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

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 (: n = 1; : n = 1; : n = 1; : n = 1) or a fusion activating the JAK-STAT pathway (: n = 8; : n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant deletion (n = 11). In univariate analysis, fusion-positivity and deletion were each associated with inferior event-free survival; deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; = .019). Our findings support therapy intensification for -altered patients, irrespective of the presence of a kinase-activating fusion.