1117 - EVOLUTION IN THE FRONTLINE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA: EXPERIENCE FROM ONE EUROPEAN CENTER

Treatment of chronic lymphocytic leukemia (CLL) has dramatically evolved over the last decades thanks to the introduction of targeted therapies. Chemoimmunotherapy was a big step forward in CLL therapy, and since 2014 several small molecules inhibiting different pathways have been introduced in the CLL treatment algorithms. International guidelines (ESMO 2021, NCCN 2022) recommend targeted therapies including covalent BTK inhibitors (cBTKi; ibrutinib, acalabrutinib, zanubrutinib) and BCL2 inhibitors (BCL2i; venetoclax) combinations as preferred regimens for most treatment naïve CLL patients.

The main objective of this study was to describe the evolution in the patterns of frontline therapies in CLL patients from a single referral institution. As a secondary objective, we aimed to evaluate the impact of the targeted therapies on time to next treatment (TTNT) and overall survival (OS) in our cohort.

This is a retrospective, single-center, and non-interventional study. We included patients treated in clinical trials and in routine clinical practice. Front-line treatment was classified into 5 groups: (1) alkylating agents, (2) purine analogs, (3) chemoimmunotherapy, (4) targeted therapies, and (5) other therapies. TTNT and OS were defined from the date of starting therapy to the event (next treatment or death, respectively), or loss to follow-up.

We included 780 patients with a diagnosis of CLL. After a median of 6.4 years (0.1-36.4) of follow-up from diagnosis, 323 of 780 CLL patients (41.4%) required frontline therapy. The median age at the time of treatment was 69.8 years (32.2-92.4). IGHV genes were unmutated in 59% (138/234), del(11q) in 17.7% (46/260), and TP53 alterations (del(17p) and/or TP53 mutations) in 13.7% (36/262) of patients.

As first-line therapy, 120 patients received alkylating agents (37.2%), 43 purine analogs (13.3%), 101 chemoimmunotherapy regimens (31.3%), 53 targeted therapies (16.4%), and 6 other treatments (1.9%). Before 2012 alkylating agents in monotherapy (chlorambucil) were the therapy most frequently used, and from that year onwards, chemoimmunotherapy (FCR, R-Bendamustine) was particularly given (Figure 1). Since 2018, targeted therapies have been those most frequently employed, namely Ibrutinib, (29/55, 53.7%), and Venetoclax-based therapies (11/55, 20.4%).

After a median time of 2.4 years (0-14.2), 168/323 patients (52%) received second-line therapy. Targeted therapies (Figure 2), chemoimmunotherapy, and mutated IGHV were related to a longer TTNT in the multivariant analysis. At the time of the closure of the study, 216/323 patients (66.9%) had died. The median OS was 7.5 years (0.2-35.1). The median OS was not reached in patients treated with targeted therapies, and it was 5.9 years (CI 95% 4.8-7) for the rest of the patients (p=0.36). In the multivariant analysis, age younger than 65 years, female sex, and mutated IGHV were related to better OS.

In summary, our data confirm that targeted therapies have become the most used treatment as frontline therapy in CLL, emphasizing the need for treatment algorithms including best sequential treatments and optimal treatment duration.