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1. Heterogeneity in long-term outcomes for patients with Revised International Staging System stage II, newly diagnosed multiple myeloma

Author

Anais Schavgoulidze, Valerie Lauwers-Cances, Aurore Perrot, Titouan Cazaubiel, Marie-Lorraine Chretien, Philippe Moreau, Thierry Facon, Xavier Leleu, Lionel Karlin, Anne-Marie Stoppa, Olivier Decaux, Karim Belhadj, Bertrand Arnulf, Mohamad Mohty, Clara M Ariette, Cecile Fohrer-Sonntag, Pascal Lenain, Jean-Pierre Marolleau, Mourad Tiab, Carla Araujo, Frederique Orsini-Piocelle, Arnaud Jaccard, Murielle Roussel, Lotfi Benboubker, Jean-Richard Eveillard, Mamoun Dib, Marion Divoux, Michel Attal, Herve Avet-Loiseau, Jill Corre, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], CHU Bordeaux [Bordeaux], Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Lille, Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Grenoble, Hôpital de Hautepierre [Strasbourg], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Amiens-Picardie, Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Service d'Hématologie [CHRU Nancy], and Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)

Subjects
Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

In the era of personalized treatment in multiple myeloma, high-risk patients must be accurately identified. The International Myeloma Working Group recommends using the Revised International Staging System (R-ISS) to pick out high-risk patients. The main purpose of our work was to explore the heterogeneity of outcome among R-ISS stage II patients assessing the impact of International Staging System (ISS) stage, chromosomal abnormalities and lactate dehydrogenase level in this subgroup. Data were collected from 1,343 patients up to 65 years old with newly diagnosed myeloma, enrolled in three clinical trials implemented by the Intergroupe Francophone du Myélome. All patients were eligible for intensive treatment. Patients in R-ISS stage II but ISS stage I had 1.6 times higher risk of death than patients in R-ISS stage I (adjusted hazard ratio=1.6; 95% confidence interval: 1.1-2.2; P=0.01) and patients in R-ISS stage II but with ISS stage III had a better overall survival than patients in R-ISS stage III (adjusted hazard ratio=0.7; 95% confidence interval: 0.4-0.9, P=0.02). However, among patients classified in R-ISS II, ISS stage and chromosomal abnormalities (del[17p] and t[4;14]) were still relevant prognostic factors for death. Dividing R-ISS stage II into three subgroups: ISS I with standard-risk chromosomal abnormalities, ISS II or III with standard-risk chromosomal abnormalities and patients with high-risk chromosomal abnormalities, median overall survival times were, respectively, not reached, 112 months and 71 months (P

Published
2022

2. All-oral triplet combination with ixazomib, lenalidomide, and dexamethasone in newly diagnosed transplant-eligible myeloma patients: final results of the phase 2 IFM study 2013-06

Author

Touzeau, Cyrille, Perrot, Aurore, Roussel, Murielle, Karlin, Lionel, Benboubker, Lotfi, Jacquet, Caroline, Mohty, Mohamad, Facon, Thierry, Manier, Salomon, Chretien, Marie-Lorraine, Tiab, Mourad, Hulin, Cyrille, Leleu, Xavier, Loiseau, Hervé, Dejoie, Thomas, Planche, Lucie, Attal, Michel, Moreau, Philippe, Service d'Hématologie Hôtel Dieu Nantes, Hôtel Dieu, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), SIRIC ILIAD [Angers, Nantes], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, CHU Lyon Sud, Pierre Benite, France, Partenaires INRAE, Service de cancérologie et d'hématologie thérapie cellulaire [CHU Bretonneau], CHU Bretonneau, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU de Lille, Service des maladies du sang, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Département d'Hématologie [CHU Haut Lévèque, Pessac], Hôpital Haut-Lévêque [CHU de Bordeaux], Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de biochimie [Hôtel-Dieu], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu, Département de la Recherche Clinique et du Développement [AP-HP Hôtel Dieu] (DRCD-URC Eco), Unité de Recherche Clinique en Economie de la Santé d'Ile-de-France, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2022

3. Diagnosis and prognosis are comforted by integrated assessment of next-generation sequencing in chronic myeloid malignancies. A real-life study

Author

Olivier Theisen, Pierre Peterlin, Viviane Dubruille, Patrice Chevallier, Pascal Godmer, Amandine Le Bourgeois, Sylvain Thepot, Anne Parcelier, Marion Loirat, Steven Le Gouill, Adrien Trebouet, Damien Luque Paz, Mélanie Mercier, S. Vigouroux, Mathilde Hunault, Céline Bossard, Marie C. Béné, Marion Eveillard, Audrey Ménard, Alice Garnier, Nadine Morineau, Camille Debord, Hervé Maisonneuve, François Subiger, Catherine Godon, Yannick Le Bris, Elsa Lestang, Jacques Delaunay, Sophie Vantyghem, Soraya Wuilleme, Anne Moreau, Ronan Le Calloch, Philippe Moreau, Lenaïg Le Clech, Thierry Guillaume, Bruno Villemagne, Valérie Ugo, Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département d'Hématologie Clinique [CHU d'Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Hématologie Biologique [CHU Nantes], Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Hôpital privé du Confluent [Nantes], Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Laboratoire de Biologie [CHD Vendée, La Roche sur Yon], CHD Vendee (La Roche Sur Yon), Centre hospitalier de Saint-Nazaire, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Université de Bretagne Sud - Lorient (UBS Lorient), Université de Bretagne Sud (UBS), Laboratoire d'Hématologie Biologique (Hémato - ANGERS), Centre Hospitalier Intercommunal de Cornouaille [Quimper] (CHI Cornouaille [Quimper]), Département de Pathologie [CHU Nantes], Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), and Bernardo, Elizabeth

Subjects
Oncology, medicine.medical_specialty, Myeloid, Somatic cell, diagnosis, theranostic, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Group B, DNA sequencing, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Neoplasms, medicine, Humans, 030304 developmental biology, 0303 health sciences, Myeloproliferative Disorders, business.industry, Myelodysplastic syndromes, Editorials, High-Throughput Nucleotide Sequencing, Hematology, Chronic Myeloproliferative Disorders, medicine.disease, Prognosis, somatic mutation by NGS, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Mutation, Bone marrow, business
Abstract

Next-generation sequencing (NGS) is used to investigate the presence of somatic mutations. The utility of incorporating routine sequencing to guide diagnosis and therapeutic decisions remains unclear. We report the findings of an observational, multicenter study that aimed to assess the impact of somatic mutation testing by NGS in a reallife setting of chronic myeloid malignancies. A total of 177 patients were enrolled, partitioned into two overlapping groups. In group A (n=94), the indication was to search for clonal hematopoiesis, in a context of suspected myelodysplastic syndrome or myeloproliferative neoplasia. In group B (n=95), the theranostic impact of somatic mutations was studied. A panel of 34 genes was used on DNA extracted from blood or bone marrow samples. Within group A, the detection of clonal hematopoiesis supported the diagnosis of chronic myeloid malignancies for 31 patients while the absence of clonal hematopoiesis ruled out the suspected diagnosis in 47 patients. Within group B, NGS identified prognostically relevant somatic mutations in 32 patients, which had a therapeutic impact in 18 cases. By determining the presence or absence of somatic mutations, the application of NGS in daily practice was found to be useful for an integrated final diagnosis in 83% of the patients. Moreover, the search for somatic mutations had a prognostic impact that led to treatment modification in 19% of the cases. This study outlines the fact that adequate implementation of new investigations may have a significant positive medico-economic impact by enabling appropriate management of patients.

Published
2021

4. Whole genome copy number analysis in search of new prognostic biomarkers in first line treatment of mantle cell lymphoma. A study by the LYSA group

Author

Stephane Minvielle, Danielle Canioni, Florence Magrangeas, Marie-Hélène Delfau-Larue, Marie-Christine Béné, Olivier Pichon, Benoit Tessoulin, Hervé Maisonneuve, Catherine Guérin-Charbonnel, Olivier Hermine, Emmanuel Gyan, Yannick Le Bris, Catherine Pellat-Deceunynck, Olivier Theisen, Anne Moreau, David Chiron, Lucie Oberic, Barbara Burroni, Catherine Thieblemont, Steven Le Gouill, Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Département de Pathologie [CHU Nantes], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Service de Pathologie [AP-HP Hôpital Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d’Hématologie Clinique [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Necker - Enfants Malades [AP-HP], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bernardo, Elizabeth

Subjects
Oncology, Male, Cancer Research, Copy number anomalies, Lymphoma, Mantle-Cell, Translocation, Genetic, Loss of heterozygosity, 0302 clinical medicine, International Prognostic Index, CDKN2A, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Cyclin D1, Prospective Studies, Univariate analysis, Hematology, General Medicine, Middle Aged, Prognosis, Combined Modality Therapy, 3. Good health, Survival Rate, prognosis, 030220 oncology & carcinogenesis, Cohort, Female, Adult, medicine.medical_specialty, DNA Copy Number Variations, Copy number analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, CCND1/IGH, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Aged, Mantle cell lymphoma, Whole Genome Sequencing, business.industry, Genome, Human, medicine.disease, Lymphoma, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, business, 030215 immunology, Follow-Up Studies, Stem Cell Transplantation
Abstract

International audience; Mantle cell lymphoma (MCL) is a lymphoproliferative disorder characterized by the t(11;14)(q13;q32) CCND1/IGH translocation. This lymphoma is however extremely heterogeneous in terms of molecular alterations. Moreover, the course of the disease can vary greatly between indolent forms with slow progression and aggressive conditions rapidly pejorative. The identification of early markers allowing to predict individual patients outcome has however been unsuccessful so far. The LyMa trial treated homogeneously a cohort of young MCL patients. This appeared as a good opportunity to search for biomarkers of response to therapy. DNA extracted from diagnostic paraffin-embedded lymph node biopsies from 100 patients with newly diagnosed MCL, homogeneously treated in this prospective clinical trial, were investigated for copy number alterations and copy neutral loss of heterozygosity using the Oncoscan® SNP-array scanning the whole genome. An independent confirmatory cohort was used to strengthen the possibly relevant anomalies observed. Here we describe the recurrent anomalies identified with this technique. Deletions of 17p(TP53) and 9p(CDKN2A) were more frequent in refractory or early relapsing patients (10%), but had no significant impact in univariate analysis on progression-free (PFS) or overall survival (OS). Regardless of the presence of TP53 or CDKN2A deletions, gains in 7p22 (8,5%) were associated with better PFS in univariate but not in multivariate analysis including MCL International Prognostic Index and treatment. Gains of 11q(CCDN1), suggesting gains of the CCND1/IGH fusion, were associated with worse OS and PFS in univariate and multivariate analyses. This worse prognosis impact was confirmed by FISH in an independent confirmatory cohort. This work, using a whole genome approach, confirms the broad genomic landscape of MCL and shows that gains of the CCND1/IGH fusion can be considered as a new prognostic structural variant. Genomic abnormalities of prognostic impact could be useful to strengthen or de-escalate treatment schedules or choosing targeted therapies or CART-cells. This article is protected by copyright. All rights reserved.

Published
2020

5. The MYRACLE protocol study: a multicentric observational prospective cohort study of patients with multiple myeloma

Author

Martine Amiot, Stephane Minvielle, Benoit Tessoulin, Anne Lok, Pierre-Antoine Gourraud, Cyrille Touzeau, Steven Le Gouill, Sophie de Visme, Lina Benaniba, Hervé Maisonneuve, Catherine Pellat-Deceunynck, Sabrina Trudel, Philippe Moreau, Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes] (INCA-DGOS-Inserm), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Santé publique - Clinique des données [CHU Nantes] (Pôle Hospitalo-Universitaire 11), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, The MYRACLE cohort is supported by L’Hema and Sodebo., Bernardo, Elizabeth, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée)

Subjects
0301 basic medicine, Male, Quality of life, Cancer Research, medicine.medical_specialty, Epidemiology, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Drug resistance, Disease, lcsh:RC254-282, 03 medical and health sciences, Study Protocol, 0302 clinical medicine, Pharmacoeconomy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Multiple myeloma, Internal medicine, Surveys and Questionnaires, Genetics, Medicine, Humans, Prospective Studies, Prospective cohort study, P53, business.industry, Cohort, medicine.disease, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Survival Analysis, 3. Good health, 030104 developmental biology, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Observational study, Female, France, Neoplasm Recurrence, Local, business
Abstract

International audience; Background: Despite recent advances in the treatment of multiple myeloma, the disease constantly relapses and is still considered as incurable. The current knowledge about the biological mechanisms underlying resistance to the different class of drugs in multiple myeloma remains poor. The primary objective of the MYRACLE (Myeloma Resistance And Clonal Evolution) cohort, a multicenter prospective cohort of patients with multiple myeloma, is to address this limitation. We here describe the study background, design and methods used for this cohort. Methods/design: All patients (> 18 year old) diagnosed with de novo or relapsed multiple myeloma and treated in two hematology department from west of France are included in the MYRACLE cohort. Patients provide a signed informed to be included in the study. All subjects are followed until refusal to participate in the study or death. The MYRACLE cohort prospectively collects data on socioeconomic status, medical status, imaging, prognosis factors, MM therapies and associated events (resistance, safety issues). Patients also complete standardized quality of life questionnaires. In addition, bone marrow samples will be collected at time of diagnosis and relapses to perform biomarkers analysis and functional assays exploring mechanisms underlying drug resistance. Discussion: The "real-life" MYRACLE cohort offers the opportunity to prospectively collect epidemiological, medical, QoL and biological data from MM patients during the course of the disease (at time of diagnosis and subsequent relapses). At mid-tem, this integrative cohort will be unique at producing a large variety of data that can be used to conceive the most effective personalized therapy for MM patients. Additionally, the MYRACLE cohort will allow integrating the medical care of MM patients in a health and pharmacoeconomic perspective.

Published
2019

6. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study

Author

Richard Delarue, Emmanuelle Nicolas-Virelizier, Reda Bouabdallah, Veronique Edeline, Bertrand Joly, Adrian Tempescul, Hassan Farhat, Luc-Matthieu Fornecker, Peggy Dartigues, René-Olivier Casasnovas, Laurent Martin, Franck Morschhauser, Aspasia Stamatoullas, Pauline Brice, Marc André, Alain Delmer, Michel Meignan, Nicolas Mounier, Hervé Ghesquières, Jehan Dupuis, Philippe Quittet, Krimo Bouabdallah, Julien Lazarovici, Alina Berriolo-Riedinger, Anne-Claire Gac, Alexandra Traverse-Glehen, Pierre Feugier, Thierry Lamy, Thomas Gastinne, Hervé Maisonneuve, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Henri Mondor, 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 hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Sud Francilien, CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital René HUGUENIN (Saint-Cloud), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Reims (CHU Reims), Département de biologie et pathologie médicales [Gustave Roussy], Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Nice (CHU Nice), LYSA Imaging (Créteil) (LYSA-IM), CHU Henri Mondor, CHU Dijon, Département d'Hematologie, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CRLCC Henri Becquerel, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Hématologie [Nantes], Hôpital Sud-Fancilien, CH Sud-Fancilien, Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie Hôpital Mignot, Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CH La Roche-sur-Yon, Service d’Hématologie Clinique [CHU Pontchaillou, Rennes], Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dinant-Godinne UCL Namur, Service de cancérologie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [Créteil], Université Grenoble Alpes (UGA), Département Hématologie (FNCLCC), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Groupe Régional d'Etudes sur le CANcer (GRECAN), IFR146-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse )-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Département d'Hématologie Clinique [CHU Nantes], Université Mohamed Boudiaf de M'sila, Service d’Hématologie Clinique [CHRU Nancy], Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut d'Electronique et de Télécommunications de Rennes (IETR), Université de Nantes (UN)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre hospitalier La Roche-Sur-Yon, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie [Reims], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Pathologie morphologique, Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de Pathologie [CHU de Dijon], Service de Médecine Interne Clermont Ferrand (MéDECINE INTERNE - CLERMONT-FERRAND), Hopital, Hôpital Archet 2 [Nice] (CHU), Laboratoire d'anatomie et de cytopathologie - Centre hospitalier Lyon Sud, CH Evry-Corbeil, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, CCSD, Accord Elsevier, Service d'Hématologie Clinique (CHU de Dijon), Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d’Hématologie [Rouen], CHU Rouen, Service hématologie Créteil, CHU, Laboratoire d'Hématologie Biologique [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Service d'hématologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Département de médecine nucléaire (Institut Curie, Saint-Cloud), Institut Curie [Paris], Hématologie clinique [CH La Roche-sur-Yon], service hématologie Strasbourg, CHU Strasbourg, Service d’Hématologie Clinique [Rennes], Service hématologie Nice, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'hématologie, CHU Henri Mondor [Créteil], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, and Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM)

Subjects
Adult, Male, medicine.medical_specialty, Vincristine, Dacarbazine, [SDV]Life Sciences [q-bio], Salvage therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Procarbazine, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Neoplasm Staging, business.industry, Standard treatment, medicine.disease, Hodgkin Disease, 3. Good health, Vinblastine, Drug Therapy, Computer-Assisted, [SDV] Life Sciences [q-bio], Oncology, ABVD, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Female, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract

International audience; Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPPescalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.Methods: AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPPescalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPPescalated, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPPescalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPPescalated and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPPescalated). BEACOPPescalated consisted of bleomycin 10 mg/m2 and vincristine 1·4 mg/m2 intravenously on day 8, etoposide 200 mg/m2 intravenously on days 1-3, doxorubicin 35 mg/m2 and cyclophosphamide 1250 mg/m2 intravenously on day 1, 100 mg/m2 oral procarbazine on days 1-7, and 40 mg/m2 oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.Findings: From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPPescalated after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (

Published
2019

7. Emergence and evolution of TP53 mutations are a key feature of disease progression in myelodysplastic patients with lower-risk del(5q) treated with lenalidomide

Author

Anne-Laure Gagez, Jacques Delaunay, Pascal Godmer, Olivier Theisen, Catherine Pellat-Deceunynck, Guillaume Cartron, Laurent Flet, Steven Richebourg, Audrey Ménard, Thérèse Commes-Maerten, Marie C. Béné, Marion Eveillard, Catherine Godon, Marion Loirat, Odile Luycx, Bruno Villemagne, Pierre Peterlin, Laurence Lodé, Thierry Soussi, Yannick Le Bris, Service d'Hématologie Biologique [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service d'hématologie biologique [Nantes] (Cytologie Hématologique), Hôtel-Dieu de Nantes-Centre hospitalier universitaire de Nantes (CHU Nantes), Dynamique des interactions membranaires normales et pathologiques (DIMNP), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Montpellier 1 (UM1), Bio2M team (Inserm U1183), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Unité de Pharmacie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Cytogenetics [Québec, Canada], Centre Hospitalier Universitaire du Québec (CHUQ)-Hôpital du Saint-Sacrement [CHU Québec] (HSS), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval)-CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Service d'Hématologie [CHRU Montpellier], Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Hématologie Clinique [CH Lorient], CH de Lorient, Hématologie Clinique [CH Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Société d'Hématologie du Confluent [Nantes], Société D'hematologie Du Confluent - Nantes, Biogenouest ® Genomics core facility for technical support., Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Bernardo, Elizabeth

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, Karyotypic abnormality, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tp53 mutation, Lower risk, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Humans, TP53, Online Only Articles, Lenalidomide, ComputingMilieux_MISCELLANEOUS, Laboratory Hematology, business.industry, Myelodysplastic syndromes, Disease progression, Hematology, Middle Aged, Key features, medicine.disease, Prognosis, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Myelodysplastic Syndromes, Mutation, Disease Progression, Chromosomes, Human, Pair 5, Female, Chromosome Deletion, Tumor Suppressor Protein p53, business, Median survival, medicine.drug
Abstract

The cytogenetic anomaly of isolated del(5q) characterizes a subgroup of patients with lower-risk myelodysplastic syndrome (MDS). In the 2016 World Health Organization classification, one additional karyotypic abnormality (except −7 or del7q) can be present in such patients.[1][1] Median survival

Published
2018

8. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study

Author

Antoine Toubert, Agnès Guerci-Bresler, Hélène Moins-Teisserenc, Gabriel Etienne, Delphine Rea, Françoise Huguet, Laurence Legros, François Guilhot, Frédéric Maloisel, Zena Khaznadar, Joelle Guilhot, Martine Gardembas, Philippe Rousselot, Francois-Xavier Mahon, Bruno Villemagne, Jean-Christophe Ianotto, Franck E. Nicolini, Nicolas Dulphy, Viviane Dubruille, Aude Charbonnier, Guylaine Henry, Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Institut Bergonié [Bordeaux], UNICANCER, INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital l'Archet - CHU de Nice, Service des maladies du sang [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'Hématologie Clinique [Hôpital Hôtel Dieu, Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Hôtel Dieu, Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alloimmunité-Autoimmunité-Transplantation (A2T), and Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.drug_class, Receptor expression, Chronic Myeloid Leukemia, Cell Count, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Tyrosine-kinase inhibitor, Article, Disease-Free Survival, Natural killer cell, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Recurrence, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, Cytotoxic T cell, Humans, Protein Kinase Inhibitors, business.industry, Degranulation, Myeloid leukemia, Imatinib, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Killer Cells, Natural, Leukemia, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Imatinib Mesylate, Receptors, Natural Killer Cell, business, medicine.drug
Abstract

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).

Published
2017

9. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study

Author

Bruno Villemagne, Martine Escoffre-Barbe, Michel Tulliez, Valérie Coiteux, Francois-Xavier Mahon, Gaelle Guillerm, Marie-Pierre Noel, Laurence Legros, François Guilhot, Joelle Guilhot, Franck E. Nicolini, Martine Gardembas, Jean-Christophe Ianotto, Philippe Rousselot, Agnès Guerci-Bresler, Hyacinthe Johnson-Ansah, Jean-Michel Pignon, Aude Charbonnier, Gabriel Etienne, Delphine Rea, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'hématologie (Labo Hémato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHU Pontchaillou [Rennes], CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Université de Poitiers, Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Dasatinib, Fusion Proteins, bcr-abl, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, medicine, Humans, RNA, Messenger, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Univariate analysis, business.industry, Incidence, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, Middle Aged, medicine.disease, Interim analysis, Confidence interval, 3. Good health, Surgery, Discontinuation, Leukemia, Pyrimidines, Treatment Outcome, Nilotinib, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, medicine.drug
Abstract

STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.

Published
2016

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