How I treat Ph+ acute lymphoblastic leukemia

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is characterized by the BCR:ABL1 fusion gene which produces a constitutively active tyrosine kinase which drives disease pathogenesis and is associated with resistance to conventional chemotherapy. Intensive cytotoxic chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT), the historical treatment paradigm for Ph+ ALL, was associated with poor outcomes. The introduction of inhibitors of ABL1 revolutionized the treatment of Ph+ ALL. Imatinib, the first BCR:ABL1 tyrosine kinase inhibitor (TKI), significantly improved survival, and was followed by more potent TKIs (dasatinib, nilotinib, and ponatinib) with activity also against resistance mutations. The introduction of blinatumomab, a CD19-CD3 bispecific T-cell engager, has further transformed the treatment of Ph+ ALL, allowing some patients to be treated without cytotoxic chemotherapy and/or HSCT. Still, HSCT remains an essential treatment option for select high-risk cases. Ongoing investigation focuses on more accurately identifying clinical and genetic features which predict for systemic or central nervous system relapse and determining the most effective approach to successfully risk-adapt therapy, including appropriate allocation to HSCT. This review highlights recent advances in treatment, emphasizing the importance of TKIs, the emerging role of immunotherapy, and the evolving position of HSCT in the management of Ph+ ALL.