title: Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion.
abstract: Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France; Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: Virginie
authors.initials: V
authors.lastname: Chesnais
authors.affiliation: Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France;
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Clinique, Hôpital Henri-Mondor, Créteil, France;
authors.forename: Andrea
authors.initials: A
authors.lastname: Toma
authors.affiliation: Service de Biostatistique et d'Information Médicale, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; Epidémiologie Clinique et Statistiques pour la Recherche en Santé, Unité Mixte de Recherche 1153, INSERM, Université Paris Diderot, Sorbonne Paris Cité, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lambert
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France;
authors.forename: Marie
authors.initials: M
authors.lastname: Passet
authors.affiliation: Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: Florent
authors.initials: F
authors.lastname: Dumont
authors.affiliation: Service de Biostatistique et d'Information Médicale, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; Epidémiologie Clinique et Statistiques pour la Recherche en Santé, Unité Mixte de Recherche 1153, INSERM, Université Paris Diderot, Sorbonne Paris Cité, France;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Service de Biostatistique et d'Information Médicale, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France; Epidémiologie Clinique et Statistiques pour la Recherche en Santé, Unité Mixte de Recherche 1153, INSERM, Université Paris Diderot, Sorbonne Paris Cité, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Lejeune
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France; Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: Anna
authors.initials: A
authors.lastname: Raimbault
authors.affiliation: Centre de Lutte contre le Cancer Henri-Becquerel, Rouen, France;
authors.forename: Aspasia
authors.initials: A
authors.lastname: Stamatoullas
authors.affiliation: Service d'Hématologie, Hôpital Saint Vincent de Paul, Université Catholique de Lille, Lille, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.affiliation: Service de Médecine Interne, Institut Universitaire du Cancer, Toulouse, France;
authors.forename: Odile
authors.initials: O
authors.lastname: Beyne-Rauzy
authors.affiliation: Service d'Hématologie, Centre Hospitalier Universitaire, Nantes, France;
authors.forename: Jacques
authors.initials: J
authors.lastname: Delaunay
authors.affiliation: Institut Gustave Roussy, INSERM 1009, Université Paris Sud, Villejuif, France; and.
authors.forename: Eric
authors.initials: E
authors.lastname: Solary
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Senior, Hôpital Saint-Louis, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fenaux
authors.affiliation: Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.affiliation: Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire de Lille, Lille, France;
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France; Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: Olivier
authors.initials: O
authors.lastname: Kosmider
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Service d'Hématologie Biologique, Hôpitaux Universitaires Paris Centre, Paris, France; Institut Cochin, INSERM U1016, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Université Paris Descartes, Paris, France;
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
mesh_terms: D000368:Aged; D000748:Anemia, Macrocytic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D060965:Clonal Evolution / Q000187:drug effects* / Q000235:genetics; D002999:Clone Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis; D004921:Erythropoietin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011994:Recombinant Proteins / Q000008:administration & dosage; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D011994:Recombinant Proteins; C103998:epoetin beta; D004921:Erythropoietin; D013792:Thalidomide; D000077269:Lenalidomide