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 (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion.

Graphical abstract

Figure 1.

Overall and event-free survival of NCI high-risk, Ph-negative, B-ALL patients by fusion and IKZF1 status. (A-B) The 5-year OS and EFS for patients with Fusion⁺ patients were 68% (95% confidence interval [CI], 39% to 85%) and 48% (95% CI, 22% to 70%), respectively, in comparison with 88% (95% CI, 79% to 93%) and 78% (95% CI, 67% to 85%) for fusion-negative patients. (C-D) The 5-year OS and EFS for patients with IKZF1 deletion were 66% (95% CI, 45% to 81%) and 45% (95% CI, 25% to 62%), respectively, in comparison with 90% (95% CI, 79% to 95%) and 81% (95% CI, 69% to 89%) for patients without IKZF1 deletion. (E-F) The 5-year OS and EFS were 62% (95% CI, 28% to 84%) and 44% (95% CI, 15% to 70%), respectively, for patients with both fusion-positivity and IKZF1 deletion in comparison with 91% (95% CI, 79% to 96%) (P = .005) and 83% (95% CI, 71% to 90%) (P = .006) for those with neither. Del, deletion.