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]
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]
Raphael Itzykson
- Fonction : Auteur
- PersonId : 767594
- ORCID : 0000-0003-2139-6262
- IdRef : 169090930
Delphine Lebon
- Fonction : Auteur
- PersonId : 1151789
- ORCID : 0000-0002-4073-1559
- IdRef : 182804038
Philippe Rousselot
- Fonction : Auteur
- PersonId : 759734
- ORCID : 0000-0001-6798-7805
Sylvain Chantepie
- Fonction : Auteur
- PersonId : 776420
- ORCID : 0000-0003-0457-2252
Claude Preudhomme
- Fonction : Auteur
- PersonId : 762197
- ORCID : 0000-0002-1267-9546
- IdRef : 07342255X
Nicolas Duployez
- Fonction : Auteur
- PersonId : 735703
- IdHAL : nicolas-duployez
- ORCID : 0000-0002-3927-1022
- IdRef : 172536154
Résumé
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.