1217 - Evolution of natural history and prolongation of overall survival in patients with chronic lymphocytic leukemia: analysis of a long-term follow-up of an unselected cohort in the Hradec Králové district, Czech Republic.

Introduction: One of the fundamental characteristics of chronic lymphocytic leukemia (CLL) is the extreme variability of prognosis: approximately half of patients never require treatment due to an indolent course. Over the last 20 years, there has been a revolution in the therapeutic approach to CLL, from chemotherapy through chemoimmunotherapy to oral targeted inhibitors (especially Bruton tyrosin kinase inhibitors ibrutinib and acalabrutinib and bcl-2 inhibitor venetoclax). However, analyses of the changes in the natural history and overall survival at large specialised centres are hampered by the selection bias from the regional hospitals which usually refer only patients requiring therapy and therefore have a poorer prognosis. Therefore, we eliminated the selection bias by analyzing a large unselected cohort of CLL patients with a long follow – up from a well – defined geographical region (the Hradec Králové district, Czech Republic) where all newly diagnosed cases could be recorded as the 4th Department of Internal Medicine – Hematology at our University Hospital serves as the primary hematology center. The aims of this retrospective study was to evaluate the natural history of the disease and evolution of time to first – line therapy (TTFT) and overall survival (OS) over time. Patients and methods: Between 1999 – 2019, a total of 311 patients were diagnosed in the Hradec Králové district. Basic characteristics and prognostic factors are listed in Table 1. At the median follow-up of 127 months, 44% patients progressed to first-line (1L) therapy and 54% patients died. To compare baseline characteristics and clinical course, we divided our cohort into three subgroups according to the years of diagnosis: Group 1 (1999-2005) included 97 patients, Group 2 (2006-2012) 101 patients and Group 3 (2013-2019) 113 patients. Statistical evaluation was performed using MedCalc v. 20.109 (Medcalc, Mariakerke, Belgium) software, with appropriate nonparametric tests to compare differences in individual variables. Time to first-line treatment and overall survival were assessed using the log-rank test and Kaplan-Meier curves. P values were double – sided and considered significant if < 0.05.

Results: Patients in Group 3 were significantly younger than those in Group 1 (median age 68 vs. 71 years, p=0.043). Regarding time to endpoint variables, there were no significant differences between the 3 regarding TTFT (p=0.32); however, there was a statisticaly and clinically highly significant increase in overall survival (median 80 vs. 143 months vs. not reached, p < 0.0001; Fig. 1a). We hypothesized that more effective treatment (introduction of chemoimmunotherapy and targeted inhibitors) contributed most significantly to longer overall survival. Indeed, OS from the initiation of 1L treatment was significantly prolonged in Groups 2 and 3 (median 41 vs. 92 months vs. not reached, p=0.0001). Patients who received 1L chemoimmunoterapy had significantly longer OS from the start of treatment than those treated by chemotherapy only (median 112 vs. 43 months, p < 0.0001). Similarly, patients who were treated anytime during their course of CLL by targeted oral inhibitors had markedly better OS from initiation of 1L than those who did not receive such therapy (median 129 vs. 50 months, p < 0.0001; Fig. 1b). In addition, the use of chemoimmunotherapy in 1L (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0,30 to 0.77; p=0.0025) and targeted oral inhibitors in R/R disease (HR, 0.40; 95% CI, 0.21 to 0.79; p=0.0079) retained their significance in multivariate analysis.

Conclusion: Analysis of a large, unselected cohort of CLL patients with a long follow – up revealed a significant decrease of age at diagnosis in recently diagnosed patients (Group 3). The key findings were significant prolongation of overall survival both from CLL diagnosis and start of first-line therapy, which was shown to be mainly thanks to introduction of chemoimmunotherapy and targeted oral inhibitors. Supported by programme COOPERATIO (research area ONCO) and DRO MH CZ (UHHK, 00179906).