Dynamics of in vivo immune remodeling in Ph+ all patients receiving frontline ponatinib and blinatumomab therapy

Tyrosine kinase inhibitor (TKI)-based chemotherapy-free strategies, combining dasatinib or ponatinib with the bispecific monoclonal antibody blinatumomab, have substantially improved the response rates and outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. The extent to which this highly effective treatment strategy also impacts on the modulation of the host immune system, in the absence of systemic chemotherapy, remains not fully investigated. In the phase II D-ALBA trial, frontline dasatinib followed by 2–5 blinatumomab cycles (dasa+blina) [ 2 , 4 ] induced a marked immune modulation, characterized by a broad lymphocyte activation, a selective reduction of regulatory T cells (Tregs), and an expansion of NK and T-NK cells [ 2 , 8 , 9 ]. In the subsequent phase III GIMEMA ALL2820 trial (NCT04722848) the administration of the third generation TKI ponatinib plus blinatumomab (pona+blina) is associated with clinical outcomes that appear superior to those obtained with the D-ALBA protocol [ 6 ]. Our previous comparative analysis suggested a broader host immune activation associated with dasa+blina compared to pona+blina [ 9 ]. The present study was specifically designed to characterize more in depth the longitudinal immune effects of pona+blina through an integrated peripheral blood (PB) and bone marrow (BM) profiling with a specific focus on lymphocyte subset kinetics, phenotypic maturation, and functional competence at different treatment timepoints.