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.
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.
Hematology Department, Lille University Hospital, Lille, France.|Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.
Houria
H
Debarri
Hematology Department, Amiens University Hospital, Amiens, France.
Delphine
D
Lebon
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Christophe
C
Roumier
UMR-S 1172, Team 3, INSERM, Lille, France.|Functional Genomic Platform, Cancer Research Institute, Lille, France.
Meyling
M
Cheok
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Alice
A
Marceau-Renaut
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Olivier
O
Nibourel
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Sandrine
S
Geffroy
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.
Nathalie
N
Helevaut
Hematology Department, Versailles Hospital, Le Chesnay, France.
Philippe
P
Rousselot
Hematology Department, Amiens University Hospital, Amiens, France.
Bérengère
B
Gruson
Hematology Department, Avicenne Hospital, APHP, University Paris 13, Bobigny, France.
Claude
C
Gardin
Hematology Department, CHU de Dijon - Le Bocage Hospital, Dijon, France.
Marie-Lorraine
ML
Chretien
Functional Genomic Platform, Cancer Research Institute, Lille, France.
Shéhérazade
S
Sebda
Functional Genomic Platform, Cancer Research Institute, Lille, France.
Martin
M
Figeac
Hematology Department, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Céline
C
Berthon
Hematology Department, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Bruno
B
Quesnel
Hematology Department, Saint-Louis Hospital, APHP, Paris, France.
Nicolas
N
Boissel
Hematology Department, Versailles Hospital, Le Chesnay, France.
Sylvie
S
Castaigne
Hematology Department, Saint-Louis Hospital, APHP, Paris, France.
Hervé
H
Dombret
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Aline
A
Renneville
Hematology Laboratory, Biology and Pathology Center, Lille University Hospital, Lille, France.|UMR-S 1172, Team 3, INSERM, Lille, France.
Claude
C
Preudhomme
D000208:Acute Disease; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005602:France; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D055815:Young Adult
D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
acute myeloid leukemia; minimal residual disease; next-generation sequencing