Ph+ ALL without chemotherapy: when TKIs reshape the immune response – A dialogue between Robin Foà, Filippo Milano e Michela Ansuinelli

In this episode, Prof. Robin Foà and Dr. Filippo Milano explore the evolving treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), focusing on the transition from intensive chemotherapy and transplantation toward targeted therapies combined with immunotherapy. What emerges from the discussion is not only a new therapeutic strategy, but a deeper understanding of how these treatments profoundly reshape the immune system.The conversation centers on the biological effects of combining tyrosine kinase inhibitors with blinatumomab, revealing unexpected patterns of immune activation. Patients treated with Dasatinib showed significant expansion of T cells and NK cells, while the addition of blinatumomab further enhanced immune responses and reduced immunosuppressive regulatory T cells. Particularly striking was the observation that patients achieving early complete molecular responses also displayed the strongest immune modulation, suggesting a direct link between immune activation and clinical outcome.The episode also examines the differences between Dasatinib and Ponatinib. While Dasatinib appears to induce a broad quantitative immune response, Ponatinib seems to act more through qualitative and phenotypic changes, promoting maturation and functional activity of immune effector cells. These findings highlight how different TKIs may interact with the immune system in distinct ways, opening new perspectives for individualized treatment strategies.Looking ahead, the discussion expands to the broader role of the tumor microenvironment, checkpoint inhibition, and CAR-T cell therapy, emphasizing how future advances in Ph+ ALL will increasingly depend on understanding the dialogue between leukemia cells and host immunity at the single-cell level.A thoughtful exploration of how targeted therapy and immunotherapy are redefining the concept of leukemia treatment—moving beyond disease control toward immune-driven eradication of residual disease.