Research Summary

Real-World Analysis Finds Higher Discontinuation and Hospitalization Rates With BTK Inhibitors vs Fixed-Duration Venetoclax in Older Adults With CLL

Kate Young

Key Highlights

  • Bruton’s tyrosine kinase inhibitor (BTKi) discontinuation was more frequent and occurred earlier than venetoclax-obinutuzumab (VEN-O) discontinuation (median 4.0 vs 11.9 months).
  • Few VEN-O discontinuers required further therapy, whereas 39% of BTKi discontinuers initiated another CLL treatment.
  • Hospitalization rates were lower post-VEN-O discontinuation compared with BTKi discontinuation (2.0 vs 3.3 all-cause hospitalizations per 100 patient-months).
  • Fixed-duration VEN-O was associated with more durable outcomes and fewer downstream interventions in Medicare patients 66 years and older with CLL.

A recent study conducted by Scott F. Huntington, MD, MPH, MSc, and colleagues found that older adults with chronic lymphocytic leukemia (CLL) initiating frontline venetoclax-obinutuzumab (VEN-O) experienced more durable treatment courses and fewer downstream health care needs compared with those starting a Bruton’s tyrosine kinase inhibitor (BTKi). Discontinuation was more common and occurred earlier among BTKi patients, who also had substantially higher rates of subsequent therapy and hospitalization.

CLL predominantly affects older adults, with a median age at diagnosis of 69 years. Traditional chemoimmunotherapy regimens have historically carried substantial toxicity, particularly in elderly populations. Targeted therapies such as BTKis and venetoclax have shifted the treatment paradigm, offering improved efficacy and tolerability. BTKis are given continuously until disease progression or intolerance, raising concerns about cumulative toxicity. Venetoclax, approved in 2019 with obinutuzumab as a fixed-duration regimen, offers a time-limited approach and has shown favorable tolerability and quality-of-life outcomes. However, real-world comparative evidence on postdiscontinuation patterns of VEN-O versus BTKis in older patients has been lacking.

This retrospective analysis of 1770 Medicare beneficiaries (≥66 years) initiating VEN-O (n = 193) or BTKi therapy (n = 1577) between June 2019 and June 2020 evaluated discontinuation, subsequent therapy, and hospitalization over 18 months. Discontinuation was defined as an at least 90-day gap in therapy. VEN-O patients were expected to complete 11 months of therapy, while BTKi patients were intended for continuous treatment.

Among VEN-O recipients, 52.8% completed the fixed-duration course, and 29.5% discontinued prematurely, with a median discontinuation time of 11.9 months. In contrast, 37.9% of BTKi patients discontinued early, with a median time of 4.0 months. Very few VEN-O discontinuers required subsequent therapy over a median follow-up of 6.1 months, whereas 39.0% of BTKi discontinuers initiated further CLL treatment within a median 13.8 months. Post-BTKi therapies included BCL-2 regimens (35.6%), another BTKi (31.8%), chemotherapy (14.6%), and anti-CD20 monotherapy (9.9%). Hospitalization rates per 100 patient-months were lower after VEN-O discontinuation than after BTKi discontinuation for both all-cause (2.0 vs 3.3) and CLL-related hospitalizations (1.5 vs 2.9).

Limitations include reliance on claims data, which may contain coding errors and lack reasons for discontinuation or hospitalization. Differential follow-up time between groups and the descriptive study design may also introduce bias. Findings are generalizable only to the fee-for-service Medicare population.

“Our findings underscore the potential role that fixed-duration treatments such as venetoclax may play in reducing the ongoing unmet need for tolerable, efficacious therapies in older adults with CLL,” Huntington and colleagues concluded. “Future research is needed to confirm these findings once additional years of follow-up data become available for venetoclax and next-generation BTKis.”

Reference:
Huntington SF, Rhodes JM, Manzoor BS, et al. Real-world treatment patterns after discontinuation of venetoclax or BTKis in the frontline setting among older adults with chronic lymphocytic leukemia. JCO Oncol Pract. 2025;21(8):1124-1133. doi:10.1200/OP.24.00220