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

Abstract

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 <i>BCR::ABL1</i> fusion. A subgroup of these patients have fusions or rearrangements involving genes such as <i>ABL1</i>, <i>ABL2</i>, <i>PDGFRβ</i>, <i>JAK2</i>, and <i>EPOR</i>, some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions. 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. We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had <i>ABL</i> class fusions (eight <i>ABL1</i>, one <i>ABL2,</i> and five <i>PDGFRβ</i>) and nine had <i>JAK2</i> class fusions (five <i>JAK2</i> and four <i>EPOR</i>). 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 <i>ABL1</i> fusion (n = 8), <i>PDGFRβ</i> fusion (n = 4), and <i>EPOR</i> fusion (n = 1). All four patients with <i>ABL1</i> fusions who received TKI with induction chemotherapy are alive in first remission. 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.