Oncotarget

Clinical Research Papers:

IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association

Houria Debarri _, Delphine Lebon, Christophe Roumier, Meyling Cheok, Alice Marceau-Renaut, Olivier Nibourel, Sandrine Geffroy, Nathalie Helevaut, Philippe Rousselot, Bérengère Gruson, Claude Gardin, Marie-Lorraine Chretien, Shéhérazade Sebda, Martin Figeac, Céline Berthon, Bruno Quesnel, Nicolas Boissel, Sylvie Castaigne, Hervé Dombret, Aline Renneville and Claude Preudhomme

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Oncotarget. 2015; 6:42345-42353. https://doi.org/10.18632/oncotarget.5645

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Abstract

Houria Debarri1,2,*, Delphine Lebon3,*, Christophe Roumier2,4, Meyling Cheok4,5, Alice Marceau-Renaut2,4, Olivier Nibourel2,4, Sandrine Geffroy2,4, Nathalie Helevaut2, Philippe Rousselot6, Bérengère Gruson3, Claude Gardin7, Marie-Lorraine Chretien8, Shéhérazade Sebda5, Martin Figeac5, Céline Berthon1,4, Bruno Quesnel1,4, Nicolas Boissel9, Sylvie Castaigne6, Hervé Dombret9, Aline Renneville2,4, Claude Preudhomme2,4

1Hematology Department, Lille University Hospital, Lille, France

2Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France

3Hematology Department, Amiens University Hospital, Amiens, France

4UMR-S 1172, Team 3, INSERM, Lille, France

5Functional Genomic Platform, Cancer Research Institute, Lille, France

6Hematology Department, Versailles Hospital, Le Chesnay, France

7Hematology Department, Avicenne Hospital, APHP, University Paris 13, Bobigny, France

8Hematology Department, CHU de Dijon - Le Bocage Hospital, Dijon, France

9Hematology Department, Saint-Louis Hospital, APHP, Paris, France

*These authors have contributed equally to this work

Correspondence to:

Claude Preudhomme, e-mail: [email protected]

Keywords: acute myeloid leukemia, minimal residual disease, next-generation sequencing

Received: June 04, 2015     Accepted: October 02, 2015     Published: October 12, 2015

ABSTRACT

Acute myeloid leukemia (AML) is a heterogeneous disease. Even within the same NPM1-mutated genetic subgroup, some patients harbor additional mutations in FLT3, IDH1/2, DNMT3A or TET2. Recent studies have shown the prognostic significance of minimal residual disease (MRD) in AML but it remains to be determined which molecular markers are the most suitable for MRD monitoring. Recent advances in next-generation sequencing (NGS) have provided the opportunity to use multiple molecular markers. In this study, we used NGS technology to assess MRD in 31 AML patients enrolled in the ALFA-0701 trial and harboring NPM1 mutations associated to IDH1/2 or DNMT3A mutations. NPM1 mutation-based MRD monitoring was performed by RTqPCR. IDH1/2 and DNMT3A mutations were quantified by NGS using an Ion Torrent Proton instrument with high coverage (2 million reads per sample). The monitoringof IDH1/2 mutations showed that these mutations were reliable MRD markers that allowed the prediction of relapse in the majority of patients. Moreover, IDH1/2 mutation status predicted relapse or disease evolution in 100% of cases if we included the patient who developed myelodysplastic syndrome. In contrast, DNMT3A mutations were not correlated to the disease status, as we found that a preleukemic clone with DNMT3A mutation persisted in 40% of the patients who were in complete remission, reflecting the persistence of clonal hematopoiesis.


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