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 the WT1 gene and NUP98-NSD1 fusion are predictors of poor survival outcome/prognosis that frequently occur in combination with internal tandem duplications of the juxta-membrane domain of FLT3 (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 mutated WT1 and FLT3-ITD in 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 (only FLT3-ITD; n=33, only WT1 mutation; n=29) or none of these mutations (n=272). Including NUP98-NSD1 and high allelic ratio (AR) of FLT3-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 of WT1 mutation, NUP98-NSD1, and FLT3-ITD with 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.
Highlights
Pediatric acute myeloid leukemia (AML) is a rare and heterogeneous disorder, for which continuous improvement of risk-adapted treatment approaches over the last 30 years has led to overall survival rates of approximately 70% [1, 2]
It has been clearly established that the occurrence of WILMS TUMOR 1 (WT1) mutations in AML blasts with normal karyotypes is associated with adverse clinical outcomes in adult [6,7,8,9] as well as pediatric patients [10, 11]
We previously demonstrated in a cohort of 298 pediatric patients with de novo AML treated before 2004 on AML-BFM protocols that the combination of FLT3ITD and mutated WT1 is associated with even worse survival [10]
Summary
Pediatric acute myeloid leukemia (AML) is a rare and heterogeneous disorder, for which continuous improvement of risk-adapted treatment approaches over the last 30 years has led to overall survival rates of approximately 70% [1, 2]. 25% of pediatric patients have AML blasts with a normal karyotype, but even these cases often harbor somatic mutations in genes such as WILMS TUMOR 1 (WT1), NPM1, NRAS, KRAS, Fms-like tyrosine kinase 3 (FLT3), and/or c-KIT/CD117 [1, 2]. In AML, WT1 mutations are present in approximately 10% of patients and predominantly located in exons 7 and 9, which contain the DNA-binding zinc finger domains of the protein. The majority of these mutations are out-of-frame deletion/insertions or premature termination codons that will lead to truncated proteins with altered functional consequences for the cells [5]. It has been clearly established that the occurrence of WT1 mutations in AML blasts with normal karyotypes is associated with adverse clinical outcomes in adult [6,7,8,9] as well as pediatric patients [10, 11]
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