Prognostic Significance of FLT3 and NPM1 Mutations in Acute Myeloid Leukemia
Date of Award
Restricted Access Thesis
College of Theology, Arts, & Sciences
Math & Science
Mihail Iordanov, Ph.D.
Acute myeloid leukemia (AML) is one of the most common and deadly hematopoietic malignancies. Currently, age, performance status (a patient’s general well being and activities), and cytogenetic status remain most predictive prognostic factors for AML. In addition, genomic mutations within nucleophosmin 1 (NPM1) and fms-like tyrosine kinase (FLT3) have been found to be clinically relevant prognostic factors for AML patients, especially those with normal cytogenetics. But it is unknown if the prognostic significance of FLT3 and NPM1 will apply to contemporary treatment strategies.
Therefore, we examined the potential clinical significance of NPM1 and FLT3 mutations in a large cohort of adult de novo AML patients enrolled on South West Oncology Group (SWOG) trial S0106. In this randomized phase III trial, patients ages 18-60 with de novo AML were enrolled to compare the effects of adding Gemtuzumab Ozogamicin (GO) to standard induction therapy (Cytosine Arabinoside and Daunomycin, AD) vs. standard treatment alone. Samples from 198 of the 600 eligible patients were evaluated. Genomic mutation analyses for nucleotide insertions in exon 12 of the NPM1 gene and internal tandem duplications (ITDs) within exons 14-15 of FLT3 were performed using fragment analyses in diagnostic bone marrow (BM) and peripheral blood (PB) samples. Mutant/wild type allelic ratios were computed for all mutations. Analyses evaluating the prognostic significance of the mutation status of the two genes identified 3 mutational risk groups for overall survival (OS) and relapse-free survival (RFS). AML patients with NPM1 mutations and without FLT3-ITD mutations had a much more favorable prognosis than all other evaluated AML patients.