The Biology of Philadelphia Chromosome-like ALL

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described subtype of B-cell precursor ALL with a gene expression profile similar to Ph-positive ALL and a high frequency of IKZF1 alterations. The prevalence of Ph-like ALL increases with age, ranging from 10-15% of children to over 25% of young adults with ALL. It occurs more frequently in males and is associated with adverse clinical features including elevated minimal residual disease levels and poor survival in both children and adults. The genomic landscape of Ph-like ALL is characterized by a diverse range of genetic alterations that dysregulate cytokine receptor and kinase signaling pathways, including rearrangement of CRLF2 and other tyrosine kinases (predominantly ABL-class and Janus kinases). Compelling preclinical data suggest patients harboring ABL-class rearrangements are candidates for ABL1-inhibitors, whilst alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. The success of combinatorial treatment of tyrosine kinase inhibitors with chemotherapy in Ph-positive ALL provides a framework for testing this approach in Ph-like ALL. Ongoing prospective studies will determine if incorporation of targeted therapy with intensive chemotherapy regimens will improve the outcome of patients with Ph-like ALL.