Immunomodulatory Effect of Dasatinib Plus Blinatumomab Versus Ponatinib Plus Blinatumomab in Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia Patients

Introduction. Tyrosine kinase inhibitors (TKIs) have profoundly impacted on the outcome of Ph⁺ acute lymphoblastic leukemia (Ph⁺ ALL). Several frontline studies are currently associating TKIs and immunotherapy. The GIMEMA group proved the feasibility and effectiveness of an induction with dasatinib followed by 2-5 cycles of blinatumomab as consolidation (Foà et al, NEJM 2020), with long-term survival rates approaching 80% in Ph⁺ ALL patients of all ages (Foà et al, JCO, 2023). The combination of dasatinib and blinatumomab (dasa+blina) exerted a marked host immunomodulatory effect with a significant increase of NK, T-NK and CD8⁺ T cells, and a reduction of T regulatory cells (Tregs), more evident after repeated cycles of blinatumomab (Puzzolo et al, Blood 2021). To further improve the outcome of adult Ph⁺ ALL, a phase III trial (GIMEMA ALL2820) was designed in which, in the experimental arm, dasatinib was replaced with ponatinib, followed by 2-5 cycles of blinatumomab (pona+blina). Little is known on the immunomodulatory role of ponatinib either alone or in combination with blinatumomab. In this study, we compared the modulation of the host immune system in two cohorts of patients treated frontline with dasa+blina and pona+blina, in the absence of systemic chemotherapy.

Methods. An extensive panel of markers was used to define circulating immune cells by flow cytometry at specific timepoints: after TKI induction (T0) and after 2, 4 and 5 blinatumomab cycles (T2, T4, T5). The absolute quantification of immune cells was based on their proportion, as determined by flow cytometry, applied to the absolute white blood cell counts and lymphocyte counts. Immunologic parameters were analyzed descriptively and compared using the Wilcoxon rank-sum test for group comparisons and the Wilcoxon Signed-Rank test for paired comparisons. All tests were 2-sided at a significance level of 0.05.

Results. Immune modulation was evaluated in 153 Ph⁺ ALL patients, 43 treated with dasa+blina and 110 with pona-blina. At T0 we found no differences in lymphocytes and T cells in the two cohorts. A significant increase in the median absolute lymphocyte count was documented in the dasa+blina cohort at T4 and T5 [median lymphocyte values 2.080 cells/µL vs 1470 cells/µL at T4 (P =.02) and 1.990 cells/µL vs 1450 cells/µL L at T5 (P =.04)], while in the pona+blina cohort lymphocytes remained unchanged. The T-cell counts showed an overall increase after repeated cycles of blinatumomab, with no significant differences between the two cohorts. A similar trend was shown also for CD8⁺ T cells and for CD4⁺ conventional T cells (Tcon, CD25^low/-CD127^+/-). Interestingly, with regard to the Treg subset distribution (CD25^highCD127^-), a progressive overall decrease was recorded after repeated blinatumomab cycles only in the dasa-blina cohort and was statistically significant at T4 and T5 [median Treg values: 26 cells/µL vs 10 cells/µL at T4 (P =.008) and 34 cells/µL vs 12 cells/µL at T5 (P =.002)]. Both the T-NK (CD3⁺/CD56⁺) and NK (CD3⁻CD56⁺) lymphocyte populations increased significantly during blinatumomab treatment, more significantly in the dasa-blina treated patients. The median T-NK cell counts in the dasa-blina vs pona-blina cohorts were, respectively, 186 cells/µL vs 85 cells/µL at T2 (P=.0001), 185 cells/µL vs 92 cells/µL at T4 (P=.02) and 166 cells/µL vs 81 cells/µL at T5 (P=.03). NK cells were the only subset that was significantly higher in the dasa-blina than pona-blina cohort since T0, with median values of 188 vs 135 cells/µL (P=.05); this increase was progressively more evident in dasa-blina cohort after subsequent blinatumomab cycles [median NK cells: 238 cells/µL vs 105 cells/µL at T2 (P=.0005); 377 cells/µL vs 149 cells/µL at T4 (P=.00001) and 283 cells/µL vs 90 cells/µL at T5 (P=.001)].

Conclusions. Our study shows that in adult Ph+ ALL front-line treatment with dasatinib and blinatumomab induces a more profound NK, T-NK and Treg immune modulation compared to ponatinib and blinatumomab, in agreement with the known immunomodulatory activity of dasatinib. Though ponatinib appears to be more potent than dasatinib and the association with blinatumomab is highly effective, the sustained immune modulation documented with dasatinib plus blinatumomab - in the absence of systemic chemotherapy - may contribute to disease control. This can be beneficial in particular in patients with a higher risk of cardiovascular complications.