Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

Abstract

Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (<i>ETV6-ABL1</i>: n = 1; <i>FOXP1-ABL1</i>: n = 1; <i>SFPQ-ABL1</i>: n = 1; <i>ZC3HAV1-ABL2</i>: n = 1) or a fusion activating the JAK-STAT pathway (<i>P2RY8-CRLF2</i>: n = 8; <i>PAX5-JAK2</i>: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant <i>IKZF1</i> deletion (n = 11). In univariate analysis, fusion-positivity and <i>IKZF1</i> deletion were each associated with inferior event-free survival; <i>IKZF1</i> deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; <i>P</i> = .019). Our findings support therapy intensification for <i>IKZF1</i>-altered patients, irrespective of the presence of a kinase-activating fusion.