Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a subset of high-risk B-ALL associated with high relapse risk and inferior clinical outcomes across the pediatric-to-adult age spectrum. Ph-like ALL is characterized by frequent IKZF1 alterations and a kinase-activated gene expression profile similar to that of Philadelphia chromosome-positive (Ph+) ALL, yet lacks the canonical BCR-ABL1 rearrangement. Advances in high-throughput sequencing technologies during the past decade have unraveled the genomic landscape of Ph-like ALL, revealing a diverse array of kinase-activating translocations and mutations that may be amenable to targeted therapies that have set a remarkable precision medicine paradigm for patients with Ph + ALL. Collaborative scientific efforts to identify and characterise Ph-like ALL during the past decade has directly informed current precision medicine trials investigating the therapeutic potential of tyrosine kinase inhibitor-based therapies for children, adolescents, and adults with Ph-like ALL, although the most optimal treatment paradigm for this high-risk group of patients has yet to be established. Herein, we describe the epidemiology, clinical features, and biology of Ph-like ALL, highlight challenges in implementing pragmatic and cost-effective diagnostic algorithms in the clinic, and describe the milieu of treatment strategies under active investigation that strive to decrease relapse risk and improve long-term survival for patients with Ph-like ALL as has been successfully achieved for those with Ph + ALL.

Keywords: ABL; Acute lymphoblastic leukemia; CRLF2; Clinical trials; JAK/STAT; Philadelphia chromosome-like; Precision medicine; Tyrosine kinase inhibitor.