Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study

Author:

Duployez Nicolas1ORCID,Largeaud Laëtitia2ORCID,Duchmann Matthieu3ORCID,Kim Rathana34ORCID,Rieunier Julie2,Lambert Juliette5ORCID,Bidet Audrey6,Larcher Lise34ORCID,Lemoine Jean7,Delhommeau François8,Hirsch Pierre8,Fenwarth Laurène1ORCID,Kosmider Olivier9,Decroocq Justine10,Bouvier Anne11ORCID,Le Bris Yannick1213ORCID,Ochmann Marlène14,Santagostino Alberto15,Adès Lionel37ORCID,Fenaux Pierre37,Thomas Xavier16,Micol Jean-Baptiste17,Gardin Claude1819,Itzykson Raphael37ORCID,Soulier Jean34ORCID,Clappier Emmanuelle34,Recher Christian20ORCID,Preudhomme Claude1ORCID,Pigneux Arnaud21,Dombret Hervé719ORCID,Delabesse Eric2ORCID,Sébert Marie37

Affiliation:

1. 1Hematology Laboratory, Unité 1277-Cancer Heterogeneity Plasticity and Resistance to Therapies (CANTHER), Centre Hospitalier Universitaire (CHU) de Lille, University of Lille, INSERM, Lille, France;

2. 2Hematology Laboratory, CHU de Toulouse–Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France;

3. 3Université de Paris, Unité 944/7212-GenCellDi, INSERM and Centre National de la Recherche Scientifique (CNRS), Paris, France;

4. 4Hematology Laboratory, Saint Louis Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), Paris, France;

5. 5Hematology Department, Versailles Hospital, Le Chesnay, France;

6. 6Hematology Laboratory, CHU de Bordeaux, Bordeaux, France;

7. 7Hematology Department, Saint Louis Hospital, AP-HP, Paris, France;

8. 8Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Laboratoire d’hématologie biologique, Hôpital Saint-Antoine, Paris, France;

9. 9Hematology Laboratory, Cochin Hospital, AP-HP, Paris, France;

10. 10Hematology Department, Cochin Hospital, AP-HP, Paris, France;

11. 11Hematology Laboratory, CHU Angers, Angers, France;

12. 12Hematology Biology, Nantes University Hospital, Nantes, France;

13. 13CRCINA, INSERM, CNRS, Université de Nantes, Université d'Angers, Nantes, France;

14. 14Hematology Department, CHU Orléans, Orléans, France;

15. 15Hematology Department, CHU Troyes, Troyes, France;

16. 16Hematology Department, Hospices Civils de Lyon, Lyon-Sud Hospital, Lyon, France;

17. 17Hematology Department, Gustave Roussy Institute, University of Paris-Saclay, Villejuif, France;

18. 18Hematology Department, Avicenne Hospital, AP-HP, Bobigny, France;

19. 19Unité 3518, Saint-Louis Institute for Research, Université de Paris, Paris, France;

20. 20Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France; and

21. 21Hematology Department, CHU de Bordeaux, Bordeaux, France

Abstract

Abstract 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).

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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