Ibrutinib vs chlorambucil: Immunophenotypic and quantitative impacts on circulating immune cells in chronic lymphocytic leukemia (CLL).

Abstract

7524 Background: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by FDA for treatment (Tx) of patients (pts) with CLL. Following the outcome of the RESONATE-2 trial, ibr was approved as the first chemotherapy-free Tx option for treatment-naïve (TN) pts. In this study, ibr reduced the risk of progression or death by 84% compared with chlorambucil (chl). To assess the impact of ibrutinib vs this traditional chemotherapeutic agent on the immune system, quantitative changes in circulating cells were studied throughout the first year of Tx. Methods: Immunophenotypic analyses were performed by flow cytometry on peripheral blood to assess lymphoid and myeloid cells of TN CLL pts who received 420 mg ibr once daily (n=50) or 0.5-0.8 mg/kg chl twice a month (n=30). Medians of statistically significant changes (p<0.05, Wilcoxon test) in absolute counts of 1-year paired samples (pre-dose vs 1-year) are reported. Results: Chl progressively reduced circulating B, T, NK, NKT cells, myeloid derived suppressor cells (MDSC), and monocytes by 69%-99%. All development stages of CD4+ and CD8+ T cells, except stem cell memory T cells (TSCM), decreased by 51%-90%. Regulatory T cells (Treg) and PD1+ T cells also decreased similarly; however, long-term activated T cells (TLA) were not impacted. On the other hand, ibr mainly reduced B cells (90%), MDSC (61%) and some T cells, specifically TLA, PD1+ T cells, Treg and effector T cells (27-52%). Naïve T cells, TSCM, central memory T cells and NK cells were spared throughout the full year of Tx. Classical monocytes were increased (+187%), while non-classical monocytes and intermediate monocytes remained relatively steady. Conclusions: Chl, a traditional chemotherapy, affected non-specifically most immune cell subsets in circulation, although surprisingly it did not affect TLA which have been reported as dysfunctional in CLL. Ibr represents a more targeted Tx approach than cytotoxic chemotherapy; essentially B cells, abnormal T subsets (TLA, PD1+T, Treg) and pro-tumor MDSCs were reduced. However, ibr preserved naïve T cells, NK cells and monocytes, which are important for mounting anti-tumor responses. Clinical trial information: NCT01722487.