Toward a chemotherapy and allo-HSCT free future: the evolution of treatment for Philadelphia chromosome-positive...

The treatment landscape for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation over the past two decades. The integration of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has shifted the paradigm from reliance on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) towards targeted and immunotherapy-based strategies. Imatinib significantly improved initial complete remission (CR) rates and survival, enabling more patients to proceed to transplant. Second-generation and third-generation TKIs further improved outcomes by targeting most imatinib-resistant mutations, with ponatinib-based regimens achieving deep molecular responses and long-term survival in most patients. Concurrently, immunotherapies like blinatumomab and CAR-T cells have enabled potent chemotherapy-free strategies, yielding high molecular response rates and challenging the necessity of allo-HSCT for all patients. Current evidence supports reserving allo-HSCT for high-risk patients, while those with sustained minimal residual disease (MRD) negativity may be cured with TKI and immunotherapy alone. Future progress hinges on optimizing combinations, integrating novel agents like asciminib and venetoclax, and leveraging MRD and genomic profiling for precision medicine.