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 (U944 / UMR7212) - 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
11 AP-HP - Hopital Saint-Louis [AP-HP]
12 UPCité - 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]

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.

Domaines: Sciences du Vivant [q-bio]

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⟩