Ph+ ALL: new approaches for upfront therapy

Philadelphia chromosome-positive (Ph+) ALL is the most common genetic subtype of ALL and primarily affects adults. Ph+ ALL is characterized by the constitutively active ABL1 kinase and is resistant to conventional chemotherapy. Thus, Ph+ ALL was historically associated with a dismal prognosis, particularly among patients who did not undergo allogeneic hematopoietic stem cell transplantation (alloHCT) in first complete remission (CR). Imatinib, the first tyrosine kinase inhibitor (TKI) effective against ABL1, transformed the treatment and prognosis of Ph+ ALL, allowing more patients to achieve CR and become eligible for alloHCT, thereby improving outcomes. In recent years, there has been an improved understanding of the biology of Ph+ ALL, including recognition of distinct subtypes (multilineage and lymphoblast-only Ph+ ALL). There has also been a dramatic expansion of effective therapeutic and diagnostic tools for management of Ph+ ALL, including more potent TKIs, which have activity against ABL kinase–resistance mutations; refinement of the chemotherapy and alloHCT regimens that accompany TKI therapy; introduction of immunotherapy (blinatumomab); and better assays for measurable residual disease monitoring. This article reviews recent advancements and future directions for the initial treatment of Ph+ ALL in adults.