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1. Rapid and complete response to idelalisib in a case of Richter syndrome

Author: Christian Berthou, Cristina Bagacean, Hussam Saad, Mihnea Zdrenghea, Adrian Tempescul, and Yves Renaudineau
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Chronic lymphocytic leukemia, Aggressive lymphoma, Malignancy, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Chemoimmunotherapy, hemic and lymphatic diseases, Internal medicine, medicine, Pharmacology (medical), Prospective cohort study, B cell, business.industry, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, business, Idelalisib
Abstract: Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS.
Published: 2019
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2. Intravenous high-dose methotrexate based systemic therapy in the treatment of isolated primary vitreoretinal lymphoma: an LOC network study

Author: Gandhi Damaj, Khê Hoang-Xuan, Emmanuel Gyan, Marion Lam, Laurent Meyer, Magali Sampo, Anna Schmitt, Sylvain Choquet, Cécile Moluçon-Chabrot, Remy Gressin, Caroline Houillier, Adrien Chauchet, Jérôme Tamburini-Bonnefoy, Laurent Kodjikian, Marie-Laure Le Lez, Lucie Oberic, Roch Houot, Christelle Schneider, Sarra Gattoussi, Hélène Massé, Béatrice Cochener, Jean-Claude Quintyn, Nathalie Cassoux, Priscille Ollé, Karine Angioi-Duprez, Luc-Matthieu Fornecker, Carole Soussain, Jean-Pierre Marolleau, Guido Ahle, Marie-Pierre Moles, Christophe Chiquet, Claire Schwartz, Marie Blonski, Fabien Croisé, Valérie Touitou, Laurent Ballonzoli, Frédéric Mouriaux, Hervé Ghesquières, Bahram Bodaghi, Adrian Tempescul, Magali Le Garff-Tavernier, Emeline Tabouret, Eve Rousseau, Paul Franciane, Benjamin Jany, Antoine P. Brézin, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Institut Curie [Paris], Université de Paris (UP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Croix-Rousse [CHU - HCL], Institut Bergonié [Bordeaux], UNICANCER, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Bordeaux Pellegrin [Bordeaux], Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ophtalmologie [Hôpital de la Timone - APMH], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), 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 ), CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital pasteur [Colmar], CHU Grenoble, 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), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Clermont-Ferrand, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Strasbourg, Institut de neurosciences translationnelles de Paris (NeurATRIS - IHU-A-ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), None, Université Paris Cité (UPCité), 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 ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 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), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chard-Hutchinson, Xavier, 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Adult, Male, medicine.medical_specialty, Antimetabolites, Antineoplastic, medicine.medical_treatment, Retinal Neoplasms, [SDV]Life Sciences [q-bio], Population, Disease, Systemic therapy, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Intraocular Lymphoma, Internal medicine, medicine, Humans, education, Aged, Aged, 80 and over, Chemotherapy, education.field_of_study, business.industry, Hematology, Middle Aged, Prognosis, High dose methotrexate, 3. Good health, [SDV] Life Sciences [q-bio], Methotrexate, Treatment Outcome, 030220 oncology & carcinogenesis, Toxicity, 030221 ophthalmology & optometry, Administration, Intravenous, Female, business, medicine.drug, Vitreoretinal lymphoma
Abstract: International audience; The treatment of primary vitreoretinal lymphoma (PVRL) remains controversial regarding the use of local, systemic, or combined treatments. The aim of this study was to analyze the efficacy and toxicity of intravenous high-dose methotrexate (IV HD-MTX) based systemic therapy in a uniformly treated population of PVRL patients. From a nationwide French database, we retrospectively selected 59 patients (median age: 70 years, median Karnofsky Performance Status: 90%) with isolated PVRL at diagnosis who received first-line treatment with HD-MTX between 2011-2018. 8/59 patients also received a local treatment. No deaths or premature discontinuations of MTX due to toxicity were reported. A complete response was obtained in 40/57 patients after chemotherapy. Before treatment, IL-10 was elevated in the aqueous humor (AH) or in the vitreous in 89% of patients. After treatment, AH IL-10 was undetectable in 87% of patients with a CR/uCR/PR and detectable in 92% of patients with PD/SD. After a median follow-up of 61 months, 41/59 (69%) patients had relapsed, including 29 isolated ocular relapses as the first relapse and a total of 22 brain relapses. The median overall survival, progression-free survival, ocular-free survival and brain-free survival were 75, 18, 29 and 73 months, respectively. IV HD-MTX based systemic therapy as a first-line treatment for isolated PVRL is feasible, with acceptable toxicity, even in an elderly population. This strategy seems efficient to prevent brain relapse with prolonged overall survival. However, the ocular relapse rate remains high. New approaches are needed to improve local control of this disease, and ocular assessment could be completed by monitoring AH IL-10.
Published: 2021
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3. Gonadal Function Recovery in Patients With Advanced Hodgkin Lymphoma Treated With a PET-Adapted Regimen: Prospective Analysis of a Randomized Phase III Trial (AHL2011)

Author: Roch Houot, Emmanuelle Nicolas Virelizier, Jehan Dupuis, Magda Alexis, Virginie De Wilde, Luc-Matthieu Fornecker, Julien Lazarovici, Marc André, Franck Morschhauser, David Sibon, Judith Racapé, Hervé Ghesquières, Anne-Claire Gac, Delphine Pranger, Hannah Moatti, Isabelle Demeestere, Hervé Maisonneuve, Julie Dechene, Adrian Tempescul, René-Olivier Casasnovas, Mohamed Touati, UCL - SSS/IREC/MONT - Pôle Mont Godinne, and UCL - (MGD) Service d'hématologie
Subjects: Oncology, Adult, Anti-Mullerian Hormone, Male, Cancer Research, medicine.medical_specialty, endocrine system, Dacarbazine, Bleomycin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Testis, medicine, Humans, Doxorubicin, In patient, Prospective Studies, Etoposide, 030219 obstetrics & reproductive medicine, business.industry, Ovary, Recovery of Function, Hodgkin Disease, Vinblastine, Regimen, chemistry, ABVD, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Female, business, medicine.drug
Abstract: PURPOSE The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) in early responders on the basis of a positron emission tomography (PET)–driven strategy was safe and minimized toxicity compared with standard 6 BEACOPPescalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old. METHODS Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up. RESULTS A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPPescalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004). CONCLUSION Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma.
Published: 2021

4. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial

Author: Margaret Macro, Andrew Ar Belch, Antoine Tinel, Nathalie Meuleman, Jean Yves Mary, Christian Rose, Paula Rodriguez-Otero, Philippe Moreau, Wenming Chen, Michel Attal, Marie Lorraine Chretien, William Renwick, Kihyun Kim, Meletios A. Dimopoulos, Eileen M Boyle, Xavier Leleu, Michael Sturniolo, Thierry Facon, Heinz Ludwig, Mara Silvia Monzini, Vanessa Houck, Elena Zamagni, Adrian Tempescul, Salomon Manier, Cyrille Hulin, Shien Guo, Mohamad Mohty, Bruno M. Costa, Facon T., Dimopoulos M.A., Meuleman N., Belch A., Mohty M., Chen W.-M., Kim K., Zamagni E., Rodriguez-Otero P., Renwick W., Rose C., Tempescul A., Boyle E., Manier S., Attal M., Moreau P., Macro M., Leleu X., Lorraine Chretien M., Ludwig H., Guo S., Sturniolo M., Tinel A., Silvia Monzini M., Costa B., Houck V., Hulin C., Yves Mary J., CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, National and Kapodistrian University of Athens (NKUA), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Cross Cancer Institute [Edmonton, AB, Canada], Service d'immunologie et hématologies biologiques [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), Capital Medical University, Beijing, Samsung Medical Center Sungkyunkwan University School of Medicine, Institute Division of Hematology/Oncology, Azienda Ospedaliero-Universitaria, Universidad de Navarra [Pamplona] (UNAV), Western Health The University of Melbourne, Université catholique de Lille (UCL), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Hôtel-Dieu de Nantes - Centre Hospitalier Universitaire de Nantes (Hôpital Hôtel-Dieu de Nantes - CHU de Nantes), Hôpital Universitaire de Caen, Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Wilhelminenspital Vienna, Evidera, Celgene Corporation, Celgene International, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Michel, Geneviève, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), 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 Wilhelminenspital Vienna = Wilhelminen Hospital
Subjects: 0301 basic medicine, Male, Cancer Research, [SDV]Life Sciences [q-bio], Dexamethasone, 0302 clinical medicine, Clinical trials, Multiple myeloma, Antineoplastic Combined Chemotherapy Protocols, Stage (cooking), Lenalidomide, Melphalan, Aged, 80 and over, Frailty, Hematology, Middle Aged, 3. Good health, Thalidomide, [SDV] Life Sciences [q-bio], Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Female, Multiple Myeloma, Haematological diseases, Human, Adult, medicine.medical_specialty, FIRST (MM-020) trial, Frail Elderly, Newly diagnosed, Transplant ineligible, Anesthésiologie, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, In patient, Adverse effect, Aged, Antineoplastic Combined Chemotherapy Protocol, business.industry, medicine.disease, Clinical trial, Cancérologie, 030104 developmental biology, Charlson comorbidity index, Prednisone, business, Hématologie
Abstract: Patients with multiple myeloma are generally older and vary in fitness levels, which may influence the clinical benefit of treatment. Patients from the large, phase 3 FIRST trial in newly diagnosed multiple myeloma (NDMM) were retrospectively investigated to determine outcomes based on frailty using scores for age, Charlson Comorbidity Index (CCI), and Eastern Cooperative Oncology Group performance status (ECOG PS), instead of the EQ-5D quality-of-life questionnaire, as previously reported. ECOG PS (n = 1618) was investigated in frailty groups: frail (49%) and nonfrail (51%). Frail patients experienced worse progression-free and overall survival vs nonfrail patients. Prognostic assessment was improved when combining frailty and International Staging System stage (I/II vs III). Frail patients had a higher risk of developing grade 3/4 treatment-emergent adverse events. Treatment effects observed in the FIRST trial were confirmed per frailty group and per frailty and ISS group. The use of this ECOG PS–containing frailty scale as a predictive measure of clinical outcomes in patients with transplant-ineligible NDMM is supported by data from the FIRST trial. This score, based on age, CCI, and ECOG PS, can be easily replicated and may help design future myeloma studies in frail or nonfrail elderly patients., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019
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5. A case of IgE myeloma transformed into IgE-producing plasma cell leukaemia

Author: Jean-Richard Eveillard, Hélène Kerspern, Eric Lippert, Nicolas Galakhoff, Cyril Leven, Jean-Luc Carré, Maël Padelli, Caroline Buors, Cécile Aubron, Adrian Tempescul, Laboratoire de Biochimie (BREST - Biochimie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de soins intensifs [Brest], Laboratoire d'hématologie (Labo Hémato - BREST), INSERM U1078, Université de Brest (UBO), and Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique]
Subjects: 0301 basic medicine, Immunofixation, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Case Reports, Immunoglobulin light chain, Immunoglobulin E, immunoglobulin E, 03 medical and health sciences, 0302 clinical medicine, Gammopathy, medicine, Multiple myeloma, biology, medicine.diagnostic_test, business.industry, immunofixation, Biochemistry (medical), monoclonal gammopathy of undetermined significance, multiple myeloma, plasma cell leukaemia, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Serum protein electrophoresis, Monoclonal, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Monoclonal gammopathy of undetermined significance
Abstract: International audience; This is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.
Published: 2020
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6. Non-adherence to treatment with cytoreductive and/or antithrombotic drugs is frequent and associated with an increased risk of complications in patients with polycythemia vera or essential thrombocythemia (OUEST study)

Author: Stéphane Giraudier, Jean-Richard Eveillard, Christelle Le Gall-Ianotto, Ronan Le Calloch, Eric Lippert, Jean-Christophe Ianotto, Valérie Ugo, Karine Lacut, Morgane Abiven, Emmanuel Nowak, Gaelle Guillerm, Florence Dalbies, Adrian Tempescul, Christian Berthou, Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Médecine Interne et Maladies Infectieuses Quimper, Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Laboratoire de Neurosciences de Brest (LNB), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université d'Angers (UA), Hôpital Saint-Louis, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'hématologie (Labo Hémato - BREST), Laboratoire d'hématologie, CHU Bordeaux [Bordeaux], Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), Laboratoires de Intéractions Epithéliums-Neurones, Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO)
Subjects: Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Antineoplastic Agents, Article, Medication Adherence, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Fibrinolytic Agents, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, Surveys and Questionnaires, hemic and lymphatic diseases, Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Antithrombotic, Humans, Medicine, Polycythemia Vera, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, Myeloproliferative Disorders, business.industry, Essential thrombocythemia, Incidence (epidemiology), Age Factors, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, medicine.disease, Thrombosis, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, Pill, Concomitant, Female, business, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Thrombocythemia, Essential, 030215 immunology
Abstract: The purpose of this study was to identify the incidence, causes and impact of non-adherence to oral and subcutaneous chronic treatments for patients with polycythemia vera or essential thrombocythemia. Patients receiving cytoreductive drugs for polycythemia vera or essential thrombocythemia were recruited at our institution (Observatoire Brestois des Néoplasies Myéloprolifératives registry). They completed a one-shot questionnaire designed by investigators (Etude de l’Observance Thérapeutique et des Effets Secondaires des Traitements study). Data about complications (thrombosis, transformation and death) at any time in the patient’s life (before diagnosis, up until consultation and after the completion of the questionnaire) were collected. Sixty-five (22.7%) of 286 patients reported poor adherence (
Published: 2017
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7. Immune checkpoint blockade: the role of PD-1-PD-L axis in lymphoid malignancies

Author: Mihnea Zdrenghea, Corina Bocsan, Cristina Ilcus, Cristian Popescu, Mihai Cenariu, Cristina Bagacean, Andrada Parvu, Adrian Tempescul, Department of Hematology, Cluj-Napoca, University of Medicine and Pharmacy, Luliu-Hatieganu, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), LabEX IGO Immunothérapie Grand Ouest, Department of Clinical Hematology, Institute of Cancerology and Hematology, CHU Morvan, Computer Science Department [Bucarest], University Politehnica of Bucharest [Romania] (UPB), Biotechnology Research Center, Roumanie, University of Agricultural Sciences and Veterinary Medicine, Roumanie, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, and 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca
Subjects: 0301 basic medicine, Chronic lymphocytic leukemia, b7 antigens, lymphoma, Review, hematological cancer, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Pharmacology (medical), Lung cancer, Effector, business.industry, Cancer, immune checkpoint blockade, medicine.disease, Immune checkpoint, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, programmed cell death 1, 030220 oncology & carcinogenesis, Immunology, Cancer cell, [SDV.IMM]Life Sciences [q-bio]/Immunology, chronic lymphocytic leukemia, business
Abstract: International audience; The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin's lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin's lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies.
Published: 2017

8. Prognostic Value of Baseline Total Metabolic Tumor Volume Measured on FDG PET in Patients With Richter Syndrome

Author: Clémence Pontoizeau, Thierry Lamy, Florence Le Jeune, Habiba Mesbah, Laure-Anne Haumont, Adrian Tempescul, Xavier Palard-Novello, Antoine Girard, Anne Devillers, Pierre-Yves Salaun, CRLCC Eugène Marquis (CRLCC), Département de médecine nucléaire [Rennes], Centre Hospitalier Universitaire [Rennes], CHRU Brest - Service de médecine nucléaire (CHU - BREST - Med Nucléaire), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), 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 ), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Multivariate analysis, Chronic lymphocytic leukemia, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, International Prognostic Index, immune system diseases, Fluorodeoxyglucose F18, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Stage (cooking), neoplasms, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Univariate analysis, Performance status, business.industry, General Medicine, Metabolic tumor volume, Middle Aged, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Lymphoma, Tumor Burden, Cell Transformation, Neoplastic, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, 030220 oncology & carcinogenesis, Multivariate Analysis, Female, Lymphoma, Large B-Cell, Diffuse, business, Glycolysis
Abstract: PURPOSE We evaluated the prognostic value of baseline total metabolic tumor volume (TMTV) measured using pretreatment FDG PET for patients with transformation of chronic lymphocytic leukemia (CLL) into diffuse large B-cell lymphoma (DLBCL). METHODS A total of 28 patients with transformation of CLL into DLBCL who had undergone FDG PET before treatment were retrospectively reviewed. Univariate and multivariate analysis of conventional clinicopathologic variables (sex, age, World Health Organization performance status score, International Prognostic Index score, Binet stage, lactate dehydrogenase serum level [LDH], platelet count, presence or not of prior therapies for CLL, the time from CLL to Richter syndrome, Ann Arbor stage, Bulky or not) and metabolic parameters (SUVmax, SUVmean, TMTV, and total lesion glycolysis) at the time of the transformation of CLL into DLBCL were tested for overall survival (OS). RESULTS Of the 28 patients, 14 patients (50%) died during the follow-up period. Low platelet count, World Health Organization performance status score >1, high LDH, and high TMTV were found to be significant prognostic factors for OS on univariate analysis. The 5-year estimates of OS were 63% in the low metabolic burden group (TMTV ≤1200 cm) and 0% in the high metabolic burden group (TMTV >1200 cm). Multivariate analysis revealed that only high LDH was a significant predictor after adjustment for other variables of OS. CONCLUSIONS TMTV extracted from FDG PET at the time of the transformation of CLL into DLBCL is a predictor of OS.
Published: 2019
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9. STIM1 at the plasma membrane as a new target in progressive chronic lymphocytic leukemia

Author: Nelig Le Goux, Marie Potier-Cartereau, Olivier Mignen, Adrian Tempescul, Tinhinane Fali, Sarra Melayah, Yves Renaudineau, Patrice Hemon, Cristina Bagacean, Christophe Vandier, Paul Buscaglia, Marjolaine Debant, Miguel Burgos, Christian Berthou, Jacques-Olivier Pers, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie et Immunothérapie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle Grand-Ouest, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Laboratoire d'Immunologie et Immunothérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Michel, Geneviève, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)
Subjects: Male, 0301 basic medicine, Cancer Research, ORAI1 Protein, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], chemistry.chemical_compound, Antineoplastic Agents, Immunological, 0302 clinical medicine, hemic and lymphatic diseases, Tumor Cells, Cultured, Immunology and Allergy, Prospective Studies, RNA, Small Interfering, TRPC, B-Lymphocytes, Constitutive Ca2+ entry, Voltage-dependent calcium channel, Chemistry, breakpoint cluster region, Antibodies, Monoclonal, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Neoplasm Proteins, [SDV] Life Sciences [q-bio], Treatment Outcome, medicine.anatomical_structure, Oncology, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Disease Progression, Molecular Medicine, Female, Signal transduction, Research Article, Thapsigargin, Cell Survival, STIM1, Primary Cell Culture, Immunology, B-cell receptor, lcsh:RC254-282, 03 medical and health sciences, medicine, Humans, Calcium Signaling, Stromal Interaction Molecule 1, Disease outcome, B cell, Aged, TRPC Cation Channels, Pharmacology, Cell Membrane, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, Cancer research, Calcium, CLL
Abstract: Background Dysregulation in calcium (Ca2+) signaling is a hallmark of chronic lymphocytic leukemia (CLL). While the role of the B cell receptor (BCR) Ca2+ pathway has been associated with disease progression, the importance of the newly described constitutive Ca2+ entry (CE) pathway is less clear. In addition, we hypothesized that these differences reflect modifications of the CE pathway and Ca2+ actors such as Orai1, transient receptor potential canonical (TRPC) 1, and stromal interaction molecule 1 (STIM1), the latter being the focus of this study. Methods An extensive analysis of the Ca2+ entry (CE) pathway in CLL B cells was performed including constitutive Ca2+ entry, basal Ca2+ levels, and store operated Ca2+ entry (SOCE) activated following B cell receptor engagement or using Thapsigargin. The molecular characterization of the calcium channels Orai1 and TRPC1 and to their partner STIM1 was performed by flow cytometry and/or Western blotting. Specific siRNAs for Orai1, TRPC1 and STIM1 plus the Orai1 channel blocker Synta66 were used. CLL B cell viability was tested in the presence of an anti-STIM1 monoclonal antibody (mAb, clone GOK) coupled or not with an anti-CD20 mAb, rituximab. The Cox regression model was used to determine the optimal threshold and to stratify patients. Results Seeking to explore the CE pathway, we found in untreated CLL patients that an abnormal CE pathway was (i) highly associated with the disease outcome; (ii) positively correlated with basal Ca2+ concentrations; (iii) independent from the BCR-PLCγ2-InsP3R (SOCE) Ca2+ signaling pathway; (iv) supported by Orai1 and TRPC1 channels; (v) regulated by the pool of STIM1 located in the plasma membrane (STIM1PM); and (vi) blocked when using a mAb targeting STIM1PM. Next, we further established an association between an elevated expression of STIM1PM and clinical outcome. In addition, combining an anti-STIM1 mAb with rituximab significantly reduced in vitro CLL B cell viability within the high STIM1PM CLL subgroup. Conclusions These data establish the critical role of a newly discovered BCR independent Ca2+ entry in CLL evolution, provide new insights into CLL pathophysiology, and support innovative therapeutic perspectives such as targeting STIM1 located at the plasma membrane. Electronic supplementary material The online version of this article (10.1186/s40425-019-0591-3) contains supplementary material, which is available to authorized users.
Published: 2019
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10. A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study

Author: Labreche, Karim, Daniau, Mailys, Sud, Amit, Law, Philip, Royer-Perron, Louis, Holroyd, Amy, Broderick, Peter, Went, Molly, Benazra, Marion, Ahle, Guido, Soubeyran, Pierre, Taillandier, Luc, Chinot, Olivier, Casasnovas, Olivier, Bay, Jacques-Olivier, Jardin, Fabrice, Oberic, Lucie, Fabbro, Michel, Damaj, Gandhi, Brion, Annie, Mokhtari, Karima, Philippe, Cathy, Sanson, Marc, Houillier, Caroline, Soussain, Carole, Hoang-Xuan, Khê, Houlston, Richard, Alentorn, Agusti, Moles-Moreau, Marie-Pierre, Gressin, Rémy, Morschhauser, Franck, Agapé, Philippe, Jaccard, Arnaud, Ghesquières, Hervé, Tempescul, Adrian, Gyan, Emmanuel, Marolleau, Jean-Pierre, Houot, Roch, Fornecker, Luc, Stefano, Anna-Luisa Di, Detrait, Ines, Rahimian, Amithys, Lathrop, Mark, Genet, Diane, Davi, Frederic, Cassoux, Nathalie, Touitou, Valérie, Choquet, Sylvain, Vital, Anne, Polivka, Marc, Figarella-Branger, Dominique, Benouaich-Amiel, Alexandra, Campello, Chantal, Charlotte, Fréderic, Martin-Duverneuil, Nadine, Feuvret, Loïc, Kas, Aurélie, Navarro, Soledad, Villa, Chiara, Bielle, Franck, Chrétien, Fabrice, Tortel, Marie Christine, Gauchotte, Guillaume, Uro-Coste, Emmanuelle, Godfrain, Catherine, Rigau, Valérie, Costopoulos, Myrto, Garff-Tavernier, Magalie Le, Meyronnet, David, Rousseau, Audrey, Adam, Clovis, Lamy, Thierry, Chabrot, Cécile, Boyle, Eileen, Blonski, Marie, Schmitt, Anna, The institute of cancer research [London], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], Cancer Genetics, Institute of cancer research, Service de Neurologie [Hôpitaux Civils de Colmar], Hôpitaux Civils Colmar, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Recherche en Automatique de Nancy (CRAN), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), 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), UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle (ICM), CRLCC Val d'Aurelle - Paul Lamarque, Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université des sciences et de la Technologie d'Oran Mohamed Boudiaf [Oran] (USTO MB), Institut de Radiobiologie Cellulaire et Moléculaire (IRCM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CRLCC René Huguenin, Biologie des Interactions Neurones / Glie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Biophysique, Médecine Nucléaire et Technologies Médicales (EA 1049), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), 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 clinique des Maladies du Sang, CHU Pontchaillou [Rennes], Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Institut Curie [Paris], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Laboratoire d'Imagerie Biomédicale [Paris] (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de mécanique des fluides de Toulouse (IMFT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Hôpital Claude Huriez [Lille], CHU Lille, Service de Neuro-Oncologie [CHRU Nancy], UNICANCER, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [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)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), USTO (USTO), Centre de référence sur les démences rares et maladie de Pick, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rangueil, Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Service de Radiothérapie [CHU Pitié-Salpêtrière], Laboratoire d'Imagerie Biomédicale (LIB), Service de Neurochirurgie [CHU Pitié-Salpêtrière], Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Service de neuro-pathologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Institut Bergonié - CRLCC Bordeaux, Unité de transplantation médullaire et laboratoire d'oncologie moléculaire, CRLCC Jean Perrin, UNICANCER - Institut régional du Cancer [Montpellier] (ICM), Service hématologie Amiens, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hopital d'Amiens, Laboratoire de Spectrométrie de Masse BioOrganique, Département des Sciences Analytiques, Institut Pluridisciplinaire Hubert Curien (LSMBO-DSA-IPHC), Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université McGill, Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Institut Curie, Service d'Ophthalmologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Service d'Hépato-Gastroentérologie [CHU Pitié-Salpêtrière], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Bergonié - Département de médecine, Université Bordeaux Segalen - Bordeaux 2-Centre régional de lutte contre le cancer [CRLCC], Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Central Nervous System, Cancer Research, Genome-wide association study, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Central Nervous System Neoplasms, 03 medical and health sciences, 0302 clinical medicine, primary CNS lymphoma, hemic and lymphatic diseases, medicine, Genetic predisposition, Humans, GWAS, 1000 Genomes Project, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, Lymphoma, Non-Hodgkin, Primary central nervous system lymphoma, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, cancer susceptibility, 3. Good health, Lymphoma, Oncology, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Neurology (clinical), Lymphoma, Large B-Cell, Diffuse, Diffuse large B-cell lymphoma, Imputation (genetics), Genome-Wide Association Study
Abstract: BackgroundPrimary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.MethodsWe performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.ResultsWe identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10−8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10−13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.ConclusionTo our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.
Published: 2019
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11. Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation

Author: Diane Damotte, Remy Dulery, Olivier Casasnovas, Caroline Regny, Lysa, Guillaume Manson, Adrien Chauchet, Georges Garnier, Emmanuelle Nicolas-Virelizier, Aspasia Stamatoullas, Jean-Marc Schiano, Krimo Bouabdallah, Hervé Ghesquières, Charles Herbaux, Jean-Baptiste Mear, Roch Houot, Marie-Pierre Moles-Moreau, Pauline Brice, Adrian Tempescul, Alain Delmer, Bénédicte Deau, Anna Schmitt, Laurent Dercle, Cécile Borel, CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Bergonié [Bordeaux], UNICANCER, Hôpital Princesse Grace [Monaco], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service d'hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département Hématologie (FNCLCC), Centre Léon Bérard [Lyon], CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 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 [Rouen], Normandie Université (NU)-Normandie Université (NU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Columbia University Medical Center (CUMC), Columbia University [New York], Hopital Saint-Louis [AP-HP] (AP-HP), 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 ), Bristol-Myers SquibbBristol-Myers Squibb, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), 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), École Pratique des Hautes Études (EPHE), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), CCSD, Accord Elsevier, and 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)
Subjects: 0301 basic medicine, Oncology, Male, Cancer Research, Time Factors, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, 0302 clinical medicine, Antineoplastic Agents, Immunological, Risk Factors, Anti pd1, ComputingMilieux_MISCELLANEOUS, Allogenic haematopoietic stem cell transplantation, Hematopoietic Stem Cell Transplantation, Middle Aged, Hodgkin Disease, Progression-Free Survival, 3. Good health, [SDV] Life Sciences [q-bio], Haematopoiesis, Nivolumab, 030220 oncology & carcinogenesis, Disease Progression, Female, France, Immunotherapy, Stem cell, Checkpoint inhibitors, Adult, medicine.medical_specialty, Adolescent, Risk Assessment, 03 medical and health sciences, Young Adult, Refractory, Internal medicine, medicine, Humans, Transplantation, Homologous, Aged, Retrospective Studies, Anti-PD1, business.industry, Transplantation, 030104 developmental biology, Hodgkin lymphoma, business
Abstract: Long-term efficacy of anti-PD1 therapy and the need for a consolidation with allogenic haematopoietic stem cell transplantation (allo-HSCT) remain unclear in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL).We retrospectively analysed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcomes according to subsequent allo-HSCT.After a median follow-up of 34.3 months, the best overall response rate was 65.8%, including 38.2% complete responses (CRs). The median progression-free survival (PFS) was 12.1 months. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a partial response (PR) (median = not reached vs 9.3 months, p 0.001). In our cohort, 13 patients who responded (i.e. in CR or PR) to nivolumab monotherapy underwent consolidation with allo-HSCT. Among responding patients, none of those who underwent subsequent allo-HSCT (N = 13) relapsed, whereas 62.2% of those who were not consolidated with allo-HSCT (N = 37) relapsed (p 0.001). There was no difference in overall survival (OS) between the two groups. Five of 6 patients who were not in CR at the time of transplantation (4 PRs and 1 progressive disease) converted into a CR after allo-HSCT.Most patients with R/R HL treated with anti-PD1 monotherapy eventually progressed, notably those who did not achieve a CR. Patients undergoing consolidation with allo-HSCT after anti-PD1 therapy experienced prolonged disease-free survival compared with non-transplanted patients, but this difference did not translate into a benefit in OS. This information should be considered when evaluating the risk/benefit ratio of allo-HSCT after anti-PD1 therapy.
Published: 2019
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12. Complement System: a Neglected Pathway in Immunotherapy

Author: Adrian Tempescul, Anne Bordron, Yves Renaudineau, Cristina Bagacean, Sophie Hillion, Christian Berthou, Eléonore Bettacchioli, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Immunologie et Immunothérapie [Brest], and Laboratoire d'Immunologie et Immunothérapie
Subjects: 0301 basic medicine, Monoclonal antibody, medicine.drug_class, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Complement Pathway, Alternative, Complement, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Animals, Humans, Immunologic Factors, Complement Pathway, Classical, Cytotoxicity, Complement Activation, 030203 arthritis & rheumatology, Mutation, business.industry, Antibodies, Monoclonal, General Medicine, Immunotherapy, Complement System Proteins, In vitro, 3. Good health, Complement (complexity), Complement system, 030104 developmental biology, Treatment Outcome, Mechanism of action, Cancer research, Autoimmunity cancer, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, business, Biomarkers
Abstract: International audience; Approved for the treatment of autoimmune diseases, hematological malignancies, and solid cancers, several monoclonal antibodies (mAb) make use of complement in their mechanism of action. Such an assessment is based on comprehensive investigations that used mouse models, in vitro studies, and analyses from patients at initiation (basal level to highlight deficiencies) and after treatment initiation (mAb impact on complement), which have further provided key insights into the importance of the complement activation and/or complement deficiencies in mAb activity. Accordingly, new approaches can now be developed with the final objective of increasing the clinical efficacy of mAb. These improvements include (i) the concurrent administration of fresh frozen plasma during mAb therapy; (ii) mAb modifications such as immunoglobulin G subclass switching, Fc mutation, or IgG hexamerization to improve the fixation and activation of C1q; (iii) optimization of the target recognition to induce a higher complement-dependent cytotoxicity (CDC) and/or complement-dependant cellular cytotoxicity (CDCC); and (iv) the control of soluble and cellular complement inhibitors.
Published: 2019
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13. Management and outcome of primary CNS lymphoma in the modern era: An LOC network study

Author: Daniel Delgadillo, Carole Soussain, Bachir Aidaoui, Eileen M Boyle, Philippe Agapé, Vincent Delwail, Agusti Alentorn, Adrien Chauchet, Olivier Casasnovas, Hassen Douzane, Franck Morschhauser, Magali Le Garff-Tavernier, Marie Blonski, Olivier Chinot, Luc Taillandier, Matthieu Peyre, Myrto Costopoulos, Chantal Campello, Fabrice Jardin, Jerome Tamburini, Aurélie Kas, Alexandra Amiel, Frédéric Charlotte, Michel Fabbro, Karima Mokhtari, Emeline Tabouret, Caroline Houillier, Valérie Touitou, Agathe Waultier, Jacques-Olivier Bay, Gandhi Damaj, Nadine Martin-Duverneuil, Lucie Oberic, Julie Abraham, Roch Houot, Hervé Ghesquières, Marie-Pierre Moles-Moreau, Remy Gressin, Corinne Haioun, Adrian Tempescul, Diane Genet, Thierry Lamy, Safia Chebrek, Philippe Colin, Anna Schmitt, Sylvain Choquet, Cécile Moluçon-Chabrot, Jean-Pierre Marolleau, Guido Ahle, Loïc Feuvret, Luc-Matthieu Fornecker, Khê Hoang-Xuan, Emmanuel Gyan, Kamel Laribi, Bertrand Mathon, Caroline Serrier, Pierre Soubeyran, Nathalie Cassoux, Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), 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 ), CHU Pontchaillou [Rennes], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), 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 ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: Adult, medicine.medical_specialty, Antimetabolites, Antineoplastic, Palliative care, Adolescent, Databases, Factual, Lymphoma, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, Article, Central Nervous System Neoplasms, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Antineoplastic Agents, Immunological, Internal medicine, hemic and lymphatic diseases, Outcome Assessment, Health Care, medicine, Humans, Progression-free survival, Young adult, education, Aged, Retrospective Studies, education.field_of_study, business.industry, Age Factors, Retrospective cohort study, Middle Aged, Combined Modality Therapy, Progression-Free Survival, 3. Good health, Transplantation, Clinical trial, Methotrexate, 030220 oncology & carcinogenesis, Rituximab, Neurology (clinical), France, Cranial Irradiation, business, 030217 neurology & neurosurgery, medicine.drug, Stem Cell Transplantation
Abstract: ObjectiveReal-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL.MethodsThe French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed.ResultsWe identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively (60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis.ConclusionsOur study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.
Published: 2019
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14. 17p deletion strongly influences rituximab elimination in chronic lymphocytic leukemia

Author: Yves Renaudineau, Anne Banet, Gilles Paintaud, David Ternant, Nathalie Douet-Guilbert, Boutahar Bendaoud, Adrian Tempescul, Anne Bordron, Cristina Bagacean, Mihnea Zdrenghea, Christian Berthou, Hussam Saad, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Génétique moléculaire et génétique épidémiologique, Laboratoire d'Immunologie et Immunothérapie [Brest], Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Michel, Geneviève, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Tours
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Chronic lymphocytic leukemia, Antineoplastic Agents, Immunological, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Immunology and Allergy, Molecular Targeted Therapy, Aged, 80 and over, Anti-CD20 monoclonal antibody, Middle Aged, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 17p deletion, Chemotherapy regimen, 3. Good health, Fludarabine, [SDV] Life Sciences [q-bio], Leukemia, 030220 oncology & carcinogenesis, Clearance, Molecular Medicine, Female, Rituximab, Chromosome Deletion, IGHV@, medicine.drug, Adult, Bendamustine, medicine.medical_specialty, Cyclophosphamide, Immunology, Short Report, lcsh:RC254-282, 03 medical and health sciences, Internal medicine, medicine, Humans, Pharmacokinetics, Aged, Neoplasm Staging, Pharmacology, business.industry, Genetic Variation, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, Tumor Suppressor Protein p53, business, Chromosomes, Human, Pair 17
Abstract: International audience; Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.
Published: 2019
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15. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma (AHL2011): a randomised, multicentre, non-inferiority, phase 3 study

Author: Richard Delarue, Emmanuelle Nicolas-Virelizier, Reda Bouabdallah, Veronique Edeline, Bertrand Joly, Adrian Tempescul, Hassan Farhat, Luc-Matthieu Fornecker, Peggy Dartigues, René-Olivier Casasnovas, Laurent Martin, Franck Morschhauser, Aspasia Stamatoullas, Pauline Brice, Marc André, Alain Delmer, Michel Meignan, Nicolas Mounier, Hervé Ghesquières, Jehan Dupuis, Philippe Quittet, Krimo Bouabdallah, Julien Lazarovici, Alina Berriolo-Riedinger, Anne-Claire Gac, Alexandra Traverse-Glehen, Pierre Feugier, Thierry Lamy, Thomas Gastinne, Hervé Maisonneuve, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Henri Mondor, Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Sud Francilien, CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital René HUGUENIN (Saint-Cloud), Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire de Reims (CHU Reims), Département de biologie et pathologie médicales [Gustave Roussy], Université Catholique de Louvain = Catholic University of Louvain (UCL), Centre Hospitalier Universitaire de Nice (CHU Nice), LYSA Imaging (Créteil) (LYSA-IM), CHU Henri Mondor, CHU Dijon, Département d'Hematologie, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CRLCC Henri Becquerel, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d'Hématologie [Nantes], Hôpital Sud-Fancilien, CH Sud-Fancilien, Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie Hôpital Mignot, Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CH La Roche-sur-Yon, Service d’Hématologie Clinique [CHU Pontchaillou, Rennes], Service d'hématologie et immunologie pédiatrique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Dinant-Godinne UCL Namur, Service de cancérologie, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de médecine nucléaire [Créteil], Université Grenoble Alpes (UGA), Département Hématologie (FNCLCC), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Groupe Régional d'Etudes sur le CANcer (GRECAN), IFR146-Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse )-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Département d'Hématologie Clinique [CHU Nantes], Université Mohamed Boudiaf de M'sila, Service d’Hématologie Clinique [CHRU Nancy], Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut d'Electronique et de Télécommunications de Rennes (IETR), Université de Nantes (UN)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Centre hospitalier La Roche-Sur-Yon, Microenvironnement et cancer (MiCa), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie [Reims], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Pathologie morphologique, Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Service de Pathologie [CHU de Dijon], Service de Médecine Interne Clermont Ferrand (MéDECINE INTERNE - CLERMONT-FERRAND), Hopital, Hôpital Archet 2 [Nice] (CHU), Laboratoire d'anatomie et de cytopathologie - Centre hospitalier Lyon Sud, CH Evry-Corbeil, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, CCSD, Accord Elsevier, Service d'Hématologie Clinique (CHU de Dijon), Institut Universitaire d'Hématologie [Hôpital Saint-Louis - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d’Hématologie [Rouen], CHU Rouen, Service hématologie Créteil, CHU, Laboratoire d'Hématologie Biologique [CHU Caen], Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Service d'hématologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Département de médecine nucléaire (Institut Curie, Saint-Cloud), Institut Curie [Paris], Hématologie clinique [CH La Roche-sur-Yon], service hématologie Strasbourg, CHU Strasbourg, Service d’Hématologie Clinique [Rennes], Service hématologie Nice, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'hématologie, CHU Henri Mondor [Créteil], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, and Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM)
Subjects: Adult, Male, medicine.medical_specialty, Vincristine, Dacarbazine, [SDV]Life Sciences [q-bio], Salvage therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Procarbazine, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, Neoplasm Staging, business.industry, Standard treatment, medicine.disease, Hodgkin Disease, 3. Good health, Vinblastine, Drug Therapy, Computer-Assisted, [SDV] Life Sciences [q-bio], Oncology, ABVD, 030220 oncology & carcinogenesis, Positron-Emission Tomography, Female, business, Febrile neutropenia, 030215 immunology, medicine.drug
Abstract: International audience; Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPPescalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.Methods: AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPPescalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPPescalated, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPPescalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPPescalated and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPPescalated). BEACOPPescalated consisted of bleomycin 10 mg/m2 and vincristine 1·4 mg/m2 intravenously on day 8, etoposide 200 mg/m2 intravenously on days 1-3, doxorubicin 35 mg/m2 and cyclophosphamide 1250 mg/m2 intravenously on day 1, 100 mg/m2 oral procarbazine on days 1-7, and 40 mg/m2 oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.Findings: From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPPescalated after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (
Published: 2019
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16. Biosimilars of filgrastim in autologous stem cell transplantation: certain differences for myeloma patients only

Author: Christian Berthou, Gaelle Guillerm, Jean-Christophe Ianotto, Pascal Delépine, Chloé Henry, Caroline Buors, Christophe Nicol, Marie-Anne Couturier, Céline Tripogney, Adrian Tempescul, Institut des Sciences du Mouvement Etienne Jules Marey (ISM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang Bretagne, EFS, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'hématologie (Labo Hémato - BREST), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Michel, Geneviève, Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), and Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: Male, Oncology, Drug, Cancer Research, medicine.medical_specialty, Filgrastim, [SDV.IMM] Life Sciences [q-bio]/Immunology, media_common.quotation_subject, Treatment outcome, Neutropenia, Transplantation, Autologous, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Biosimilar Pharmaceuticals, Internal medicine, Granulocyte Colony-Stimulating Factor, medicine, Humans, ComputingMilieux_MISCELLANEOUS, media_common, Postoperative Care, business.industry, Hematopoietic Stem Cell Transplantation, Biosimilar, Hematology, medicine.disease, Recombinant Proteins, 3. Good health, Transplantation, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Multiple Myeloma, business, 030215 immunology, medicine.drug
Abstract: RhuG-CSF reduces the duration of neutropenia induced by chemotherapies. The most frequent drug used for this indication is filgrastim (initially Neupogen®-AMGEN SA). Filgrastim biosimilars have bee...
Published: 2017
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17. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma

Author: Loic Ysebaert, Anne Banos, Vincent Delwail, Roch Houot, Nicolas Daguindau, Reda Garidi, Margaret Macro, Ghandi Damaj, Bertrand Joly, Jean Pierre Vilque, Sylvain Carras, Mary Callanan, Fabrice Jardin, Marie Pierre Moles, Magda Alexis, Steven Le Gouill, Emmanuelle Tchernonog, Laurent Voillat, Hacene Zerazhi, Christiane Mounier, J. Fleury, Sandy Amorin, Anne Moreau, Jean Michel Pignon, Adrian Tempescul, Véronique Dorvaux, Yazid Arkam, Luc Fornecker, Caroline Dartigeas, Cecile Chabrot, Philippe Solal Celigny, Pierre Feugier, Remy Gressin, Anna Schmitt, Jean Fontan, Clémentine Sarkozy, Nadine Morineau, Jehan Dupuis, Selim Corm, Krimo Bouadallah, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Service d'Hématologie [CH Annecy], CH Annecy, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Département de Pathologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Département d'hématologie biologique[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Dpt hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Département d'Hématologie Clinique [CHU Rennes], CHU Pontchaillou [Rennes], Département d’Hématologie Clinique [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service d'hématologie (CH de Dunkerque), Centre Hospitalier Dunkerque, Service Hématologie [CH Métropole Savoie, Chambery], Centre Hospitalier Métropole Savoie [Chambéry], Hôpital de Bayonne, CH de la Côte Basque, Hématologie de liaison avec Institut de Cancérologie de la Loire [CHU de Saint-Etienne], CHU Saint-Etienne, Centre hospitalier universitaire Henri-Mondor [Créteil], Hôpital Universitaire de Caen, Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service d’Hématologie [CHU de Clermont Ferrand], Centre Hospitalier Universitaire de Clermont-Ferrand, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Département d’Hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), 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), Service hématologie Amiens, CHU Amiens-Picardie, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'hématologie [CHR Metz-Thionville], Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Service d'Hématologie [Bordeaux], Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex-Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint-Quentin, Service d'hématologie et oncologie [Centre Hospitalier de Chalon-sur-Saône William Morey], Centre Hospitalier Chalon-sur-Saône William Morey, Hôpital de Corbeil, Service d'Oncologie médicale [Clinique Victor Hugo], Clinique Victor Hugo, Centre Catherine-de-Sienne [Nantes] (CCS), 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), Médecine Interne Onco-hématologie, Centre Hospitalier Général, Hopital d'Avignon, Service d'hématologie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service Hématologie, Mulhouse, Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA)-Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Hématologie Biologique [CHR d'Orléans], Centre Hospitalier Régional d'Orléans (CHR), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Service d'Hématologie [Nantes], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Hématologie Clinique [Rennes], 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, Laboratoire d'Hématologie [CHU Amiens], Centre Hospitalier Henri Duffaut (Avignon), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Régional d'Orléans (CHRO), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), and Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)
Subjects: Bendamustine, Male, medicine.medical_specialty, Time Factors, Non-Hodgkin Lymphoma, Lymphoma, Mantle-Cell, Neutropenia, Gastroenterology, Dexamethasone, Disease-Free Survival, Article, Bortezomib, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Bendamustine Hydrochloride, Humans, Survival rate, Aged, Aged, 80 and over, business.industry, Hematology, Middle Aged, medicine.disease, Minimal residual disease, 3. Good health, Lymphoma, Survival Rate, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Mantle cell lymphoma, Female, business, 030215 immunology, medicine.drug
Abstract: International audience; We present results of a prospective, multicenter, phase II study evaluating rituximab, bendamustine, bortezomib and dexamethasone as first-line treatment for patients with mantle cell lymphoma aged 65 years or older. A total of 74 patients were enrolled (median age, 73 years). Patients received a maximum of six cycles of treatment at 28-day intervals. The primary objective was to achieve an 18-month progression-free survival rate of 65% or higher. Secondary objectives were to evaluate toxicity and the prognostic impact of mantle cell lymphoma prognostic index, Ki67 expression, [18F]fluorodeoxyglucose-positron emission tomography and molecular minimal residual disease, in peripheral blood or bone marrow. With a median follow-up of 52 months, the 24-month progression-free survival rate was 70%, hence the primary objective was reached. After six cycles of treatment, 91% (54/59) of responding patients were analyzed for peripheral blood residual disease and 87% of these (47/54) were negative. Four-year overall survival rates of the patients who did not have or had detectable molecular residual disease in the blood at completion of treatment were 86.6% and 28.6%, respectively (P
Published: 2018
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18. The regulatory capacity of B cells directs the aggressiveness of CLL

Author: Sophie Hillion, Audrey Mohr, Hussam Saad, Yves Renaudineau, Christophe Jamin, Christelle Le Dantec, Marie Cumin, Jacques-Olivier Pers, Cristina Bagacean, Pierre Pochard, Adrian Tempescul, Anne Bordron, and Christian Berthou
Subjects: 0301 basic medicine, tlr9, lcsh:Immunologic diseases. Allergy, Lymphocytosis, T cell, Chronic lymphocytic leukemia, Immunology, Biology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, b cells, Receptor, B cell, cll, Original Research, TLR9, aggressiveness, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, regulatory capacity, medicine.symptom, lcsh:RC581-607
Abstract: Chronic lymphocytic leukemia (CLL) is associated with abnormal T-cell responses responsible for defective anti-tumor activities. Intriguingly, CLL B cells share phenotypical characteristics with regulatory B (Breg) cells suggesting that they might negatively control the T-cell activation and immune responses. We elaborated an in vitro co-culture system with T cells to evaluate the Breg capacities of CLL B cells following innate Toll-like receptor 9 (TLR9) engagement. We demonstrated that B cells from half of the patients exhibited regulatory capacities, whilst B cells from the remaining patients were unable to develop a Breg function. The T cell sensitivities of all patients were normal suggesting that defective Breg activities were due to intrinsic CLL B cell deficiencies. Thus, TLR-dedicated gene assays highlighted differential signature of the TLR9 negative regulation pathway between the two groups of patients. Furthermore, correlations of the doubling time of lymphocytosis, the time to first treatment, the mutational status of IgVH and the Breg functions indicate that patients with efficient Breg activities have more aggressive CLL than patients with defective Breg cells. Our in vitro observations may open new approaches for adjusting therapeutic strategies targeting the Breg along with the evolution of the disease.
Published: 2018

19. Superiority of Allogenic Stem Cell Transplantation after Anti-PD1 Therapy over Anti-PD1 Monotherapy Alone in Relapse/Refractory Hodgkin Lymphoma Real World Evidence from the French Early Access Program

Author: Emmanuelle Nicolas-Virelizier, Remy Dulery, Adrien Chauchet, Roch Houot, Jean Marc Schiano de Collela, Herv Ghesquieres, Guillaume Manson, Anna Schmitt, Alain Delmer, Aspasia Stamatoullas, Jean-Baptiste Mear, Cécile Borel, Charles Herbaux, Georges Garnier, Rene-Olivier Casasnovas, Marie-Pierre Moles, Krimo Bouabdallah, Adrian Tempescul, Pauline Brice, Laurent Dercle, Lysiane Molina, Bénédicte Deau-Fisher, 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 ), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, CHU Pontchaillou [Rennes], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CRLCC Centre Paoli - Calmettes [Marseille], Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Bergonié [Bordeaux], UNICANCER, Hôpital Princesse Grace [Monaco], CHU Grenoble, CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Léon Bérard [Lyon], Centre Hospitalier Universitaire de Reims (CHU Reims), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-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)-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), Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Médecine nucléaire, Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hopital Saint-Louis [AP-HP] (AP-HP), 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)-Hôpital Pontchaillou, 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], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Real world evidence, Biochemistry, 3. Good health, Transplantation, 03 medical and health sciences, 030104 developmental biology, Internal medicine, medicine, Refractory Hodgkin Lymphoma, Stem cell, Anti pd1, business, ComputingMilieux_MISCELLANEOUS
Abstract: Background: Nivolumab demonstrated remarkable activity in patients with relapse or refractory (R/R) Hodgkin lymphoma (HL). However, long term efficacy and the need for a consolidation with allogenic stem cell transplantation remain unclear. Patient and method: We retrospectively analyzed 78 patients with R/R HL treated with nivolumab in the French Early Access Program and compared their outcome according to subsequent alloHSCT. Results: After a median follow-up of 31.5 months, the best overall response rate was 64%, including 37.3% complete response (CR). The median progression-free survival (PFS) was 12.1 months and median overall survival (OS) was not reached. At 3 years, PFS and OS rates were 35% and 65%, respectively. Patients reaching a CR upon nivolumab had a significantly longer PFS than those reaching a PR (median = not reached vs 10.1 months). In our cohort, 17 patients underwent consolidation with allogenic stem cells transplantation (alloHSCT) after nivolumab therapy (Figure 1). At the time of transplantation, 8 patients were in CR, 5 in partial response (PR) and 4 had progressed of whom 3 received a salvage therapy before alloHSCT. Interestingly, 6 out of 7 patients who were not in CR at the time of transplantation (5 PR and 1 progressive disease) converted into a CR after alloHSCT. At the time of analysis, 14 patients were alive and 13 remained disease-free after a median follow-up of 30.4 months. One-year OS and PFS from alloHSCT were 82% and 76%, respectively. Among responding patients (i.e. in CR or PR) after nivolumab monotherapy, those who underwent subsequent alloHSCT (N=13) had a better outcome than those who were not consolidated with alloHSCT (N=35) (Figure 2). In the transplanted group, none of the patients relapsed whereas in the non-transplanted group 60% of the patients relapsed (p Conclusions: Although patients who achieve a CR upon anti-PD1 therapy may experience prolonged remissions, most R/R HL patients treated with anti-PD1 antibody eventually progress or relapse. Our study demonstrates unprecedented disease-free survival in patients undergoing consolidation with alloHSCT after anti-PD1 therapy. Interestingly, alloHSCT post anti-PD1 can convert incomplete responses into CR in most cases. Despite expected toxicities, alloHSCT after anti-PD1 therapy appears manageable and safe in most patients. Our results suggest that consolidation with alloHSCT may represent a good option in patients treated with anti-PD1, notably in patients who are unable to achieve a CR. Disclosures Herbaux: Gilead Sciences, Inc.: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Stamatoullas:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd, Cambridge, MA, USA: Consultancy. Brice:bristol myers squibb: Consultancy, Honoraria. Houot:bristol myers squibb: Consultancy, Honoraria.
Published: 2018
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20. Distinct Mechanisms of Alterations in DNA Methylation/Demethylation Leading to Myelodysplastic Syndromes/Acute Myeloid Leukemia and Chronic Lymphocytic Leukemia

Author: Wesley H. Brooks, Jean Christophe Ianotto, Cristina Bagacean, Adrian Tempescul, Mihnea Zdrenghea, Anne Bordron, Yves Renaudineau, Marie-Anne Couturier, Christian Berthou, Gaelle Guillerm, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire d'Immunologie et Immunothérapie [Brest], Department of Chemistry, University of South Florida, Tampa, FL, USA., University of South Florida [Tampa] (USF), Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Laboratoire d'Immunologie et Immunothérapie, Michel, Geneviève, Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)
Subjects: 0303 health sciences, Myeloid, Myelodysplastic syndromes, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], Myeloid leukemia, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, Leukemia, 0302 clinical medicine, medicine.anatomical_structure, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, DNA methylation, medicine, Cancer research, Epigenetics, CD5, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Myelodysplastic syndromes (MDS) represent malignant myeloid disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). AML is a highly heterogeneous disease characterized by the presence of large chromosomal translocations, gene fusions as well as mutations in the genes involved in hematopoietic proliferation and differentiation resulting in the accumulation of poorly differentiated myeloid cells. Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia, and is characterized by the clonal proliferation and accumulation of mature, long-lived CD5+ B cells. Epigenetic dysregulations are present in both myeloid disorders and in CLL, but, in contrast to MDS and AML that present gene fusions (TET1/LCX) and somatic mutations in epigenetic regulators (DNMT3A, TET2, IDH1/2), in CLL, epigenetic modifications are not qualitative but mostly quantitative (DNMT3A, TET2) and associated with disease progression. As a consequence, in MDS, AML and CLL, the focal or global DNA methylation/demethylation process is altered. In conclusion, a better qualitative and quantitative understanding of epigenetic regulators during myeloid/lymphoid differentiation, their localization and the co-recruitment of other proteins at specific DNA target sites, could offer us the possibility to modulate hematopoiesis, restore the initial balance, and control disease progression.
Published: 2018
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21. Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial

Author: Judith Trotman, Sally F Barrington, David Belada, Michel Meignan, Robert MacEwan, Carolyn Owen, Václav Ptáčník, András Rosta, Günter R Fingerle-Rowson, Jiawen Zhu, Tina Nielsen, Deniz Sahin, Wolfgang Hiddemann, Robert E Marcus, Andrew Davies, Mark Hertzberg, Andrew Grigg, Paul Cannell, Hang Quach, Stephen Opat, Constantine Tam, Paula Marlton, Ann Janssens, Fritz Offner, Koen Van eygen, Randeep Sangha, Pam Mckay, Jonathan Wilson, Richard Van Der Jagt, Daryl Roitman, Marek Trneny, Jiri Mayer, Katell Le Du, Philippe Solal-Celigny, Guillaume Cartron, Charles Foussard, Norbert Frickhofen, Peter Schmidt, Ullrich Graeven, Tobias Gaska, Rudolf Schlag, Martin Sökler, Gabriele Prange-Krex, Axel Florschütz, Hans-Walter Lindemann, Christoph Schimmelpfennig, Solveig Tonndorf, Mathias Hänel, Georg Hess, Enrico Schalk, Heiko Hütten, Gottfried Doelken, Michael Pfreundschuh, Ulrich Keller, Michael Herold, Roswitha Forstpointner, Ursula Vehling-Kaiser, Martin Hoffmann, Zita Borbenyi, Miklos Udvardy, Judit Demeter, Alessandro Rambaldi, Enrica Morra, Federico Massimo, Ignazio Majolino, Monica Balzarotti, Gianpietro Semenzato, Miguel Angel Canales Albendea, Francisco Javier Peñalver Parraga, Alfonso Soler Campos, Juan Manuel Sancho Cia, Jose Antonio Marquez Navarro, Carlos Grande Garcia, Herman Nilsson-Ehle, Helen Mccarthy, Chris Pocock, Shalal Sadullah, Ram Malladi, John Radford, Ed Kanfer, Anton Kruger, Dominic Culligan, Martin Dyer, Ruth Pettengell, John Seymour, John Gribben, Saad Al-Ismail, Faris Al-Refaie, Norbert Blesing, Christopher Macnamara, Ann O'callaghan, Andrew Haynes, George Follows, Roderick Johnson, David Cunningham, Kristian Bowles, Graham Collins, Eve Gallop-Evans, Stephen Robinson, Chezhian Subash, James Bailey, Viran Holden, Jeffrey Neidhart, Moacyr De Oliveira, Haluk Tezcan, Kevin Kim, Suman Kambhampati, Keith Lanier, John Mcclean, Kensei Tobinai, Kiyohiko Hatake, Michinori Ogura, Toshiki Uchida, Kiyoshi Ando, Tomohiro Kinoshita, Thomas Höhler, Heribert Stauder, Andreas Kirsch, Michael Koenigsmann, Stephan Kremers, Thomas Illmer, Mathias Witzens-Harig, Paul La Roseé, Jan Dürig, Michael Kneba, Manfred Hensel, Stefan Fuxius, Lothar Bergmann, Kai Hübel, Christian Buske, Reinhard Marks, Gerald Wulf, Christian Lerchenmueller, Rudolf Schmits, Mark Reinwald, Eva Lengfelder, Fiona Scott, Takaaki Chou, Masafumi Taniwaki, Isao Yoshida, Kenichi Ishizawa, Naokuni Uike, Nobuhiko Uoshima, Yuri Kamitsuji, Shinsuke Iida, Ken Ohmine, Kisato Nosaka, Kazuhiko Ide, Takayuki Ishikawa, Pierre Desjardins, Nicholas Finn, Jun Zhu, Wei Li, Li Yu, Hanyun Ren, Yuan Kai Shi, Gang Wu, Xiaonan Hong, Qingyuan Zhang, Jifeng Feng, Rong Zhan, Tongyu Lin, Sirpa Leppa, Regis Costello, Adrian Tempescul, Laurence Sanhes, Olivier Tournilhac, Heinz Kirchen, Holger Hebart, Rudolf Weide, Kathleen Jentsch-Ullrich, Irit Avivi, Arnon Nagler, Ronit Gurion, Ofer Shpilberg, Pietro Leoni, Luca Baldini, Olga Samoylova, Alexandr Myasnikov, Tran-Der Tan, Hung Chang, Kyoya Kumagai, Norifumi Tsukamoto, Kunihiro Tsukasaki, Patrick Beatty, Noriko Usui, Koji Izutsu, Tohru Murayama, Tatsuo Ichinohe, Kohmei Kubo, Fumihiro Ishida, J. Thaddeus Beck, Frank Griesinger, Dzhelil Osmanov, Shaker Dakhil, Aline Clavert, Dai Maruyama, Yasuhito Terui, Kazuhito Yamamoto, Ekkehard Eigendorff, Tsutomu Kobayashi, Satoshi Ichikawa, Ilseung Choi, Katsuya Wada, Yoshitaka Kikukawa, Masao Matsuoka, Takayuki Yoshino, Yosuke Minami, Dürig, Jan (Beitragende*r), The University of Sydney, Service de médecine nucléaire [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Prince of Wales Medical Research Institute, University of New South Wales [Sydney] (UNSW), University of Melbourne, Universiteit Gent = Ghent University [Belgium] (UGENT), Service d'hématologie et oncologie médicale, Hôpital Lapeyronie-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Semmelweis University of Medicine [Budapest], Queens Elizabeth Hospital [Birmingham], Queen Mary University of London (QMUL), IBM Thomas J. Watson Research Center, IBM, Department of Computing and Information Systems, and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie-Université de Montpellier (UM)
Subjects: Male, Time Factors, [SDV]Life Sciences [q-bio], Follicular lymphoma, Medizin, chemistry.chemical_compound, 0302 clinical medicine, Antineoplastic Agents, Immunological, Obinutuzumab, Antineoplastic Combined Chemotherapy Protocols, Clinical endpoint, Prospective Studies, Lymphoma, Follicular, Randomized Controlled Trials as Topic, education.field_of_study, Manchester Cancer Research Centre, Hazard ratio, Middle Aged, Progression-Free Survival, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Female, Immunotherapy, Rituximab, medicine.drug, Bendamustine, medicine.medical_specialty, Population, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Progression-free survival, education, Aged, Neoplasm Staging, Retrospective Studies, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, medicine.disease, chemistry, Clinical Trials, Phase III as Topic, Positron-Emission Tomography, business, Tomography, X-Ray Computed, Progressive disease, 030215 immunology
Abstract: BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.
Published: 2018
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22. DNA demethylation marks in chronic lymphocytic leukemia: it is time to let the cat out of the bag

Author: Christelle Le Dantec, Mihnea Zdrenghea, Yves Renaudineau, Cristina Bagacean, Christian Berthou, Adrian Tempescul, LabEX IGO Immunothérapie Grand Ouest, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Immunologie et Immunothérapie [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Nantes Université (Nantes Univ), Lymphocytes B, Autoimmunité et Immunothérapies (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and Michel, Geneviève
Subjects: 0301 basic medicine, DNA Hydroxymethylation, DNA methylation, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], DNMT, Biology, medicine.disease, Virology, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, DNA demethylation, Editorial, DNA hydroxymethylation, medicine, chronic lymphocytic leukemia, TET, ComputingMilieux_MISCELLANEOUS, Biotechnology
Abstract: International audience
Published: 2018
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23. Combining cytogenetic and epigenetic approaches in chronic lymphocytic leukemia improves prognosis prediction for patients with isolated 13q deletion

Author: Adrian Tempescul, Anne Bordron, Christelle Le Dantec, Victor Cristea, Yves Renaudineau, Christian Berthou, Hussam Saad, Cristina Bagacean, Nathalie Douet-Guilbert, Mihnea Zdrenghea, LabEX IGO Immunothérapie Grand Ouest, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de cytogénétique [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Laboratoire d'Immunologie et Immunothérapie, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)
Subjects: Epigenomics, Male, 0301 basic medicine, Lymphocytosis, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], lcsh:Medicine, DNMT, DNA Methyltransferase 3A, Mixed Function Oxygenases, DNA (Cytosine-5-)-Methyltransferases, In Situ Hybridization, Fluorescence, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, DNA methylation, Middle Aged, Prognosis, 3. Good health, DNA-Binding Proteins, Cytogenetic Analysis, 5-Methylcytosine, Disease Progression, Female, Chromosome Deletion, medicine.symptom, medicine.medical_specialty, lcsh:QH426-470, Short Report, Biology, Dioxygenases, Cytogenetics, 03 medical and health sciences, Proto-Oncogene Proteins, Complex Karyotype, Genetics, medicine, Humans, Epigenetics, Molecular Biology, Aged, Retrospective Studies, Chromosomes, Human, Pair 13, lcsh:R, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, lcsh:Genetics, 030104 developmental biology, DNA demethylation, Immunology, Cancer research, Active DNA demethylation, Trisomy, TET, Developmental Biology
Abstract: Background Both defective DNA methylation and active DNA demethylation processes are emerging as important risk factors in chronic lymphocytic leukemia (CLL). However, associations between 5-cytosine epigenetic markers and the most frequent chromosomal abnormalities detected in CLL remain to be established. Methods CLL patients were retrospectively classified into a cytogenetic low-risk group (isolated 13q deletion), an intermediate-risk group (normal karyotype or trisomy 12), and a high-risk group (11q deletion, 17p deletion, or complex karyotype [≥ 3 breakpoints]). The two 5-cytosine derivatives, 5-methylcytosine (5-mCyt) and 5-hydroxymethylcytosine (5-hmCyt), were tested by ELISA (n = 60), while real-time quantitative PCR was used for determining transcriptional expression levels of DNMT and TET (n = 24). Results By using global DNA methylation/demethylation levels, in the low-risk disease group, two subgroups with significantly different clinical outcomes have been identified (median treatment-free survival [TFS] 45 versus > 120 months for 5-mCyt, p = 0.0008, and 63 versus > 120 months for 5-hmCyt, p = 0.04). A defective 5-mCyt status was further associated with a higher percentage of 13q deleted nuclei (> 80%), thus suggesting an acquired process. When considering the cytogenetic intermediate/high-risk disease groups, an association of 5-mCyt status with lymphocytosis (p = 0.0008) and the lymphocyte doubling time (p = 0.04) but not with TFS was observed, as well as a reduction of DNMT3A, TET1, and TET2 transcripts. Conclusions Combining cytogenetic studies with 5-mCyt assessment adds accuracy to CLL patients’ prognoses and particularly for those with 13q deletion as a sole cytogenetic abnormality.
Published: 2017
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24. Alterations in DNA methylation/demethylation intermediates predict clinical outcome in chronic lymphocytic leukemia

Author: Nathalie Douet-Guilbert, Christelle Le Dantec, Adrian Tempescul, Anne Bordron, Hussam Saad, Cristina Bagacean, Pierre-François Cartron, Valerie Olivier, Christian Berthou, Mihnea Zdrenghea, Victor Cristea, Yves Renaudineau, Audrey Mohr, LabEX IGO Immunothérapie Grand Ouest, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), 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), Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de cytogénétique [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], and Laboratoire d'Immunologie et Immunothérapie
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Methyltransferase, Chronic lymphocytic leukemia, SAT1, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Epigenetics, Progression-free survival, ComputingMilieux_MISCELLANEOUS, Hematology, business.industry, hydroxymethylation, medicine.disease, 3. Good health, 030104 developmental biology, DNA demethylation, 030220 oncology & carcinogenesis, Immunology, DNA methylation, chronic lymphocytic leukemia, [SDV.IMM]Life Sciences [q-bio]/Immunology, methylation, IGHV@, business, TET, Research Paper
Abstract: // Cristina Bagacean 1, 2, 3 , Adrian Tempescul 1, 4 , Christelle Le Dantec 1 , Anne Bordron 1 , Audrey Mohr 1 , Hussam Saad 4 , Valerie Olivier 2 , Mihnea Zdrenghea 3, 5 , Victor Cristea 3 , Pierre-Francois Cartron 6 , Nathalie Douet-Guilbert 7 , Christian Berthou 1, 4 and Yves Renaudineau 1, 2 1 U1227 B Lymphocytes and Autoimmunity, University of Brest, INSERM, IBSAM, Labex IGO, Networks IC-CGO and REpiCGO from Canceropole Grand Ouest, Brest, France 2 Laboratory of Immunology and Immunotherapy, Brest University Medical School Hospital, Brest, France 3 Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania 4 Department of Hematology, Brest University Medical School Hospital, Brest, France 5 Department of Hematology, ‘Ion Chiricuta’ Oncology Institute, Cluj-Napoca, Romania 6 Inserm, U892, Epigenetics Network from Canceropole Grand Ouest, Nantes, France 7 Laboratory of Cytogenetics, Brest University Medical School Hospital, Brest, France Correspondence to: Yves Renaudineau, email: yves.renaudineau@univ-brest.fr Keywords: chronic lymphocytic leukemia, methylation, hydroxymethylation, TET, SAT1 Received: June 08, 2017 Accepted: July 26, 2017 Published: August 09, 2017 ABSTRACT Cytosine derivative dysregulations represent important epigenetic modifications whose impact on the clinical outcome in chronic lymphocytic leukemia (CLL) is incompletely understood. Hence, global levels of 5-methylcytosine (5-mCyt), 5-hydroxymethylcytosine (5-hmCyt), 5-carboxylcytosine (5-CaCyt) and 5-hydroxymethyluracil were tested in purified B cells from CLL patients ( n = 55) and controls ( n = 17). The DNA methylation ‘writers’ (DNA methyltransferases [ DNMT1/3A/3B ]), ‘readers’ (methyl-CpG-binding domain [ MBD2/4 ]), ‘editors’ (ten-eleven translocation [ TET1/2/3 ]) and ‘modulators’ ( SAT1 ) were also evaluated. Accordingly, patients were stratified into three subgroups. First, a subgroup with a global deficit in cytosine derivatives characterized by hyperlymphocytosis, reduced median progression free survival (PFS = 52 months) and shorter treatment free survival (TFS = 112 months) was identified. In this subgroup, major epigenetic modifications were highlighted including a reduction of 5-mCyt, 5-hmCyt, 5-CaCyt associated with DNMT3A , MBD2/4 and TET1/2 downregulation. Second, the cytosine derivative analysis revealed a subgroup with a partial deficit (PFS = 84, TFS = 120 months), mainly affecting DNA demethylation (5-hmCyt reduction, SAT1 induction). Third, a subgroup epigenetically similar to controls was identified (PFS and TFS > 120 months). The prognostic impact of stratifying CLL patients within three epigenetic subgroups was confirmed in a validation cohort. In conclusion, our results suggest that dysregulations of cytosine derivative regulators represent major events acquired during CLL progression and are independent from IGHV mutational status.
Published: 2017
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25. Clinical characteristics of aquagenic pruritus in patients with myeloproliferative neoplasms

Author: Jean-Christophe Ianotto, Laurent Misery, Karine Lacut, Valérie Ugo, Maelenn Gouillou, Jean-Luc Carré, Adrian Tempescul, C. Le Gall‐Ianotto, Emilie Brenaut, Christian Berthou, Emmanuel Nowak, Université de Brest (UBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de dermatologie (Dermato - BREST), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Département de Médecine Interne et Pneumologie [Brest] (DMIP - Brest), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Laboratoire d'Hématologie Biologique, Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Laboratoire de Neurosciences de Brest (LNB), and Calvez, Ghislaine
Subjects: Adult, Pathology, medicine.medical_specialty, Juvenile xanthogranuloma, [SDV]Life Sciences [q-bio], Sweating, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Humans, In patient, Prospective Studies, skin and connective tissue diseases, Myeloproliferative neoplasm, ComputingMilieux_MISCELLANEOUS, Myeloproliferative Disorders, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Hypereosinophilic syndrome, Pruritus, Water, food and beverages, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Aquagenic pruritus, Itching, medicine.symptom, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract: Aquagenic pruritus (AP) is a diffuse itching sensation that develops immediately after water contact without any visible skin changes. AP is classically associated with polycythemia vera (PV), a BCR-ABL1-negative myeloproliferative neoplasm (MPN), and can precede the diagnosis of the disease1,2. Alternatively, AP can be drug-induced or associated with various disorders (e.g., myelodysplastic syndrome, hypereosinophilic syndrome, and juvenile xanthogranuloma)3,4. This article is protected by copyright. All rights reserved.
Published: 2017
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26. Exudative pericarditis in the evolution of a diffuse large B-cell lymphoma

Author: Dana Pop, Mihnea Zdrenghea, Jean-Christophe Ianotto, Véronique Marion, Adrian Tempescul, Cristina Bagacean, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Laboratoire d'hématologie, Hôpital Morvan [Brest], Cardiology Department (CardioDep - CLUJ-NAPOCA), Rehabilitation Hospital, and 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca
Subjects: Male, Pathology, medicine.medical_specialty, lymphomatous pericarditis, [SDV]Life Sciences [q-bio], medicine.medical_treatment, [SDV.CAN]Life Sciences [q-bio]/Cancer, Case Report, 030204 cardiovascular system & hematology, Multimodal Imaging, Cardiac Ultrasound, 03 medical and health sciences, Pericarditis, Fatal Outcome, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, cardiac involvement, medicine, Humans, Chemotherapy, medicine.diagnostic_test, business.industry, Exudates and Transudates, General Medicine, Middle Aged, medicine.disease, 3. Good health, Lymphoma, Positron emission tomography, Positron-Emission Tomography, DLBCL, 030220 oncology & carcinogenesis, Heart failure, Lymphoma, Large B-Cell, Diffuse, Lymph, Tomography, X-Ray Computed, Cardiology and Cardiovascular Medicine, business, Diffuse large B-cell lymphoma, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Cardiac involvement in non-Hodgkin's lymphoma is a rare occurrence with a dismal prognosis, which may evolve with different clinical presentations, the most frequent being heart failure. Diagnosis of cardiac involvement is generally made by cardiac ultrasound. We report a case of lymphomatous pericarditis in the evolution of a non-Hodgkin's lymphoma, diagnosed by PET-CT scan, and occurring concomitantly with complete isotopic remission of enlarged mediastinal lymph nodes following chemotherapy.
Published: 2015
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27. Atypical aleukemic presentation of large granular lymphocytic leukemia: a case report

Author: Cristina Bagacean, Horia Bumbea, Bogdan Fetica, Mariana Patiu, Mihnea Zdrenghea, Adrian Tempescul, LabEX IGO Immunothérapie Grand Ouest, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca, Department of Hematology, Ion Chiricuta Oncology Insitute, 'Ion Chiricuta' Cancer Institute, University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Large granular lymphocytic leukemia, Case Report, 030204 cardiovascular system & hematology, Neutropenia, Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, lymphoproliferative, medicine, neutropenia, Pharmacology (medical), Bortezomib, business.industry, bortezomib, medicine.disease, 3. Good health, Regimen, Felty, Oncology, large granular lymphocytes, 030220 oncology & carcinogenesis, Immunology, Proteasome inhibitor, [SDV.IMM]Life Sciences [q-bio]/Immunology, Methotrexate, business, medicine.drug
Abstract: International audience; Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs) in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen.
Published: 2016

28. Late relapsing mantle cell lymphoma showing preserved sensitivity to single-agent lenalidomide

Author: Cristina Bagacean, Mihnea Zdrenghea, Jean-Christophe Ianotto, Corina Bocsan, Adrian Tempescul, Pierre-Yves Salaun, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), LabEX IGO Immunothérapie Grand Ouest, CHRU Brest - Service de médecine nucléaire (CHU - BREST - Med Nucléaire), Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, and 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca
Subjects: Oncology, medicine.medical_specialty, MESH: Remission Induction, health care facilities, manpower, and services, Lymphoma, Mantle-Cell, Disease, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Immunologic Factors, Single agent, Relapse, IMiD, Lenalidomide, Aged, MESH: Treatment Outcome, MESH: Aged, Hematology, Mantle cell lymphoma, MESH: Humans, business.industry, MESH: Immunologic Factors, Remission Induction, MESH: Thalidomide, medicine.disease, Thalidomide, 3. Good health, MESH: Recurrence, Regimen, Treatment Outcome, 030220 oncology & carcinogenesis, Immunology, Refractory Mantle Cell Lymphoma, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Lymphoma, Mantle-Cell, business, 030215 immunology, medicine.drug
Abstract: International audience; Mantle cell lymphoma is a hematologic malignancy characterized by poor therapeutic outcomes. Immunomodulatory drugs are a focus of attention in this disease, especially for the elderly and frail patients not able to tolerate the typically intensive therapeutic approaches used in fitter patients. We here present the case of refractory mantle cell lymphoma of the elderly that achieved complete remission following the use of single-agent lenalidomide, and a second complete response to the same regimen on relapse 5 years later.
Published: 2016

29. The bendamustine plus rituximab regimen is active against primary nodal marginal zone B-cell lymphoma: Bendamustine-rituximab in nodal MZL

Author: Alix Baugier de Materre, Delphine Bolle, Adrien Tempescul, Anne Besançon, Stéphanie Poulain, Catherine Truong, Kamel Laribi, Jonathan Farhi, Pierre Lemaire, Jean Christophe Ianotto, Andreea Anghel, Habib Ghnaya, Nathalie Denizon, Centre hospitalier du Mans, Centre Hospitalier Le Mans (CH Le Mans), and Pôle Santé Sud
Subjects: Bendamustine, Cancer Research, medicine.medical_specialty, Neutropenia, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Nodal marginal zone B cell lymphoma, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Secondary Myelodysplastic Syndrome, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, General Medicine, medicine.disease, 3. Good health, Surgery, Regimen, Oncology, 030220 oncology & carcinogenesis, Rituximab, business, 030215 immunology, medicine.drug, Rare disease
Abstract: International audience; Primary nodal marginal zone lymphoma (NMZL) is a rare disease. There is no current consensus on how to treat it. The bendamustine plus rituximab (BR) regimen is effective for the treatment of follicular and other indolent lymphomas, but its efficacy in NMZL is not known. We analyzed the outcome of 14 patients diagnosed with NMZL (median age 67 years) who were treated with 375 mg/m2 of rituximab on day 1 and 90 mg/m2 of bendamustine on days 1 and 2. The overall and complete response rates were 93% and 71%, respectively. Major toxicity (grade 3/4 neutropenia) occurred in 5% of treatment courses. After a median follow-up of 22 months (range: 18-55), the overall survival and the free survival rates were 100% and 93%, respectively. None of the patients showing a complete or partial response developed secondary myelodysplastic syndrome/acute myeloid leukemia. Bendamustine plus rituximab was found to be an active and well-tolerated regimen leading to the rapid control of disease.
Published: 2016
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30. Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network

Author: Olivier Chinot, D. Larrieu, Sophie Langner-Lemercier, Hervé Ghesquières, Fabrice Jardin, Luc Taillandier, Thierry Lamy, Khê Hoang-Xuan, Emmanuel Gyan, Pierre Soubeyran, Remy Gressin, Annie Brion, Cécile Moluçon-Chabrot, Olivier Casasnovas, Franck Morschhauser, Jean-Pierre Marolleau, Carole Soussain, Guido Ahle, Caroline Houillier, Florian Naudet, Alexandra Benouaich-Amiel, Sylvain Choquet, Ghandi Damaj, Philippe Colin, Michel Fabbro, Arnaud Jaccard, Roch Houot, Marie-Pierre Moles-Moreau, Pascal Bourquard, Oumedaly Reman, Adrian Tempescul, CHU Pontchaillou [Rennes], Centre de référence sur les démences rares et maladie de Pick, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Hématologie (FNCLCC), Centre Léon Bérard [Lyon], Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Service de Neuro-Oncologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Clermont-Ferrand, CHU Amiens-Picardie, Groupe d'étude des proliférations lymphoïdes (GPL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CIC - Tours, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hématologie clinique, CHU Grenoble, Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de radiothérapie [Reims], Institut du cancer Courlancy-Reims, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service clinique des Maladies du Sang, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], OncoNeuroTek [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Microenvironnement et cancer (MiCa), 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 ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut National du Cancer (INCa), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], 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)-Hôpital Pontchaillou, Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), and Service de neurologie 1 [CHU Pitié-Salpétrière]
Subjects: Oncology, Male, Cancer Research, Palliative care, [SDV]Life Sciences [q-bio], Salvage therapy, Central Nervous System Neoplasms, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Prospective cohort study, relapse, Aged, 80 and over, Progression, Lymphoma, Non-Hodgkin, Primary central nervous system lymphoma, Hematopoietic Stem Cell Transplantation, Middle Aged, Prognosis, Chemotherapy regimen, Combined Modality Therapy, 3. Good health, Survival Rate, 030220 oncology & carcinogenesis, Disease Progression, Female, Adult, medicine.medical_specialty, Transplantation, Autologous, 03 medical and health sciences, primary CNS lymphoma, Internal medicine, medicine, Humans, Progression-free survival, Clinical Investigation, Survival rate, Aged, Neoplasm Staging, Salvage Therapy, business.industry, medicine.disease, Surgery, Transplantation, Drug Resistance, Neoplasm, Neurology (clinical), Neoplasm Recurrence, Local, business, 030217 neurology & neurosurgery
Abstract: International audience; Background - Treatment of relapsed/refractory (R/R) primary CNS lymphoma (PCNSL) is poorly defined, because randomized trials and large studies are lacking. The aim of this study was to analyze the characteristics, management, and outcome of R/R PCNSL patients after first-line therapy in a nationwide cohort.Methods - We analyzed R/R PCNSL patients following first-line treatment who had been prospectively registered in the database of the French network for oculocerebral lymphoma (LOC) between 2011 and 2014.Results - Among 563 PCNSL patients treated with first-line therapy, we identified 256 with relapsed (n = 93, 16.5%) or refractory (n = 163, 29.0%) disease. Patients who were asymptomatic at relapse/progression (25.5%), mostly diagnosed on routine follow-up neuroimaging, tended to have a better outcome. Patients who received salvage therapy followed by consolidation (mostly intensive chemotherapy plus autologous hematopoietic stem cell transplantation [ICT + AHSCT]) experienced prolonged survival compared with those who did not receive salvage or consolidation therapy. Independent prognostic factors at first relapse/progression were: KPS ≥ 70 vs KPS < 70), sensitivity to first-line therapy (relapsed vs refractory disease), duration of first remission (progression-free survival [PFS] ≥1 y vs Conclusions - About a third of PCNSL patients are primary refractory to first line treatment. We identified several independent prognostic factors that can guide the management of R/R PCNSL patients.
Published: 2016
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31. FDG PET/CT for Initial Staging of Diffuse Large B-Cell Lymphoma: Is Diffuse Bone Marrow Uptake a Reflection of Disease Involvement?

Author: Adrian Tempescul, Pierre-Yves Salaun, Xavier Palard, Solène Querellou, Christian Berthou, Philippe Robin, Ronan Abgral, Naelle Lombion, Nathalie Keromnes, Pierre-Yves Le Roux, Service de médecine nucléaire [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Clinical Hematology, Institute of Cancerology and Hematology, CHU Morvan, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)
Subjects: medicine.diagnostic_test, business.industry, Standardized uptake value, Disease, medicine.disease, Fibrinogen, 3. Good health, 030218 nuclear medicine & medical imaging, Lymphoma, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Positron emission tomography, 030220 oncology & carcinogenesis, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Fdg pet ct, Bone marrow, business, Nuclear medicine, Diffuse large B-cell lymphoma, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract: Objectives: Bone marrow assessment is a diagnostic challenge in staging diffuse large B-cell lymphoma (DLBCL). Diffuse bone marrow uptake (BMU) can be observed on FDG PET/CT performed for initial staging of DLBCL, but remains difficult to analyze. The aim of this study was to evaluate the meaning of this diffuse BMU, and especially to assess its correlation with bone marrow involvement (BMI). Methods: Patients who underwent FDG PET/CT for initial staging of DLBCL were analyzed. Diffuse BMU was assessed using a visual qualitative analysis according to liver uptake (grade 1=below liver uptake, 2=equal to liver uptake, 3=above liver uptake), and a semi-quantitative analysis, by measurement of maximum standardized uptake value (SUV) in the sacral promontory. We compared the BMU with BMI, parameters of disease extension and inflammatory markers. Results: 86 patients (median age 59, range: 19-91, 54 men, 32 women) were included. BMU grade was 1, 2 and 3 in 45, 28 and 13 cases respectively. Bone marrow was considered involved in 13 patients. No statistical correlation was found between diffuse BMU and BMI, using qualitative (p=0.594) or semi-quantitative method (p=0.116). Diffuse BMU visual grading was correlated with inflammatory markers: biological systemic symptoms (p=0.003), CRP (p=0.002) and fibrinogen (p=0.020). Conclusions: Our study suggests that a diffuse BMU seen on FDG PET/CT at initial staging of DLBCL is not representative of bone marrow involvement, but can be due to inflammatory changes.
Published: 2016
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32. Isolated Cardiac Richter Syndrome: a Case Report

Author: Mihnea Zdrenghea, Horia Marin, Dana Pop, Pierre-Yves Salaun, Adrian Tempescul, Cristina Bagacean, Yves Renaudineau, Michel, Geneviève, Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, 'Prof. Dr. Ion Chiricuta' Oncologic Insitute Cluj-Napoca, LabEX IGO Immunothérapie Grand Ouest, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service de médecine nucléaire [Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Departement of Radiology Neuroscience Institute (Henry Ford Health System), Henry Ford Health System, Cardiology Department (CardioDep - CLUJ-NAPOCA), Rehabilitation Hospital, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), and CHRU Brest - Service de médecine nucléaire (CHU - BREST - Med Nucléaire)
Subjects: Richter syndrome, Pathology, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Chronic lymphocytic leukemia, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Heart neoplasms, 0302 clinical medicine, Neoplasm Recurrence, Autologous stem-cell transplantation, Internal medicine, medicine, B cell, ComputingMilieux_MISCELLANEOUS, Hematology, business.industry, General Medicine, medicine.disease, Leukemia, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract: International audience
Published: 2016

33. FIRST LINE TREATMENT BY THE RIBVD REGIMEN ELICITS HIGH CLINICAL AND MOLECULAR RESPONSE RATES AND PROLONGED SURVIVAL IN ELDERLY MCL PATIENTS; FINAL RESULTS OF a LYSA GROUP TRIAL

Author: Jehan Dupuis, Selim Corm, Remy Gressin, Roch Houot, Christiane Mounier, Sylvain Carras, Caroline Dartigeas, M. Macro, Ghandi Damaj, Nicolas Daguindau, Mary Callanan, Jean-Michel Pignon, Anne-Sophie Moreau, S. Le Gouill, Adrien Tempescul, P. Feugier, Fabrice Jardin, Guillaume Cartron, Luc Mathieu Fornecker, I. Ysebaert, A. Bannos, Lionel Karlin, J. Fleury, Anna Schmitt, and Cecile Chabrot
Subjects: Cancer Research, Pediatrics, medicine.medical_specialty, Group trial, business.industry, Hematology, General Medicine, First line treatment, 03 medical and health sciences, Regimen, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Molecular Response, Internal medicine, medicine, business, 030215 immunology
Published: 2017
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34. Le syndrome thoracique aigu de l’adulte drépanocytaire

Author: Francis Couturaud, A. Tempescul, Christophe Leroyer, G. Quéré, N. Paleiron, and L. de Saint-Martin
Subjects: Pulmonary and Respiratory Medicine, Gynecology, 03 medical and health sciences, medicine.medical_specialty, 0302 clinical medicine, business.industry, medicine, 030212 general & internal medicine, 030204 cardiovascular system & hematology, business, 3. Good health
Abstract: Resume La drepanocytose est une pathologie repandue mais parfois mal apprehendee par les pneumologues qui y sont peu confrontes. Elle merite d’etre connue, compte tenu de sa principale complication respiratoire : le syndrome thoracique aigu (STA). Etat des connaissances La drepanocytose est une maladie autosomique recessive provoquant dans certaines conditions, une falciformation des hematies. Elle touche principalement les individus originaires des pays d’Afrique centrale, de l’ouest et des Antilles. Le STA associe une douleur thoracique ou de la fievre a des infiltrats radiologiques d’apparition recente, chez un individu porteur d’un syndrome drepanocytaire majeur. Ses principales etiologies sont l’infection, l’embolie graisseuse, et l’hypoventilation alveolaire. Il est cependant souvent difficile d’en determiner l’etiologie car il realise un cercle vicieux auto-entretenu. Les bases de la prise en charge, largement sous-evaluees, reposent sur le traitement etiologique, et les mesures visant a eviter l’aggravation liee principalement aux complications, en particulier microcirculatoires, de la maladie. Conclusions Le STA est une complication respiratoire grave de la drepanocytose a laquelle le pneumologue peut etre amene a etre confronte. Une prise en charge adaptee et rapide est necessaire. Les mesures therapeutiques sont simples mais sous-evaluees.
Published: 2011
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35. Peripheral blood stem cell collection in elderly patients

Author: Ljubomir Petrov, Francoise Quivoron, Adrian Tempescul, Jean-Christophe Ianotto, Christian Berthou, Elisabeth Hardy, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), ONERA - The French Aerospace Lab [Châtillon], ONERA-Université Paris Saclay (COmUE), EFS Bretagne, Université européenne de Bretagne - European University of Brittany (UEB), and Michel, Geneviève
Subjects: medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lymphoma, CD34, Antigens, CD34, Cell Count, MESH: Multiple Myeloma, MESH: Peripheral Blood Stem Cell Transplantation, Peripheral Blood Stem Cells, MESH: Hematopoietic Stem Cell Mobilization, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Aged, Retrospective Studies, MESH: Age Factors, MESH: Aged, Peripheral Blood Stem Cell Transplantation, MESH: Humans, Hematology, MESH: Cell Count, business.industry, Age Factors, MESH: Retrospective Studies, Retrospective cohort study, MESH: Antigens, CD34, General Medicine, medicine.disease, Hematopoietic Stem Cell Mobilization, 3. Good health, Surgery, MESH: Blood Component Removal, Apheresis, Peripheral blood stem cell collection, 030220 oncology & carcinogenesis, Blood Component Removal, Feasibility Studies, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, Multiple Myeloma, MESH: Feasibility Studies, MESH: Lymphoma, business, 030215 immunology
Abstract: International audience; Intensive treatments like autologous blood stem cell transplantations are standard consolidation treatments for lymphoma and myeloma in young people. The upper age limit for these procedures is constantly increasing. Instead of studying the impact of aging on harvesting peripheral blood stem cells (PBSC), we performed a retrospective study to explore the feasibility of collecting stem cells from patients older than 65 years and compared the efficacy to harvest in younger patients. During a period of 7 years, we identified 108 patients with myeloma or lymphoma who were older than 65 years who underwent PBSC collection. Only eight patients failed to produce a successful harvest. The majority of patients only needed one apheresis (71%). There was a median number of 5.3 x 10(6) CD34+ cells/kg. Our study demonstrated that older patients can also undergo PBSC harvests similar to younger patients.
Published: 2009
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36. Ofatumumab capacity to deplete B cells from chronic lymphocytic leukaemia is affected by C4 complement exhaustion

Author: Marjolaine Debant, Cristina Bagacean, Sophie Hillion, B. Bendaoud, Yves Renaudineau, Catherine Riou, Caroline Buors, Christian Berthou, Adrian Tempescul, Lymphocyte B et Auto-immunité (LBAI), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), LabEX IGO Immunothérapie Grand Ouest, Modélisation, Intelligence, Processus et Système (MIPS), Université de Haute Alsace - Mulhouse : EA2332, Laboratoire d'Immunologie et Immunothérapie, and Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL)
Subjects: 0301 basic medicine, Male, MESH: Combined Modality Therapy, Lymphocytosis, Cell, MESH: Antibodies, Monoclonal, chemistry.chemical_compound, 0302 clinical medicine, immune system diseases, MESH: Child, hemic and lymphatic diseases, complement, Child, MESH: Leukemia, Lymphocytic, Chronic, B-Cell, MESH: Treatment Outcome, MESH: Aged, B-Lymphocytes, MESH: Middle Aged, biology, FcγRIII polymorphism, MESH: Complement C3, Antibodies, Monoclonal, MESH: Complement C4, Complement C4, Hematology, General Medicine, Complement C3, Middle Aged, MESH: Infant, Combined Modality Therapy, 3. Good health, medicine.anatomical_structure, Treatment Outcome, MESH: Young Adult, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Adult, MESH: Immunophenotyping, Adolescent, medicine.drug_class, Antineoplastic Agents, MESH: Receptors, IgG, Ofatumumab, Monoclonal antibody, Antibodies, Monoclonal, Humanized, CD19, Lymphocyte Depletion, Immunophenotyping, 03 medical and health sciences, Young Adult, MESH: B-Lymphocytes, MESH: Polymorphism, Genetic, medicine, Humans, Aged, MESH: Adolescent, MESH: Lymphocyte Depletion, MESH: Humans, Lymphocytic leukaemia, Polymorphism, Genetic, business.industry, MESH: Child, Preschool, Receptors, IgG, Infant, MESH: Adult, Leukemia, Lymphocytic, Chronic, B-Cell, MESH: Male, Complement system, 030104 developmental biology, chemistry, Immunology, MESH: Biomarkers, biology.protein, MESH: Antineoplastic Agents, CD5, business, MESH: Female, chronic lymphocytic leukaemia, ofatumumab, Biomarkers, 030215 immunology
Abstract: International audience; The management of patients with chronic lymphocytic leukaemia (CLL) has improved with the utilisation of ofatumumab as a novel anti-CD20 monoclonal antibody. However, as half of the patients fail to respond to the treatment, the aim of this study was to evaluate circulating CLL cell depletion and clinical response according to the context of complement activation and FcγRIIIA polymorphism in ten CLL patients with relapsed/refractory disease. At the end of the treatment, results indicated that circulating CD5(+) CD19(+) CLL cell depletion was major (50% decrease) in 4 of 10 patients and ineffective for the two other patients. No clinical modifications were observed following ofatumumab introduction. Ofatumumab administration leads to a rapid and important exhaustion of complement C4 levels in patients with initial lymphocytosis. C4 exhaustion was accelerated in a non-responder patient, and incomplete in two patients with partial circulating depletion. Moreover, delaying weekly to monthly ofatumumab injections improved CLL cell depletion in two patients. FcγRIIIA 158 polymorphism (FF n = 6 and VF n = 4) was not associated with major and/or partial circulating CLL cell depletion. In conclusion, ofatumumab induces an important C4 exhaustion that needs to be taken into account when treating CLL patients with ofatumumab.
Published: 2015

37. The French LOC Network for Primary CNS Lymphoma (PCNSL) Patients: What Can We Learn from a Large National Database?

Author: Olivier Chinot, Luc Fornecker, Valérie Touitou, Pierre Soubeyran, Adrian Tempescul, Luc Taillandier, Franck Morschhauser, Roch Houot, Vincent Delwail, Arnaud Jaccard, Philippe Agape, Marie-Pierre Moles, Cécile Chabrot, Nathalie Cassoux, Carole Soussain, Khê Hoang-Xuan, Emmanuel Gyan, Caroline Houillier, Michel Fabbro, Guido Ahle, Annie Brion, Sylvain Choquet, Olivier Casanovas, Remy Gressin, Herve Ghesquieres, Pascal Bourquard, Gandhi Damaj, and Fabrice Jardin
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Palliative care, business.industry, Immunology, Primary central nervous system lymphoma, Induction chemotherapy, Cell Biology, Hematology, medicine.disease, Biochemistry, Chemotherapy regimen, 03 medical and health sciences, Regimen, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Rituximab, business, Diffuse large B-cell lymphoma, Progressive disease, medicine.drug
Abstract: Background The shared knowledge regarding management and outcome of PCNSL patients are usually based on results of clinical phase II studies that include limited series of selected patients, which imperfectly reflect the medical care in "real life". Methods The LOC network, certified by the national cancer institute (INCa), is a national network of expert centres for PCNSL. Since 2011, we are prospectively recording in the LOC database all newly diagnosed PCNSL patients from the 22 regional expert centres for PCNSL that cover the whole country. Data from PCNSL patients registered in the LOC database from January 2011 to March 18, 2016 were analyzed. Results Data from 971 patients were available in the LOC database at the time of analysis: sex ratio: 1.05, median age: 67 (18-92), median Karnofsky Performance Status: 60 (20-100), diffuse large B cell lymphoma: 97%, ocular involvement: 20%, cerebrospinal (CSF) involvement: 18%. Diagnosis procedure was biopsy (80%), tumor resection (9%), vitrectomy (8%), CSF cytology (3%). Treatment was initiated either by a neuro-oncology or a haematology team in 38% and 62%, respectively. Median delay between first symptoms and onset of treatment was 62 days. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) (90%), other chemotherapy regimen (6%), or palliative care (4%). The use of Rituximab has gradually increased from 50 % of patients between 2011 and 2013, up to 87 % of patients in 2016. 16 % of patients were included in prospective trials. After first-line induction chemotherapy, responder patients < 60 years received a consolidation treatment in 75 % of cases consisting of either whole brain radiotherapy (WBRT) (49 %) or HD CT with autologous stem cell transplantation (HD CT-ASCT) (26 %). Low dose WBRT (23,4) is being used in younger CR patients since 2014. In responder patients > 60 years, WBRT was seldom given (9%) according to national guideline, and HD CT-ASCT was offered to 1% of patients. Response rates to first-line treatment among evaluable patients (n = 655) were: complete response: 59%; partial response: 10%; stable disease: 3%; progressive disease: 28%. Relapse occurred in 42 % patients < 60 y and in 62 % in older patients. At relapse, second line chemotherapy, HD CT-ASCT, WBRT and palliative care were offered in 50%, 18%, 12%, 20% of patients respectively. With a median follow-up of 20.4 months, median progression free survival (PFS) was 9.9 months for the whole population (< 60 years: 34.6 months; > 60 years: 7.9 months). Median overall survival (OS) and 5-year OS were 30 months and 41% respectively (< 60 years: not reached, 68%; > 60 years: 15 months, 30%). Conclusion The therapeutic practices in France reflect the current knowledge and controversies in PCNSL. Long-term survival has become frequent, especially among youngest patients who usually receive a consolidation treatment and to whom HD CT-ASCT can be offered at relapse. Relapse rate remains frequent and especially in elderly patients in whom consolidation treatment is omitted. Such an overview points out a couple of issues. Despite homogeneous treatments following national guidelines in accordance with the state of the art of medical care, standards of care are to be challenged, both for increasing the CR and decrease the relapse rates. The development of target and innovative therapies in PCNSL alone or in combinatorial regimen is needed. PFS and OS of patients according to age Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Soussain: Roche: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding. Ghesquieres:Mundipharma: Consultancy; Roche France: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choquet:Janssen: Consultancy; Celgene: Consultancy. Morschhauser:Servier: Consultancy, Honoraria; Janssen: Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria.
Published: 2016
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38. Bendamustine-Based (BeEAM) Conditioning before Autologous Stem Cell Transplantation: Result of a French Multicenter Study of 386 Patients from Lysa Centers

Author: Anne-Claire Gac, Olivier Tournilhac, Ibrahim Yakoub-Agha, Benjamin Carpentier, Emmanuel Gyan, Sandra Malak, Caroline Delette, Eric Durot, Mohamed Amine Bekadja, Emmanuelle Tchernonog, Roch Houot, Momar Diouf, Thomas Gastinne, Adrien Chauchet, Sylvain Chantepie, Arnaud Jaccard, Marie-Virginie Larcher, Bachra Choufi, Ahmad Ibrahim, Rene-Olivier Casasnovas, Luc Mathieu Fornecker, Reda Garidi, Gandhi Damaj, Carole Soussain, Krimo Bouabdallah, Frederic Peyrade, Stéphanie Guidez, Jean-Pierre Vilque, Adrian Tempescul, and Remy Gressin
Subjects: Bendamustine, medicine.medical_specialty, Immunology, Biochemistry, Gastroenterology, Nephrotoxicity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Autologous stem-cell transplantation, Intensive care, Internal medicine, Medicine, Creatinine, business.industry, Cell Biology, Hematology, medicine.disease, Surgery, Regimen, chemistry, 030220 oncology & carcinogenesis, Mantle cell lymphoma, business, Packed red blood cells, 030215 immunology, medicine.drug
Abstract: Unavailability of Carmustine and its dramatically increased cost by nearly 10 fold has led to its replacement by bendamustine (Be) and an increase use of Bendamustine-based (BeEAM) conditioning regimen before autologous stem cell transplantation for lymphoma. The aim of this study was to evaluate the safety of the BeEAM regimen in the real life use in several French centers. Median age of the 386 patients (233 male, 153 female) was 55 years (17-72). The majority of patients had aggressive B-cell (40%), follicular (17%), Hodgkin's (17%) and mantle cell lymphoma (15%). Two hundred and forty six patients (64%) were transplanted after 2nd line chemotherapy and the median number of prior lines of chemotherapy of 2 (1-9). Two hundred and sixty patients (67%) had received prior platinum chemotherapy and only 4% had a history of prior chronic renal failure (Table 1). The median creatinine level at conditioning initiation was 71(36-206) µmol/l. Be was administered at a median dose of 191 mg/m2/day (50-250) on day -7 and -6. Thirty two percent received 100-160 mg/m²/d and 58% of patients received more than 160 mg/m²/d. Median 24h-hydration volume was 3 l (1-6) which began within median time of 18 h (1-72) prior to conditioning initiation. The median duration time of Be perfusion was 60 min (30-143). Grade 1-4 acute renal failure (ARF) was reported in 107 cases (28%) (G ≥2; 34%) and appeared after a median time of 2 days (1-18) after conditioning start. Melphalan dosage was reduced, due to renal failure, in 10% of patients (Table 2). 84% of patients normalized their creatinine level within a median time of 10 days (1-77). The most frequent reported Grade 1-4 toxicities were mucositis (84%), gastroenteritis (53%), skin toxicity (34%), colitis (29%), liver toxicity (19%), pneumonitis (5%) and cardiac rhythm disorders (4%). Opportunistic infection was documented in 9.5% of patients, HHV6 reactivation in 6% of patients. Ten percent of patients needed intensive care management and toxic death was estimated at 5% (Table 3). Patients received a median of 3 (0-34) packed red blood cells and 4 (0-56) platelets units. The median time to neutrophils > 0.5 G/L and platelets > 20 G/L were 10 (0-50) and 12 (0-210) days. The median time of hospital stay was 23 (12-85) days. In comparison with the group of patient without renal failure, the group of patients with ARF had older age (58 vs 54), higher rate of pre-transplant chronic renal failure (10% vs 1%), higher rate of platinum treatment (77% vs 64%), higher day1 creatinine level (81 vs 69) and received higher median bendamustine (199 vs 182). Colitis (p=0.039), pneumonitis (p=0.008), cardia arrhythmia (p=160mg/m2 and age were independent prognostic factors for ARF. A three-point clinical predictor score for acute renal failure was identified and included creatinine level>65µmol/l, bendamustine dose >160mg/m² and age>57 years. ARF stratified by score, was 4% with score 0, 17% with score 1, 30% with score 2 and 45% with score 3. In conclusion, BeEAM induced 5% non-relapse mortality with high rate of renal toxicity. A simple, three-point scoring system can stratify patients by levels of risk for ARF. Rapid identification of higher risk patients may allow a reduction of the bendamustine dose to improve clinical outcomes. Prospective comparative studies are needed to confirm toxicity extents of this conditioning as compared with other type of high dose therapy. Disclosures Soussain: Pharmacyclics: Research Funding; Celgene: Research Funding; Roche: Research Funding. Malak:Novartis: Membership on an entity's Board of Directors or advisory committees.
Published: 2016
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39. Efficacy of the Ribvd Regimen in High Risk Mantle Cell Lymphoma Patients As Defined By the Mipic Prognostic Score: Identification of KI67, LDH and Performance Status As Most Important Prognostic Factors (PF). a French Lysa Group Study

Author: Krimo Bouabdallah, Guillaume Cartron, Christiane Mounier, Jehan Dupuis, Selim Corm, Caroline Dartigeas, Nicolas Daguindau, Roch Houot, Steven Le Gouill, J. Fleury, Fabrice Jardin, Luc Fornecker, Anne Schmitt, Adrien Tempescul, Loic Ysebaert, Barbara Burroni, Anne Moreau, Remy Gressin, Jean-Michel Pignon, Sylvain Carras, and Lionel Karlin
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Proliferation index, Immunology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Median follow-up, Internal medicine, medicine, Univariate analysis, Performance status, business.industry, Cell Biology, Hematology, medicine.disease, Surgery, Log-rank test, Regimen, 030104 developmental biology, B symptoms, 030220 oncology & carcinogenesis, Mantle cell lymphoma, medicine.symptom, business
Abstract: Background The proliferation index (PI), defined by KI67 protein expression has been identified as a key prognostic factor (PF) in mantle cell lymphoma (MCL) (1, 2). A GOELAMS/LYSA study (n = 113 patients) identified a cut point of 26% for KI67 positivity as an independent predictor of overall survival together with LDH levels, B symptoms and ECOG-PS, in MCL (GOELAMS index : GI). (1) Recently, the European MCL network confirmed the independent prognostic power of KI67 protein expression levels to predict OS in MCL (n = 508) and proposed a new score "MIPIc" (KI67cut-off of 30%). (2) While these scores show prognostic impact in the immuno-chemotherapy setting, with or without ASCT and / or maintenance therapy, their predictive power in the setting of targeted therapy remains uncertain. Objective The aim of this study was to test the predictive power of the MIPIc and GI prognostic indices in a cohort of elderly MCL patients treated by a proteasome-inhibitor-based immunochermotherapy regimen within a prospective phase II trial of the LYSA group (LyMa SA 2010 ; Rituximab, Bendamustine, Velcade and Dexamethasone regimen : RiBVD). (3) Material and method The final analysis of the LyMA SA 2010, presented at ASH 2014 (3), showed overall clinical and molecular response rates of 86.5% and 85%. The 24 months estimated OS and PFS was respectively 80% and 70%. (3) In order to assess the prognostic power of KI67 expression levels for OS, all survival data were updated. KI67 staining was performed and reviewed centrally by one pathologist of the LYSA-P, according to the European guidelines. (4) The MIPIc and GI scores were calculated and their impact on survival analyzed (Logrank). In addition, all 6 variables comprising the MIPc and the GI indices were assessed separately by univariate analyzes for prognostic value (these were LDH, ECOG and KI67 that are common to the 2 indices, and Age and WBC for the MIPIc and B Symptoms for GI). Finally a Logrank permitted to define 3 groups of patients with a high statistically impact on survivals with the 3 common variables of MIPIc and GI. Results Among the 74 elderly MCL patients treated in first line by the RiBVD regimen, 59 are alive with a median follow up of 40 months. Estimated OS and PFS at 36 months are respectively 78.4% and 65%. The MIB1 was evaluated on 58 samples for which the MIPIc and GI could be calculated for 57 patients (no LDH value for one patient). MIPIc and GI were not able to define relevant prognostic subgroups for OS (p =0.55 and 0.11). Only the 3 common variables LDH (N vs >N), ECOG (O-1 vs >1) and MIB1 (with a cut-off at 46% corresponding to the fourth quartile of MIB1 expression levels) were individually predictive of OS by univariate analysis (respectively with p=0.0006, p=0.048 and p=0.0031). With these three variables the Logrank test separated three groups that were statistically discriminant for OS and PFS: one group with 0 risk factors n=24 patients, 42%), a second group with one risk factor (n=20 patients, 32%) and the last group with 2 or 3 risk factors (n=13 patients, 23%). Hence the 3 year OS of these 3 groups was respectively 96%, 75% and 30% (p In Conclusion The proteasome-inhibitor-based immunochemotherapy regimen, RiBVD, induces prolonged survival of "High risk" patients, as defined by this modified MIPIc score. More proliferative disease, defined by a KI67 superior to 46%, combined with a high LDH level and/or a high PS defines a high subgroup of patients under the RiBVD regimen (median PFS and OS of respectively 15 and 10 months). Ref: 1 Gressin R, Haematologica 2010. 2 Hoster E et al, J Clin Oncol 2016. 3 Gressin R et al, ASH Blood 2014. 4 Klapper W, H Hematop 2009. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Dartigeas:Roche: Consultancy; Mundipharma: Other: travel grant. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Karlin:takeda: Consultancy; Bristol: Consultancy; celgene: Consultancy, Honoraria; janssen-cilag: Consultancy, Honoraria; amgen: Consultancy, Honoraria.
Published: 2016
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40. Identification of patients with indolent B cell lymphoma sensitive to rituximab monotherapy

Author: Christophe Jamin, Pierre Youinou, Solène Querellou, Christian Berthou, Pascal Hutin, Yves Renaudineau, Boutahar Bendaoud, Jacques-Olivier Pers, Divi Cornec, Adrian Tempescul, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Department of Nuclear Medicine, and Laboratoire d'Immunologie et Immunothérapie
Subjects: Oncology, Male, MESH: Tumor Burden, MESH: Complement C1q, MESH: Neoplasm Grading, Multimodal Imaging, Antibodies, Monoclonal, Murine-Derived, 0302 clinical medicine, hemic and lymphatic diseases, B-Cell Activating Factor, Norleucine, Medicine, B-cell lymphoma, MESH: Treatment Outcome, MESH: Aged, Hematology, MESH: Middle Aged, biology, General Medicine, Middle Aged, Prognosis, 3. Good health, Tumor Burden, Treatment Outcome, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, Antibody, medicine.drug, Adult, medicine.medical_specialty, Lymphoma, B-Cell, Antineoplastic Agents, MESH: Positron-Emission Tomography and Computed Tomography, MESH: Receptors, IgG, MESH: Prognosis, 03 medical and health sciences, Pharmacokinetics, Internal medicine, MESH: Polymorphism, Genetic, Humans, MESH: Norleucine, MESH: B-Cell Activating Factor, B-cell activating factor, Aged, MESH: Lymphoma, B-Cell, Polymorphism, Genetic, MESH: Humans, business.industry, Complement C1q, Receptors, IgG, MESH: Adult, medicine.disease, MESH: Male, Lymphoma, Non-Hodgkin's lymphoma, MESH: Antibodies, Monoclonal, Murine-Derived, Positron-Emission Tomography, Immunology, biology.protein, MESH: Antineoplastic Agents, Neoplasm Grading, business, Tomography, X-Ray Computed, MESH: Female, 030215 immunology
Abstract: International audience; The potential predictive value of tumor bulk, genetic, and immunological variants in patients with low-grade non-Hodgkin's lymphoma to respond to treatment with rituximab (RTX) monotherapy was evaluated. Thus, the value of assessing the effect of 18-fluoro-desoxy-D-glucose (FDG) uptake on PET scan, polymorphisms in Fc gamma receptor (FcγR) IIIa-158, FcγRIIa-131, and C1qA-276 genes in predicting the response to treatment were evaluated in 50 low-grade non-Hodgkin's lymphoma patients. The influence of RTX pharmacokinetics, plasma levels of the B cell-activating factor (BAFF), and human antichimeric antibodies was also investigated. The therapeutic response was evaluated 10 weeks after treatment using revised Cheson's criteria. Lower maximal standardized uptake values (SUV(max)) at baseline were predictive of complete response. FcγRIIIa-158 polymorphism was also associated with complete response to RTX confirming previous findings, whereas polymorphisms in the FcγRIIa-131 and C1qA-276 genes were not. Lower blood levels of RTX were observed in males, but the effectiveness of RTX in males and females was the same. BAFF was not detectable in plasma before or after treatment, and no patients developed human antichimeric antibodies. Low-grade non-Hodgkin's lymphoma patients with a low SUV(max) at baseline and an FcγRIIIa-158 V/V genotype generally had a complete response to RTX.
Published: 2012
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41. Membrane microdomain sphingolipids are required for anti-CD20-induced death of chronic lymphocytic leukemia B cells

Author: Pierre Youinou, Christian Berthou, Jacques-Olivier Pers, Anne Bordron, Gabriel J. Tobón, Adrian Tempescul, Mariam Hammadi, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Laboratoire d'Immunologie et Immunothérapie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato)
Subjects: Male, MESH: Cell Death, Chronic lymphocytic leukemia, MESH: Membrane Microdomains, MESH: Antigens, CD20, MESH: Antibodies, Monoclonal, 0302 clinical medicine, rituximab, MESH: Aged, 80 and over, MESH: Leukemia, Lymphocytic, Chronic, B-Cell, Cells, Cultured, CD20, Aged, 80 and over, MESH: Aged, 0303 health sciences, B-Lymphocytes, MESH: Middle Aged, biology, Cell Death, Antibodies, Monoclonal, Hematology, Middle Aged, Transmembrane protein, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Rituximab, Female, Sphingomyelin, medicine.drug, MESH: Cells, Cultured, Adult, chronic lymphocytis leukemia, medicine.drug_class, tositumomab, P-glycoprotein, Monoclonal antibody, sphingomyelin, MESH: Sphingolipids, 03 medical and health sciences, Membrane Microdomains, MESH: B-Lymphocytes, medicine, Humans, 030304 developmental biology, Aged, Sphingolipids, Ganglioside, MESH: Humans, MESH: Adult, medicine.disease, Antigens, CD20, Leukemia, Lymphocytic, Chronic, B-Cell, MESH: Male, Immunology, biology.protein, Cancer research, CD5, Original Articles and Brief Reports, MESH: Female, 030215 immunology
Abstract: International audience; BACKGROUND Chronic lymphocytic leukemia remains incurable, despite the addition of rituximab to chemotherapy as an available means of treatment. The resistance of certain patients to this monoclonal antibody prompted us to set up in vitro studies of another CD20-specific monoclonal antibody, B1 (later termed tositumomab). We hypothesized that the membrane lipid organization of leukemic B cells might be instrumental in the cells' sensitivity to the B1 monoclonal antibody. DESIGN AND METHODS B lymphocytes from 36 patients with chronic lymphocytic leukemia and 13 patients with non-Hodgkin's lymphoma were investigated for B1-triggered cell death. Membrane components, such as sphingomyelin and ganglioside M1, were investigated by flow cytometry, immunofluorescence and co-immunoprecipitation, together with the Csk-binding protein. RESULTS Chronic lymphocytic leukemia patients segregated into two groups: B cells from one group were sensitive to B1, whereas those from the second group were not. Further results ascribed the resistance of these latter cases to a defective recruitment of Csk-binding protein, resulting in a lack of sphingomyelin and ganglioside M1 at the outer leaflet of the plasma membrane of their malignant B cells. Sphingolipids were indeed retained in the cytoplasm, because of lowered activity of P-glycoprotein. Supporting this mechanism, rifampicin, an inducer of P-glycoprotein, improved the activity of this transmembrane efflux pump, normalized the quantity of sphingomyelin within the membrane, and thereby restored the efficacy of the B1 monoclonal antibody in the formerly B1-resistant cases of chronic lymphocytic leukemia. CONCLUSIONS The lipid organization of membranes of B cells from patients with chronic lymphocytic leukemia differs from one patient to another. In practice, given the relevance of the membrane lipid distribution to the efficacy of biotherapies, this observation is of potential importance.
Published: 2012
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42. ESHAP chemotherapy regimen associated to lenalidomide induces complete isotopic remission in Hodgkin's lymphoma relapsing after autologous stem cell transplantation

Author: Christian Berthou, Gaelle Guillerm, Jean-Christophe Ianotto, Jean-Richard Eveillard, Adrian Tempescul, Michel, Geneviève, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), and Université européenne de Bretagne - European University of Brittany (UEB)
Subjects: Oncology, MESH: Remission Induction, medicine.medical_treatment, Hematopoietic stem cell transplantation, 0302 clinical medicine, Autologous stem-cell transplantation, Recurrence, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, MESH: Cytarabine, Lenalidomide, Etoposide, MESH: Etoposide, Remission Induction, MESH: Thalidomide, Cytarabine, Hematopoietic Stem Cell Transplantation, Hematology, General Medicine, Chemotherapy regimen, Hodgkin Disease, MESH: Transplantation, Autologous, MESH: Hodgkin Disease, 3. Good health, Thalidomide, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug, Adult, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transplantation, Autologous, 03 medical and health sciences, Internal medicine, medicine, Humans, MESH: Hematopoietic Stem Cell Transplantation, MESH: Humans, business.industry, MESH: Adult, Hodgkin's lymphoma, medicine.disease, MESH: Recurrence, MESH: Cisplatin, Immunology, Prednisone, Cisplatin, business, ESHAP, MESH: Prednisone, 030215 immunology
Abstract: International audience; One way for intravenous Ig (IVIg) to affect responses of the B cells might be to operate through their TLR7 and TLR9. We confirm the ability of TLR agonists to induce CD25 expression in B cells. For this to occur, sialylated Fc-gamma of IgG included in the IVIg preparation are required. As a result, IVIg suppresses TLR-induced production of the proinflammatory IL-6, but not that of the anti-inflammatory IL-10. That is, IVIg mimics the effects of the MyD88 inhibitor. Finally, as we previously showed that IVIg induces CD22 to recruit the inhibitory SHP-1, we established that this enzyme was also involved in IVIg-induced inhibition of TLR9 signaling. This is the first report to demonstrate such a mechanism underlying the negative impact of IVIg on B lymphocytes.
Published: 2011

43. Combined therapy associating systemic platinum-based chemotherapy and local radiotherapy into the treatment of primary intraocular lymphoma

Author: Christian Berthou, Jean-Christophe Ianotto, Catherine Marianowski-Cochard, Adrian Tempescul, Olivier Pradier, Michel, Geneviève, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Service Hématologie, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Laboratoire de Traitement de l'Information Medicale (LaTIM), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Mines-Télécom [Paris] (IMT), Department of Ophthalmology, University Hospital Brest, and Université européenne de Bretagne - European University of Brittany (UEB)
Subjects: Oncology, medicine.medical_specialty, MESH: Combined Modality Therapy, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, MESH: Eye Neoplasms, 03 medical and health sciences, 0302 clinical medicine, MESH: Aged, 80 and over, Internal medicine, Medicine, Combined Modality Therapy, ComputingMilieux_MISCELLANEOUS, MESH: Aged, Chemotherapy, Hematology, MESH: Humans, business.industry, General Medicine, medicine.disease, MESH: Injections, Intravenous, 3. Good health, Radiation therapy, MESH: Antineoplastic Combined Chemotherapy Protocols, Local radiotherapy, 030220 oncology & carcinogenesis, MESH: Radiotherapy, Conformal, 030221 ophthalmology & optometry, Combined therapy, [SDV.IMM]Life Sciences [q-bio]/Immunology, Intraocular lymphoma, MESH: Platinum Compounds, business, MESH: Lymphoma
Abstract: International audience
Published: 2011

44. 18F-FDG PET/CT in primary non-Hodgkin's lymphoma of the sinonasal tract

Author: Sylvie Boisramé, Christian Berthou, Gerald Valette, Solène Querellou, Adrian Tempescul, Jean-Christophe Ianotto, Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, Department of Nuclear Medicine, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Department of Odontology, Department of ORL, Université européenne de Bretagne - European University of Brittany (UEB), and Michel, Geneviève
Subjects: medicine.medical_specialty, Pathology, MESH: Remission Induction, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Tomography, Emission-Computed, MESH: Vincristine, MESH: Prognosis, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, MESH: Doxorubicin, 0302 clinical medicine, MESH: Lymphoma, Non-Hodgkin, MESH: Fluorodeoxyglucose F18, Internal medicine, medicine, MESH: Cytarabine, ComputingMilieux_MISCELLANEOUS, MESH: Aged, MESH: Paranasal Sinus Neoplasms, Hematology, MESH: Humans, MESH: Middle Aged, business.industry, MESH: Organoplatinum Compounds, MESH: Cyclophosphamide, General Medicine, Sinonasal Tract, medicine.disease, MESH: Positron-Emission Tomography, Non-Hodgkin's lymphoma, MESH: Antineoplastic Combined Chemotherapy Protocols, 030220 oncology & carcinogenesis, MESH: Dexamethasone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Fdg pet ct, Radiology, business, MESH: Paranasal Sinuses, MESH: Prednisone
Abstract: International audience
Published: 2010

45. Lenalidomide, as a single agent, induces complete remission in a refractory mantle cell lymphoma

Author: Marc De Braekeleer, Christian Berthou, Frédéric Morel, Jean-Christophe Ianotto, Véronique Marion, Adrian Tempescul, Department of Clinical Hematology, Institute of Cancerology and Hematology, CHU Morvan, Laboratory of Histology, Embryology and Cytogenetics, Faculty of Medicine and Health Sciences, Université de Brest (UBO), and Laboratory of Haematology
Subjects: medicine.medical_specialty, Lymphocytosis, Antineoplastic Agents, Lymphoma, Mantle-Cell, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Recurrence, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Lenalidomide, ComputingMilieux_MISCELLANEOUS, Aged, Hematology, business.industry, Remission Induction, General Medicine, medicine.disease, 3. Good health, Lymphoma, Thalidomide, 030220 oncology & carcinogenesis, Immunology, Cancer research, Refractory Mantle Cell Lymphoma, Medicine, Mantle cell lymphoma, Female, CD5, medicine.symptom, business, 030215 immunology, medicine.drug
Abstract: Dear Editor,Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin s lymphoma that is characterized by a typicalcytological presentation, the presence of the t(11;14)(q13;q32) chromosomal translocation, and overexpression ofcyclin D1. MCL has a low response rate and shortprogression-free survival (PFS) after conventional therapy.In refractory or relapsed MCL, the prognosis is even worse.Several novel therapeutic approaches have been proposed,including monoclonal antibodies, radioimmunotherapy,proteasome inhibitors, m-TOR inhibitors, and the immuno-modulatory drugs thalidomide and lenalidomide. In ourpatient with refractory MCL, the use of lenalidomide assingle agent therapy allowed for complete cytological,phenotypic, and cytogenetic remission in a very shortperiod of time.A 74-year-old woman was first seen for asthenia and thepresence of abnormally circulating B lymphocytes. Theclinical examination only identified grade I splenomegaly.The blood count revealed lymphocytosis at 8.96 Giga/L with30% circulating lymphocytes, which presented with thetypical MCL phenotype, CD5
Published: 2008
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46. A combination therapy with fludarabine, mitoxantrone and rituximab induces complete immunophenotypical remission in B-cell prolymphocytic leukaemia

Author: Marc De Braekeleer, Christian Berthou, Véronique Marion, Marie-Josée Le Bris, Johanna Feuerbach, Adrian Tempescul, Jean-Christophe Ianotto, Florence Dalbies, Department of Clinical Hematology, Institute of Cancerology and Hematology, Laboratory of Haematology, Laboratory of Histology, Embryology and Cytogenetics, Faculty of Medicine and Health Sciences, and Université de Brest (UBO)
Subjects: medicine.medical_specialty, Lymphocytosis, Chromosomal translocation, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Medicine, ComputingMilieux_MISCELLANEOUS, CD20, Hematology, biology, business.industry, General Medicine, 3. Good health, Fludarabine, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Alemtuzumab, Rituximab, medicine.symptom, CD5, business, 030215 immunology, medicine.drug
Abstract: Dear Editor, We present here the cases of two patients with B-cell prolymphocytic leukaemia (B-PLL), both expressing a translocation t(8;14)(q24;q32) with rearrangement of cmyc gene found in FISH analysis. A treatment protocol that includes six cycles of Fludarabine and Mitoxantrone followed by four injections of Rituximab allows obtaining complete cytological and immunophenotypical remission. B-PLL is a rare disease that accounts for less than 2% of chronic lymphatic leukaemia (CLL). The characteristics of the disease include high lymphocytosis, over 4 Gigas/L, with at least 55% cells described as prolymphocytes and splenomegaly. The prolymphocytes are medium-sized cells with prominent, round or oval nuclei and a single, central nucleolus [1]. Bone marrow aspirate shows a heavy infiltration by prolymphocytes with a variable degree of residual haematopoiesis. Immunophenotypically, there is a strong expression of the B-cell antigens CD19, CD20, CD21, CD79b and FMC7 and of surface IgM, whereas CD23 is negative and CD5 is variably expressed [1]. In cytogenetic studies, the implication of the 14q32 region of the chromosome 14 is found in 50% of the cases [1]. Translocation (11;14) is present in 25% of the cases, in particular t(11;14)(q13;q32) with a rearrangement of bcl1 protein. Other partners for the IgH gene of the 14q32 region of chromosome 14 could be genes from the regions 11q23 and 13q14 [1]. A translocation (8;14)(q24;q32) typically exists in type 3, B-cell acute lymphoblastic leukaemia and Burkitt lymphomas. This anomaly, which also involves cmyc, was found in only a few cases [2, 3]. B-PLL is not treated when asymptomatic or there are no signs of bone marrow deficiency. Treatment options are various, including combination chemotherapies with alkylating agents or purine nucleoside analogues as monotherapy. Monoclonal antibodies such as Rituximab and Alemtuzumab are also used. A 63-year-old man was first seen in October 2006 with symptoms of asthenia and dyspnoea. A physical examination revealed a splenomegaly grade 3 and lymphadenopathy. The blood count showed a significant anaemia (Hb 5,4g/dL), thrombocytopenia (108 Gigas/L) and a hyperleukocytosis at 247Gigas/L with 92% abnormal circulating lymphocytes, which presented the typical morphology and phenotype of B-PLL. Genetic studies revealed a complex caryotype (Fig. 1), involving a translocation t(8;14)(q24;q32) with a rearrangement of c-myc, confirmed by fluorescence in situ hybridisation analysis (Fig. 2). Ann Hematol (2009) 88:85–88 DOI 10.1007/s00277-008-0541-5
Published: 2008
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47. Daratumumab in Combination with Dexamethasone in Resistant or Refractory Multiple Myeloma: Primary Results of the IFM2014-04 Trial

Author: Olivier Decaux, Philippe Rodon, Marie Lorraine Chretien, Clara Mariette, Brigitte Kolb, Laure Vincent, Karel Fostier, Sophie Rigaudeau, Muriel Roussel, Adrian Tempescul, Pascal Godmer, Anne-Marie Stoppa, Philippe Moreau, Eileen M Boyle, Bruno Royer, Michel Attal, David Beauvais, Charles Zarnitsky, Bertrand Arnulf, Lotfi Benboubker, Jean Claude Eisenmann, Sarah Bonnet, Thomas Longval, Thierry Facon, Chantal Doyen, Mohamad Mohty, Cécile Fohrer, Caroline Bureau, Mourad Tiab, Sabine Brechignac, Hervé Avet-Loiseau, Laurent Frenzel, Gerald Marit, Margaret Macro, Lionel Karlin, Marc Wetterwald, Mamoun Dib, Jean Valère Malfuson, Johanna Mimouni, Susanna Schraen, Charles Herbaux, Xavier Leleu, Benjamin Carpentier, Laurent Voillat, Marie-Odile Petillon, Cyrille Hulin, Aurore Perrot, Arnaud Jaccard, and Mathieu Dewevre
Subjects: 0301 basic medicine, medicine.medical_specialty, Bortezomib, business.industry, Immunology, Phases of clinical research, Daratumumab, Cell Biology, Hematology, Interim analysis, Pomalidomide, medicine.disease, Biochemistry, Surgery, Transplantation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, business, Multiple myeloma, medicine.drug, Lenalidomide
Abstract: Introduction: CD38 is highly and uniformly expressed on myeloma cells (1). Daratumumab is a human anti-CD38 IgG1κ monoclonal antibody that has previously shown a favourable safety profile as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (2). This study further assesses the efficacy of Daratumumab in combination with Dexamethasone in heavily pre-treated myeloma patients that are refractory to Lenalidomide, Pomalidomide, and Bortezomib. Methods: This study is an ongoing, open-label phase II study of Daratumumab in combination with Dexamethasone (NCT02626481). Sixty-four, heavily pretreated Patients were recruited in thirty centres in France and Belgium from November 2015, to receive Daratumumab and Dexamethasone. Daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles three through six, and monthly in Cycle seven and beyond until disease progression or unacceptable toxicity. Patients were all refractory to Lenalidomide (Len), Pomalidomide (Pom) (defined by a progression within 60 days from last drug dosing) and Bortezomib (Bz) (defined by a progression within 6 months from last drug dosing). The primary objective was overall response rate as per the International Myeloma Working Group criteria. A planned safety and efficacy interim analysis was performed after the first 19 patients were enrolled. The last patient was enrolled on the 1stof August 2016. Results: Sixty-four patients were recruited onto the study. The median age (range) at screening was 61 (30-80). The median number (range) of prior lines of therapy was 6 (2-9). Sixty-seven percent of patient had previously received an autologous stem-cell transplant. At the time of screening, 20% of patients (n=13) had a t(4;14) and 12.5% (n=8) a del(17p). Planned interim analysis after the first 19 patients were enrolled did not find any unexpected toxicity. Safety and efficacy results (data cut May 15, 2016) of Daratumumab 16 mg/kg are presented here. No patient discontinued treatment due to Treatment Emergent Adverse Event such as infusion related reactions. Ten (15%) patients discontinued treatment due to disease progression after a median of one-cycle. The most common non-haematological TEAEs included infusion related (IRR, n=5, 8%), and fatigue (n=6, 9.3%). All patients with IRRs recovered and continued to receive treatment. Only six (9.5%) patients experienced hyperthermia. Thrombocytopenia and neutropenia were the most frequently reported grade 3 or 4 TEAE (11 and 5% respectively). Planned interim efficacy assessment showed a response rate (defined as a Partial Response (PR) or greater) in 3/19 patients at the end of the first cycle and 4/19 at the end of the second cycle, and a clinically relevant response (Stable Disease (SD) or greater) at the end of the second cycle for 11 of 19 patients, thus meeting the planed futility criteria and enabling the trial to go forward. As per the 15thof May, among the 40 evaluable patients (that had received at least 2 treatment cycles or progressed within the first) the overall response rate (3) was 25%, with eight (20%) partial responses (PR) and two (5%) very good partial responses (VGPRs) after a median of two cycles (range 1-5). An additional seven patients (17.5%) obtained a Minimal Response (MR) according to the EBMT criteria (4). This is consistent with prior results. Updated results will be presented at the time of ASH. Conclusions: Daratumumab in combination with Dexamethasone is a safe treatment option with a favourable benefit/risk profile for the treatment of triple relapsed or refractory (Len, Pom and Bz) myeloma patients. 1. Stevenson GT. CD38 as a Therapeutic Target. Mol Med. 2006;12(11-12):345-6. 2. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. 3. Kyle R, Rajkumar S. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 2009 Jan;23(1):3-9. 4. Bladé J,et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. Br J Haematol. 1998 Sep;102(5):1115-23. Disclosures Boyle: Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Hulin:Amgen: Honoraria; Janssen: Honoraria; Bristol: Honoraria; celgene: Honoraria; takeda: Honoraria. Moreau:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Fohrer:amgen: Consultancy; celgne: Consultancy. Decaux:SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding; The Binding Site: Other: supply of free light chain assays , Research Funding. Avet-Loiseau:celgene: Consultancy; amgen: Consultancy; janssen: Consultancy; sanofi: Consultancy. Attal:celgene: Consultancy, Research Funding; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Facon:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau.

48. Acute dyspnoea and single tracheal localisation of mantle cell lymphoma

Author: Jean-Richard Eveillard, Frédéric Morel, Jean-Christophe Ianotto, Christian Berthou, Adrian Tempescul, Isabelle Quintin-Roué, Norbert André, Service Hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Immunologie et Pathologie (EA2216), Université de Brest (UBO)-IFR148, CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de recherche en astrophysique et planétologie (IRAP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Laboratoire Angevin de Mécanique, Procédés et InnovAtion (LAMPA), Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Arts et Métiers Sciences et Technologies, HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), CHRU Brest - Laboratoire d'Anatomo-Pathologie (CHU - AnaPath), Université européenne de Bretagne - European University of Brittany (UEB), Michel, Geneviève, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], Institut national des sciences de l'Univers (INSU - CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), and HESAM Université (HESAM)-HESAM Université (HESAM)
Subjects: Pathology, medicine.medical_specialty, Cancer Research, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lymphoma, Mantle-Cell, 030204 cardiovascular system & hematology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, Tracheal Neoplasm, hemic and lymphatic diseases, medicine, Humans, Letter to the Editor, Molecular Biology, Aged, MESH: Aged, Hematology, MESH: Humans, business.industry, lcsh:RC633-647.5, lcsh:Diseases of the blood and blood-forming organs, MESH: Tracheal Neoplasms, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, medicine.anatomical_structure, Dyspnea, Oncology, MESH: Dyspnea, 030220 oncology & carcinogenesis, Acute Disease, MESH: Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mantle cell lymphoma, Tracheal Neoplasms, Bone marrow, MESH: Lymphoma, Mantle-Cell, business
Abstract: Background Mantle cell lymphoma is a lymphoid entity characterized by adenopathy, blood and bone marrow involment which only recurrent mucosal localisation is the lymphomatoid polyposis. Few other mucosal infiltrations have been already reported. Results We report here the first case of a unique tracheal localisation of mantle cell lymphoma at presentation of the disease. The presence of classical t(11;14)(q13;q32) confirmed the diagnosis of mantle cell lymphoma by eliminating MALT or cancer localisation. Conclusion This case illustrates the necessity to ensure the diagnosis of mucosal lymphoma versus MCL since these diseases need different treatment regimens and prognoses.
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