35.6 months (95% CI, 26.3-40.6), and 38.2 months (95% CI, 11.6-not evaluable [NE]). The respective median times to next treatment or death (TTNT-D) were 39.6 months (95% CI, 35.0-49.0), NE (95% CI, 49.4-NE), and NE (95% CI, NE-NE), respectively. The respective median durations of follow-up were 35.6 months (IQR, 21.1-45.7), 42.3 months (IQR, 27.4-46.5), and 16.1 months (IQR, 13.5-23.7). Shorter time to treatment discontinuation was associated with moderate/severe comorbidity burden (HR, 1.74; 95% CI, 1.18-2.58; P < .01).

In terms of safety, the most common any-grade AEs in the ibrutinib group included fatigue (43.2%), anemia (23.2%), and diarrhea (22.1%). The most common any-grade AEs among patients who received acalabrutinib included fatigue (62.0%), headache (36.7%), and anemia (33.3%). Fatigue (54.0%), joint pain (20.0%), and diarrhea (20.0%) were the most common any-grade AEs in the zanubrutinib group.

“Estimation of TTD and TTNT-D may be affected by variable follow-up durations, incomplete documentation of treatment changes, and potential misclassification of discontinuation or subsequent therapy events,” Burke and his coauthors wrote in their conclusion. “Extended follow-up is needed to evaluate long-term outcomes with second-generation covalent BTK inhibitors, including TTD and its associated factors.”

References

1. Burke JM, De Nigris E, Wang Y, et al. Real-world (RW) treatment (Tx) patterns, factors associated with discontinuation and toxicity across covalent BTK inhibitors (cBTKis) in first-line (1L) tx of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Blood. 2025;146(suppl 1):2111. doi:10.1182/blood-2025-2111
2. Liu Q, Zhao J, Li Y, Jia Y. Comparative safety of different first-line treatments for chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and network meta-analysis. Ann Hematol. 2025;104(1):1-34. doi:10.1007/s00277-024-06136-6