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Prognostic Significance of Concurrent Gene Mutations in Intensively Treated Patients with IDH1/2 Mutated AML

Authors :
Raphael Itzykson
Lionel Ades
Hervé Dombret
Jean Valère Malfuson
Juliette Lambert
Céline Berthon
Claude Preudhomme
Christine Terré
Emmanuel Raffoux
Cécile Pautas
Jean-Baptiste Micol
Matthieu Duchmann
Jean-Pierre Marolleau
Nicolas Duployez
Emilie Lemasle
Karine Celli-Lebras
Arnaud Pigneux
Claude Gardin
Christian Recher
Xavier Thomas
Pascal Turlure
Nicolas Boissel
Stéphane de Botton
Thorsten Braun
Denis Caillot
Norbert Vey
Sylvain Chantepie
Hôpital d'instruction des Armées Percy
Service de Santé des Armées
Service d'Hématologie Biologique [Mondor]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor
Thérapie génique et contrôle de l'expansion cellulaire (UMR E007)
Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Recherche clinique appliquée à l'hématologie (URP_3518)
Université Paris Cité (UPCité)
Service d'Hématologie [AP-HP Hôpital Saint-Louis]
Hopital Saint-Louis [AP-HP] (AP-HP)
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Service d'Hématologie Clinique (CHU de Dijon)
Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges]
CHU Limoges
Centre de Recherche en Cancérologie de Marseille (CRCM)
Aix Marseille Université (AMU)-Institut Paoli-Calmettes
Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux.
Biothérapies des maladies génétiques et cancers
Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)
Centre de Recherches en Cancérologie de Toulouse (CRCT)
Université Toulouse III - Paul Sabatier (UT3)
Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Département de Génétique [CH Versailles]
Centre Hospitalier de Versailles André Mignot (CHV)
Service d'hématologie clinique [Avicenne]
Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Hématopoïèse normale et pathologique
Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc)
Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
Institut Gustave Roussy (IGR)
Département d'hématologie [Gustave Roussy]
Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212))
Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Service de pathologie [CHU Lille]
Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Service d'hématologie biologique
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)
Hospices Civils de Lyon (HCL)
Service clinique des Maladies du Sang
CHU Amiens-Picardie
Hôpital Saint-Louis
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)
Institut d'Hématologie de Basse-Normandie (IHBN)
Université de Caen Normandie (UNICAEN)
Normandie Université (NU)-Normandie Université (NU)-CHU Caen
Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC)
Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER
Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
DESSAIVRE, Louise
Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Source :
Blood, Blood, 2019, 134 (1), ⟨10.1182/blood-2019-127082⟩
Publication Year :
2019
Publisher :
HAL CCSD, 2019.

Abstract

Background : Point mutations in isocitrate dehydrogenase (IDH) genes are seen in 20% of adult patients (pts) with acute myeloid leukemia (AML). Prognostic significance of each IDH1/2 mutation (mut) analyzed with co-occurring mutations treated with intensive chemotherapy (IC) remains inconsistent, particularly with the advent of IDH inhibitors. Furthermore, the role of allogeneic stem cell transplantation (SCT) in IDH-mutated without favorable-risk features is not known. Patients & Methods: Between 2009 and 2016, 262 pts with IDH1/2 mutated AML (101 IDH1mut, 115 IDH2R140Qmutand 46 IDH2R172mut) were treated with IC in younger ALFA-0702 (NCT00932412, n = 133) and older ALFA-1200 (NCT01966497, n = 129) prospective trials. Median age was 50 [42-54] and 67 y [64-71], respectively (resp). Targeted 37-gene next-generation sequencing (NGS) information was available for all pts. According to ELN 2010 classification, non-favorable CR/CRp pts were eligible for SCT if they had a sibling or matched unrelated donor. Correlation between IDHmutand covariates was realized by Pearson correlation coefficient and point biserial correlation for continuous and dichotomic variables, resp. Impact on response and survival was assessed for all covariates present in at least 10% of patients. SCT was considered as a time-dependent variable. Informative variables selected by LASSO were included in multivariate logistic regression for response and multivariate Cox model for survival. All analyses were stratified on the clinical trial. Results: IDH1 mut was significantly associated with NPM1mut(p=0.025), DNMT3Amut(p=0.009) and mutually exclusive with TET2mut(p=0.009). 80% (81/101) of IDH1 mutated pts achieved CR/CRp [96 % (46/48) if concomitant NPM1mut vs 66% (35/53) if not (p=0.0009)]. With a median FU of 39 months, overall median OS was not reached and median EFS was 15 months (Fig 1A). Presence of NPM1mutwas the only variable associated with longer OS (HR=0.33, p=0.001) and EFS (HR = 0.4, p = 0.001) in multivariate analysis. At 5 years, OS was estimated at 68% and 35% and EFS at 55% and 26%, resp (Fig 1B). Effect of concomitant NPM1mutwas reinforced in the absence of DNMT3Amut(HR=0.14, p=0.0006 and HR=0.16, p IDH2R140Q mut was significantly associated with NPM1mut(p=0.0004) and SRSF2mut(p IDH2R172K mut was significantly associated with DNMT3Amut(p=0.0004) and BCORmut(p Finally, in non-favorable ELN 2010 pts (74, 74 and 46 with IDH1mut, IDH2R140Qmutand IDH2R172Kmut, resp), SCT in first CR only benefited to pts with IDH1mut(p=0.004 for OS) or with IDH2R172Kmut(p=0.03 for EFS). Conclusion: In a large prospective series, NPM1mutis the main better risk factor in the IDH1mutand IDH2R140Qmutsubgroups and may be used as stratification factor in clinical trials testing frontline specific IDH inhibitors with IC. Allogeneic SCT in first CR appears to improve the outcome of pts with non-favorable IDH1 or IDH2R172K mutated AML. Figure 1 Disclosures Micol: Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy. Thomas:ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria; PFIZER: Honoraria. Braun:Institut de Recherches Internationales Servier (IRIS): Research Funding. Ades:Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Boissel:NOVARTIS: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Pigneux:Astellas: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Daichi: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding. De Botton:Daiichi: Consultancy; Janssen: Consultancy; Agios: Consultancy, Research Funding; Astellas: Consultancy; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Bayer: Consultancy.

Details

Language :
English
ISSN :
00064971 and 15280020
Database :
OpenAIRE
Journal :
Blood, Blood, 2019, 134 (1), ⟨10.1182/blood-2019-127082⟩
Accession number :
edsair.doi.dedup.....1b740b3f35d0bee296b4286b97152052
Full Text :
https://doi.org/10.1182/blood-2019-127082⟩