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Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy

Raphael Itzykson 1 Elise Fournier 2 Celine Berthon 3 Christoph Rollig 4 Thorsten Braun 5 Alice Marceau-Renaut 6 Cecile Pautas 7 Olivier Nibourel 8, 6 Emilie Lemasle 9 Jean-Baptiste Micol 10 Lionel Ades 11, 12 Delphine Lebon 13, 14 Jean-Valere Malfuson 15 Lauris Gastaud 16 Laure Goursaud 17 Emmanuel Raffoux 11 Kevin-James Wattebled 18 Philippe Rousselot 19, 20 Xavier Thomas 21 Sylvain Chantepie 22 Thomas Cluzeau 23 Hubert Serve 24 Nicolas Boissel 11 Christine Terre 20 Karine Celli-Lebras 25 Claude Preudhomme 6 Christian Thiede 4 Herve Dombret 11 Claude Gardin 26 Nicolas Duployez 6
1 GenCellDi (UMR_S_944) - Génomes, biologie cellulaire et thérapeutiques
2 Hôpital Claude Huriez [Lille]
3 CHU Lille
4 TU Dresden - Technische Universität Dresden = Dresden University of Technology
5 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
6 CANTHER - Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
7 Service d'hématologie clinique
8 Service d'Hématologie Cellulaire [Lille]
9 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
10 CSHMyelo - Cellules souches hématopoïétiques et développement des hémopathies myéloïdes
INSERM - Institut National de la Santé et de la Recherche Médicale : UMR 1287, Université Paris-Saclay
11 AP-HP - Hopital Saint-Louis [AP-HP]
12 UPC - Université Paris Cité
13 CHU Amiens-Picardie
14 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
15 CTSA - Centre de Transfusion Sanguine des Armées
16 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
17 EFS Bretagne - Etablissement français du sang [Rennes]
18 CH Dunkerque
19 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
20 CHV - Centre Hospitalier de Versailles André Mignot
21 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
22 IHBN - Institut d'Hématologie de Basse-Normandie
23 XLIM - XLIM
24 Universitätsklinikum Frankfurt am Main [Germany]
25 IUH - Institut Universitaire d'Hématologie
26 Hôpital Avicenne [AP-HP]
Abstract : To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) >= 60 years of age treated with 7+3, we sequenced 37 genes in 471patients fromtheALFA1200 (Acute Leukemia FrenchAssociation) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patientswith good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10(-4)) allelic ratio, DNMT3A (HR, 1.86; P < 10(-4)), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P=.0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a ``go-go'' tier with a 2-year OS of 66.1%, 7.6% to the ``no-go'' group (2-year OS 2.8%), and 3.3% of to the ``slow-go'' group (2-year OS of 39.1%; P < 10(-5)). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences inOS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; andSAL [StudyAlliance Leukemia], n=46; AMLSG [AML Study Group], n = 223, both P < 10(-5)). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients >= 60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7+3 standard of care with less intensive regimens.
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https://hal-u-picardie.archives-ouvertes.fr/hal-03606388
Contributeur : Louise Dessaivre Connectez-vous pour contacter le contributeur
Soumis le : vendredi 11 mars 2022 - 17:44:04
Dernière modification le : jeudi 7 avril 2022 - 13:58:33

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HEMATIM | U-PICARDIE | CDF | HCL | SSA | UNILIM | RIIP | CHLS | PSL | UPEC-UPEM | UPEC | XLIM | UNIV-COTEDAZUR | UNIV-LILLE | UNICAEN | UP-SANTE | COMUE-NORMANDIE | UVSQ | CANTHER | CNRS | UNIV-PARIS | UNIV-PARIS-SACLAY

Citation

Raphael Itzykson, Elise Fournier, Celine Berthon, Christoph Rollig, Thorsten Braun, et al.. Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy. BLOOD, 2021, 138 (7), pp.507-519. ⟨10.1182/blood.2021011103⟩. ⟨hal-03606388⟩

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