Document Type

Article

Publication Date

5-14-2024

Identifier

DOI: 10.1182/bloodadvances.2023011980; PMCID: PMC11063409

Abstract

We sought to define the cooccurring mutational profile of FLT3-ITD-positive (ITDpos) acute myeloid leukemia (AML) in pediatric and young adult patients and to define the prognostic impact of cooperating mutations. We identified 464 patients with FLT3-ITD mutations treated on Children's Oncology Group trials with available sequencing and outcome data. Overall survival, event-free survival (EFS), and relapse risk were determined according to the presence of cooccurring risk stratifying mutations. Among the cohort, 79% of patients had cooccurring alterations across 239 different genes that were altered through mutations or fusions. Evaluation of the prognostic impact of the cooccurring mutations demonstrated that patients with ITDpos AML experienced significantly different outcomes according to the cooccurring mutational profile. Patients with ITDpos AML harboring a cooccurring favorable-risk mutation of NPM1, CEBPA, t(8;21), or inv(16) experienced a 5-year EFS of 64%, which was significantly superior to of 22.2% for patients with ITDpos AML and poor-risk mutations of WT1, UBTF, or NUP98::NSD1 as well to 40.9% for those who lacked either favorable-risk or poor-risk mutation (ITDpos intermediate; P < .001 for both). Multivariable analysis demonstrated that cooccurring mutations had significant prognostic impact, whereas allelic ratio had no impact. Therapy intensification, specifically consolidation transplant in remission, resulted in significant improvements in survival for ITDpos AML. However, patients with ITDpos/NUP98::NSD1 continued to have poor outcomes with intensified therapy, including sorafenib. Cooccurring mutational profile in ITDpos AML has significant prognostic impacts and is critical to determining risk stratification and therapeutic allocation. These clinical trials were registered at www.clinicaltrials.gov as NCT00002798, NCT00070174, NCT00372593, and NCT01371981.

Journal Title

Blood Adv

Volume

8

Issue

9

First Page

2094

Last Page

2103

MeSH Keywords

Humans; Leukemia, Myeloid, Acute; fms-Like Tyrosine Kinase 3; Mutation; Child; Prognosis; Nucleophosmin; Adolescent; Female; Male; Child, Preschool; Infant; Young Adult; Adult

Keywords

Acute Myeloid Leukemia; fms-Like Tyrosine Kinase 3; Mutation; Prognosis; Nucleophosmin

Comments

Grants and funding

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://ashpublications.org/bloodadvances/article/8/9/2094/514791/Prognostic-impact-of-cooccurring-mutations-in-FLT3

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