Keeping PACE with Ph Positive to Ph-Like Detection in B-Lineage Acute Lymphoblastic Leukemia: A Practical and Cost Effective (PACE) Approach in a Resource Constrained Setting.

Abstract

Philadelphia (Ph)-like or BCR-ABL like acute lymphoblastic leukemia (ALL) is defined on the basis of a gene expression profile that is similar to Ph-positive ALL. It comprises a wide spectrum of genetic lesions affecting primarily the cytokine receptor and/or kinase signalling genes. It accounts for approximately 10-15% of pediatric ALL, and is more common in patients who are high-risk according to the National Cancer Institute criteria. Presence of Ph-like mutations is an independent predictor of poor outcome. However, there is vast potential to utilize targeted therapy to improve survival in this group. The sizeable range of genetic lesions varying from translocations, fusions, point mutations and deletions make the diagnosis challenging. Hence, a practical and cost effective approach is required to enable identification in resource constrained settings. Patients with recurrent cytogenetic abnormalities such as ETV6-RUNX1, high hyperdiploidy, TCF3-PBX1, BCR-ABL1 and KMT2A (MLL) rearrangement need not be tested, as these are mutually exclusive with BCR-ABL like mutations. Detection of CRLF2 overexpression, which is the commonest abnormality, is employed as the first step. In patients lacking overexpression, testing for tyrosine kinase fusions can be performed. However, the goal should be to employ a combination of molecular diagnostic techniques such as reverse transcriptase polymerase chain reaction (PCR), real time quantitative PCR, fluorescence in situ hybridization and Sanger sequencing to detect genetic lesions that are amenable to targeted therapy.