Development of precision medicine trials for Philadelphia chromosome-like acute lymphoblastic leukaemia


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Stephen Hunger1,2
1University of Colorado School of Medicine, Aurora, USA,2Children's Hospital Colorado, Aurora, USA

Abstract

While the overall survival for paediatric acute lymphoblastic leukaemia (ALL) is now 85-90%, high risk subsets can be identified that have significantly inferior outcomes. Ph-like (or BCR-ABL1-like) ALL is one recently identified high risk ALL subset that is defined by a gene expression profile similar to that of Philadelphia chromosome-positive (Ph+) ALL but without BCR-ABL1 fusion. Our studies in the Children's Oncology Group (COG) have shown that the frequency of Ph-like ALL increases in age from 10% in children younger than 10 years to 27% in young adults 21-40 years old and that it is associated with a high relapse rate and inferior survival. Genomic studies of Ph-like ALL (as defined by the COG) have shown that about half of cases have chromosome rearrangements leading to over-expression of the cytokine receptor CRLF2, with JAK1/2 point mutations present in about half of CRLF-rearranged cases. Most of the remaining Ph-like ALL cases have chromosome rearrangements, often cryptic, that create ABL1, ABL2, CSF1R, PDGFRB and JAK2 fusion proteins. The ABL1, ABL2, CSF1R, and PDGFRB fusions phenocopy BCR-ABL1 in that they transform factor dependent cell lines and are exquisitely sensitive to the ABL1 class tyrosine kinase inhibitors imatinib and dasatinib in vitro, in animal models, and anecdotally in humans with Ph-like ALL. COG investigators have developed assays to rapidly identify Ph-like ALL cases and characterise the underlying genomic lesions and are preparing to implement a clinical trial that will test addition of dasatinib to chemotherapy in Ph-like ALL cases with ABL1, ABL2, CSF1R, and PDGFRB fusions. Additional studies are being developed to test the JAK2 inhibitor ruxolitinib in cases with JAK1/2 point mutations and JAK2 fusions.