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Journal of Cancer Research and Clinical Oncology
Published in: Journal of Cancer Research and Clinical Oncology 9/2021

01-09-2021 | Acute Myeloid Leukemia | Original Article – Clinical Oncology

Clinical significance of FLT3-ITD/CEBPA mutations and minimal residual disease in cytogenetically normal acute myeloid leukemia after hematopoietic stem cell transplantation

Authors: Hong Wang, Xue-Qian Li, Tian-Tian Chu, Shi-Yu Han, Jia-Qian Qi, Ya-Qiong Tang, Hui-Ying Qiu, Cheng-Cheng Fu, Xiao-Wen Tang, Chang-Geng Ruan, De-Pei Wu, Yue Han

Published in: Journal of Cancer Research and Clinical Oncology | Issue 9/2021

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Abstract

Purpose

Genetic changes have prognostic significance in cytogenetically normal acute myeloid leukemia (CN-AML). We set out to evaluate the prognostic of 6 gene mutations in CN-AML.

Methods

We performed a mutational analysis and evaluated prognostic findings of six genes (NPM1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD, and C-KIT) in 428 CN-AML patients at our center over 10 years.

Results

A total of 282 patients (65.9%) had at least one gene mutation, and the mutation frequencies were as follows: 29.7% (NPM1), 24.1% (CEBPA), 20.1% (FLT3-ITD), 4.0% (FLT3-TKD), 11.9% (DNMT3A), and 4.7% (C-KIT). Multivariate analysis indicated that FLT3-ITDmut and CEBPAwt were independent risk factors correlated with poor overall survival (OS) and disease-free survival (DFS) of CN-AML. Compared with patients who received chemotherapy as consolidation, hematopoietic stem cell transplantation (HSCT) significantly improved OS of CN-AML patients. For standard/high risk patients, HSCT improved both OS and DFS. Combined analysis showed that patients with CEBPAmut/FLT3-ITDwt had the best prognosis, and patients with CEBPAwt/FLT3-ITDmut had the worst OS, with 3-year OS of only 44%. In 212 patients who received HSCT, FLT3-ITD/CEBPA mutations and minimal residual disease (MRD) were correlated with OS and DFS in univariate analysis.

Conclusions

We found that HSCT significantly improves the prognosis of standard/high risk CN-AML patients with superior OS and DFS. Molecular marker analyses, especially combined analysis of the FLT3-ITD and CEBPA status revealed a correlation with the prognosis of CN-AML. For patients who have received HSCT, MRD before transplantation was a strong prognostic marker predicting patient outcome.
Literature
Cairoli R, Beghini A, Grillo G et al (2006) Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107:3463–3468CrossRef
Chang YJ, Wang Y, Liu YR et al (2017) Haploidentical allograft is superior to matched sibling donor allograft in eradicating pre-transplantation minimal residual disease of AML patients as determined by multiparameter flow cytometry: a retrospective and prospective analysis. J Hematol Oncol 10:134CrossRef
de Jonge HJ, Valk PJ, de Bont ES et al (2011) Prognostic impact of white blood cell count in intermediate risk acute myeloid leukemia: relevance of mutated NPM1 and FLT3-ITD. Haematologica 96:1310–1317CrossRef
DeZern AE, Sung A, Kim S et al (2011) Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transpl 17:1404–1409CrossRef
Dohner H, Estey EH, Amadori S et al (2010) Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 115:453–474CrossRef
Dohner H, Estey E, Grimwade D et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129:424–447CrossRef
Falini B, Martelli MP, Bolli N et al (2011) Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood 117:1109–1120CrossRef
Frohling S, Schlenk RF, Breitruck J et al (2002) Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood 100:4372–4380CrossRef
Frohling S, Schlenk RF, Stolze I et al (2004) CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. J Clin Oncol 22:624–633CrossRef
Gale RE, Green C, Allen C et al (2008) The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 111:2776–2784CrossRef
Grimwade D, Walker H, Oliver F et al (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 92:2322–2333CrossRef
Jones PA, Liang G (2009) Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10:805–811CrossRef
Ley TJ, Ding L, Walter MJ et al (2010) DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363:2424–2433CrossRef
Lin PH, Li HY, Fan SC et al (2017) A targeted next-generation sequencing in the molecular risk stratification of adult acute myeloid leukemia: implications for clinical practice. Cancer Med 6:349–360CrossRef
Linch DC, Hills RK, Burnett AK et al (2014) Impact of FLT3(ITD) mutant allele level on relapse risk in intermediate-risk acute myeloid leukemia. Blood 124:273–276CrossRef
Marcucci G, Haferlach T, Dohner H (2011) Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol 29:475–486CrossRef
O’Donnell MR, Tallman MS, Abboud CN et al (2017) Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw 15:926–957CrossRef
Oran B, Jimenez AM, De Lima M et al (2015) Age and modified European LeukemiaNet Classification to predict transplant outcomes: an integrated approach for acute myelogenous leukemia patients undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transpl 21:1405–1412CrossRef
Qin YZ, Wang Y, Xu LP et al (2017) The dynamics of RUNX1-RUNX1T1 transcript levels after allogeneic hematopoietic stem cell transplantation predict relapse in patients with t(8;21) acute myeloid leukemia. J Hematol Oncol 10:44CrossRef
Renneville A, Boissel N, Nibourel O et al (2012) Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association. Leukemia 26:1247–1254CrossRef
Schlenk RF, Dohner K, Krauter J et al (2008) Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med 358:1909–1918CrossRef
Schnittger S, Kohl TM, Haferlach T et al (2006) KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107:1791–1799CrossRef
Schnittger S, Eder C, Jeromin S et al (2013) ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome. Leukemia 27:82–91CrossRef
Schuurhuis GJ, Heuser M, Freeman S et al (2018) Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 131:1275–1291CrossRef
Taskesen E, Bullinger L, Corbacioglu A et al (2011) Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 117:2469–2475CrossRef
Thol F, Damm F, Ludeking A et al (2011) Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29:2889–2896CrossRef
Verhaak RG, Goudswaard CS, van Putten W et al (2005) Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance. Blood 106:3747–3754CrossRef
Versluis J, Hout FEI, Devillier R et al (2017) Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio. Leukemia 31:26–33CrossRef
Walter RB, Gooley TA, Wood BL et al (2011) Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 29:1190–1197CrossRef
Wang Y, Wu DP, Liu QF et al (2014) In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood 124:1880–1886CrossRef
Wouters BJ, Lowenberg B, Erpelinck-Verschueren CA et al (2009) Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 113:3088–3091CrossRef
Yamada K, Furusawa S, Saito K et al (1995) Concurrent use of granulocyte colony-stimulating factor with low-dose cytosine arabinoside and aclarubicin for previously treated acute myelogenous leukemia: a pilot study. Leukemia 9:10–14PubMed
Yan XJ, Xu J, Gu ZH et al (2011) Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43:309–315CrossRef
Yan CH, Liu DH, Liu KY et al (2012) Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 119:3256–3262CrossRef
Zhao XS, Yan CH, Liu DH et al (2013) Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity. Ann Hematol 92:1111–1119CrossRef
Metadata
Title
Clinical significance of FLT3-ITD/CEBPA mutations and minimal residual disease in cytogenetically normal acute myeloid leukemia after hematopoietic stem cell transplantation
Authors
Hong Wang
Xue-Qian Li
Tian-Tian Chu
Shi-Yu Han
Jia-Qian Qi
Ya-Qiong Tang
Hui-Ying Qiu
Cheng-Cheng Fu
Xiao-Wen Tang
Chang-Geng Ruan
De-Pei Wu
Yue Han
Publication date
01-09-2021
Publisher
Springer Berlin Heidelberg
Published in
Journal of Cancer Research and Clinical Oncology / Issue 9/2021
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI
https://doi.org/10.1007/s00432-021-03530-9

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