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Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

Authors :
Serge Carillo
Aurélie Chauveau
Stéphane Giraudier
Jean-Jacques Kiladjian
Emmanuelle Verger
Valérie Ugo
Mohammed A. Yassin
Bruno Cassinat
Christine Chomienne
Marie-Hélène Schlageter
Jean-Christophe Ianotto
Eric Legouffe
Nader Al-Dewik
Christine Dosquet
Unite de Biologie Cellulaire (Biol Cell - ST LOUIS - PARIS)
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Laboratoire d'hématologie (Labo Hémato - BREST)
Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Unité de Formation de Recherche de Médecine (UFRM - BREST)
Université de Brest (UBO)
Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Laboratoire d'hématologie
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)
Institut de cancérologie et d'hématologie
Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO)
Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM)
Université de Brest (UBO)-Université de Brest (UBO)
Department of Hematology and Bone Marrow Transplant (DHBMT - DOHA - QATAR)
National Center for Cancer Care and Research (NCCCR - DOHA - QATAR)
Qatar Medical Genetic Center (QMGC - DOHA - QATAR)
Hamad medical corporation
Département de Cytologie Clinique (Dep Cyto Clin - NIMES)
Centre Hospitalier Universitaire de Nîmes (CHU Nîmes)
Service d'hématologie et oncologie médicale
Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM)
ONCOGARD - NIMES
Institut de Cancérologie du GARD ICG - CHU Nîmes (Instit Cancéro - GARD)
Université d'Angers - Faculté de médecine (UA UFR Médecine)
Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers)
PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)
Laboratoire d'Hématologie Biologique (Hémato - ANGERS)
Centre Hospitalier Universitaire d'Angers (CHU Angers)
Hématologie -Immunologie -Cibles thérapeutiques
Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Centre d'Investigations Cliniques
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)
Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)
Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM)
Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM)
Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Source :
Blood, Blood, American Society of Hematology, 2015, 126 (24), pp.2585-91. ⟨10.1182/blood-2015-07-659060⟩
Publication Year :
2015
Publisher :
American Society of Hematology, 2015.

Abstract

International audience; Myeloproliferative neoplasms are clonal disorders characterized by the presence of several gene mutations associated with particular hematologic parameters, clinical evolution, and prognosis. Few therapeutic options are available, among which interferon α (IFNα) presents interesting properties like the ability to induce hematologic responses (HRs) and molecular responses (MRs) in patients with JAK2 mutation. We report on the response to IFNα therapy in a cohort of 31 essential thrombocythemia (ET) patients with CALR mutations (mean follow-up of 11.8 years). HR was achieved in all patients. Median CALR mutant allelic burden (%CALR) significantly decreased from 41% at baseline to 26% after treatment, and 2 patients even achieved complete MR. In contrast, %CALR was not significantly modified in ET patients treated with hydroxyurea or aspirin only. Next-generation sequencing identified additional mutations in 6 patients (affecting TET2, ASXL1, IDH2, and TP53 genes). The presence of additional mutations was associated with poorer MR on CALR mutant clones, with only minor or no MRs in this subset of patients. Analysis of the evolution of the different variant allele frequencies showed that the mutated clones had a differential sensitivity to IFNα in a given patient, but no new mutation emerged during treatment. In all, this study shows that IFNα induces high rates of HRs and MRs in CALR-mutated ET, and that the presence of additional nondriver mutations may influence the MR to therapy.

Details

ISSN :
15280020 and 00064971
Volume :
126
Database :
OpenAIRE
Journal :
Blood
Accession number :
edsair.doi.dedup.....6122024723dc80df636d35f315c3f630
Full Text :
https://doi.org/10.1182/blood-2015-07-659060