Real-world outcomes of younger patients with chronic lymphocytic leukemia treated with first-line BTK inhibitor or BCL2 inhibitor therapy

Abstract Background Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia, predominantly affecting older adults. However, a minority of patients (pts) are diagnosed before age 55. Younger pts (<55 years) with CLL represent a distinct subgroup given their predisposition to high-risk biological features and the likelihood of requiring multiple lines of therapy during their lifetime. As such, treatment decisions in this population carry unique long-term implications and warrant an individualized approach. Current first-line (1L) standard-of-care options include continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy or time-limited B-cell lymphoma 2 inhibitor (BCL2i) therapy. However, direct comparisons of BTKi vs. BCL2i efficacy in younger pts are lacking, and existing guidelines do not provide age-specific recommendations to guide therapeutic choice. In this study, we evaluate real-world outcomes of younger pts with CLL treated with 1L BTKi or BCL2i therapy. Methods This study utilized the nationwide Flatiron Health electronic health record-derived de-identified database. Pts <55 years with CLL who received 1L therapy between 01/2015 and 04/2024 were included. Pts were grouped by 1L therapy: BTKi (ibrutinib, acalabrutinib, or zanubrutinib) or BCL2i (venetoclax ± rituximab or obinutuzumab). Time to next treatment or death (TTNT-D) was defined as the time from initiation of 1L therapy to the start of second-line therapy or death. TTNT-D and overall survival (OS) were estimated using Kaplan-Meier analysis and compared using adjusted Cox regression modeling. Competing risks modeling was used to assess incidence of second-line (2L) therapy. Results A total of 426 pts met inclusion criteria; 333 (78.2%) received BTKi and 93 (21.8%) received BCL2i as 1L therapy. Most pts were White (69.5%), male (66%), and had an ECOG performance status of 0–1 (71.4%). The median age at diagnosis was 50 years (IQR 45–53). The most common FISH abnormality was del(13q) (37.3%), followed by del(11q) (22.8%), trisomy 12 (20.9%), and del(17p) (12%). The two cohorts had generally balanced baseline characteristics. However, del(11q) was more frequently observed in BTKi-treated pts (25.8%) compared to BCL2i (11.8%) (p=0.007). IGHV mutation was documented in 19.5% of pts and was more common in those treated with BCL2i (30.1%) vs. BTKi (16.5%) (p=0.005). TP53 mutations were present in 5.4% of pts (BTKi: 6.3% vs. BCL2i: 2.2%; p=0.191). The median follow-up from treatment initiation was 32 months (mos) (19.5-53.2) for BTKi and 20.7 mos for BCL2i (12.6-33.4). Among BTKi-treated pts, ibrutinib was most commonly used (n = 223; 67.0%), followed by acalabrutinib (n = 94; 28.2%), and zanubrutinib (n = 16; 4.8%). In the BCL2i cohort, venetoclax + obinutuzumab was used in 86.0% of pts (n=80), venetoclax monotherapy in 9.7% (n=9), and venetoclax + rituximab in 4.3% (n=4). Median duration of therapy was 20.7 mos for BTKi and 11.9 mos for the full BCL2i regimen (p<0.001). With a median follow-up of 29.2 mos (16-48), no significant OS difference was observed between pts treated with 1L BTKi and BCL2i therapy (p = 0.286). At 2 years, TTNT-D was significantly higher in the BCL2i group (90.1%) compared to BTKi (70.8%) (p < 0.001), reflecting a greater proportion of pts who had not yet required 2L therapy or died. On Cox regression analysis, 1L BTKi was associated with a significantly shorter TTNT-D compared to BCL2i (HR 3.84; 95% CI 1.66–8.88; p=0.002). On competing risks analysis, 3-year incidence of 2L therapy was higher with BTKi (33.5%) vs. BCL2i (24%) (HR 3.90; 95% CI 1.54–9.86; p=0.004). On multivariable analysis, ECOG ≥2, del(11q), del(13q), trisomy 12, del(17p), TP53 mutation, and IGHV mutation were not significantly associated with OS, TTNT-D, or 2L therapy incidence. Conclusion This is the largest study to date evaluating frontline treatment outcomes of younger pts with CLL treated with targeted agents. In this population, 1L BCL2i therapy was associated with significantly longer TTNT-D compared to BTKi, with no observed difference in OS. These findings suggest that fixed duration BCL2i-based regimens may delay the need for 2L therapy in a population likely to require multiple treatments over their lifetime. Although limited by the absence of treatment discontinuation rationale, these results underscore the importance of long-term planning in younger pts and support the need for prospective studies to guide age-specific treatment decisions.