Pb1933: treatment sequencing and outcome of chronic lymphocytic leukemia patients treated at fondazione policlinico universitario agostino gemelli irccs: a thirty-year single-center experience.

Topic: 6. Chronic lymphocytic leukemia and related disorders - Clinical Background: The introduction of new targeted agents into the chronic lymphocytic leukemia (CLL) care pathway has changed the treatment approach over the years. Covalent Bruton’s Tyrosine Kinase inhibitors (cBTKi), B-Cell Lymphoma-2 inhibitor (BCL2i), chemotherapy and rituximab are all possible treatment options, but there is still no clear treatment sequencing strategy. Aims: This monocentric retrospective observational study describes the treatment patterns and outcomes of patients with CLL, to better understand the impact of treatment sequencing in the novel targeted-agents era. Methods: Adult CLL patients treated between 1992 and 2022 and registered in the institution’s electronic database were included. Time-to-event outcomes were evaluated using Kaplan Meier method. Time to next treatment (TTNT) was defined as time from treatment start to the start of subsequent therapy or death. Time to next treatment failure or death (TTNTF) was defined as time from treatment discontinuation to the discontinuation of subsequent therapy or death. Results: Of 637 registered patients, 318 (49.9%) received treatment (characteristics in Figure). Of 318 treated patients, cBTKi-exposed were 157 (49.4%). Patients BCL2-exposed, but cBTKi-naïve, were 34 (10.7%). Patients who received both a cBTKi and BCL2i +/- antiCD20 (double-exposed) were 26 (8.2%). Seventeen patients (5.3%) received chemoimmunotherapy, cBTKi, and BCL2i. Patients cBTKi- and BCL2i-naïve were 127 (39.9%). Of 157 patients, 77 (49%) received cBTKi frontline, 55 (35%) in second line, 28 (17.8%) after >2 lines of treatment. Need for a subsequent treatment or death after cBTKi therapy was 10.4% (n=8) after frontline cBTKi, 41.8% (n=23) after second line, 67.9% (n=19) after >2 lines of treatment; collectively, it was 30.6% (48/157). Deaths during BTKi were 16 (10.2%). Four patients were retreated with cBTKi. For the 34 BCL2i-exposed cBTKi-naïve patients, BCL2i was administered frontline in 13 (38.2%), in second line in 12 (35.3%), after >2 lines of treatment in 11 (32.3%). Need for a subsequent treatment or death after BCL2i therapy in this group was 7.7% (n=1) after frontline BCL2i, 25% (n=3) after second line, 27.3% (n=3) after >2 lines of treatment; collectively, it was 17.6% (6/34). Deaths during BTKi were 7 (11.7%). Four patients were retreated with BCL2i. For the 26 double-exposed patients, 96.1% (n=25) received BCL2i after cBTKi. Collectively, the need for subsequent treatment or death was 38.5% (10/26). Deaths in double-exposed were 4 (15.4%). Five-year TTNT in cBTKi-exposed patients were 80% (median not reached), 40% (median 40 months), 21% (median 24 months) in first, second and subsequent lines respectively (p<0.0001). Five-year TTNT in BCL2i-exposed patients were 83% (median not reached), 72% (median not reached), 12% (median 28 months) in first, second and subsequent lines respectively (p=0.185). Kaplan Meier curves are shown in Figure. Median TTNTF was 9 months (range 1-87) for all patients who discontinued the cBTKi independently of the line of treatment, and 17 months (range 8-49) for those who discontinued both a cBTKi and BCL2i. TTNTF in double-exposed patients was higher probably because 4 patients in this group underwent allogeneic hematopoietic stem cell transplantation for high-risk CLL features or Richter’s transformation. Summary/Conclusion: Despite its limitations, this study shows how anticipating target therapy improved the outcome of CLL patients. Nonetheless, the poor outcomes in advanced lines of therapy also highlight the need for even more effective treatments, especially for younger and high-risk patients.Keywords: Chronic lymphocytic leukemia, Targeted therapy