MutatedWT1,FLT3-ITD,andNUP98-NSD1Fusion in Various Combinations Define a Poor Prognostic Group in Pediatric Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia is a life-threatening malignancy in children and adolescents treated predominantly by risk-adapted intensive chemotherapy that is partly supported by allogeneic stem cell transplantation. Mutations in theWT1gene andNUP98-NSD1fusion are predictors of poor survival outcome/prognosis that frequently occur in combination with internal tandem duplications of the juxta-membrane domain ofFLT3(FLT3-ITD).To re-evaluate the effect of these factors in contemporary protocols, 353 patients (<18 years) treated in Germany with AML-BFM treatment protocols between 2004 and 2017 were included. Presence of mutatedWT1andFLT3-ITDin blasts (n=19) resulted in low 3-year event-free survival of 29% and overall survival of 33% compared to rates of 45-63% and 67-87% in patients with only one (onlyFLT3-ITD; n=33,onlyWT1mutation; n=29) or none of these mutations (n=272). IncludingNUP98-NSD1and high allelic ratio (AR) ofFLT3-ITD(AR ≥0.4) in the analysis revealed very poor outcomes for patients with co-occurrence of all three factors or any of double combinations. All these patients (n=15) experienced events and the probability of overall survival was low (27%). We conclude that co-occurrence ofWT1mutation,NUP98-NSD1,andFLT3-ITDwith an AR ≥0.4 as triple or double mutations still predicts dismal response to contemporary first- and second-line treatment for pediatric acute myeloid leukemia.