DP055 | DISTINCT RELAPSE PATTERNS IN CHRONIC LYMPHOCYTIC LEUKEMIA AFTER THERAPY WITH BTK OR BCL2 INHIBITORS

Introduction Bruton tyrosine kinase inhibitors (BTKi) and venetoclax exert their effect on two different populations of chronic lymphocytic leukemia (CLL) cells: while BTKi act on the dividing subpopulation of CLL cells, which is killed after mobilization from the lymph nodes into the circulation, venetoclax targets the resting CLL subpopulation. Given this action on different compartments, we hypothesized that the pattern of CLL relapses could differ after therapy with each drug. Methods We reviewed the medical charts of patients treated with BTKi, venetoclax (VEN) or ibrutinib+venetoclax (IV) at our institution, and subsequently developed progressive disease (PD) since. Clinical and biological variables were registered along with the date at which patients presented with PD, according to the 2018 iwCLL guidelines. We also registered paired results of cytogenetic and TP53/NOTCH1 mutational analyses before treatment and at the time of PD to explore whether any treatment led to faster clonal evolution. Results Fifty patients with PD were included. The median age was 70 years (range 43-88), 23 (46%) were females, 15 (30%) patients were previously untreated while 35 (70%) were relapsed/refractory. 30 (60%) were treated with BTKi (n=1 acalabrutinib, n=29 ibrutinib), 14 (28%) with R-VEN and 6 (12%) with IV. Patients treated with BTKi more frequently experienced PD with lymphocytosis (LY) compared to patients treated with VEN (63% vs 21%; p=0.03), which instead more frequently relapsed with lymphadenopathy (LN) in 57% of cases (Figure). Results of paired FISH analysis were available for 24 (48%) patients (17 treated with BTKi, 4 with VEN, 3 with I+V). 4/17 (24%) and 3/4 (7%) patients treated with BTKi and VEN respectively acquired a new FISH abnormality. Paired karyotypes were available for 14 patients treated with BTKi, who acquired a median of 1 karyotype abnormality (range 0-11), and for 2 patients with VEN who acquired each one a single new abnormality. 3/14 (21%) and 0/2 (0%) patients relapsed with a complex karyotype after therapy with BKTi and R-VEN respectively. No new TP53/NOTCH1 mutations were observed. Conclusion Our results suggest that relapses after BTKi could be mainly driven by treatment-resistant proliferating cells previously mobilized from the lymph nodes, while those after venetoclax may be mainly driven by residual cells still residing in lymph nodes. Further study is required to clarify if either treatment leads to faster clonal evolution.