Advances and Controversies in the Management of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Navigating First-Line Therapies.

purpose of reviewThe goal of this review is to provide an updated synthesis of therapeutic advances and remaining controversies in the management of Philadelphia chromosome-positive (Ph +) B-cell acute lymphoblastic leukemia (ALL). We sought to examine how modern tyrosine kinase inhibitors (TKIs), immunotherapies, and response-adapted strategies have reshaped treatment paradigms, including the role of allogeneic hematopoietic stem cell transplantation (allo-HCT), central nervous system (CNS) prophylaxis, and emerging chemotherapy-free approaches. RECENT

findingsSuccessive generations of TKIs have transformed Ph + ALL from a uniformly fatal leukemia into a highly treatable disease, with dasatinib or ponatinib-based and TKI-blinatumomab regimens achieving high rates of complete molecular remission. Achieving early measurable residual disease (MRD) negativity predicts long-term survival and identifies patients who may safely defer allo-HCT. Genomic profiling has uncovered prognostic subgroups, notably IKZF1^plus, T315I mutated, and multilineage disease, which remain resistant or challenging to current therapy. Novel agents, including asciminib and olverembatinib, are expanding options for resistant or relapsed disease, while CAR-T cell therapy and next-generation bispecific T-cell engagers are emerging as promising tools for refractory and post-TKI settings. Ph + ALL exemplifies the paradigm shift toward precision, MRD-directed, and chemotherapy-sparing treatment. Integrating potent TKIs with immunotherapy enables deep and durable remissions, potentially eliminating the need for upfront transplantation in selected patients. Future research should define molecular predictors of treatment-free remission, optimize CNS prophylaxis in targeted regimens, and establish standardized monitoring for safe TKI discontinuation.