PB1905 PREDICTIVE VALUE OF PERIPHERAL LYMPHOCYTES SUBPOPULATIONS ON BCR INHIBITORS ACTIVITY IN HIGH‐RISK CHRONIC LYMPHOCYTIC LEUKEMIA
Authors: M. Gambella, M. Bergamaschi, A. Ibatici, N. Di Felice, G. Rivoli, M. Miglino, M. Cea, E. Angelucci, A. Cagnetta, R.M. Lemoli
Journal: HemaSphere (2019)

Background: BCR inhibitors (ibrutinib and idelalisib) have dramatically changed clinical scenario of High Risk CLL patients (del17p13, early relapsed or refractory disease), with prolonged responses observed in more than 50% of cases. Both these molecules have immunomodulating properties, with ibrutinib inducing a Th1 phenotype through inhibition of IL2‐inducible kinase (ITK) in Th2 cells and idelalisib promoting autoimmunity in presence of lower T‐regulatory cells (Tregs) levels. Importantly, CLL is characterized by high levels of circulating Tregs, which in turn represents a plausible mechanism of immune‐tolerance. Although several reports indicate that BCR inhibitors‐activity results in the recovery of anti‐cancer immunity, the impact of pre‐treatment lymphocytes subpopulations on these drugs activity has not been investigated yet. Aims: In this study we investigate the role of T and NK Cell compartment in peripheral blood in mediating biological activity of novel BCR inhibitors. Methods: We analysed 50 CLL consecutive pts treated with ibrutinib‐ or idelalisib‐ based regimens from 2015 to 2018 at our centre. Among these patients, we identified 10 (8 treated with ibrutinib and 2 with idelalisib) characterized by high unfavourable biological risk profile according to 2018 iwCLL criteria (del17p13 and/or relapse within 24‐36 months and/or refractory disease): 5 treatment‐naïve pts showed 17p13 deletion, 4 pts relapsed within 24 months from the last treatment and 1 presented a combination of del17p13 and early relapse. An unmutated IgHV status characterized 5 out of 10 pts (50%). All patients have not been treated within the last 12 months and showed adequate lymphocyte recovery at time of analysis. All selected pts received BCR inhibitors treatment at least for 6 consecutive months and no occurrence of toxicity/intolerance were reported. Patients achieving less than partial remission (PR), were considered non‐responders (NRs) based on iwCLL criteria. Absolute number of lymphocytes subpopulations (CD3+ T cells, CD19+ B cells, CD16+ CD56+ CD3‐ NK cells, CD3+ CD4+ T cells and CD3+ CD8+ T cells) was evaluated by flow‐cytometry before starting treatment; T and NK cells compartments were compared to the leukemic monoclonal B‐cells (MBC) defining a T/MBC and NK/MBC ratio. Results: Six patients achieved at least a PR within 6 months of starting treatment, whilst 4 were considered NRs. At baseline, NRs exhibited higher levels of T (median, responders vs NRs: 1875 vs 2261) and NK (median, responders vs NRs: 379 vs 500) circulating lymphocytes than responders. In detail, among T cell compartment, high CD8 positive cells were observed in not responders (median, responders vs NRs: 864 vs 1296) with no significant difference in CD4 positive T cells count (median, responders vs NRs: 1073 vs 927). Further analysis on ibrutinib‐treated pts, revealed that such differences were more pronounced: NRs exhibited a 2‐fold increased levels of circulating T cells (median, responders vs NRs: 1767 vs 3526), NK cells (median, responders vs NRs: 317 vs 756) and circulating CD4 positive cells (median, responders vs NRs: 976 vs 1385) than responders. Moreover, higher T/MBC and NK/MBC ratios were observed among the former. Summary/Conclusion: Higher levels of circulating lymphocytes have been reported to be associated with CLL, probably reflecting a tumour‐permissive status. In this study, although the small size of analysis, our data suggest an hypothetical enhanced activity of BCR inhibitors in CLL patients carrying a normal lymphocytes subpopulation, thus supporting the immunomodulating activity of these molecules.