Abstract
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) was historically associated with a very poor prognosis in the pre-tyrosine kinase inhibitors (TKIs) era. While consolidation with allogeneic hematopoietic cell transplantation (HCT) was associated with improved outcomes in patients with Ph+ ALL treated with chemotherapy alone, the advent of BCR::ABL1-targeting TKIs revolutionized the therapeutic landscape, enhancing response rates, increasing the proportion of patients proceeding to HCT, and improving survival. Compared to earlier generation TKIs, ponatinib, a third-generation TKI, is more potent and overcomes a broader array of preexisting and emerging resistant mutations, and clinical studies have illustrated superiority in attaining a negative measurable residual disease (MRD) state, leading to excellent long-term survival outcomes, even without the application of consolidative allogeneic HCT. Ponatinib has been successfully integrated into various treatment regimens, including both low- and high-intensity chemotherapy regimens, and in combination with blinatumomab, for adult patients with newly diagnosed Ph+ ALL. Herein, we summarize landmark trials, specifically their efficacy and toxicity profile, that established ponatinib as a standard of care for patients with newly diagnosed Ph+ ALL who are suitable medically for it.