Population-Based Registry Data over 15 Years Suggests Comparable Overall Survival for CLL Patients Treated with Chemoimmunotherapy and Targeted Therapies As First-Line Treatments

Phase 3 clinical trials have shown that targeted therapies (TT), significantly improve progression-free survival (PFS) compared to chemoimmunotherapy (CIT) for patients with chronic lymphocytic leukemia (CLL) with very few demonstrating a difference in overall survival (OS). TT are now the preferred first-line treatment for CLL patients across all age groups. Nevertheless, evidence demonstrating differences in OS in real-world settings remains scarce. This study aims to evaluate OS in patients who began treatment with either chemotherapy (CT) or CIT compared to those who received TT as their first-line treatment over a period of 15 years (diagnosed Jan 2005 to Dec 2020, follow-up 2024). Data were abstracted from a population-based registry collating information from 14 hospitals serving a population of 4 million people in northern England (https://hmrn.org/). Patients were registered on the day of diagnosis and were regularly followed up with laboratory and clinical data from their medical records. Standard statistical methods were used including net survival (NS) to consider patients dying from competing causes. A total of 4002 patients were included in the study, of which 63% were male. The median age at diagnosis was 71.3 (range (R) 23.3-98.1) yrs, with 17.6% of patients being under 60 and 21.5% over 80 years old. After a median follow-up of 9.7 yrs (95% confidence interval (CI) 9.3 - 9.9), the median OS for the entire group was 9.5 years (95% CI 9.1 - 10.0). Of all patients 1157 (28.9%) received treatment for CLL, 51 received only supportive treatment, 2786 continued with a watch-and-wait (W&W) approach with disease transforming in 8 patients initially on W&W. Median age at initiation of treatment was 70.2 (R 26.1 - 93.2) yrs, with 17.5% being under 60 years and 17.6% being over 80 years; 828 (71.6%) of the treated patients were male. 268 (23.2%) patients had only one line of treatment and 889 (76.8%) had subsequent lines of treatment (median 2- R 1-9). Among the 1157 treated patients, 658 (56.9%) received CIT, 334 (28.9%) received CT, and 165 (14.3%) received TT. The first-line treatments with CT included chlorambucil (Chl) 60.8%, fludarabine ± cyclophosphamide (FC) 32.6%, and bendamustine (Ben) 6.6%. CIT included FC/FCM (mitoxantrone) with a CD20 antibody (ab) 52.1%, Ben with a CD20 ab 16.6%, Chl with a CD20 ab 27.2%, alemtuzumab ± CT 2.0%, and other regimens 4.0%. TT included acalabrutinib ± Obinutuzumab (O) 29.7%, ibrutinib ± rituximab (R) 36.4%, venetoclax ± O or ibrutinib 26.1%, idelalisib ± R 3.6%, and zanubrutinib 3.6%. Median time from diagnosis to treatment initiation in CT group was 4.8 (R 0-120) months, CIT group was 17.3 (R 0-175) months and TT group was 19.2 (R 0-147) months. Median follow up period was 81 months (95% CI 70.1-91.9). The median OS for the entire group of treated patients was 6.8 years (95% CI 6.3 - 7.7); 5-year OS was 61% (58-64%) and 5-year NS was 71% (67-74%). The median OS for patients treated with CT as the first line was 3.5 yrs (95% CI 2.8 - 3.9), for CIT was 8.7 yrs (95% CI 7.8 - 10.0), and for TT was 8.4 yrs. (95% CI 6.6 - NR). <60 yrs 5-year OS was 81% (74-86) vs. 29% (23-36) in 80+ yrs compared to NS of 83% (77-89) vs. 50% (38-62) respectively indicating that younger patients were dying due to their CLL, but older patients were also dying from competing causes. Patients with a good performance status (PS) also had a better prognosis: PS 0-1 (66.8%) had a median OS of 7.0 years (95% CI 6.1 - 8.7), PS 2-4 (9.9%) had 1.8 yrs (95% CI 0.5 - 3.2 yrs) but no difference between male and female patients (male: 6.7 yrs (95% CI 6.1 - 7.7), female: 6.9 yrs (95% CI 6.2 - 8.5), p=0.57). Of the 331 patients (28.6%) who had minimal residual disease (MRD) assessment after the first line of treatment, 165 (49.8%) were MRD negative (-), 143 (43.2%) remained MRD positive (+), and 23 (6.9%) had an undetermined MRD status. The median OS for MRD - patients was 14 yrs (95% CI 12.0 - 16.9) and for MRD + patients was 9.7 yrs (95% CI 8.0 - 12.0 (p<0.001). Median treatment free survival for patients treated with CT at first line was 1.9 years (95% CI 1.6-2.1), CIT was 4.9 years (95% CI 4.4-5.3) and TT was 7.0 years (95% CI 5.4-NR). In this population-based registry study, it was shown that only around a third of patients with CLL required treatment, and there was no OS advantage from initiating patients on targeted therapy as a first line compared to chemoimmunotherapy followed by targeted therapy upon relapse. This concept should be validated in prospective trials.