Abstract
Monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML) plays an important role in predicting relapse and outcome. The applicability of the leukemia-initiating nucleophosmin1 (NPM1) gene mutations in MRD detection is well-established, while that of isocitrate dehydrogenase1/2 (IDH1/2) mutations are matter of debate. The aim of this study was to investigate the stability of NPM1 and IDH1/2 mutations at diagnosis and relapse retrospectively in 916 adult AML patients. The prognostic value of MRD was evaluated by droplet digital PCR on the DNA level in a selected subgroup of patients in remission. NPM1 re-emerged at relapse in 91% (72/79), while IDH1/2 in 87% (20/23) of mutation-positive cases at diagnosis. NPM1 mutation did not develop at relapse, on the contrary novel IDH1/2 mutations occurred in 3% (3/93) of previously mutation-negative cases. NPM1 MRD-positivity after induction (n = 116) proved to be an independent, adverse risk factor (MRDpos 24-month OS: 39.3±6.2% versus MRDneg: 58.5±7.5%, p = 0.029; HR: 2.16; 95%CI: 1.25-3.74, p = 0.006). In the favorable subgroup of mutated NPM1 without fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) or with low allelic ratio, NPM1 MRD provides a valuable prognostic biomarker (NPM1 MRDpos versus MRDneg 24-month OS: 42.9±6.7% versus 66.7±8.6%; p = 0.01). IDH1/2 MRD-positivity after induction (n = 62) was also associated with poor survival (MRDpos 24-month OS: 41.3±9.2% versus MRDneg: 62.5±9.0%, p = 0.003; HR 2.81 95%CI 1.09-7.23, p = 0.032). While NPM1 variant allele frequency decreased below 2.5% in remission in all patients, IDH1/2 mutations (typically IDH2 R140Q) persisted in 24% of cases. Our results support that NPM1 MRD even at DNA level is a reliable prognostic factor, while IDH1/2 mutations may represent pre-leukemic, founder or subclonal drivers.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
Aged
-
Aged, 80 and over
-
Female
-
Genetic Markers / genetics
-
Humans
-
Isocitrate Dehydrogenase / genetics*
-
Leukemia, Myeloid, Acute / genetics*
-
Leukemia, Myeloid, Acute / mortality
-
Male
-
Middle Aged
-
Mutation / genetics
-
Nuclear Proteins / genetics*
-
Nucleophosmin
-
Polymerase Chain Reaction
-
Survival Analysis
-
Treatment Outcome
-
Young Adult
Substances
-
Genetic Markers
-
NPM1 protein, human
-
Nuclear Proteins
-
Nucleophosmin
-
IDH2 protein, human
-
Isocitrate Dehydrogenase
-
IDH1 protein, human
Grants and funding
The study was supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences (AnB: BO/00809/18/8,
https://mta.hu/bolyai-osztondij/bolyaijanos-kutatasi-osztondij-105319), by the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund (PK: ÚNKP-20-3-II-SE-79, AnB: ÚNKP-19-4-SE-83,
http://www.unkp.gov.hu/unkp-rol), by grants from the National Research, Development and Innovation Office (PK, ZO, AnB, AK, LG, JD, NL, JH, GM, IV-N, PR, HA: NVKP_16-1-2016-0005,
https://www.dpckorhaz.hu/informaciok/palyazatok/projektek/hazai-projektek/kiemelkedo-halalozasi-kockazattal-jaro-betegsegek-gyogyitasanak-eredmenyesseget-lenyegesen-javito-nemzeti-program-nemzeti-innovacios-onkogenomikai-es-precizios-onkoterapias-program-elinditasa-es-kapc/), by the Development of a Translational Medicine Research Center and an Innovative Center for Cellular Therapy at the Central Hospital of Southern Pest – National Institute of Hematology and Infectious Diseases (ZO, AnB, LG, JD, GM, IV-N, HA: TKP2020-NKA-19,
https://nkfih.gov.hu/palyazoknak/tkp-2020) and by grants of Ministry of Human Capacities (AnB, HA: EMMI IV/219-4/2021/EKF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.