Long-term outcomes in high-risk patients with chronic lymphocytic leukemia treated with targeted therapies in the real-world

Abstract Introduction: The development of targeted agents for chronic lymphocytic leukemia (CLL) has changed the paradigm for the treatment of patients with CLL. While targeted therapies have demonstrated substantial efficacy in clinical trials, real-world evidence comparing targeted therapies in CLL remains limited. Our study evaluated the real-world use of venetoclax and BTK inhibitors (BTKi) in CLL in predominantly high-risk and relapsed/refractory (RR) patients. Methods A total of 294 patients with CLL were included in the study, with a median age of 68 years (range 37-87 years). Of these, 102 initiated treatment with venetoclax (continuous or fixed-duration with anti-CD20 antibody), 155 initiated ibrutinib, and 37 either acalabrutinib or zanubrutinib. In total, 235 (80%) patients were RR (a median of one previous therapy line, range 0-6), 127 (43%) had TP53 aberrations (del (17p) and/or TP53 mutations), 242 (82%) had unmutated IGHV status, and only 29 (10%) patients had both mutated IGHV and wild-type TP53. The median follow-up was 31 months (range 5-109). Results In the ibrutinib group, the 3-year progression free survival (PFS) rate was 62%, the treatment discontinuation due to toxicity (toxicity rate) was 15%, and resistance-associated mutations in BTK or PLCG2 genes occurred in 13% of patients among those who progressed by the third year of treatment. Among 96 patients followed 5 years, the 5-year PFS rate was 30%, the toxicity rate 26% and resistance-associated mutations occurred in 21% who progressed. The median PFS of patients on ibrutinib therapy was 5. 9 years. Patients receiving reduced dose of ibrutinib (250 mg) had a shorter median PFS (4. 6 years) than those receiving full or partially reduced dose (420-280 mg; median PFS 6. 9 years; p=0. 01). In the venetoclax group, the 3-year PFS rate was 53%, the toxicity rate 7% and resistance-associated mutations in BCL2 gene occurred in 1% of those who progressed by the third year of treatment. Notably, 25% of patients treated with venetoclax had prior exposure to BTKi. The median PFS of patients on venetoclax was 4. 3 years. All patients receiving targeted therapy showed improved outcomes compared to high-risk patients treated with chemoimmunotherapy combinations (CIT) based on our retrospective data: the median PFS of patients on targeted therapy reached 5. 9 years compared to 1. 2 years for patients with TP53 aberrations (n=70) and 2. 3 years for patients with unmutated IGHV disease (n=259), all treated with CIT (p0. 0001). Conclusions Targeted therapies improve long-term outcomes for high-risk and RR patients with CLL in the real-world setting compared to the chemoimmunotherapy era. However, targeted therapies are not curative, and a significant proportion of high-risk patients ultimately experience disease progression during long-term follow-up. Grant support: JG₂024₀35, MH CZ – DRO (FNOl, 00098892), IGALF₂025₀14.