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1. The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition

Author: Decombis, Salomé, Papin, Antonin, Bellanger, Céline, Sortais, Clara, Dousset, Christelle, Le Bris, Yannick, Riveron, Thiphanie, Blandin, Stéphanie, Hulin, Philippe, Tessoulin, Benoit, Rouel, Mathieu, Le Gouill, Steven, Moreau-Aubry, Agnès, Pellat-Deceunynck, Catherine, Chiron, David, 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), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Biologique [CHU Nantes], Plate-forme de 'transgénèse immunophénomique du rat' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), and Chiron, David
Subjects: immune system diseases, hemic and lymphatic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Hematology, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Abstract: International audience; Aggressive B-cell malignancies, such as mantle cell lymphoma (MCL), are microenvironment-dependent tumors and a better understanding of the dialogs occurring in lymphoma protective ecosystems will provide new perspectives to increase treatment efficiency. To identify novel molecular regulations, we performed a transcriptomic analysis based on the comparison of circulating (n=77) versus MCL lymph nodes (n=107) together with RNA sequencing of malignant (n=8) versus normal B-cell (n=6) samples. This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of the interleukin-32 beta (IL32β), whose expression was confirmed in situ within MCL lymph nodes by multiplex immunohistochemistry. Using ex vivo models of primary MCL cells (n=23), we demonstrated that, through the secretion of IL32β, the tumor was able to polarize monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFNB inhibition to counteract microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. This data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophages polarization and tumor survival, which could be counteracted through selective NIK inhibition.
Published: 2022
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2. Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study

Author: Emmanuel Bachy, Roch Houot, Pierre Feugier, Krimo Bouabdallah, Reda Bouabdallah, Emmanuelle Nicolas Virelizier, Marie Maerevoet, Christophe Fruchart, Sylvia Snauwaert, Steven Le Gouill, Jean-Pierre Marolleau, Lysiane Molina, Cécile Moluçon-Chabrot, Catherine Thieblemont, Hervé Tilly, Fontanet Bijou, Corinne Haioun, Eric Van den Neste, Bettina Fabiani, Michel Meignan, Guillaume Cartron, Gilles Salles, Olivier Casasnovas, Franck Morschhauser, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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 ), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Innovative Leukemia Organization (Filo), CHU Bordeaux [Bordeaux], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Léon Bérard [Lyon], Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CH Dunkerque, Department of ENT surgery, AZ Sint Jan Brugge Oostende, Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), NF-kappaB, Différenciation et Cancer (OncokappaB (URP_7324)), Université Paris Cité (UPCité), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Bergonié [Bordeaux], UNICANCER, Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cliniques Universitaires Saint-Luc [Bruxelles], Service de neurophysiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), LYSA Imaging (Créteil) (LYSA-IM), CHU Henri Mondor, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Weill Medical College of Cornell University [New York], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Lille, The study was funded by the LYSARC, and financially supported in part by investigator-initiated study grants from Celgene/BMS and Roche., Université de Rennes (UR)-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 ), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (SLuc) Centre du cancer, UCL - (SLuc) Service de gastro-entérologie, and UCL - (SLuc) Unité d'oncologie médicale
Subjects: Adult, Neutropenia, Adolescent, [SDV]Life Sciences [q-bio], Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Antibodies, Monoclonal, Humanized, Biochemistry, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols, Humans, Lenalidomide, Lymphoma, Follicular
Abstract: Obinutuzumab and lenalidomide (referred to as the GALEN combination) is an active immunomodulatory combination with a manageable safety profile in multiple types of lymphoma. We report efficacy and safety results for the phase 2 GALEN study in previously untreated patients with advanced follicular lymphoma (FL). Eligible patients aged ≥18 years had an Eastern Cooperative Oncology Group performance status ≤2 and high-tumor burden, grade 1 to 3a FL. Induction treatment was obinutuzumab (1000 mg IV, days 8, 15, and 22, cycle 1; day 1, cycles 2-6) plus lenalidomide (20 mg/d, days 1-21, cycle 1; days 2-22, cycles 2-6) for six 28-day cycles. Maintenance included obinutuzumab (1000 mg every 2 cycles) plus lenalidomide (10 mg, days 2-22) for ≤12 cycles (year 1) followed by obinutuzumab (1000 mg every 56 days) for 6 cycles (year 2). The primary end point was complete response rate (CRR) after induction per the 1999 International Working Group criteria. From October 2015 to February 2017, a total of 100 patients were enrolled. CRR after induction was 47%, and the overall response rate (ORR) was 92%. Post hoc analyses per the 2014 Lugano classification, including patients with missing bone marrow assessments, identified an additional 13 patients fulfilling CRR criteria, resulting in a complete metabolic response of 80% and an ORR of 94%. At a median follow-up of 3.7 years, 3-year progression-free survival and overall survival were 82% and 94%, respectively. The most common adverse event was neutropenia (48% any grade; 47% grade ≥3). Only 2% of patients presented with febrile neutropenia; others were mainly grade ≤2. No other specific grade ≥3 toxicity occurred at a frequency >3%. Overall, these results showed promising clinical efficacy for the chemotherapy-free GALEN backbone in previously untreated patients with high tumor burden FL. Except for neutropenia, the safety profile of the combination is remarkable. The study was registered at clinicaltrials.gov as #NCT01582776.
Published: 2022
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3. ALL relapse after anti-CD19 CAR-T cells therapy in a young adult: which therapeutic options?

Author: Grain, Audrey, Ollier, Jocelyn, Guillaume, Thierry, Chevallier, Patrice, Le Calvez, Baptiste, Eveillard, Marion, Clémenceau, Béatrice, Ollier, Jocelyn, Manipulation of Lymphocytes for Immunotherapy (CRCI2NA / Eq 12), 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)-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 (Nantes Univ)-Nantes Université (Nantes Univ), Service d'Hématologie et Oncologie pédiatriques [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'Hématologie [CHU Nantes], and Service d'Hématologie Biologique [CHU Nantes]
Subjects: [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
Abstract: International audience; T-cells expressing a Chimeric Antigen Receptor (CAR) recognizing the CD19 antigen allowed high early response rates in high-risk B acute lymphoblastic leukemias (B-ALL). Nevertheless, 35% to 44% of patients relapse. Among the mechanisms of immune evasion in CD19+ relapses of ALL, expression and secretion of molecules inhibiting cytotoxic T-lymphocytes, or lack of expression of co-stimulatory molecules, have been described. Expansion, persistence and cytotoxic activity of CAR-T cells could also be deficient.Here, we present the case of a young adult who presented successive relapses of ALL after chemotherapy, hematopoietic stem cell transplant (HSCT) and anti-CD19 CAR-T cells. An extended immunophenotype of leukemic cells and sensitivity to anti-CD19 CAR-T cells mediated lysis are analysed.
Published: 2022

4. Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell–Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide

Author: Dhon Roméo Makanga, Catherine Willem, Marie C. Béné, Alice Garnier, Thierry Guillaume, Katia Gagne, Anne Cesbron, Nolwenn Legrand, Christelle Retière, Bercelin Maniangou, Amandine Le Bourgeois, Patrice Chevallier, Pierre Peterlin, Bernardo, Elizabeth, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Etablissement Français du Sang [Nantes], LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Service d'Hématologie Biologique [CHU Nantes], 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), and LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes]
Subjects: Adult, Male, Cyclophosphamide, medicine.medical_treatment, Immunology, Cell, Graft vs Leukemia Effect, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Human leukocyte antigen, Hematopoietic stem cell transplantation, 03 medical and health sciences, 0302 clinical medicine, Receptors, KIR, [SDV.CAN] Life Sciences [q-bio]/Cancer, HLA Antigens, medicine, Humans, Immunology and Allergy, Receptor, Aged, business.industry, Donor selection, Hematopoietic Stem Cell Transplantation, Middle Aged, 3. Good health, Killer Cells, Natural, Transplantation, Treatment Outcome, medicine.anatomical_structure, Blood Group Incompatibility, Transplantation, Haploidentical, Female, business, Immunosuppressive Agents, 030215 immunology, medicine.drug
Abstract: P.C. and C.R. have equally contributed to this work; International audience; Little is known regarding the effect of KIR/HLA incompatibilities (inc.) in the setting of T-replete haploidentical allogeneic he-matopoietic stem cell transplantation using posttransplant cyclophosphamide (PTCy). In this retrospective study, the impact of KIR/HLA inc. on clinical outcomes and NK cell reconstitution was studied in a cohort of 51 consecutive patients receiving a T cell-replete haploidentical allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning using peripheral blood stem cells as the source of the graft and PTCy as graft-versus-host disease (GvHD) prophylaxis. The NK cell repertoire reconstitution was examined by multiparameter flow cytometry in 34 of these 51 patients from day 0 to day 100 post-transplant. Genetic KIR2DL/HLA inc. were found to be significantly associated with more GvHD (81.2 versus 45.7%, p = 0.01) and less relapse (6.2 versus 42.8%, p = 0.008) in this context. GvHD is associated with increased levels of differentiated and activated NK cells. A significant loss of KIR2DL2/3 + NK cells was observed at day 30 in patients with inhibitory KIR/HLA inc., suggesting that responsive KIR NK cells are particularly targeted by the immunosuppressive PTCy treatment. Further investigations are needed from a larger cohort with an identical clinical approach to consolidate these results and to identify the NK cell subsets that may be beneficial for the graft-versus-leukemia effect observed. Because many haploidentical donors can be identified in a family, the prediction of KIR NK cell alloreactivity could be of crucial importance for donor selection and patient outcome.
Published: 2019
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5. A phase I/II feasibility vaccine study by autologous leukemic apoptotic corpse-pulsed dendritic cells for elderly AML patients

Author: Patrice Chevallier, Nadine Juge-Morineau, Thierry Guillaume, Céline Bossard, Marie C. Béné, Pierre Peterlin, Virginie Dehame, Brigitte Dréno, Isabelle Gauvrit, Yannick Le Bris, Marc Grégoire, Soraya Saiagh, Sylvain Bercegeay, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), 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), 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), Anti-Tumor Immunosurveillance and Immunotherapy (CRCINA-ÉQUIPE 3), Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Service d'Hématologie Biologique [CHU Nantes], Laboratoire d'anatomie et cytologie pathologiques [CHU Nantes], Etablissement Français du Sang [Pays de la Loire] (EFS Pays de la Loire), EFS, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Bernardo, Elizabeth, 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), and 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)
Subjects: 030231 tropical medicine, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer Vaccines, Dendritic cells, 03 medical and health sciences, 0302 clinical medicine, AML, [SDV.CAN] Life Sciences [q-bio]/Cancer, vaccine, Cadaver, Immunology and Allergy, Medicine, Humans, 030212 general & internal medicine, Adverse effect, Aged, Pharmacology, business.industry, Complete remission, Myeloid leukemia, apoptotic corpses, 3. Good health, Leukemia, Myeloid, Acute, Phase i ii, Apoptosis, Cancer research, Feasibility Studies, business, Research Paper
Abstract: This was a phase I/II study testing the feasibility of a vaccine by autologous leukemic apoptotic corpse-pulsed dendritic cells (DC) in elderly acute myeloid leukemia (AML) patients in first or second complete remission. Pulsed DC were administered at doses of 9 × 10(6) subcutaneously (1 mL) and 1 × 10(6) intra-dermally (0.1 mL). Five doses of vaccine were planned on days +1 + 7 + 14 + 21 and +35. Five DC-vaccines were produced and injected for all five patients included in the study. No severe adverse event was documented. Larger Phase 2 studies are now required to precise the role of DC-vaccines with leukemic apoptotic bodies in older as well as younger AML populations. (Clinicaltrials.gov NCT01146262)
Published: 2021
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6. 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
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7. Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation

Author: Dubreuil, Léa, Maniangou, Bercelin, Chevallier, Patrice, Quéméner, Agnès, Legrand, Nolwenn, Béné, Marie C., Willem, Catherine, David, Gaëlle, Alizadeh, Mehdi, Makanga, Dhon Roméo, Cesbron, Anne, Gendzekhadze, Ketevan, Gagne, Katia, Retière, Christelle, Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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), Etablissement Français du Sang [Nantes], LabEx IGO 'Immunotherapy, Graft, Oncology' [Nantes], Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Biologique [CHU Nantes], Etablissement français du sang [Rennes] (EFS Bretagne), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), City of Hope Medical Center [Duarte, CA, USA] (HLA laboratory), 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), LabEX IGO Immunothérapie Grand Ouest, and Nantes Université (Nantes Univ)
Subjects: HLA, haplo-identical HSCT, [SDV.CAN] Life Sciences [q-bio]/Cancer, leukemia, [SDV.CAN]Life Sciences [q-bio]/Cancer, NK cells, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article, KIR, polymorphism
Abstract: Simple Summary We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia, highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply investigated KIR2DL NK cell repertoire in combining high-resolution KIR allele typing and multicolor flow cytometry from a cohort of 108 blood donors. Our data suggest that centromeric (cen) AA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in T-replete haplo-identical Hematopoietic Stem Cell Transplantation (HSCT) context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection. Abstract We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1+ and KIR2DL3+ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL+ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection.
Published: 2020
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8. 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
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9. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma

Author: Philippe Moreau, Laurent Garderet, Bertrand Arnulf, Sabrina Maheo, Lotfi Benboubker, Mamoun Dib, Sabine Brechignac, Nelly Robillard, Mohamad Mohty, Margaret Macro, Brigitte Pegourie, Thierry Facon, Brigitte Kolb, Karim Belhadj, Nikhil C. Munshi, Bruno Royer, Olivier Decaux, Arnaud Jaccard, Valérie Lauwers-Cances, Marie-Lorraine Chretien, Anne-Marie Stoppa, Hervé Avet-Loiseau, Xavier Leleu, Kenneth C. Anderson, Jean-Richard Eveillard, Martin Moorhead, Chantal Doyen, Cecile Fohrer, Lionel Karlin, Jill Corre, Victoria Carlton, Paul G. Richardson, Malek Faham, Jean-Luc Harousseau, Michel Attal, Nathalie Meuleman, Thomas D. Willis, Aurore Perrot, Cyrille Hulin, Thomas Dejoie, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'épidémiologie [Toulouse], CHU Toulouse [Toulouse], 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), Université Fédérale Toulouse Midi-Pyrénées, Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de Biochimie [Nantes], 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), Centre Hospitalier Universitaire [Grenoble] (CHU), 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), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'hématologie [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 [Rennes], CHU Pontchaillou [Rennes], Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Universitaire de Bobigny, 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), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-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 de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Universitaire de Caen, Department of Energy / Joint Genome Institute (DOE), Los Alamos National Laboratory (LANL), Département d'Hématologie Clinique [CHU Nantes], Département d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Département d'Hématologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département d'Hématologie [CHU Nantes], Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Hématologie [IUCT Oncopole, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), UCL - (MGD) Service d'hématologie, UCL - SSS/IREC/MONT - Pôle Mont Godinne, Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Département d'hématologie [CHU Saint-Antoine, AP-HP], AP-HP - Hôpital Saint-Antoine, Institut Jules Bordet, Service hématologie (CHU d'Amiens), Département d'Hématologie Clinique [CHU Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Service d'Hématologie [CHU Toulouse]
Subjects: Male, 0301 basic medicine, Oncology, Neoplasm, Residual, Biochemistry, Dexamethasone, Bortezomib, Observations Lymphoid Neoplasia, 0302 clinical medicine, Maintenance therapy, Bone Marrow, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Lenalidomide, Multiple myeloma, Lymphoid Neoplasia, Hazard ratio, High-Throughput Nucleotide Sequencing, Hematology, Minimal Residual Disease Negativity, Middle Aged, Prognosis, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, medicine.drug, medicine.medical_specialty, Plasma Cells, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, Maintenance Chemotherapy, 03 medical and health sciences, Internal medicine, medicine, Humans, Clinical Trials, Survival rate, Aged, business.industry, Cell Biology, medicine.disease, Minimal residual disease, Transplantation, 030104 developmental biology, business, Follow-Up Studies
Abstract: IF 15.132 (2017); International audience; The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (
Published: 2018
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10. Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

Author: Marc Fouassier, Nathalie Trillot, Claude Preudhomme, Véronique Tintiller, Coralie Derrieux, Elise Fournier, Céline Berthon, Nicolas Duployez, Camille Debord, Soraya Wuilleme, Valérie Soenen, Thomas Boyer, Louis Terriou, Camille Paris, Fanny Gonzales, Sophie Susen, Anne Lambilliotte, Pierre Boisseau, Wadih Abou Chahla, Hôpital Claude Huriez [Lille], CHU Lille, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille], Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Lille (CHU de Lille), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Régional de Traitement des Hémophiles [CHU Nantes], DESSAIVRE, Louise, and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011)
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, business.industry, Platelet disorder, [SDV]Life Sciences [q-bio], MEDLINE, Infant, Hematology, Middle Aged, Gastroenterology, Thrombocytopenia, [SDV] Life Sciences [q-bio], Internal medicine, Hematologic Neoplasms, medicine, Humans, Female, Genetic Predisposition to Disease, Blood Platelet Disorders, Baseline (configuration management), business, ComputingMilieux_MISCELLANEOUS, Germ-Line Mutation
Abstract: International audience
Published: 2020
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11. Comparison of MALDI‐TOF mass spectrometry analysis of peripheral blood and bone marrow‐based flow cytometry for tracking measurable residual disease in patients with multiple myeloma

Author: Amanda Ciardiello, Even H Rustad, Yanming Zhang, Mikhail Roshal, Marion Eveillard, Neha Korde, Sydney X. Lu, Alexander M. Lesokhin, Sham Mailankody, Malin Hultcrantz, Ola Landgren, Katie L. Thoren, Urvi A Shah, Hani Hassoun, Eric L. Smith, Bernardo, Elizabeth, 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), 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), Memorial Sloane Kettering Cancer Center [New York], Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Myeloma Service [New York, NY, USA] (Department of Medicine), Department of Pathology [New-York, NY, USA], 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), and 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)
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Neoplasm, Residual, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mass spectrometry, Article, Flow cytometry, 03 medical and health sciences, Immunoglobulin kappa-Chains, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, medicine, Humans, In patient, Multiple myeloma, Aged, mass spectrometry, medicine.diagnostic_test, business.industry, flow cytometry, Cancer, Bone Marrow Examination, Hematology, Middle Aged, medicine.disease, Peripheral blood, 3. Good health, multiple myeloma, medicine.anatomical_structure, Myeloma Proteins, 030220 oncology & carcinogenesis, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Monoclonal, Female, Bone marrow, business, 030215 immunology
Abstract: International audience; Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) may soon replace routine electrophoretic methods for monitoring monoclonal proteins in patients with multiple myeloma. To further evaluate the clinical utility of this assay, we compared the performance of MALDI-TOF-MS head-to-head with an established bone marrow-based measurable residual disease assay by flow cytometry (Flow-BM-MRD), using Memorial Sloan Kettering Cancer Center's 10-color, single-tube method. Our results suggest that MALDI-TOF-MS adds value to bone marrow-based MRD testing and may be most useful for early detection of relapse in peripheral blood compared to current electrophoretic methods.
Published: 2020
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12. CSF1R and BTK inhibitions as novel strategies to disrupt the dialogue between mantle cell lymphoma and macrophages

Author: Papin, Antonin, Tessoulin, Benoit, Bellanger, Céline, Moreau, Anne, Le Bris, Yannick, Maisonneuve, Hervé, Moreau, Philippe, Touzeau, Cyrille, Amiot, Martine, Pellat-Deceunynck, Catherine, Le Gouill, Steven, Chiron, David, Bernardo, Elizabeth, NExT (I-SITE) - - NExT (I-SITE)2016 - ANR-16-IDEX-0007 - IDEX - VALID, 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), Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours-Centre National de la Recherche Scientifique (CNRS), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Anatomie Pathologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre Hospitalier Universitaire G. R. Laennec (HGRL Saint-Herblain), Service d'Hématologie Biologique [CHU Nantes], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), This study was supported by la Ligue Contre le Cancer Grand-Ouest, i-Site NexT (ANR-16-IDEX-0007) and the SIRIC ILIAD (INCa-DGOS-Inserm_12558). We thank Janssen-Cilag and Roche for supporting in part this study., ANR-16-IDEX-0007,NExT (I-SITE),NExT (I-SITE)(2016), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), 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), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée)
Subjects: Lymphoma, CD163+ macrophages, [SDV.CAN] Life Sciences [q-bio]/Cancer, immune system diseases, ibrutinib, hemic and lymphatic diseases, CSF1, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract: International audience; The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. Here, we focused on the interplay between MCL cells and associated monocytes/macrophages. Using circulating MCL cells (n=58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163+ M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n=8) highlighted a rapid decrease of CSF1, IL-10 and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.
Published: 2019

13. FLT3 ligand plasma levels in acute myeloid leukemia

Author: Nelly Robillard, Alice Garnier, Soraya Wuilleme, Marion Eveillard, Olivier Theisen, Patrice Chevallier, Michel Chérel, Yannick Le Bris, Thierry Guillaume, Nicolas Blin, Steven Le Gouill, Camille Debord, Beatrice Mahe, Philippe Moreau, Pierre Peterlin, Amandine Le Bourgeois, Viviane Dubruille, Catherine Godon, Anne Lok, Joëlle Gaschet, Thomas Gastinne, Antoine Bonnet, Marie-Christine Béné, Cyrille Touzeau, Nuclear Oncology (CRCINA-ÉQUIPE 13), 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 Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Service d'Hématologie Biologique [CHU Nantes], Unité de Médecine Nucléaire [ICO, Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), This study was supported by a grant from the DHU Oncogreffe of 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 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 Bernardo, Elizabeth
Subjects: Acute Myeloid Leukemia, Myeloid, Time Factors, [SDV.CAN]Life Sciences [q-bio]/Cancer, Kaplan-Meier Estimate, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Online Only Articles, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Proportional Hazards Models, 0303 health sciences, business.industry, Myeloid leukemia, Disease Management, Membrane Proteins, Hematology, Plasma levels, Induction Chemotherapy, medicine.disease, Prognosis, cytokines, Leukemia, Leukemia, Myeloid, Acute, Adult Acute Lymphoblastic Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Flt3 ligand, business, Biomarkers
Abstract: International audience; no abstract
Published: 2019
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14. A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset

Author: Selimoglu-Buet, Dorothée, Rivière, Julie, Ghamlouch, Hussein, Bencheikh, Laura, Lacout, Catherine, Morabito, Margot, Diop, M’boyba, Meurice, Guillaume, Breckler, Marie, Chauveau, Aurélie, Debord, Camille, Debeurme, Franck, Itzykson, Raphael, Chapuis, Nicolas, Willekens, Christophe, Wagner-Ballon, Orianne, Bernard, Olivier A., Droin, Nathalie, Solary, Eric, Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Plateforme de Bioinformatique [Gustave Roussy], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etude du Polymorphisme des Génomes Végétaux (EPGV), Institut National de la Recherche Agronomique (INRA), Service d'Hématologie Biologique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), 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), Direction des systèmes d'information, Ministére des Affaires Etrangères, Ministère de l'Europe et des Affaires étrangères (MEAE), Service d'Hématologie Clinique [CHU Lille], Hôpital Claude Huriez, CHU Henri Mondor, Université Paris-Sud 11 - Faculté de médecine (UP11 UFR Médecine), Centre de Recherches Juridiques de l'Université de Franche-Comté - UFC (EA 3225) (CRJFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Franche-Comté (UFC), Département d'hématologie [Gustave Roussy], and Institut Gustave Roussy (IGR)
Subjects: Male, Mice, Knockout, Gene Expression Regulation, Leukemic, Science, Primary Cell Culture, Down-Regulation, Leukemia, Myelomonocytic, Chronic, [SDV.CAN]Life Sciences [q-bio]/Cancer, DNA Methylation, Article, Monocytes, Dioxygenases, DNA-Binding Proteins, Mice, MicroRNAs, Proto-Oncogene Proteins, Animals, Humans, Female, lcsh:Q, K562 Cells, Promoter Regions, Genetic, lcsh:Science
Abstract: Non-classical monocyte subsets may derive from classical monocyte differentiation and the proportion of each subset is tightly controlled. Deregulation of this repartition is observed in diverse human diseases, including chronic myelomonocytic leukemia (CMML) in which non-classical monocyte numbers are significantly decreased relative to healthy controls. Here, we identify a down-regulation of hsa-miR-150 through methylation of a lineage-specific promoter in CMML monocytes. Mir150 knock-out mice demonstrate a cell-autonomous defect in non-classical monocytes. Our pulldown experiments point to Ten-Eleven-Translocation-3 (TET3) mRNA as a hsa-miR-150 target in classical human monocytes. We show that Tet3 knockout mice generate an increased number of non-classical monocytes. Our results identify the miR-150/TET3 axis as being involved in the generation of non-classical monocytes., A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.
Published: 2018
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15. Two novel variants of uncertain significance in GP9 associated with Bernard–Soulier syndrome: Are they true mutations?

Author: G. Landeau, Marc Fouassier, S. Bezieau, Marie C. Béné, Camille Debord, Pierre Boisseau, C. Thomas, B. Pan Petesch, M. Giraud, M. Sigaud, Marion Eveillard, Agnès Quéméner, P. Talarmain, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service d'Hématologie Biologique [CHU Nantes], Immunobiology of Human αβ and γδ T cells and Immunotherapeutic Applications ( CRCINA - Département INCIT - Equipe 1 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), 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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre Régional de Traitement des Hémophiles [CHU Nantes], Centre Régional de Traitement des Hémophiles [CHU Brest], Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Centre hospitalier universitaire de Nantes (CHU Nantes), Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), 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 Hospitalier Régional Universitaire de Brest (CHRU Brest), 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 Bernardo, Elizabeth
Subjects: 0301 basic medicine, Models, Molecular, Genotype, Protein Conformation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bernard–Soulier syndrome, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Von Willebrand factor, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glycoprotein complex, Thrombocytopathy, medicine, Humans, Platelet, Alleles, Genetic Association Studies, chemistry.chemical_classification, biology, GP9, Bernard-Soulier Syndrome, Computational Biology, Genetic Variation, Hematology, General Medicine, Sequence Analysis, DNA, medicine.disease, 3. Good health, 030104 developmental biology, Phenotype, chemistry, Platelet Glycoprotein GPIb-IX Complex, Child, Preschool, Immunology, Mutation, biology.protein, Anisocytosis, Female, Glycoprotein, Biomarkers, 030215 immunology, Rare disease
Abstract: International audience; Bernard–Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x10[9]/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets.
Published: 2017
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16. Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial

Author: Didier Bouscary, E. Tavernier, Mathilde Hunault-Berger, A Saad, Chantal Himberlin, Severine Lissandre, Christian Recher, Isabelle Luquet, F Orsini-Piocelle, M-A Couturier, Etienne Daguindau, N. Maillard, M C Béné, Caroline Bonmati, Francois Dreyfus, Martin Carre, J-P Marolleau, A Schmidt-Tanguy, Jacques Delaunay, Norbert Ifrah, Luc Fornecker, Mario Ojeda-Uribe, M Puyade, B. Choufi, J-F Hamel, Arnaud Pigneux, Marc Bernard, Anne Banos, L Sutton, V Rouillé, Laurence Sanhes, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie pédiatrique - CHU Reims, Centre Hospitalier Universitaire de Reims (CHU Reims), 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), Service d'Hématologie [CH Boulogne/Mer], CH Boulogne sur Mer, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut de cancérologie et d'hématologie [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Service d'Hématologie [CH Annecy], CH Annecy, Service d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie [ CHU Saint-Etienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Service d'Hématologie et thérapie cellulaire [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'Hématologie [CH Mulhouse], Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Service d'Hématologie [CH Perpignan], CH Perpignan, Service d'Hématologie [CH Argenteuil], CH Argenteuil, Service d'hématologie (CH de la Côte Basque), Centre Hospitalier de la Côte Basque (CHCB), Département d'Oncologie Médicale et d'Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématologie [CH Béziers], CH Béziers, Service d'Hématologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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 Biologique [CHU Nantes], Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’hématologie Clinique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Celgene for providing azacitidine, lenalidomide and financial support for the monitoring., 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [Saint-Etienne], Institut de Cancérologie de la Loire [Saint-Etienne], Le CHCB, Centre Hospitalier de la Côte Basque, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Hématologie Biologique [CHU Toulouse], CHU Toulouse [Toulouse]-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Bernardo, Elizabeth, 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), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3)
Subjects: Oncology, Male, medicine.medical_specialty, Azacitidine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, Maintenance Chemotherapy, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Internal medicine, Medicine, Humans, Lenalidomide, Letter to the Editor, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Hematology, business.industry, Myeloid leukemia, Middle Aged, medicine.disease, 3. Good health, Lymphoma, Thalidomide, Survival Rate, Leukemia, Haematopoiesis, Leukemia, Myeloid, Acute, 030220 oncology & carcinogenesis, Immunology, Female, business, 030215 immunology, medicine.drug
Abstract: Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial
Published: 2017
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17. Clot formation risk in the clearing fluid after arterial catheter blood sampling: coagulation factors consumption over time - a prospective pilot study.

Author: Dauvergne JE, Boissier E, Rozec B, Lakhal K, and Muller D
Abstract: After blood sampling from an arterial catheter, the reinjection of the clearing fluid (a mixture of saline solution and blood) is proposed to limit blood loss. However, reinjecting clots may cause embolic complications. The primary objective was to assess fibrinogen consumption in the clearing fluid as an indicator of clot formation over time. Additionally, we searched for macroscopic clots, evaluated changes in prothrombin time, factors II and V. In this prospective observational pilot study, we enrolled adult patients in an intensive care unit with a radial artery catheter who required measurements of hemostasis parameters. We used a locally developed closed blood sampling system. Hemostasis parameters were measured in patients' pure blood (reference) and in the clearing fluid, at 2, 3, and 5 min after the complete filling of the reservoir. Thirty patients were included and 120 samples were analyzed. Fibrinogen levels decreased over time: median [interquartile range (IQR)] of 4.3 [IQR:3.1;5.9] as reference level, 3.6 [IQR:2.7;4.7] at 2 min (p < 0.001), 3.4 [IQR:2.1;4.3] at 3 min (p < 0.001) and 3.0 [IQR:1.7;4.1] g/L at 5 min (p < 0.001). No clot was macroscopically detected in any samples. An antiplatelet agent was administered in 11 (37%) patients. Unfractionated heparin anti-Xa activity was higher than 0.10 UI/ml in 17 (57%). Although no macroscopic clots were observed in the clearing fluid, its coagulation factors decreased over the 5 min following reservoir filling, indicating potential initiation of clot formation. Our findings stress the need for further studies assessing the safety of reinjecting clearing fluid as part of patient blood management., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the ethics committee, Groupe Nantais d’Ethique dans le Domaine de la Santé (GNEDS) on December 8, 2022 (ref. 22-12-60). Oral and written information was given to the patient or his/her next of kin and their non-opposition to participate in the research was systematically sought. Consent to participate: All patients and/or their next of kin received oral and written information about data collection and their non-opposition was systematically sought. Clinical trial registration: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)
Published: 2024
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18. CSF1R and BTK inhibitions as novel strategies to disrupt the dialog between mantle cell lymphoma and macrophages.

Author: Papin A, Tessoulin B, Bellanger C, Moreau A, Le Bris Y, Maisonneuve H, Moreau P, Touzeau C, Amiot M, Pellat-Deceunynck C, Le Gouill S, and Chiron D
Subjects: Adenine analogs & derivatives, Aged, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Female, Humans, Interleukin-10 metabolism, Lymphoma, Mantle-Cell metabolism, Macrophages metabolism, Male, Monocytes drug effects, Monocytes metabolism, Piperidines, Protein-Tyrosine Kinases antagonists & inhibitors, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Receptors, Cell Surface metabolism, Tumor Microenvironment drug effects, CD163 Antigen, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, Lymphoma, Mantle-Cell drug therapy, Macrophages drug effects, Protein Kinase Inhibitors therapeutic use, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Abstract: The microenvironment strongly influences mantle cell lymphoma (MCL) survival, proliferation, and chemoresistance. However, little is known regarding the molecular characterization of lymphoma niches. Here, we focused on the interplay between MCL cells and the associated monocytes/macrophages. Using circulating MCL cells (n = 58), we showed that, through the secretion of CSF1 and, to a lesser extent, IL-10, MCL polarized monocytes into specific CD163 + M2-like macrophages (MϕMCL). In turn, MϕMCL favored lymphoma survival and proliferation ex vivo. We next demonstrated that BTK inhibition abrogated CSF1 and IL-10 production in MCL cells, leading to the inhibition of macrophage polarization and consequently resulting in the suppression of microenvironment-dependent MCL expansion. In vivo, we showed that CSF1 and IL-10 plasma concentrations were higher in MCL patients than in healthy donors, and that monocytes from MCL patients overexpressed CD163. Further analyses of serial samples from ibrutinib-treated patients (n = 8) highlighted a rapid decrease of CSF1, IL-10, and CD163 in responsive patients. Finally, we showed that targeting the CSF1R abrogated MϕMCL-dependent MCL survival, irrespective of their sensitivity to ibrutinib. These data reinforced the role of the microenvironment in lymphoma and suggested that macrophages are a potential target for developing novel therapeutic strategies in MCL.
Published: 2019
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19. Early (Day 15 Post Diagnosis) Peripheral Blood Assessment of Measurable Residual Disease in Flow Cytometry is a Strong Predictor of Outcome in Childhood B-Lineage Lymphoblastic Leukemia.

Author: Loosveld M, Nivaggioni V, Arnoux I, Bernot D, Michel G, Béné MC, and Eveillard M
Subjects: Adolescent, Child, Child, Preschool, Cohort Studies, Female, Humans, Infant, Male, Neoplasm, Residual blood, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma blood, Flow Cytometry, Neoplasm, Residual diagnosis, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma diagnosis
Abstract: Background: In children with acute lymphoblastic leukemia (ALL) low levels of minimal residual disease (MRD) after induction, essentially assessed in the bone marrow, have been shown to be of good prognosis. However, only few studies have tested the peripheral blood for MRD., Methods: Here, we report the impact on survival of peripheral blood (PB) MRD assessment by multiparameter flow cytometry (MFC) at early time points of treatment in 125 B-ALL children, compared to Day 35 molecular bone marrow (BM) MRD. Patients were sampled for MFC one week postdiagnosis after a pre-phase of corticotherapy (Day 8), then after one week of chemotherapy (Day 15). The study enrolled 67 boys and 58 girls with a median follow-up of 52 months. Over the duration of the study, 20 patients relapsed and eight died. MFC was performed based on the leukemia-associated immunophenotype at diagnosis, using panels of 10 antibodies., Results: Although, PB MFC-MRD had no prognostic impact at Day 8, Day 15 MRD negativity was associated with a significantly better 4 years DFS (91.6 ± 3% vs. 67.6 ± 9% P = 0.0013). Furthermore, while MFC and molecular data were concordant in most cases, patients with detectable PB MRD on Day 15, yet negative in BM on Day 35 had a significantly lower DFS (P < 0.0001)., Conclusion: This study demonstrates that the less invasive procedure of MFC-MRD assessment in PB can be informative for childhood ALL patients at the early point of Day 15 of the treatment schedule. © 2019 International Clinical Cytometry Society., (© 2019 International Clinical Cytometry Society.)
Published: 2019
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20. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study.

Author: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, and Leblond V
Subjects: Aged, Female, Humans, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Rituximab pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Rituximab therapeutic use
Abstract: Background: Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR)., Methods: This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m 2 per day] and oral cyclophosphamide [250 mg/m 2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m 2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m 2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m 2 ) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606., Findings: Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4-65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6-not estimable) was improved compared with the observation group (49·0 months, 39·9-60·5; hazard ratio 0·55, 95% CI 0·40-0·75; p=0·0002). Neutropenia and grade 3-4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3-4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group., Interpretation: 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy., Funding: French National Cancer Institute (INCa), Roche, Chugai., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
Published: 2018
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20 results on '"Service d'Hématologie Biologique [CHU Nantes]"'

1. The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition

2. Obinutuzumab plus lenalidomide in advanced, previously untreated follicular lymphoma in need of systemic therapy: a LYSA study

3. ALL relapse after anti-CD19 CAR-T cells therapy in a young adult: which therapeutic options?

4. Impact of KIR/HLA Incompatibilities on NK Cell Reconstitution and Clinical Outcome after T Cell–Replete Haploidentical Hematopoietic Stem Cell Transplantation with Posttransplant Cyclophosphamide

5. A phase I/II feasibility vaccine study by autologous leukemic apoptotic corpse-pulsed dendritic cells for elderly AML patients

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

7. Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation

8. 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

9. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma

10. Baseline dysmegakaryopoiesis in inherited thrombocytopenia/platelet disorder with predisposition to haematological malignancies

11. Comparison of MALDI‐TOF mass spectrometry analysis of peripheral blood and bone marrow‐based flow cytometry for tracking measurable residual disease in patients with multiple myeloma

12. CSF1R and BTK inhibitions as novel strategies to disrupt the dialogue between mantle cell lymphoma and macrophages

13. FLT3 ligand plasma levels in acute myeloid leukemia

14. A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset

15. Two novel variants of uncertain significance in GP9 associated with Bernard–Soulier syndrome: Are they true mutations?

16. Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial

17. Clot formation risk in the clearing fluid after arterial catheter blood sampling: coagulation factors consumption over time - a prospective pilot study.

18. CSF1R and BTK inhibitions as novel strategies to disrupt the dialog between mantle cell lymphoma and macrophages.

19. Early (Day 15 Post Diagnosis) Peripheral Blood Assessment of Measurable Residual Disease in Flow Cytometry is a Strong Predictor of Outcome in Childhood B-Lineage Lymphoblastic Leukemia.

20. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study.

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