Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like or BCR::ABL1-like ALL)

Two groups reported in 2009 that a subset of B-ALL without BCR::ABL1 shared its gene-expression profile and its poor prognosis: 'BCR-ABL1-like' from the Dutch Childhood Oncology Group and 'Ph-like' from St Jude and the Children's Oncology Group. Whole-genome and transcriptome sequencing, reported in the New England Journal of Medicine in 2014, showed that nearly all of these leukaemias carried a kinase-activating lesion: rearrangements of CRLF2 in about half, with JAK1 or JAK2 mutations in roughly half of those; ABL-class fusions of ABL1, ABL2, CSF1R or PDGFRB in about one in eight; JAK2 or EPOR rearrangements; and mutations in IL7R, SH2B3, FLT3 and the RAS pathway. IKZF1 deletions accompany most. In cell lines and patient samples, ABL-class fusions responded to imatinib and dasatinib and JAK-STAT lesions to ruxolitinib.

Ph-like ALL is now a WHO 2022 entity, B-ALL with BCR::ABL1-like features, and cooperative groups screen for it at diagnosis by a low-density gene expression array or RNA sequencing followed by FISH or PCR for the specific lesion. Its outcome on chemotherapy is poor because induction leaves high residual disease, so most patients are treated as high risk with intensified therapy and, when residual disease persists, allogeneic transplant. The Children's Oncology Group added dasatinib to chemotherapy for ABL-class fusions in AALL1131 and tested ruxolitinib with chemotherapy for CRLF2 and JAK-pathway disease in AALL1521, and the same lesions are treated with kinase inhibitors in adults on trial. Because the CD19 antigen is unaffected, blinatumomab and CD19 CAR T-cells work as in other B-ALL and are the standard rescue when residual disease does not clear.

Whether a kinase inhibitor added to chemotherapy improves cure, rather than just early response, is not settled: the Ph-positive experience with imatinib is the model, but Ph-like disease is heterogeneous, and CRLF2-rearranged leukaemia, which also carries JAK and RAS mutations, is less kinase-dependent than ABL-class disease. Screening is still uneven outside trial centres and in lower-income countries, so many patients are never identified. Down syndrome-associated ALL, CRLF2-rearranged in over half of cases, sits at the boundary and has its own toxicity constraints. Ph-like ALL is also over-represented among Hispanic and Latino children, linked to inherited GATA3 variants, one of the clearest examples of an inherited contribution to a childhood cancer subtype.