Introduction Management of chronic lymphocytic leukemia (CLL) has advanced significantly over the past decade with the introduction of targeted therapies (TT). Despite that, important challenges persist in optimizing treatment, especially for patients (pts) with concurrent cardiovascular comorbidities (CVC). We examined real-world treatment patterns and outcomes among pts with CLL and CVC, aiming to better understand therapeutic approaches and effectiveness in this complex population.

Methods This retrospective multicenter longitudinal study included pts diagnosed with CLL between 2010 and 2020 (index period), who had at least one CVC at diagnosis or prior to first-line treatment (1L) initiation. Demographic and clinical variables were collected from physician-reported records. Pts were followed from the index date until the last follow-up (f/u), end of study (September 2024), or death, whichever came first. Clinical outcomes were assessed following 1L initiation and were described for both the overall study population and pts who received only TT.

Results A total of 1393 pts from 20 centers in 7 countries were included. Most pts were male (898/1393, 64.5%) and had received at least 1 line of CLL-directed treatment (857/1393, 61.6%). The median f/u from diagnosis and 1L initiation were 8.4 years (yrs) [IQR=8-9] and 4 yrs [IQR=1.9-6.9], respectively. The median age (mAge) at diagnosis and 1L was 69 (IQR=62-76) and 71 (IQR=64-78) yrs, respectively. Most pts were diagnosed with arterial hypertension (1112/1393, 79.8%), followed by atrial fibrillation/flutter (AF) (180, 12.9%). Ischemic heart disease [excluding myocardial infarction (MI)], stroke, cardiomyopathy, MI, heart failure, other cardiac arrythmias (excluding AF), and cardiac valve disease were present in 139 (10%), 85 (6.1%), 61 (4.4%), 59 (4.2%), 52 (3.7%), 41 (2.9 %), 31 (2.2%), respectively.

At the time of 1L initiation, most pts had unmutated IGHV genes (316/547, 57.8%), while 94/641 (14.7%) had TP53 aberrations. The most common 1L treatments were chlorambucil-based (CHL) regimens [295/857 (34.4%), CHL monotherapy: 117 (13.7%) and CHL plus anti-CD20 monoclonal antibody: 178 (20.1%)] and BTK inhibitors (BTKis) [141/857 (16.5%), ibrutinib (I): 92 (10.7%), acalabrutinib (A): 45 (5.3%), zanubrutinib (Z): 4 (0.5%)]. Fludarabine-cyclophosphamide-rituximab (FCR) and bendamustine-rituximab (BR) were used in 133 (15.6%) and 53 (6.2%), respectively. Venetoclax-based (ven) regimens were used in 55 [6.4%, 50 (5.8%) received ven-obinutuzumab] pts. I plus ven was used in 7 (0.8%) pts.

After 2020, the use of BTKis [86/234 (36.7%), A: 43 (18.8%), I: 39 (16.7%), Z: 4 (1.7%)] and ven regimens (48, 20.5%) increased markedly, while chemoimmunotherapy use declined [CHL regimens: 43 (18.4%), BR: 12 (5.1%) and FCR: 5 (2.1%)].

The overall survival (mOS) and time to next treatment or death (mTTNTD) from 1L initiation were 8.4 yrs (95%CI=7.7-9.4) and 3.6 yrs (95%CI=3.2-4), respectively. Of the pts who received TT only, the mOS was not reached [95%CI=5.6 yrs, not estimable (NE)], and mTTNTD was 5.6 yrs (95%CI=4.5-NE).

The 3-year-TTNTD for BTKis [mAge: 73yrs], ven regimens (mAge: 69yrs), FCR (mAge: 61), and CHL regimens (mAge: 75yrs) was 71% (95%CI=62-80), 87.1% (95%CI=74-100), 67.5% (95%CI=60-76) and 44.2% (95%CI=39-51), respectively. Overall, 54/141 (38.3%) pts discontinued BTKis in 1L. The reasons were toxicity (tox) (20, 14.2%, CV tox: 9/20 and non-CV tox: 11/20), disease progression (PD) (15, 10.6%), CLL-unrelated (CLL-u) deaths (13, 9.2%) and other reasons (6, 4.2%). Of the 55 pts who received ven regimens, 6 (10.9%) discontinued treatment earlier than scheduled [non-CV tox: 3 (5.5%), other reasons: 2 (3.6%), and CLL-u death: 1 (1.8%)]. FCR (n=133) was discontinued earlier than scheduled in 15 (11.3%) pts [non-CV tox: 12 (9%), PD: 1 (0.8%), other reasons: 2 (1.5%)]. Finally, CHL regimens (n=295) were discontinued in 36 (12.2%) pts [non-CV tox: 14 (4.7%), PD: 12 (4.1%), other reasons: 9 (0.8%), CLL-u death: 1 (0.3%)].

Conclusion We highlight a shift toward the use of TT in pts with CLL and CVC and illustrate differential patterns in TTNTD and discontinuation according to regimen. Differences in pts age and treatment duration across regimens may have contributed to the varying incidence of CV tox leading to discontinuation, especially in pts receiving BTKi. The study's retrospective nature, age and f/u differences preclude any comparison of TTNTD between treatments.

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2025
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