Causes of death in chronic lymphocytic leukemia/small lymphocytic lymphoma during the novel agent era: A population-based analysis

Abstract Background: Chemoimmunotherapy (CIT) had long been used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) until 2014 when the first novel agent, ibrutinib, was approved in the US. Numerous novel therapies, including second generation covalent BTKi and BCL2 inhibitors, have since become available. Nevertheless, as novel therapies have largely replaced CIT in CLL/SLL, its impact on survival outcomes has yet to be examined on the population level. Particularly, novel therapies often have superior efficacy and drastically different adverse event profiles compared with CIT, in some cases due to continuous treatment. Access to novel therapies may thus have different impacts on various causes of death (COD) in this population, which will be examined in this study. Methods: We used the SEER (Surveillance, Epidemiology, and End Results) database and included adult patients diagnosed with CLL/SLL between the years 2008 and 2019 (excluding 2013-2014 as a washout period). We defined the pre-novel agent (pre-NVA) era as the years of CLL/SLL diagnosis between 2008 and 2012, and the novel agent (NVA) era between 2015 and 2019. Patients in this analysis were followed until death, loss of follow-up, or December 31, 2022, whichever occurred first. Given the relatively short follow-up for the NVA era, we limited the analyses to patients who required treatment within two years of CLL/SLL diagnosis (higher-risk population). We used Kaplan-Meier method to estimate the 5-year OS in the two cohorts. We also applied flexible parametric regression methods to extrapolate the median OS. In the multivariable analysis, we used proportional hazard Cox regression model to compare the OS between the NVA and pre-NVA eras, reporting hazard ratio (HR) with 95% confidence interval (CI). We performed competing risk analysis to compare mortality from 1) CLL/SLL, 2) cardiovascular diseases (CVD), 3) infection, 4) cancers other than CLL/SLL, respectively, between the two eras, reporting sub-distribution of HR (sub-HR) with 95% CI. We adjusted for age, sex, race, and area of residence. Patients with follow-up longer than 5 years were censored at the end of the fifth year for the multivariable analyses. Results: We included 9913 patients (4876 and 5037 for pre-NVA and NVA eras), who started treatment within two years of CLL/SLL diagnosis, with a median age of 67 years, 65.7% men, 85.2% White, and 85.8% residing in metropolitan regions. The median follow-up was 7.8 years (12.5 and 5.42 years for pre-NVA and NVA eras). The 5-year OS was 61.0% and 65.3% for pre-NVA and NVA cohorts, respectively, with an estimated median OS of 7.1 and 8.3 years. In the multivariable analyses, patients in the NVA cohort had superior OS, compared with those in the pre-NVA cohort (HR: 0.86, 95% CI: 0.81, 0.92). During the NVA era, CLL/SLL remained a leading COD in this population, accounting for 38.1% of all-cause mortality. In the multivariable analyses, patients in the NVA cohort had a significantly lower risk of death from CLL (sub-HR: 0.69, 95% CI: 0.62, 0.76) and other cancers (sub-HR: 0.77, 95% CI: 0.67, 0.88), a nonsignificant trend toward higher risk of death from CVD (sub-HR: 1.17, 95% CI: 0.98, 1.40), but similar risk of death from infection (sub-HR: 0.94, 95% CI: 0.69, 1.32). Conclusions: This large, population-based analysis demonstrated significantly improved OS among CLL/SLL patients who received treatment within two years of diagnosis in the NVA era. In addition, decreased mortality due to CLL/SLL is consistent with the better efficacy in CLL/SLL demonstrated in novel therapies compared with CIT. Nevertheless, limitations of this analysis include the potential misclassification of COD in the SEER database and the duration of follow-up not including the impacts of noncovalent BTKi and chimeric antigen receptor T cell therapy. Future analyses using databases that allow verification of COD (e.g., electronic health records) and based on longer follow-up are needed.