C026 | IMMUNOMODULATORY EFFECT OF DASATINIB PLUS BLINATUMOMAB VERSUS PONATINIB PLUS BLINATUMOMAB IN NEWLY DIAGNOSED PH+ ACUTE LYMPHOBLASTIC LEUKEMIA (PH+ ALL) PATIENTS

Introduction. In newly diagnosed Ph+ ALL, TKIs combined with immunotherapy are being increasingly explored. The GIMEMA D-ALBA trial used dasatinib in induction followed by blinatumomab as consolidation (dasa+blina), reporting long-term OS of 80% and 100% DFS in patients achieving complete molecular response (CMR) at the end of induction (Foà et al, JCO 2024). This regimen showed significant immune-modulation with increased NK, NK-T, and CD8+ T cells and reduced T regulatory cells (Tregs) (Puzzolo et al, Blood 2021). In the GIMEMA ALL2820, ponatinib followed by blinatumomab (pona+blina) showed promising preliminary results, with an estimated 1-year OS of 96% (Chiaretti at al, ASH 2024). Little is known about pona+blina immunomodulatory effect. This study compares immune-modulation between frontline dasa+blina vs pona+blina. Methods. Immune cells were analyzed by flow cytometry after induction (T0) and after 2, 4, and 5 blinatumomab cycles (T2, T4, T5). Results. Analysis was performed on 43 dasa+blina and 110 pona+blina patients. At T0, only patients receiving dasatinib in induction showed significantly higher levels of NK and NK-T cells (P=.05 and .01). After the addition of blinatumomab, a significant increase in the median absolute lymphocytes was documented in the dasa+blina group at T4 (P=.02) and T5 (P=.04), while they remained stable in the pona+blina group. Interestingly, Tregs showed a progressive decrease after repeated blinatumomab cycles only in the dasa-blina cohort, in particular at T4 (P=.008) and T5 (P=.002). The NK and NK-T cells increased significantly in the dasa-blina group after blinatumomab addition (P=.0005 and P=.0001 at T2; P=.0001 and P=.02 at T4 and P=.001 and P=.05, respectively). Stratifying patients based on the CMR status at T0, CMR patients in the dasa-blina group (12) had significantly higher lymphocytes (P=.01), T cells (P=.0004), particularly CD4+ effector and CD8+ T cells, and NK cells (P=.003) than non-CMR patients (31), while immune subsets did not differ in CMR (41) vs non-CMR (69) patients in the pona-blina group. Conclusions. In adult Ph+ ALL, dasa-blina treatment induces a more profound NK, NK-T and Treg immune modulation compared to pona-blina. This effect seems to be greater in patients achieving a CMR at the end of induction. The long-term follow-up of the ALL2820 trial will clarify if the more potent immune modulation observed with dasa-blina is counteracted by the more potent anti-leukemic effect of ponatinib.