SOHO State of the Art Updates and Next Questions | Management of High-Risk Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) was historically associated with dismal outcomes. The introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs) transformed this disease, and more recently, chemotherapy-free regimens combining TKIs with the bispecific T-cell engager blinatumomab have achieved excellent long-term survival without routine allogeneic stem cell transplantation (allo-SCT). However, relapses still occur, particularly in the central nervous system, highlighting the need for refined risk stratification to guide treatment intensification. As treatment paradigms have evolved from chemotherapy plus TKI to chemotherapy-free regimens, the prognostic significance of individual risk factors has shifted. Pretreatment factors (including white blood cell count, additional chromosomal abnormalities, and genomic alterations), and response-related factors (including timing and depth of molecular response, measurable residual disease assessment method, ABL1 kinase domain mutations) jointly influence prognosis. However, the significance of these factors is modulated by treatment-related factors, specifically TKI generation/potency and backbone therapy. Features that were strongly adverse in the chemotherapy plus TKI era may carry different weight in the chemotherapy-free setting, and prognostic factors differ across chemotherapy-free regimens depending on the TKI employed. These observations underscore that risk stratification in Ph+ ALL is not static but must be interpreted within the context of the specific treatment used. In this review, we examine the key prognostic determinants in Ph+ ALL, their evolving relevance across treatment eras, and the emerging risk-adapted strategies for treatment intensification in the chemotherapy-free era.