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

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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.

authors

  • Tran, Thai Hoa
  • Harris, Marian H
  • Nguyen, Jonathan V
  • Blonquist, Traci M
  • Stevenson, Kristen E
  • Stonerock, Eileen
  • Asselin, Barbara L
  • Athale, Uma
  • Clavell, Luis A
  • Cole, Peter D
  • Kelly, Kara M
  • Laverdiere, Caroline
  • Leclerc, Jean-Marie
  • Michon, Bruno
  • Schorin, Marshall A
  • Welch, Jennifer JG
  • Reshmi, Shalini C
  • Neuberg, Donna S
  • Sallan, Stephen E
  • Loh, Mignon L
  • Silverman, Lewis B

publication date

  • March 13, 2018