DP046 | ABSENCE OF LYMPHOCYTOSIS INCREASE AFTER STARTING TREATMENT WITH CBTKI IS UNUSUAL AND ASSOCIATED TO SPECIFIC BIOLOGICAL MARKERS

Background: Bruton tyrosine kinase inhibitors (BTKi) are a class of drugs that have revolutionized Chronic Lymphocytic Leukemia (CLL) therapy. They inhibit Bruton tyrosine kinase (BTK), an enzyme able to trigger a lot of metabolic ways involved in B lymphocytes surviving, proliferation and migration. BTK inhibition results in neoplastic lymphocytes demarginalization from lymph nodes to the peripheral blood. This phenomenon of redistribution lymphocytosis was deeply studied until to define a standard kinetics of lymphocytosis during therapy with BTKi: an initial further rise of the pre-existing lymphocytosis occurs during the first month of treatment, followed by a gradual decrease over time, in some cases until to normalization of the absolute lymphocyte count (ALC). Aims and Methods: we studied the kinetics of lymphocytosis in patients with CLL, treated in I line with Ibrutinib, Acalabrutinib and Zanubrutinib. We enrolled 326 patients from 13 Italian centers, evaluating for each one the median ALC at baseline and at well-defined time-points, then we carried out a descriptive statistics study. Results: we observed an anomalous behavior in 48/326 patients: the 15% of patients didn’t show an increase of baseline ALC, but an immediate reduction of circulating lymphocytes. The majority of these patients was affected by an IGHV unmutated CLL (about 70%). The 42% (20/48) had a trisomy 12 CLL, while the 18% (9/48) had a del17p, the 25% (12/48) a del11q, the 35% (17/48) a del13q, the 15% (7/48) a normal karyotype. Only for the half of our cohort (24/48 patients) we had data about CD49d (VLA-4 integrin subunit) expression. Among these, 19 had a CD49d expression (15 patients CD49d+ and 4 patients CD49d- bimodal) and 5 had a CLL CD49d- (79% vs 21%). Discussion: our data make IGHV unmutated, trisomy 12 and CD49d expression possible predictive markers of absence of lymphocytosis increase in CLL patients starting cBTKi therapy. More data are need to understand the significance of this atypical kinetics of lymphocytosis in terms of clinical outcome: it could reflect a more rapid neoplastic lymphocytes clearance or, by contrast, it could be the consequence of a more marked cell entrapment in lymphoid tissues. In the former case, “no lymphocytosis patients” would have better prognosis, while in the latter case they could have worse outcomes, because neoplastic lymphocytes retention in lymph nodes could be associated to a higher risk of developing resistance mutations to BTKi.