Impact of prior venetoclax use on mortality in CLL patients treated with pirtobrutinib: A propensity-matched cohort study

Abstract Background Pirtobrutinib is a highly selective, non-covalent Bruton tyrosine kinase inhibitor (BTKi) approved for patients (pts) with relapsed/refractory (R/R) chronic lymphocytic lymphoma (CLL) who have previously received a covalent BTKi (cBTKi) and a BCL-2 inhibitor such as venetoclax. Pirtobrutinib monotherapy has demonstrated a median duration of response of 12.2 months in the BRUIN trial. Pirtobrutinib is increasingly being used as a second-line therapy after failure of a cBTK inhibitor without prior BCL-2 inhibitor exposure. We aim to characterize short-term survival outcomes and adverse events of pirtobrutinib in venetoclax-naïve versus venetoclax-exposed pts with R/R CLL. Methods We conducted a retrospective cohort study using TriNetX Global Collaborative Network, comprising data from 152 healthcare organizations. Adults (≥18 years) with R/R CLL who received pirtobrutinib after venetoclax were classified into the “V+P” cohort. Pts who received pirtobrutinib without prior venetoclax exposure were included in the “P” cohort. 1:1 propensity score matching (PSM) was performed, and the cohorts were balanced for gender and age. The primary outcome was all-cause mortality (ACM). Secondary outcomes assessed were anemia, neutropenia, sepsis, neutropenic fever, tumor lysis syndrome (TLS), and major adverse cardiovascular and cerebrovascular events (MACCE). Kaplan-Meier analysis and risk analysis were used to assess outcomes at 6 months and 1 year. Results We identified 200 pts in V+P and 172 pts in P, with 149 matched pts in each group after PSM. The mean age of pts in V+P and P was 72.4 +/- 8.6 years and 72.7 +/- 10.5 years, respectively. 6-month ACM was 15.5% in V+P, and 12.7% in P. However, the odds ratio of ACM at 6 months, in pts in V+P when compared to P was 1.259 (95% CI 0.654 to 2.425, p = 0.490) and was not statistically significant. At 6 months, the odds ratios of the secondary outcomes in the V+P pts were higher when compared to P pts, but were not statistically significant; anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.445 (95% CI 0.599 to 3.486, p = 0.411), sepsis 1.196 (95% CI 0.477 to 2.998, p = 0.703), neutropenic fever 1.353 (95% CI 0.573 to 3.195, p = 0.490), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.046 (95% CI 0.541 to 2.024, p = 0.893). 1 year ACM was 18.75% in V+P vs. 10.55% in P (OR 1.96; 95% CI 1.03-3.71; p=0.038) and was statistically significant. However, the secondary outcomes were clinically significant but statistically insignificant in V+P pts when compared to P pts- anemia 1.614 (95% CI 0.617 to 4.225, p = 0.327), neutropenia 1.269 (95% CI 0.568 to 2.834, p = 0.561), sepsis 1.077 (95% CI 0.438 to 2.650, p = 0.872), neutropenic fever 1.24 (95% CI 0.589 to 2.607, p = 0.571), TLS 1.180 (95% CI 0.474 to 2.939, p = 0.722), and MACCE 1.338 (95% CI 0.724 to 2.472, p = 0.352). Conclusion Pirtobrutinib use in venetoclax-exposed pts was associated with a statistically significant higher odds of all-cause mortality at 1 year, which was not present at 6 months. Although adverse event rates of anemia, neutropenia, TLS, sepsis, and neutropenic fever were numerically higher in the venetoclax-exposed cohort, these differences did not reach statistical significance. These findings suggest early survival benefit of pirtobrutinib in venetoclax-naïve patients and aligns with existing evidence supporting its role as a second-line therapy following covalent BTK inhibitor failure, including results from the BRUIN trial. Prospective studies are needed to validate these preliminary observations.