Philadelphia-Like Genetic Rearrangements in Adults With B-Cell ALL: Refractoriness to Chemotherapy and Response to Tyrosine Kinase Inhibitor in ABL Class Rearrangements

Abstract

PURPOSE Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a BCR::ABL1 fusion. A subgroup of these patients have fusions or rearrangements involving genes such as ABL1, ABL2, PDGFRβ, JAK2, and EPOR, some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions. PATIENTS AND METHODS We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI. RESULTS We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had ABL class fusions (eight ABL1, one ABL2, and five PDGFRβ) and nine had JAK2 class fusions (five JAK2 and four EPOR). Notably, several of these fusions were cryptic by conventional cytogenetics and fluorescent in situ hybridization (FISH) assays and identified only by multiplex fusion assay. Thirteen of these 23 patients received a TKI as part of their treatment; this included ABL1 fusion (n = 8), PDGFRβ fusion (n = 4), and EPOR fusion (n = 1). All four patients with ABL1 fusions who received TKI with induction chemotherapy are alive in first remission. CONCLUSION Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, multiplex fusion assays can help identify recurrent chromosomal translocations that are seen in patients with Ph-like ALL. Early initiation of TKI appears beneficial; larger studies are required to fully understand the benefit of TKI and to design rational combination therapies for these patients.