High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML

Abstract

Acute myeloid leukemia (AML) with mutated is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than ) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated to evaluate the potential significance of variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; < .0001) compared with the other -mutated cases. In both univariate and multivariable analyses, high VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission ( = .0004) and in patients with mutated ( < .0001). Our findings indicate that the prognostic effect of mutation in de novo AML may be influenced by the relative abundance of the mutated allele.

High NPM1 mutant allele burden at diagnosis correlates with minimal residual disease at first remission in de novo acute myeloid leukemia

“…[15][16][17][18][19][20][21] Recent guidelines for MRD evaluation issued by the European LeukemiaNet (ELN) MRD Working Party, recommend sensitive MRD evaluation be performed every 3 months for 24 months for NPM1-mutated disease, ideally on both peripheral blood and bone marrow samples using the current gold-standard quantitative polymerase chain reaction (qPCR) assay; limitations to this approach might include lack of access to this testing, at least in U.S. centers, and increased cost associated with testing at this frequency. 12 Our results suggest a relationship between the mutant allele burden at diagnosis and MRD at CR1, and also suggest that NPM1c IHC is a potentially useful adjunctive tool for disease monitoring after therapy. IHC for NPM1c may be particularly useful, given that NPM1-mutated AML is classically CD34-negative and lacks other distinctive immunophenotypic characteristics, features that limit the use of flow cytometric detection of MRD in this AML subtype.…”

“…12 All patients were treated with standard anthracycline-cytarabine induction chemotherapy, with or without subsequent allogeneic SCT. 12 All patients were treated with standard anthracycline-cytarabine induction chemotherapy, with or without subsequent allogeneic SCT.…”

“…12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53. 12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53.…”

“…12,[25][26][27] Target PRPF40b, SRSF2, SF3B1, CSF3R, BRAF, GATA2, and TP53. 12 In addition to total mutation count at diagnosis, data for co-occurring DNMT3A and/or FLT3-ITD mutations was specifically extracted for this study. 27 Details regarding variant calling have been previously described.…”

“…1-8 NPM1 mutations typically co-occur with mutations in DNA methylation and RAS pathway genes. 12 Patients with NPM1-mutated AML without FLT3-ITD mutations, or with low FLT3-ITD allelic burden, typically comprise a prognostically favorable subgroup and are often treated with induction chemotherapy and a chemotherapy-based consolidation regimen rather than allogeneic stem cell transplantation (SCT). 9,13 Recently, we identified high NPM1 mutant allele burden as an independent poor prognostic marker, associated with shorter overall survival (OS) and event-free survival (EFS).…”