Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study
Nicolas Duployez
(1)
,
Laëtitia Largeaud
(2)
,
Matthieu Duchmann
(3)
,
Rathana Kim
(3, 4)
,
Julie Rieunier
(2)
,
Juliette Lambert
(5)
,
Audrey Bidet
(6)
,
Lise Larcher
(3, 4)
,
Jean Lemoine
(4)
,
François Delhommeau
(7)
,
Pierre Hirsch
(7)
,
Laurène Fenwarth
(1)
,
Olivier Kosmider
(8)
,
Justine Decroocq
(8)
,
Anne Bouvier
(9)
,
Yannick Le Bris
(10, 11)
,
Marlène Ochmann
(12)
,
Alberto Santagostino
(13)
,
Lionel Adès
(3, 4)
,
Pierre Fenaux
(3, 4)
,
Xavier Thomas
(14)
,
Jean-Baptiste Micol
(15)
,
Claude Gardin
(16, 4)
,
Raphael Itzykson
(3, 4)
,
Jean Soulier
(3, 4)
,
Emmanuelle Clappier
(3, 4)
,
Christian Recher
(2)
,
Claude Preudhomme
(1)
,
Arnaud Pigneux
(6)
,
Hervé Dombret
(4)
,
Eric Delabesse
(2)
,
Marie Sébert
(3, 4)
1
CANTHER -
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277
2 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
3 GenCellDis (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
4 AP-HP - Hopital Saint-Louis [AP-HP]
5 CHV - Centre Hospitalier de Versailles André Mignot
6 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
7 CRSA - Centre de Recherche Saint-Antoine
8 Hôpital Cochin [AP-HP]
9 CHU Angers - Centre Hospitalier Universitaire d'Angers
10 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
11 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
12 CHRO - Centre Hospitalier Régional d'Orléans
13 Centre hospitalier de Troyes
14 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
15 IGR - Institut Gustave Roussy
16 Hôpital Avicenne [AP-HP]
2 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
3 GenCellDis (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
4 AP-HP - Hopital Saint-Louis [AP-HP]
5 CHV - Centre Hospitalier de Versailles André Mignot
6 CHU Bordeaux - Centre Hospitalier Universitaire de Bordeaux
7 CRSA - Centre de Recherche Saint-Antoine
8 Hôpital Cochin [AP-HP]
9 CHU Angers - Centre Hospitalier Universitaire d'Angers
10 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
11 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
12 CHRO - Centre Hospitalier Régional d'Orléans
13 Centre hospitalier de Troyes
14 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
15 IGR - Institut Gustave Roussy
16 Hôpital Avicenne [AP-HP]
Nicolas Duployez
- Fonction : Auteur
- PersonId : 735703
- IdHAL : nicolas-duployez
- ORCID : 0000-0002-3927-1022
- IdRef : 172536154
Laëtitia Largeaud
- Fonction : Auteur
- PersonId : 803089
- ORCID : 0000-0001-5341-5427
Matthieu Duchmann
- Fonction : Auteur
- PersonId : 811298
- ORCID : 0000-0002-7299-4572
- IdRef : 227847660
Rathana Kim
- Fonction : Auteur
- PersonId : 1186669
- ORCID : 0000-0002-9987-7237
Juliette Lambert
- Fonction : Auteur
- PersonId : 1250802
- ORCID : 0000-0001-5142-0310
Lise Larcher
- Fonction : Auteur
- PersonId : 1252572
- ORCID : 0000-0002-9461-0728
Laurène Fenwarth
- Fonction : Auteur
- PersonId : 803088
- ORCID : 0000-0003-2808-4843
Anne Bouvier
- Fonction : Auteur
- PersonId : 1433750
- ORCID : 0000-0003-0140-5360
Yannick Le Bris
- Fonction : Auteur
- PersonId : 818803
- ORCID : 0000-0002-0095-6999
Lionel Adès
- Fonction : Auteur
- PersonId : 762488
- ORCID : 0000-0002-9020-8766
- IdRef : 060593512
Raphael Itzykson
- Fonction : Auteur
- PersonId : 767594
- ORCID : 0000-0003-2139-6262
- IdRef : 169090930
Jean Soulier
- Fonction : Auteur
- PersonId : 1186674
- ORCID : 0000-0002-8734-5356
Christian Recher
- Fonction : Auteur
- PersonId : 975639
- ORCID : 0000-0002-3332-4525
- IdRef : 134542487
Claude Preudhomme
- Fonction : Auteur
- PersonId : 762197
- ORCID : 0000-0002-1267-9546
- IdRef : 07342255X
Hervé Dombret
- Fonction : Auteur
- PersonId : 759753
- ORCID : 0000-0002-5454-6768
Eric Delabesse
- Fonction : Auteur
- PersonId : 769021
- ORCID : 0000-0002-0928-0753
Résumé
DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).