Background With the evolution of the treatment (tx) landscape, covalent Bruton tyrosine kinase inhibitors (cBTKi) are one of the most common tx used in frontline and/or relapsed or refractory (R/R) settings among patients (pts) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL). This retrospective observational study analyzed the time to tx discontinuation or death (TTDd) and estimated rates among pts with CLL/SLL who received their first cBTKi-based tx in first (1L) or second (2L) line in the US.

Methods The nationwide Flatiron Health electronic health record-derived de-identified database was used to select adult pts diagnosed with CLL/SLL who initiated their first cBTKi-based tx (monotherapy or in combination) in either 1L (1L-cBTKi) or 2L (2L-cBTKi) on/after 01 Jan 2014. Data cutoff was 31 Jan 2025. Flatiron-derived lines of therapy were used. The date of initiation of cBTKi-based tx was defined as the index date. In both cohorts, pts who received a clinical study drug in combination with cBTKi or received >1 cBTKi agents in the same line of tx were excluded. Within each cohort, pts were grouped into subgroups of monotherapy (cBTKi-mono) and combination (cBTKi-combo). Descriptive statistics were used to summarize patient characteristics and tx regimens. Kaplan-Meier method was used to estimate TTDd from the index date, and median TTDd (95%CI) along with estimated rates at 3 months (mo) and 12 mo were reported.

Results 5520 pts received their first cBTKi-based tx in 1L. Their median (IQR) age at index date was 72 (65-79) years and ~60.2% were male. Among pts with available data, 88.4% (3225/3649) had an ECOG performance status of 0-1, 59.8% (1398/2337) had unmutated IGHV, and 18.3% (762/4156) had TP53 mutation /17p deletion at index. Median (IQR) follow-up from index date to end of study was 35.7 (17.4, 59.6) mo. Most pts received cBTKi as monotherapy (n=4898, 88.7) while some received in combination with other agents (n=622, 11.3%). Combination with CD20 monoclonal antibody (n=550, 88.4%) was the most common, of which 55.1% (303/550) were in combination with obinutuzumab. The median (95%CI) TTDd was 35.4 mo (33.3, 37.6) in the overall 1L-cBTKi cohort while it was 36.8 mo (34.7, 38.9) in cBTKi-mono and 25.1 mo (20.9, 28.4) in cBTKi-combo. The estimated proportion (95% CI) of pts continuing tx at the end of 3- and 12 mo in the overall 1L-cBTKi cohort were 87.4% (86.5, 88.3) and 70.5% (69.2, 71.7), respectively. These rates at the end of 3- and 12 mo, respectively, were 88.0% (87.1, 88.9) and 71.2% (69.9, 72.5) in cBTKi-mono while they were 82.4% (79.1, 85.2) and 64.6% (60.5, 68.3) in cBTKi-combo.

1798 pts received their first cBTKi-based tx in 2L following chemoimmunotherapy (n=1033, 57.5%) or anti-CD20 monotherapy (n=434, 24.1%) in 1L. Their median (IQR) age at index date was 72 (65-78) years and majority were also male (63.7%). Among pts with available data, 86.7% (1066/1229) had an ECOG performance status of 0-1, 68.0% (443/651) had unmutated IGHV, and 16.3% (211/1292) had TP53 mutation /17p deletion at index. Median (IQR) follow-up from index date to end of study was 38.4 mo (16.5, 67.4). Most pts received cBTKi as monotherapy (n=1621, 90.2%) while some received in combination with other agents (n=177, 9.8%). Combination with CD20 monoclonal antibody (n=147, 83.1%) was the most common, of which 45.6% (67/147) were in combination with obinutuzumab. The median (95%CI) TTDd was 29.7 (27.0, 32.4) months in the overall 2L-cBTKi cohort while it was 30.9 mo (28.3, 34.4) in cBTKi-mono and 15.9 mo (10.2, 25.9) in cBTKi-combo. The estimated proportion (95%CI) of pts continuing tx at the end of 3- and 12 mo in the overall 2L-cBTKi cohort were 86.1% (84.4, 87.7) and 66.1% (63.7, 68.3), respectively. These rates at the end of 3- and 12 mo, respectively, were 86.6% (84.9, 88.2) and 67.2% (64.7, 69.5) in cBTKi-mono while they were 81.5% (74.8, 86.5) and 55.7% (47.7, 63.0) in cBTKi-combo.

ConclusionApproximately one-third of pts receiving cBTKi discontinued tx by the end of the first year. Future analyses such as adjusted analyses comparing outcomes between cBTKi monotherapy and combination tx are under consideration. High rates of early discontinuation of cBTKi in the real world raise the need for effective and more tolerable tx options in CLL/SLL. The interpretation of the findings is constrained by the unavailability of data on reasons for tx discontinuation and sequencing of different cBTKis.

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2025
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