Evolving Paradigms in the Treatment of Philadelphia Chromosome–Positive ALL

The treatment of adults with Philadelphia chromosome-positive ALL (Ph+ ALL) has evolved significantly over the past 25 years. These changes have been driven largely by the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib, more accurate risk stratification and monitoring of measurable residual disease (MRD) and, most recently, the frontline use of blinatumomab-based, chemotherapy-free regimens. Although the historical standard of care for newly diagnosed Ph+ ALL was intensive chemotherapy followed by allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in first remission, now most patients can achieve deep and durable remissions-and even cure-with a chemotherapy-free regimen, without the routine need for allo-HSCT. Although the role of allo-HSCT in first remission is diminishing in this new treatment landscape, allo-HSCT remains a reasonable consolidative option for patients with high-risk clinical or molecular features or in treatment settings where frontline blinatumomab and/or high-sensitivity MRD monitoring are not routinely available. With optimal frontline therapy and close disease monitoring, relapses of Ph+ ALL are increasingly uncommon but still pose a significant clinical challenge. Several new agents, including novel TKIs, bispecific antibodies, and chimeric antigen receptor T-cell therapies, are being evaluated in the relapsed/refractory setting and may eventually also play a role in frontline treatment of this disease.