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1. Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial

Author

Stéphanie Dulucq, Franck E. Nicolini, Delphine Rea, Pascale Cony-Makhoul, Aude Charbonnier, Martine Escoffre-Barbe, Valérie Coiteux, Pascal Lenain, Françoise Rigal-Huguet, Jixing Liu, Agnès Guerci-Bresler, Laurence Legros, Jean-Christophe Ianotto, Martine Gardembas, Pascal Turlure, Viviane Dubruille, Philippe Rousselot, Juliana Martiniuc, Henry Jardel, Hyacinthe Johnson-Ansah, Bertrand Joly, Tawfiq Henni, Emilie Cayssials, Patricia Zunic, Marc G. Berger, Bruno Villemagne, Fanny Robbesyn, Stephane Morisset, François-Xavier Mahon, and Gabriel Etienne

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).

Published
2022
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2. Impact of renal impairment on outcomes with lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 trial in transplant-ineligible patients with multiple myeloma

Author

Meletios A. Dimopoulos, Matthew C. Cheung, Murielle Roussel, Ting Liu, Barbara Gamberi, Brigitte Kolb, H. Guenter Derigs, HyeonSeok Eom, Karim Belhadj, Pascal Lenain, Richard Van der Jagt, Sophie Rigaudeau, Mamoun Dib, Rachel Hall, Henry Jardel, Arnaud Jaccard, Axel Tosikyan, Lionel Karlin, William Bensinger, Rik Schots, Nicolas Leupin, Guang Chen, Jennifer Marek, Annette Ervin-Haynes, and Thierry Facon

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Renal impairment is associated with poor prognosis in myeloma. This analysis of the pivotal phase 3 FIRST trial examined the impact of renally adapted dosing of lenalidomide and dexamethasone on outcomes of patients with different degrees of renal impairment. Transplant-ineligible patients not requiring dialysis were randomized 1:1:1 to receive continuous lenalidomide and dexamethasone until disease progression (n=535) or for 18 cycles (72 weeks; n=541), or melphalan, prednisone, and thalidomide for 12 cycles (72 weeks; n=547). Follow-up is ongoing. Patients were grouped by baseline creatinine clearance into no (≥ 80 mL/min [n=389]), mild (≥ 50 to < 80 mL/min [n=715]), moderate (≥ 30 to < 50 mL/min [n=372]), and severe impairment (< 30 mL/min [n=147]) subgroups. Continuous lenalidomide and dexamethasone therapy reduced the risk of progression or death in no, mild, and moderate renal impairment subgroups vs. melphalan, prednisone, and thalidomide therapy (HR = 0.67, 0.70, and 0.65, respectively). Overall survival benefits were observed with continuous lenalidomide and dexamethasone treatment vs. melphalan, prednisone, and thalidomide treatment in no or mild renal impairment subgroups. Renal function improved from baseline in 52.6% of lenalidomide and dexamethasone–treated patients. The safety profile of continuous lenalidomide and dexamethasone was consistent across renal subgroups, except for grade 3/4 anemia and rash, which increased with increasing severity of renal impairment. Continuous lenalidomide and dexamethasone treatment, with renally adapted lenalidomide dosing, was effective for most transplant-ineligible patients with myeloma and renal impairment.

Published
2016
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3. Phase II study of bendamustine, bortezomib and dexamethasone as second-line treatment for elderly patients with multiple myeloma: the Intergroupe Francophone du Myelome 2009-01 trial

Author

Philippe Rodon, Cyrille Hulin, Brigitte Pegourie, Mourad Tiab, Bruno Anglaret, Lotfi Benboubker, Henry Jardel, Olivier Decaux, Brigitte Kolb, Murielle Roussel, Laurent Garderet, Xavier Leleu, Olivier Fitoussi, Carine Chaleteix, Philippe Casassus, Pascal Lenain, Bruno Royer, Anne Banos, Riad Benramdane, Pascale Cony-Makhoul, Mamoun Dib, Jean Fontan, Anne-Marie Stoppa, Catherine Traullé, Jean-Pierre Vilque, Marie-Odile Pétillon, Claire Mathiot, Thomas Dejoie, Hervé Avet-Loiseau, and Philippe Moreau

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2015
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4. Supplementary Data from Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients

Author

François-Xavier Mahon, Gabriel Etienne, Joëlle Guilhot, Fabrice Larosa, François Guilhot, Emilie Cayssials, Marc G. Berger, Bruno Villemagne, Tawfiq Henni, Patricia Zunic, Bertrand Joly, Henry Jardel, Juliana Martiniuc, Hyacinthe Johnson-Ansah, Pascal Turlure, Jean-Christophe Ianotto, Martine Gardembas, Jixing Liu, Laurence Legros, Agnès Guerci-Bresler, Delphine Rea, Philippe Rousselot, Pascal Lenain, Viviane Dubruille, Bruno Varet, Valérie Coiteux, Françoise Rigal-Huguet, Martine Escoffre-Barbe, Aude Charbonnier, Pascale Cony-Makhoul, Lisa Boureau, Stéphanie Dulucq, and Franck Emmanuel Nicolini

Abstract

Supplemental table 1: Sequence of hydrolysis probes and primers used for the ddPCR.

Published
2023

5. Data from Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients

Author

François-Xavier Mahon, Gabriel Etienne, Joëlle Guilhot, Fabrice Larosa, François Guilhot, Emilie Cayssials, Marc G. Berger, Bruno Villemagne, Tawfiq Henni, Patricia Zunic, Bertrand Joly, Henry Jardel, Juliana Martiniuc, Hyacinthe Johnson-Ansah, Pascal Turlure, Jean-Christophe Ianotto, Martine Gardembas, Jixing Liu, Laurence Legros, Agnès Guerci-Bresler, Delphine Rea, Philippe Rousselot, Pascal Lenain, Viviane Dubruille, Bruno Varet, Valérie Coiteux, Françoise Rigal-Huguet, Martine Escoffre-Barbe, Aude Charbonnier, Pascale Cony-Makhoul, Lisa Boureau, Stéphanie Dulucq, and Franck Emmanuel Nicolini

Abstract

Purpose:Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.Patients and Methods:We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.Results:A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively.Conclusions:We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.See related commentary by Yan et al., p. 6561

Published
2023

6. Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients

Author

Tawfiq Henni, Aude Charbonnier, Martine Escoffre-Barbe, Pascal Turlure, Franck E. Nicolini, Emilie Cayssials, Marc G. Berger, Agnès Guerci-Bresler, Pascale Cony-Makhoul, Juliana Martiniuc, François Guilhot, Jixing Liu, Joelle Guilhot, Gabriel Etienne, Jean-Christophe Ianotto, Patricia Zunic, Bruno Villemagne, Fabrice Larosa, Viviane Dubruille, Lisa Boureau, Henry Jardel, Philippe Rousselot, Laurence Legros, Françoise Rigal-Huguet, Stéphanie Dulucq, Bertrand Joly, Delphine Rea, Martine Gardembas, Francois-Xavier Mahon, Pascal Lenain, Hyacinthe Johnson-Ansah, Valérie Coiteux, Bruno Varet, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])

Subjects
Adult, Male, Oncology, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, medicine.drug_class, Fusion Proteins, bcr-abl, Phases of clinical research, Drug Administration Schedule, Article, Tyrosine-kinase inhibitor, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Prospective Studies, Prospective cohort study, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, Survival analysis, Aged, Gene Expression Regulation, Leukemic, business.industry, Remission Induction, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Imatinib, Middle Aged, Prognosis, medicine.disease, Survival Analysis, Confidence interval, 3. Good health, Discontinuation, Treatment Outcome, 030220 oncology & carcinogenesis, Leukemia, Myeloid, Chronic-Phase, Imatinib Mesylate, Female, Neoplasm Recurrence, Local, business, 030215 immunology, medicine.drug, Chronic myelogenous leukemia
Abstract

Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. Patients and Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. Results: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively. Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML. See related commentary by Yan et al., p. 6561

Published
2019

7. Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial

Author

Isabelle Soubeyran, Anne Moreau, David M. Goldenberg, Amandine Pallardy, Jean-Philippe Vuillez, Jacques Barbet, Loïc Campion, Olivier Tournilhac, Nadine Morineau, Caroline Bodet-Milin, Krimo Bouabdallah, Thierry Lamy, Etienne Garin, Philippe Moreau, Steven Le Gouill, Pierre Soubeyran, Pierre-Yves Salaun, Hervé Maisonneuve, Anne-Laure Cazeau, Bénédicte Deau, Sophie Sadot, Valérie Gouilleux-Gruart, Françoise Kraeber-Bodéré, Henry Jardel, Remy Gressin, Emmanuel Gyan, Christian Berthou, Etienne Daguindau, William A. Wegener, Marie-Pierre Moles, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie, Centre hospitalier La Roche-Sur-Yon, Centre René Gauducheau, CRLCC René Gauducheau, Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service d'hématologie clinique, Hôpital Hôtel-Dieu [Paris], Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias - Clermont Auvergne (CHELTER), Université Clermont Auvergne (UCA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Service de Médecine Interne, CH Bretagne Atlantique, Centre Catherine-de-Sienne [Nantes] (CCS), Université Mohamed Boudiaf de M'sila, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Grenoble-Hôpital Michallon, 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 de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Microenvironnement et remodelage, Service de médecine nucléaire, Centre régional de lutte contre le cancer-Centre régional de lutte contre le cancer, Radiopharmaceutiques biocliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement normal et pathologique des lymphocytes et signalisation, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Accélérateur pour la Recherche en Radiochimie et Oncologie [Nantes Atlantique] (GIP ARRONAX), Université de Nantes (UN)-Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Garden State Cancer Center (GSCC), Garden State Cancer Center, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service de Médecine Nucléaire [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Médecine Onco-hématologie [La Roche sur Yon], Centre Hospitalier Universitaire de Nantes, Génétique tumorale - Pathologie, UNICANCER-UNICANCER-CHU Bordeaux [Bordeaux], CIC Plurithématique de Nantes, Institut National de la Santé et de la Recherche Médicale (INSERM)-Ministère des Affaires sociales et de la Santé-Direction générale de l'offre de soins (DGOS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Médecine interne - Maladies hématologiques - Maladies infectieuses [Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), PRES Université Nantes Angers Le Mans (UNAM), 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), Institut de cancérologie et d'hématologie, Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Département de Médecine Nucléaire (NANTES - Médecine Nucléaire), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Médecine Nucléaire [Bordeaux], Foie, métabolismes et cancer, 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)-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 )-CRLCC Eugène Marquis (CRLCC), CHRU Brest - Service de médecine nucléaire (CHU - BREST - Med Nucléaire), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunomedics, Inc., Université de Rennes (UR)-Hôpital Pontchaillou, CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), 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 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 )-CRLCC Eugène Marquis (CRLCC), Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux [Bordeaux]-Centre Régional de Lutte Contre le Cancer Institut Bergonié (Bordeaux), Centre Hospitalier Bretagne Atlantique [Vannes], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Hôpital Morvan [Brest], CHU Cochin [AP-HP], and Institut Bergonié - CRLCC Bordeaux

Subjects
0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Chemoimmunotherapy, immune system diseases, Internal medicine, hemic and lymphatic diseases, medicine, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, business.industry, Induction chemotherapy, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, 3. Good health, Surgery, Transplantation, 030104 developmental biology, 030220 oncology & carcinogenesis, Radioimmunotherapy, Rituximab, business, Epratuzumab, Diffuse large B-cell lymphoma, medicine.drug
Abstract

BACKGROUND: Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 (90)Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma. METHODS: We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m(2)], cyclophosphamide [750 mg/m(2)], doxorubicin [50 mg/m(2)], and vincristine [1·4 mg/m(2), up to 2 mg] all on day 1, and prednisone [40 mg/m(2)] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m(2) (555 MBq/m(2)) (90)Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841. FINDINGS: Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy. INTERPRETATION: Fractionated radioimmunotherapy with (90)Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed. FUNDING: Immunomedics, Amgen, Canceropole Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).

Published
2017

8. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study

Author

Odile Fremin-Batteux, Juliette Clarissou-Philippe, Benoît Jauhlac, Severine Guyetand, Jacques Gasnault, Corinne Haioun, Liamine Aissaoui, Marie-Christine Pages, Marie-Pierre Fos, Christian Rose, Didier Hubert, Marie-Rose Rothe, N. Bouziges, Benoît Huc, François Devianne, Sabine Bidart, Anne Forest, Kevin Bertrand, Mohamed Eldeghedy, Annick Verhaeghe, Caroline Malderet, Anne Bertrou, Bernard Guerquin, Catherine Duche, Muriel Archambaud, Rabea Cotteret, Olivier Toullalan, Yves Devaux, Smail Bergheul, Valérie Sivadon-Tardy, Pierre-Gilles Merville, Geneviève Blanchard-Marche, Didier Raoult, Bernard Hory, Florence Richardin, Evelyne Belle, Mohamed Menouar, K Guitteaud, Mohamad Mohty, Ambroise Montcriol, Max Laurin, Aurélia Picard, Jean-Paul Mira, Marie-Charlotte Chopin, Richard Bonnet, Michel Wolff, Sébastien Maillez, Jeanne Maugein, Véronique Leblond, Nicola Walid, Bernard Gauche, Mathieu Evillard, Hassen Jeddi, Anne Bourlet, Isabelle Grawey, Thierry Jault, Sandrine Hiret, Valerie Gaborieau, Véronique Boin-Gay, An Kim, Thierry Constans, Jean-François Gaide, Martine Giraud, Eric Meaudre Desgouttes, Alain Fur, Abdallah Maakaroun, Olivier Matray, Bertrand Maubert, Frédérique Péchinot, Aurelie Garbi, Claire Delbrouck, Benoît Grandclerc, Vincent Cadiergue, Hervé Lécuyer, Bernadette Grignon, Thierry Bensaid, Nicole Constantin, Yannick Chevalier, Hassène Rahmani, Thierry Levent, Joelle Desliers, Florence Van de Velde, Xavier Adhoute, Clara Andriau, Christophe Charasse, Rémi Vatan, Benoît Martha, Alain Lecis, Didier Albert, Romain Jacobs, Hélène Lefranc, Christian Martin, Nasseur Rezgui, Bertrand Pigeon, Catherine Le Henaff, Dominique Cassignard, Françoise Cotes, Eric Pujade Lauraine, Jean-François Gattault, Nicole Ferreira-Maident, Noémie Jourde-Chiche, Hélène Garrec, Olivier Darchen, Carole Schwebel, Marie-Christine Bezian, Patrick Daoud, Tsouria Becaid, Simone Laluque, David Broche, Christine Boisselier, Pascale Martres, Sarah Hammami, Brigitte Olivier, Jean-Marie Nkunzimana, Eric Monlun, Isabelle Marterl-Lafay, Marion Carboni, Marie-Françoise Mattei, Sandrine Castelin, Isabelle Barillot, Marie-Noelle Cufi, Thomas Kaiser, Catherine Herry, Pascal Hutin, Jean-Pierre Bronowicki, Bernard Branger, Pierre Thomas, Elie Zagdoun, Anne Goquelin, Ziad Assaf, Ingrid Croquet, Bruno Pozzetto, Thomas Similowski, Anne-Isabelle Briere, Marie-Thérèse Albertini, Mariam Blaka, Christelle Tassot, Anne Gaschet, Jean-Philippe Lavigne, Antoine Pujol, Philippe Colombat, Edouard Devaud, Hana Talabani-Boizot, François Barière, Anne-Marie Cordier, Philippe Gueudet, Georges Simon, Anne-Sophie Lipovac, Françoise Bandaly, Anne Beauplet-Lepage, Sylvie Prince, Charlotte Jouzel, Jean-Luc Deboutin, Patrick Zavadil, Louis Puybasset, Marie-Cécile Petit, Loïc Guillevin, Kamel Touati, Christophe Ntalu Nkato, Sylvie Carette, Jacques Vaucel, Chantal Delasalle, Marine Gross Goupil, Laurent Gutmann, Christiane Payen, Annick Barboteau, Firouzé Bani-Sadr, Christophe Legendre, Philippe Roulier, Elie Azria, Ibrahim Farah, Isabelle Rouquette-Vincent, Anne-Sophie Erena-Penet, Philippe Labadie, Eric Josien, Aicha Derragui, Mathieu Legrand, Odile Beyne-Rauzy, Jean-Marc Nabholtz, Marie-Joelle Demarcq, Olivier Garosi, Michel Deiber, Fabrice Chaix, Bertrand Souweine, Anne Collignon, Gisèle Renard, Mickael Jego, Gilles Bernardin, Anne Allart, Jocelyn Barrier, Marc Vasse, Philippe Ménager, Marc Wurmser, Abderkader Ouazir, Olivier Gontieron, Yvon Berland, Sébastien Trouiller, David Leysenne, Christophe Ozanon, Fanny Autret, Tahar Saghi, Loïc Dopeux, Sophie Benoit-Coustou, T. 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Eugène Ngami, Fabrice Mihout, Cecilia Esnault, Vincent Bouden, Véronique Annaix, Yves Poinsignon, Aurélien Lorchleac'h, Jean-Marc Degreff, Marie Garofano, Renaud Mesnage, Anne-Marie Roque-Afonso, Alain Chevailler, Stéphane Hominal, Thierry Charbonnier, Adrianna Bildea, Fabien Fily, Benjamin Davido, Emmanuel Rassiat, Assi Assi, Stéphanie Brunet, Hervé Jacquier, Catherine Claise, Annie Durand, Yannick Monceau, Pierre Blanc, Jean-Marie Sire, Yves Sucin, Jean-Pierre Zarski, Nathalie Bronet, Ingrid Lafon, Philippe Rey, Jacques Markarian, Eric Sennevile, Olivier Wink, Guilène Barnaud, Anne-Sophie Peultier, Sabine Taylor, Rim Savatier, Patrick Valayer, Claude Negrier, Selim Jennane, Edouard Begon, Laura Hyerle, Delphine Bridoux, Claire Daurel, Benoît Dalle, Mathilde Lescat, Philippe Stolidi, Elodie Perrodeau, Xavier Heches, Pierre Castelnau, Philippe Bray, Jean-Claude Texier, Serge Rossignol, Maud Brung-Lefebvre, Jean-François Subra, Jean-Marie Delarbre, Morgane Schneerson, Guyro Jang, Mona Mehri, Nathalie Landgraf, Pierre-Marie Girard, Armand Goll, Zaineb Bekguesmia, Christophe Clement, Michel Collet, Vincent Maze, Amine Benjelloul, Solène Durliat-Ellie, Vincent Letouzey, François Schmitt, Valérie Martinez, Sarah Watson, Abderrezak Bouasria, François Barbier, Raphael Lauretta, Mirana Razafimahery, Cristina Sirbu, Patrick Malherbe, Anne Wuillai, Ludovic Lesecq, Philippe Gaudard, Serge Houssaye, Jacques Monsegu, Gilles Rival, Chantal Chaplain, Jean-Didier Grangé, Oana Zamfiri, Florence Nguyen-Khac, Marc Portneuf, Jean-Michel Pawlotsky, Delphine Bonnet, Laurent Traissac, Sophie Hamon-Charles, Didier Dreyfuss, Louis Bernard, Laurence Detourmignies, Olivier Martineau, François Pettinelli, Marc Zandecki, Michel Dreyfus, Alain Chapelle, Sébastien Sabbat, Anne-Sophie Labussiere, Jean-Louis Gaillard, Chloé Plouzeau-Jayle, Patrick Zoveda, Véronique Leflon, Marie Levy, Aurélie Labé, Bruno Soulie, Raoul Jacques Bensaude, Hecham Moussa, Sylviane Catteu, Nathalie Biron, Loïc Masson, Georges Mourad, Nejla Aissa, Dragos Ciocan, Hubert De Boysson, Jean-Luc Bouyer, Patrick Yeni, Thierry-Pascal Zame, Caroline Thomas, François Cavalié, Laurence Koulmann, Christophe Rioux, Olivier Barraud, François Bricaire, Marguerite Le Poulain, Marie-Noelle Noulard, René Thomas, Guy Semet, Laurent Mosser, Olivier Marret, Brigitte Rivière, Vincent Jarlier, Jean-Philippe Coindre, Marc Villemain, Martin Pierre, Yacine Benkaci, Philippe Chiron, Hoang Vu-Thien, Jérôme Gournay, Andrea Labaune-Kiss, Brigitte Lauzanne, Fanny Lemercier, Souad Silhadi, Imad Kansau, Christophe Poncelet, Olivier Baldesi, Francis Thuet, Olivier Leroy, Aurore Lamberet, Camille Petit Hoang, Sophie Micheli, Ayman Abokasem, Hakima Nesrine, Pierre Lureau, Christian Chidiac, Vincent Piriou, Fabien Zoulim, Dieudonné Nicobaharaye, Anne Tixier, Isabelle Matheron, Soumeth Abasse, Victoria Cacheux, Serge Herson, Christine Fuhrmann, Olivier Proost, Bernard Bedock, Olivier Rogeaux, Mostapha Hajjar, Anne Reverseau, René Courcol, Françoise Carmagnol, Yves Guénard, Céline Ménard, Bouchra Lamia, Bruno Lemmens, Damien Bouhour, L. Lequen, Gaëlle Baty, Cédric Bouet, Dominique Guerrot, Stéphane Blanc, Catherine Chirouze, Anne-Hélène Reboux, A. Vachée, Gregory Taurin, Myriam Mein-Bottini, Jean-Pierre Belot, Alain Lafeuillade, Patricia Gabez-Therou, Philippe Labrousse, Bernard Jarrousse, Philippe Noto, Vincent Brunot, Philippe Condominas, Marion Challier, Béatrice Berçot, Delphine Anuset, Mélanie Daval Cote, François Bernasconi, Y. Costa, Chandrah Goburdhun, Bernard Gressier, Alban Michaud-herbst, Franck Charlier, Moussa Hecham, Luc Boulain, Hélène Corneloup, Alix Greder Belan, Nicolas Boussekey, Claire-Antoinette Dupuy, Yannick Rouquet, Benoit Renard, Benifla Jl, Etienne Javouhey, Michèle Granier, Marie-Christine Jaffarbandjee, Emilie Piet, Benoît Bergues, Claire Malbrunot, Catherine Tiry, Philippe Mérigot, Mouna Ben Soltana, Chantal Roure Sobas, Florian Radenac, Yves Thomas, Agathe Blaise, Sylvie De Martino, Laurence Legout, Gabriel Choukroun, Jean-François Muir, Peggy Dupretz, Patrick Dupont, François Guichart, Julie Jean, Jean-Michel Descamps, Bernard Kittschke, Anne Gruson, Gerard Viquesnel, Marie Keller, Pascal Chavanet, Françis Vallet, Yvan Vaschalde, Jean-Luc Hanouz, Gerard Lina, Françoise Loison, Simon Vincent, Jean-Paul Thellier, Moncef Afi, Dominique Zagozda, Hélène Sokeng-Affoule, Marc Le Bideau, Jean-François Loriferne, Alain Gravet, Sophie Deprecq, Tarik Naceur, Severine Mielczarek, René-Jean Bensadoun, Bernard Karkous, Yves Bléher, Jocelyne Poulain, Véronique Goulet, Laurence Nicolet, Sophie Arista, Antônio Lúcio Teixeira, Jean-François Schved, Laurent Nicolet, Claire Lecomte, Faiza Benddif-Fin, Michel Aumersier, Laurence Burc-Struxiano, Maxime Thouvenin, Samia Harbi, Mathieu Detave, Catherine Rebeyrotte, Jean-Paul Kisterman, Bruno Berdin, Pascal Vincent, Laurent Argaud, Elisabeth Parisi-Duchene, Geneviève Julienne, Fernanda Farto-Bensasson, Georges-Fabrice Blum, Sad Gaizi, Tali-Anne Szwebel, Raphaël Lepeule, Marie-Thérèse Climas, Anne-Françoise Dillies, Amar Boudhane, Umberto Simeoni, Pierre-François Dequin, Gérard Oliviero, Alain Gourlaouen, Caroline Piau, Marie-France Lutz-Murphy, Benoît Claude, Jean-Paul Aubry, Nadine Dubosc-Marchenay, Kamilla Chraibi, Emmanuelle Heusse, Sylvain Le Chevallier, Nathalie Brieu, Farid Sifaoui, Lorraine Letranchant, Hélène Durox, Jean-Pierre Lagasse, Adel Ghedira, Xavier Roubert, Fatma Magdoud, Hélène Jean-Pierre, Etienne Carbonelle, Olivier Dereeper, Lionel Carbillon, Christophe Billy, Mélanie Roblin, Marie-José Kodzin, Philippe Niel, Solène Makdessi, Matteo Vassallo, Maryse Archambaud, Fabian Haccourt, Didier Blaise, Stéphane Bourgeois, Elena Marcu, Charles Kubiak, Brisse Castel, François Guinet, Marie Pouzoullic, Frédérique Nathan-Bonnet, Vincent Gendrin, Céline Becherrawy, Aline Secher, Pierre Abgueguen, Clarence Eloy, Jean-Marc Tourani, Frédéric Klapczynski, Bernard Montmasson, Philippe Real, Joanna Pofelski, Yves Welker, Karim Krechiem, Eric Caumes, Martine Elena-Daumas, Christophe Saigne, Gilles Hittinger, Chantal Delesalle, Jonathan Messika, Fabrice Lesage, Daniela Pop, Daniel Coetmeur, Renato Colamarino, Chetaou Mahaza, Patrick Plésiat, Isabelle Fredenucci, Mylène Baret, Guy Mager, Pascale Chavel, Isabelle Labourdette, Anne-Claude Menguy, Nicolas Fortineau, Ludovic Le Sec, Valérie Gauduchon, Francis Barraud, Nicolas Letellier, Didier Vincent, Janine Frey, Philippe Riegel, Michel Pavic, Jean-Luc Fabre, Jean-Pierre Fauchart, Alain Goudeau, Stéphanie Husson-Wetzel, Philippe Eymerit, Mohamed Camara, Nathalie Seta, Elisabeth Carole Ngo Bell, Philippe Repellin, Laurent Alric, Vincent Leroy, Françoise Delisle Mizon, Jean-Philippe Emond, Marie-Françoise Borie, Lise Crémet, Wladimir Chelle, Elisabeth Brottier-Mancini, Bernard Garrigues, Claire Letellier, Loïc Geffray, Frédéric Méchaï, Julien Bador, Benoit Guery, Alain-Charles Fouilhoux, Corinne Dagada, Pierre Duhaut, Julien Goustille, Arnaud Sément, Francis Carcenac, Isabelle Girard-Buttaz, Claire Chapuzet, Fabienne Jouatte, Bruno Riou, Fabrice Hayoun, Chloé Di Meglio, Youssef Ali, Michel Leneveu, Nathalie Montagne, Yves Garcera, Audrey Moustache, Pierre-Eric Danin, Geneviève Le Lay, Dominique Courouge-Dorcier, Isabelle Worcel, Emmanuel Morelon, Vincent Pestre, Jean-Pierre Vilque, Jean-Christophe Paquet, Lucien Bodson, Anne-Marie Forest, Fabrice Pierre, Christian Pommier, Fabien Dutasta, Pierre Fournel, Stéphanie Courtois, Elodie Dubois, Serge Vanden Einjden, Patrick Honderlick, Pascal Richette, Fabienne Tamion, Véronique Chassy, Richard Megbemado, Anne-Marie Le Reste, Bernard Simian, Henri Osman, Anthony Texier, Badih Ayach, François Simon, Jean-Michel Filloux, Béatrice Dubourdieu, Jean-Claude Semet, Sarah Kubab, Tawfiq Henni, Patrick Dudeffant, Delphine Hequet, Olivier Mimoz, Marc Auburtin, Amélie Chabrol, Mickael Bonnan, Caroline Léonnet, Claire Wintenberger, Serge Ilunga, Patrice Lanba, Sophie Rosello, Alexandre Damage, Flore Bouche, Michel Thibault, Frederic Faibis, Chantal Dhennain, Jean-Philippe Talarmin, Armelle Lamour, Remi Boussier, Fabien Garnier, Marie-Laure Brival, Nourredine Hedjem, Philippe Vande-perre, Raphaël Coint, Jean-Claude Reveil, Eva Weinbronn, Emmanuelle Lavalard, Alexandra Fille, Françoise Le Turdu, Lionel Leroux, Jean-Yves Lefrant, Jean Berthet, Radia Bouaziz, Alain Ravaud, Sylvaine Rousseau, Yacine Merrouche, Alain Le Coustumier, Bertrand Guider, Gisèle Dewulf, Jean-Marc Faucheux, Jacques Piquet, Franck Leibinger, Charles Cerf, Robin Stephan, Jean-Philippe Redonnet, Jean-Paul Stahl, Ella Dzeing, Simona Pavel, Guy Vernet, Ghada Hatem, Samer Kayal, Jacques Deschamps, Dominique Descamps, Marion Levast, Marc Bouiller, Sylvie Dargere, Claire Dingremont, Stéphane Gaudry, François Maillot, Sylvie Odent, Nathalie Cervantes, Hélène Zanaldi, Laurence Gachassin, Olivier Ruyer, David Patin, Benoît Cazenave, Pascal Jacquier, Michelle Boyer, Béatrice Berteaux, Virginie Zarrouk, Jacques Bor, Isabelle Legoff, Hélène Albinet, Florence Rousseau, Gilles Pialoux, Guenaelle Salaun-Beretta, Alexandra Moura, Véronique Vernet Garnier, Didier Lepelletier, Pierre-Alexandre Hauss, Joëlle Belaisch-Amart, Didier Lepeletier, Jacob Xavier, Aline Nare, Annie Motard-Picheloup, Alain Améri, Bertrand Lioger, Jean-Valère Malfuson, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-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 Référence Listeria - National Reference Center Listeria (CNRL), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Département de Médecine interne [Lariboisière], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Biologie des Infections - Biology of Infection, Service de Gynécologie et Obstétrique [Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP), Infectious Disease Department [Saint Maurice], Agence Nationale de la Santé Publique [Saint-Maurice] (ANSP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, MONALISA study group, Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency., ROZIER, marie-Claire, CHU Necker - Enfants Malades [AP-HP], Centre National de Référence Listeria - Biologie des Infections (CNRL), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre collaborateur de l'OMS Listeria - Biologie des Infections (CCOMS), CHU Pitié-Salpêtrière [APHP], Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Institut Pasteur [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre National de Référence Listeria - Biologie des Infections ( CNRL ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre collaborateur de l'OMS (CCOMS) des Listeria ( CCOMS ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Institut National de la Recherche Agronomique ( INRA ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Hôpital Lariboisière, Biologie des Infections, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Agence Nationale de la Santé Publique [Saint-Maurice] ( ANSP ), Assistance Publique - Hôpitaux de Paris, Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur [Paris]-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Bacteremia/epidemiology/mortality, 0301 basic medicine, Male, Pediatrics, bacteraemia, Infectious Disease Transmission, [SDV]Life Sciences [q-bio], Bacteremia, France/epidemiology, Infant, Newborn, Diseases, Foodborne Diseases, Meningoencephalitis, Pregnancy, Risk Factors, Vertical, Medicine, Listeriosis, Prospective Studies, Pregnancy Complications, Infectious, Prospective cohort study, ddc:618, diabetes, alcoholism, Hazard ratio, Foodborne Diseases/microbiology, immuno suppressive therapies, Prognosis, 3. Good health, [SDV] Life Sciences [q-bio], Hospitalization, Infectious Diseases, isolates, Population Surveillance, Female, France, Listeria monocytogenes/classification/isolation & purification, Cohort study, Adult, medicine.medical_specialty, 030106 microbiology, Notifiable disease, Listeriosis/diagnosis/epidemiology/microbiology, Context (language use), macromolecular substances, 03 medical and health sciences, Humans, study, Aged, [ SDV ] Life Sciences [q-bio], business.industry, Public health, cirrhosis, Infant, Newborn, Infant, Diseases/epidemiology/microbiology, HIV, Mandatory Reporting, Newborn, medicine.disease, Listeria monocytogenes, infection, Infectious Disease Transmission, Vertical, Pregnancy Complications, Infectious/epidemiology/microbiology, Meningoencephalitis/epidemiology/microbiology/mortality, Observational study, business, prognostic, mellitus
Abstract

International audience; Evidence before this study We searched PubMed on June 30, 2016, for English-language cohort studies published since Jan 1, 1980, of patients with invasive listeriosis worldwide with the keywords " listeria " , " listeriosis " , " maternal " , and " neurolisteriosis ". Studies had to include epidemiological or clinical data on listeriosis. All clinical forms of infection were included (bacteraemia, neurolisteriosis, and maternal–neonatal infection). Host risk factors for listeriosis have been well identified, but the clinical features and prognostic factors of the disease are based on retrospective studies compiling heterogeneous data or random collected cases. Furthermore, no clinical trial has ever been done and medical management is not evidence based. Added value of the study Our study is the first prospective clinical study focusing on all forms of invasive listeriosis. The study is based on a national mandatory system that allowed the nearly complete capture of microbiologically proven cases. The study shows a higher burden of listeriosis than reported before: more than 80% of infected mothers experienced major fetal or neonatal complications (fetal loss, very high prematurity, early or late onset disease); only 39% of patients with neurolisteriosis survived and fully recovered. The study provides important new data to improve management and predict outcome in listeriosis, such as determination of the time window for fetal losses (

Published
2016

9. Consolidation anti-CD22 fractionated radioimmunotherapy with

Author

Françoise, Kraeber-Bodere, Amandine, Pallardy, Hervé, Maisonneuve, Loïc, Campion, Anne, Moreau, Isabelle, Soubeyran, Steven, Le Gouill, Olivier, Tournilhac, Etienne, Daguindau, Henry, Jardel, Nadine, Morineau, Krimo, Bouabdallah, Emmanuel, Gyan, Marie-Pierre, Moles, Remy, Gressin, Christian, Berthou, Sophie, Sadot, Philippe, Moreau, Bénédicte, Deau, Caroline, Bodet-Milin, Anne-Laure, Cazeau, Etienne, Garin, Pierre-Yves, Salaun, Jean-Philippe, Vuillez, Valérie, Gouilleux-Gruart, Jacques, Barbet, William A, Wegener, David M, Goldenberg, Thierry, Lamy, and Pierre, Soubeyran

Subjects
Male, Sialic Acid Binding Ig-like Lectin 2, Middle Aged, Radioimmunotherapy, Antibodies, Monoclonal, Humanized, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Agents, Immunological, Treatment Outcome, Doxorubicin, Vincristine, Antineoplastic Combined Chemotherapy Protocols, Humans, Prednisone, Female, Yttrium Radioisotopes, Lymphoma, Large B-Cell, Diffuse, Prospective Studies, Rituximab, Cyclophosphamide, Aged
Abstract

Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/mBetween Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy.Fractionated radioimmunotherapy withImmunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).

Published
2016

10. Supplémentation en vitamine D : une hypercalcémie iatrogène chez un patient infecté par le VIH et atteint de tuberculose disséminée

Author

Yves Cano, Anabèle Dos Santos, Henry Jardel, Françoise Floc’h, Yves Poinsignon, and Alain Lescoat

Subjects
Gynecology, medicine.medical_specialty, Tuberculosis, biology, business.industry, Metabolic disorder, Retinol, General Medicine, medicine.disease, biology.organism_classification, chemistry.chemical_compound, Acquired immunodeficiency syndrome (AIDS), chemistry, Immunopathology, medicine, Vitamin D and neurology, Viral disease, business, Sida
Published
2012

11. Upfront allogeneic stem-cell transplantation for patients with nonlocalized untreated peripheral T-cell lymphoma: an intention-to-treat analysis from a single center

Author

Marion Loirat, Patrice Chevalier, Christophe Leux, Anne Moreau, Céline Bossard, Thierry Guillaume, Thomas Gastinne, Jacques Delaunay, Nicolas Blin, Beatrice Mahe, Viviane Dubruille, Karine Augel-Meunier, Pierre Peterlin, Herve Maisonneuve, Nadine Morineau, Philippe Moreau, Henry Jardel, Mohamad Mohty, and Steven Legouill

Subjects
Oncology, Adult, Male, medicine.medical_specialty, medicine.medical_treatment, Immunology, Kaplan-Meier Estimate, Single Center, Biochemistry, Disease-Free Survival, hemic and lymphatic diseases, Internal medicine, Medicine, Humans, Transplantation, Homologous, Progression-free survival, Aged, Chemotherapy, Predictive marker, Intention-to-treat analysis, business.industry, Hematopoietic Stem Cell Transplantation, Induction chemotherapy, Lymphoma, T-Cell, Peripheral, Cell Biology, Hematology, Middle Aged, medicine.disease, Chemotherapy regimen, Peripheral T-cell lymphoma, Surgery, Intention to Treat Analysis, Transplantation, surgical procedures, operative, Cord blood, Feasibility Studies, Female, business
Abstract

This study addressed the question of upfront allo-SCT in untreated PTCL patients (n = 49). The 2-year OS rate was 59% but 72.5% for transplanted patients (n = 29). Disease status at the time of transplantation was predictive marker for PFS/OS. This work shows that upfront allo-SCT is feasible with low TRM and provide long-term disease control in PTCLs but one-third of patients is chemo-refractory. Background Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases with dismal outcome when treated with chemotherapy alone. Because allogeneic stem-cell transplantation (allo-SCT) can cure relapse/refractory patients, we hypothesized that upfront allo-SCT may provide a better outcome. Therefore, all patients that presented with advanced PTCL in our institution at diagnosis were scheduled to undergo upfront allo-SCT after induction chemotherapy. Patients and methods The aim of the present work was to assess the feasibility and toxicity of upfront allo-SCT. From 2004 to 2012, 49 newly diagnosed PTCL patients were scheduled to receive upfront allo-SCT. A human leukocyte antigen-matched donor was found for 42 patients: related to the patient in 15 cases, unrelated in 20 cases, and suitable cord blood units were used in 7 cases. Results After induction chemotherapy, 17 patients reached complete remission and 29 (60%) proceeded to upfront allo-SCT. For all patients, the 1 and 2-year overall survival (OS) rates were 59% [95% confidence interval (CI) 47–75] and 55% (95% CI 43–71), respectively. The most frequent reason we did not proceed to allo-SCT was disease progression or insufficient response after induction. For transplanted patients, the 1- and 2-year OS were 76% (95% CI 62–93) and 72.5% (95% CI 58–91), respectively. Toxicity-related mortality (TRM) 1 year after allo-SCT was only 8.2% (95% CI 0–18.5). The 2-year progression-free survival (PFS) rate of patients who did not proceed to allo-SCT (n = 20) was below 30%. The disease status at the time of transplantation was a strong predictive marker for both PFS and OS in transplant patients. Conclusions Upfront allo-SCT in PTCLs is feasible with low TRM, and it provides long-term disease control. However, one-third of patients remain chemo-refractory and, thus, new therapeutic approaches are warranted. The role of upfront allo-SCT compared with other therapeutic approaches in PTCLs requires investigation in randomized studies.

Published
2014

13. Cereblon (CRBN) Splicing Could Influence Response To IMiDs : A New PCR Strategy to Easily Detect and Semi-Quantify Loss Of The IMiDs Binding Domain

Author

Audrey Ménard, Cyrille Touzeau, Anne Lok, Martine Amiot, Catherine Pellat-Deceunynck, Sophie Maiga, Florence Magrangeas, Stephane Minvielle, Nicolas Blin, Beatrice Mahe, Viviane Dubruille, Benoit Tessoulin, Maxime Halliez, Soraya Wuillème, Nelly Robillard, Philippe Moreau, Hervé Maisonneuve, Henry Jardel, Marie C. Bene, and Laurence Lodé

Subjects
Sanger sequencing, Mutation, Cereblon, Immunology, Alternative splicing, Cell Biology, Hematology, Biology, medicine.disease_cause, Biochemistry, Molecular biology, Exon skipping, symbols.namesake, Exon, RNA splicing, symbols, medicine, Gene
Abstract

Cereblon (CRBN) was recently identified as a protein binding immunomodulatory drugs (IMiDs) (Ito et al., 2010, Lopez-Girona et al., 2011) essential for the activity of thalidomide, lenalidomide and pomalidomide in patients suffering from multiple myeloma (MM) (Zhu et al., 2011 & 2012). It is known that some patients develop resistance to these drugs, raising the question of a possible role of CRBN alterations (mutations, deletions, loss of transcription...) in the development of such treatment escapes (Broyl et al., 2012, Heintel et al, 2013). Ito et al (2010) showed that loss of the C-ter fragment of CRBN or missense mutations (Y384A and W386A) in the thalidomide binding domain (TBD) indeed impair the efficacy of this drug. We investigated whether the loss of CRBN expression, particularly of full length isoforms including exons 10 and 11 encoding TBD, or missense mutations could be detected by polymerase chain reaction (PCR) followed by fragment-length analysis or Sanger bidirectional sequencing. This method was applied to a cohort of 19 patients issued from a consecutive cohort of 45 elderly patients treated with lenalidomide and dexamethasone for relapsed or refractory MM (Touzeau et al., 2012). RNA was extracted from plasma cells purified by CD138 immunomagnetic sorting (STEM CELLS® beads) at the time of diagnosis. Sanger sequencing performed on RT-PCR products revealed no missense mutations but disclosed a high frequency of alternative splicing of CRBN in samples from MM patients (Lodé et al 2013). We thus developed a new PCR strategy to detect and semi-quantify alternative spliced isoforms of CRBN involving or not a loss of CRBN specific domains, focusing on exons 10 and 11. Two PCR were performed with custom-made primers: PCR-1 was designed to encompass the whole coding sequence of CRBN and PCR-2 was specifically designed to cover TBD. Fragment-length analysis of fluorescent PCR-2 products was obtained by capillary electrophoresis on an Applied Biosystems 3130xl Genetic Analyser (Applied Biosystems, Foster City, CA) allowing for precise sizing and semi-quantification by assessing the height of peaks. This PCR strategy was highly efficient to detect both unspliced CRBN transcripts (PCR-1 and PCR-2 fragments detected at 1562 nucleotides (nt) and 568nt, respectively) and CRBN alternatively spliced variants. The sizing strategy chosen allowed to identify exon skipping. For instance, PCR-2 fragments without exon 10 were visualized as peaks of 234nt, 319nt and 436nt depending on the presence or not of exons 7, 8 and 9. Alternative CRBN splicing in TBD was seen in nearly all patients of this cohort. Examples of representative splicing patterns are shown in figure 1. Semi-quantification of CRBN spliced transcripts showed that 58% of patients had lost more than 50% of CRBN full-length isoform and that 37% had lost more than 50% of exon10. Of note, two patients with a very short duration of response to lenalidomide and dexamethasone (16 days and 58 days respectively) had lost more than 95% of full-length CRBN and more than 90% of exon 10 (see MM6179 in figure1) in initial samples in spite of proper detection of an actin fragment of 858nt.Figure1Figure1. The fragment-length PCR analysis presented here demonstrates that CRBN splicing profiles in MM patients are very heterogeneous. A correlation with response to treatment was not established in this rather small cohort of patients, but this could be due to the fact that diagnosis samples were collected too early in relation to the time of initiating lenalidomide treatment. Indeed, CRBN splicing could be therapy-induced. A prospective study is needed to determine whether the semi-quantification of CRBN alternatively spliced variants would indeed correlate with, or even predict, clinical response to IMiDs. Moreover, further mutation studies are needed to elucidate the heterogeneity of splicing profiles which could reflect the presence of subclonal mutations in genes encoding the splicing machinery. Disclosures: Moreau: CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

Published
2013

14. Bendamustine, Bortezomib and Dexamethasone (BVD) In Elderly Patients With Multiple Myeloma In First Relapse: Final Analysis Of The Intergroupe Francophone Du Myelome (IFM) 2009-01 Trial

Author

Philippe Rodon, Cyrille Hulin, Brigitte Pegourie, Mourad Tiab, Bruno Anglaret, Lotfi Benboubker, Henry Jardel, Olivier Decaux, Brigitte Kolb, Murielle Roussel, Laurent Garderet, Xavier Leleu, Olivier Fitoussi, Carine Chaleteix, Philippe Casassus, Pascal Lenain, Bruno Royer, Anne Banos, Riad Benramdane, Pascale Cony-Makhoul, Mamoun Dib, Jean Fontan, Anne-Marie Stoppa, Catherine Traulle, Jean-Pierre Vilque, Marie-Odile Petillon, Claire Mathiot, Hervé Avet-Loiseau, and Philippe Moreau

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Background Prognosis of relapses is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1stline treatment. Methods Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0-2, ANC > 1.5x109/l, platelets > 100x109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 day 1-8, V 1.3 mg/m2 day 1-8-15-22 and D 20 mg day 1-8-15-22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: Melphalan-Prednisone (MP) in 12, MP-Thalidomide in 42, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 5. Median treatment cycles administered was 7 (1-12). 51 pts (69.8%) achieved at least partial response [best response CR: 10 pts (13.6%), VGPR: 12 pts (16.5%), PR: 29 pts (39.7%), MR: 4 pts (5.5%), SD: 5 pts (6.8%), progression: 12 pts (16.5%), unrelated early death: 1 pt (1.3%)]. Median PFS was 10.8 months (95%CI: 7-18.2 months) and median OS 23 months (15.4-27.5). Adverse prognostic factors for PFS were PS ECOG 2 (p=0.0002), beta 2 microglobulin level > 3.5 mg/l (p=0.0006) and del17p (p=0.01). 26 pts (35.6%) completed the planned 12 cycles of treatment. Cause of treatment discontinuation was progressive MM in 30 pts (41.1%), failure to achieve PR in 5 pts (6.8%), adverse event in 10 pts (13.6%), patient refusal and unknown 1 pt (1.3%) each. 37 pts (50.6%) had died at time of final analysis. Cause of death was MM in 30 pts, sepsis in 5 pts, renal failure in 1 pt and unrelated in 1 pt. Grade 3-4 adverse events were neutropenia: 14 pts (19.1%), thrombocytopenia: 8 pts (10.9%), sepsis: 14 pts (19.1%), gastro-intestinal: 6 pts (8.2%), anaphylaxis: 2 pt (2.7%). Grade 2 peripheral neuropathy occurred in 8 pts (10.%) and grade 3 in 3 pts (4.1%). Conclusions In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favourably with those achieved with VD or LD. Disclosures: Roussel: CELGENE: Honoraria; JANSSEN: Honoraria. Leleu:CELGENE: Honoraria; JANSSEN: Honoraria. Cony-Makhoul:BMS: Honoraria. Avet-Loiseau:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau. Moreau:Janssen: Honoraria; Janssen and Millennium: Membership on an entity’s Board of Directors or advisory committees.

Published
2013

15. Bendamustine, Bortezomib and Dexamethasone (BVD) in Elderly Patients with Multiple Myeloma in First Relapse: Updated Results of the Intergroupe Francophone Du Myelome (IFM) 2009-01 Trial

Author

Olivier Fitoussi, Brigitte Kolb, Marie Odile Petillon, Philippe Rodon, Laurent Garderet, Cyrille Hulin, Olivier Decaux, Claire Mathiot, Brigitte Pegourie, Pascal Lenain, Xavier Leleu, Henry Jardel, Bruno Anglaret, Mourad Tiab, Philippe Moreau, Hervé Avet-Loiseau, Carine Chaleteix, Murielle Roussel, Lotfi Benboubker, and Philippe Casassus

Subjects
Bendamustine, Melphalan, medicine.medical_specialty, business.industry, Immunology, Cell Biology, Hematology, Neutropenia, medicine.disease, Biochemistry, Gastroenterology, Surgery, Thalidomide, Regimen, Prednisone, Internal medicine, medicine, business, Multiple myeloma, medicine.drug, Lenalidomide
Abstract

Abstract 4044 Background: Prognosis of relapse is severe in elderly multiple myeloma (MM). In recent studies, median survival at progression after 1st line therapy was between 9 and 13 months (T. Facon, Lancet 2007; C. Hulin, J Clin Oncol 2009). Bortezomib (V) plus dexamethasone (D) is a major regimen in the treatment of relapses. Bendamustine (B) demonstrated to be highly active in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly patients with progressive MM on or after 1st line treatment. Methods: Phase 2 IFM 2009-01 trial was dedicated to patients older than 65 years in 1st relapse or refractory to 1st line therapy. Inclusion criteria were measurable disease, PS ECOG 0–2, ANC > 1.5×109/l, platelets > 100×109/l, serum creatinine level < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Treatment regimen was B 70 mg/m2 D1–8, V 1.3 mg/m2 D1–8-15–22 and D 20 mg D1–8-15–22 every 28 days. 6 cycles were administered. Responders were assigned to receive maintenance treatment with 6 additional cycles administered 1 month out of 2. Response was evaluated according to IMWG criteria. Response rate was the primary objective. Progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Results: The present analysis is restricted to the 6 monthly cycles. From 03/2010 to 07/2011, 73 pts were included. Median age was 75.8 years (range 66–86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior line of therapy: melphalan-prednisone (MP) in 12, MP-Thalidomide in 44, Lenalidomide-Dexamethasone (LD) in 14, other IMiD-based regimen in 3. 49 pts (67.1%) achieved at least partial response [best response CR: 9 pts (12.3%), VGPR: 12 pts (16.5%), PR: 28 pts (38.3%), MR: 6 pts (8.2%), SD: 4 pts (5.5%), progression: 13 pts (17.8%), early discontinuation: 1 pt (1.3%)]. Adverse prognostic factors for response were 1st line regimen with IMiD (p=0.006) and del17p (p=0.036). At 6 months, PFS was 67.1% and OS 80.8%. Cause of death was MM in 9 pts, sepsis in 4 pts and renal failure in 1 pt. Grade 3–4 adverse events were neutropenia: 16 pts (21.9%), thrombocytopenia: 7 pts (9.6%), sepsis: 14 pts (19.2%), gastro-intestinal: 9 pts (12.3%), anaphylaxis: 1 pt (1.3%). Grade 2 peripheral neuropathy occurred in 10 pts (13.6%) and grade 3 in 2 pts (2.7%). At 6 months, treatment was discontinued in 33 pts (45.2%). Cause of discontinuation was progressive MM in 18 pts (24.6%), failure to achieve PR in 5 pts (6.8%), adverse event in 8 pts (10.9%), patient refusal or lost to follow-up 1 pt (1.3%) each. Conclusion: In this elderly population with poor prognosis MM, BVD combination provides a high overall response rate and manageable toxicity. These results compare favorably with those achieved with VD or LD. Disclosures: Hulin: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Kolb:janssen: Honoraria; celgene: Honoraria. Roussel:celgene: Honoraria; janssen: Honoraria.

Published
2012

16. Consolidation Anti-CD22 Fractionated Radioimmunotherapy with 90y-Epratuzumab Tetraxetan Following R-CHOP in Elderly DLBCL Patients: A Lysa Phase II Prospective Trial

Author

Thierry Lamy, Olivier Tournilhac, Christian Berthou, Loïc Campion, David M. Goldenberg, Krimo Bouabdallah, Françoise Kraeber-Bodéré, Anne Moreau, Henry Jardel, Eric Deconinck, Jean-Philippe Vuillez, Etienne Garin, Francois Dreyfus, Philippe Moreau, Caroline Bodet-Milin, William A. Wegener, Anne-Laure Cazeau, Hervé Maisonneuve, Pierre Soubeyran, Remy Gressin, Steven Le Gouill, Noel Milpied, Emmanuel Gyan, Charles Foussard, Annie Brion, Amandine Pallardy, and Nadine Morineau

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Phases of clinical research, Cell Biology, Hematology, Neutropenia, medicine.disease, Biochemistry, Gastroenterology, Surgery, Transplantation, Internal medicine, Concomitant, Radioimmunotherapy, Medicine, business, Diffuse large B-cell lymphoma, Progressive disease, Febrile neutropenia
Abstract

Abstract 906 Background: Consolidation using radioimmunotherapy (RIT) is a promising approach for elderly patients with diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem-cell transplantation. RIT using fractionated injections of 90Y-epratuzumab tetraxetan (Immunomedics, Inc.), a radiolabeled humanized anti-CD22 antibody, has been evaluated in relapsed patients with indolent or aggressive non-Hodgkin lymphoma (NHL), providing long-term disease control with manageable hematologic toxicities (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the LYSA group now assessed front-line treatment using fractionated RIT with 90Y-epratuzumab tetraxetan as consolidation therapy after R-CHOP in previously untreated elderly (age >60 years) patients presenting with stage I/II bulky or stage III/IV DLBCL. Methods: The trial included 6 courses of R-CHOP delivered q2wks followed by 2 infusions of 90Y-epratuzumab tetraxetan (2 × 15 mCi/m2 [555 MBq/m2], 7 days apart), 8 wks later. Patients were enrolled at time of diagnosis. Results: From October 2008 to December 2010, 75 patients (41 males, 34 females) have been accrued prospectively at 19 French institutions. The median age was 69 (range, 60–79 years); 57 patients (76.0%) were Ann Arbor stage III/IV. Seventy-one of the 75 completed 6 courses of R-CHOP-14 and 61/75 (81.2%) were eligible for RIT. Thus, 14 patients were considered ineligible for RIT because of R-CHOP toxicity (N= 5), progressive disease (PD, N=3), patient refusal (N=3), or concomitant illness (N=3). RIT toxicity consisted of grade 3–4 hematologic toxicity in 51/61 patients (83.6%): grade 3–4 neutropenia in 46 (75.4%), grade 3–4 anemia in 15 (24.6%), and grade 3–4 thrombocytopenia in 47 (77.0%), with a nadir at 42, 48, and 43 days after RIT and a median duration of 18, 5, and 17 days, respectively. Following RIT, RBC and/or platelet transfusions were given to 31 patients (50.8 %). Serious febrile neutropenia was observed in 13 cases (17.3 %) after R-CHOP and in 3 patients (4.9%) following RIT. RIT's severe non-hematologic toxicity consisted of grade 4 gastrointestinal in 1 patient (1.6 %) and grade 4 infection in 3 (4.9%). No patient had mucositis after RIT. In the follow-up, 2 patients (2.6%) developed myelodysplastic syndrome 5 and 20 months after RIT. Using the 1999 International Workshop for Response Criteria for NHL (Cheson 1999), the overall response rate (ORR) after 6 × R-CHOP14 was 94.6% (71/75); 52 patients (69.3%) achieved CR/CRu and 19 (25.3%) had a partial response (PR). Among the 4 remaining patients, one had stable disease and 2 had PD; no assessment was obtained in the other. In an intention-to-treat analysis, CR/CRu rate after 6 × R-CHOP14 followed by RIT was 72.0% (N=54). Seven patients (9.3%) remained in PR and 8 (10.7%) progressed (2 patients previously in PR with PET-positive findings, 3 previously in CRu, including 1 PET-positive, and 3 in PD before RIT and then ineligible for RIT). No response assessment was obtained in the 6 others ineligible for RIT. At a median follow-up of 24 months (range, 1–46), 18 patients experienced lymphoma progression and/or a related death, yielding an estimated 2-year event-free-survival (EFS) of 73.3% (60.7-82.5%) and an estimated 2-year overall survival (OS) of 83.2% (71.4-90.4%). For the 61 patients who received 6 courses of R-CHOP followed by RIT consolidation, ORR was 91.8% (56/61); 50 patients (81.9%) achieved CR/CRu. Eight of 16 patients (50.0%) who had less than a CR/CRu with R-CHOP converted to CR/CRu after RIT. According to a PET analysis (Cheson 2007; N=55), 12 of the 24 patients (50.0%) who were not PET-negative after R-CHOP improved their metabolic response after RIT, resulting in a CR rate of 72.7%. Among these 61 patients, 12 experienced progression and/or a related death, yielding an estimated 2-year EFS of 78.7% (65.1–87.4%) and an estimated 2–year OS of 90.1% (77.7–95.8%). Conclusions: This phase II study clearly shows that fractionated RIT with 90Y-epratuzumab as a consolidation therapy after 6 × R-CHOP-14 is feasible and tolerable in elderly untreated DLBCL patients with advanced disease. RIT markedly improved response status observed after 6 × R-CHOP14. EFS data achieved with R-CHOP plus RIT compare favourably with those achieved with R-CHOP alone in the same patient population. Disclosures: Wegener: Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Published
2012

17. Bendamustine, bortezomib, and dexamethasone (BVD) in elderly patients with relapsed/refractory multiple myeloma (RRMM): The Intergroupe Francophone du Myélome (IFM) 2009-01 protocol

Author

Lotfi Benboubker, Brigitte Kolb, Laurent Garderet, Mourad Tiab, Carine Chaleteix, Hervé Avet-Loiseau, Olivier Decaux, Murielle Roussel, Claire Mathiot, Philippe Rodon, Brigitte Pegourie, Philippe Moreau, Henry Jardel, Bruno Anglaret, Olivier Fitoussi, Cyrille Hulin, Pascal Lenain, Marie-Odile Petillon, Xavier Leleu, and Philippe Casassus

Subjects
Oncology, Bendamustine, Cancer Research, medicine.medical_specialty, Creatinine, business.industry, Bortezomib, medicine.disease, Surgery, chemistry.chemical_compound, chemistry, Internal medicine, Relapsed refractory, Clinical endpoint, medicine, Maintenance phase, business, Multiple myeloma, Dexamethasone, medicine.drug
Abstract

8014 Background: Bortezomib (V) plus dexamethasone (D) is a treatment of choice of RRMM. In small series, the addition of an alkylator was beneficial. Bendamustine (B) showed a high activity in advanced MM. The IFM 2009-01 trial evaluates the combination of B, V and D in elderly pts with MM progressive on or after 1st line therapy. Methods: We conducted a phase 2 trial combining B 70 mg/m2 D1-8, V 1.3 mg/m2 D1-8-15-22 and D 20 mg D1-8-15-22 every 28 days. 4 cycles were administered. In responders (PR or better), 2 additional cycles were provided followed by a maintenance phase with 6 cycles given every 2 months. Inclusion criteria were progression on or after 1 prior line of therapy, measurable disease, PS ECOG 1.5x109/l, platelets > 100x109/l, creatinine < 250 mcmol/l, AST and ALT < 3xULN. Pts with prior exposure to bortezomib were excluded. Response was evaluated according to IMWG criteria. Primary end point was response at end of cycle 4, secondary objectives overall response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Results: The present analysis was restricted to the first 4 cycles. From 03/2010 to 07/2011, 73 pts were included, median age 75.8 years (range 66-86). Median time from diagnosis to inclusion was 29 months. All pts received only 1 prior therapy: MP in 12, MP-thalidomide in 44, lenalidomide-dexamethasone (LD) in 14, other in 3. 42 pts (57.5%) were responders at end of cycle 4 [CR: 8 (10.9%), VGPR: 9 (12.3%), PR: 25 (34.2%), SD: 10 (13.6%), progression: 11 (15%), early discontinuation: 10 (13.6%)]. 6pts/10 were in PR and 1pt/10 in VGPR at time of discontinuation. ORR was 67.1% (49/73 pts). 11 pts died (MM: 6, sepsis: 4, renal failure: 1). Adverse events grade 3-4 were neutropenia: 16 pts, thrombocytopenia: 7 pts, sepsis: 12 pts, gastro-intestinal: 8 pts, anaphylaxis: 1 pt. 2 pts had DVT. Peripheral neuropathy grade>1 occurred in 9 pts, all grade 2. Treatment was stopped in 20 pts (lack of efficacy: 11, toxicity: 9). Conclusions: These results compare favorably with those achieved with VD or LD. The triplet BVD combination is very effective and tolerable in elderly pts with MM in 1st progression.

Published
2012

18. High Response Rate and Low Toxicity of Rituximab, Vinorelbine, Ifosfamide, Mitoxantrone and Prednisone Combination for the Treatment of Diffuse Large B Cell Lymphoma In First Relapse: Early Results of the R-NIMP GOELAMS Study

Author

Emmanuel Gyan, Julie Léger, Stéphane Courby, Anne Banos, Diane Damotte, Charles Foussard, Olivier Tournilhac, Kamel Laribi, Delphine Senecal, Philippe Quittet, Jean-Louis Dutel, Annick Le Pourhiet-Le Mevel, Philippe Solal-Celigny, Jean Fontan, Hervé Maisonneuve, François Dreyfus, Nina Arakelyan, Remy Gressin, Steven Le Gouill, Charles Dauriac, Magda Alexis, and Henry Jardel

Subjects
medicine.medical_specialty, Mitoxantrone, Ifosfamide, business.industry, Immunology, Salvage therapy, Cell Biology, Hematology, medicine.disease, Vinorelbine, Biochemistry, Gastroenterology, Chemotherapy regimen, Surgery, Regimen, Internal medicine, medicine, Rituximab, business, Diffuse large B-cell lymphoma, medicine.drug
Abstract

Abstract 2796 Background: Diffuse large B-cell lymphoma (DLBCL) relapse prognosis is poor, and the optimal salvage treatment is not known. In a previous pilot study, vinorelbine, ifosfamide, mitoxantrone, and prednisone (NIMP) without rituximab has shown a promising efficacy in the setting of relapsed DLBCL. Aims: To evaluate the efficacy and tolerability of the combination of rituximab and NIMP in the treatment of DLBCL in first relapse. Methods: This multicentric, single-arm phase II study included patients 18 to 75 years old, with CD20-positive DLBCL in first relapse (defined as having obtained at least a PR of more than 50% to an anthracycline-based front-line regimen) occurring more than 30 days after the last chemotherapy cycle or more than one year after an autologous stem cell transplantation (ASCT) in first line. Other inclusion criteria were a performance status ≤ 2, absence of CNS involvement, and having signed an informed consent form. Patients with evidence of transformation from indolent lymphoma, primary refractory disease, or positive HIV tests were excluded. Initial and relapse biopsies were centrally reviewed. Patients received intravenous (IV) rituximab 375 mg/m2 D1, ifosfamide 1000 mg/m2 as a continuous infusion from D1 to D5, IV vinorelbine 25 mg/m2 D1 and D15, IV mitoxantrone 10 mg/m2 D1, and oral prednisone 1 mg/kg D1 to D5, repeated every 28 days for three cycles. Pegfilgrastim support (6 mg at D7) was recommended. The primary endpoint was CR/CRu after 3 cycles, and was assessed by computed tomography according to the IWG criteria. Mobilization, consolidation or subsequent salvage therapy was decided at the discretion of the investigator. All the monitoring and data management were performed by the GOELAMS clinical research assistants, with a database lock on July 27, 2010. Results: Fifty patients (21[42%] women and 29[58%] men) were included in 18 centers between December 2004 and accrual closure in April 2010. All patients received at least 1 cycle of R-NIMP. Forty-five patients were available for central pathology review, toxicity and response. The central review of all patient samples confirmed DLBCL histology. Median age at study entry was 62.9 years (range: 34.8–75.6). Median time between first diagnosis of DLBCL and relapse was 18.0 months (range: 2.4–208). The following tumor responses were observed: 67.9 % overall response rate with 20 CR/CRu (43.5%), 11 PR (24.4%), 2 SD (4.4%), and 12 (26.7%) progressed under therapy. Toxicity information was available for 109/120 (91 %) of the first 3 cycles of R-NIMP administered. The following toxicities were observed (all grades, ≥ grade 3 for all cycles): anemia (87%, 8%), neutropenia (66%; 46%), thrombopenia (65%, 14%), elevated liver tests (39%, 0%), constipation (25%, 0%), kidney failure (7%, 0%), nausea (14%, 0%), vomiting (6%, 0%), allergic reactions (5%, 0%), and mucositis (5%, 0%). Twenty-nine infectious events (27%) were observed needing hospitalization in 9 cases. Twenty-nine patients received consolidation therapy at the discretion of the investigator. Of the 11 patients who received 3 additional cycles of R-NIMP, 3 remained in CR/CRu, 1 remained in PR, 4 converted from PR to CR/CRu, and 3 progressed. Among the 11 patients who underwent ASCT, 9 were in CR at the end of the procedure, one patient died of toxicity and 1 progressed. For the 12 patients mobilized after a R-NIMP cycle, a median of 1 apheresis (range 1–4) was necessary to harvest a median of 3.85 × 106 CD34+ cells/kg. The median time to second progression or relapse (TTP2) was 11.4 months, and the median survival of 55.5 months. On multivariate analysis, the variable associated with a longer TTP2 was the achievement of CR/Cru (RR: 0,12; CI95%: 0.03–0,39; p=0.0006). Within the subgroup of patients having received a consolidation treatment, having received an ASCT was associated with a longer TTP2 (RR: 0.20; CI95%: 0.04–0.98; p=0.047). Time to first relapse or previous rituximab exposure did not affect TTP2 nor OS, whereas relapse-IPI (as a continuous variable, by 1 additional risk factor) was associated with a poor survival (RR: 2.59; CI95%: 1.25–4.45; p=0.008). Conclusions: R-NIMP is a well-tolerated regimen, yields a high complete response rate, and allows for successful mobilization of CD34+ cells. This regimen is a suitable salvage treatment for relapsed DLBCL prior to appropriate consolidation. Further investigation is warranted. ClinicalTrials.gov number: NCT00842595 Disclosures: Off Label Use: Vinorelbine in Non-Hodgkin's Lymphoma (Off-label in France).

Published
2010

19. Clinical Features and Prognostic Factors in 135 NHL of the Head and Neck Treated by the GOELAMS 02 Trial

Author

Anne Le Mevel, Christian Berthou, Bernard Desablens, Thierry Lamy, Mathilde Hunault-Berger, Philippe Colombat, Norbert Ifrah, Laurent Laccourreye, François Guilhot, Henry Jardel, Christine Le Maignan, and C. Ghandour

Subjects
Univariate analysis, medicine.diagnostic_test, Salivary gland, business.industry, Immunology, Thyroid, Cell Biology, Hematology, Biochemistry, medicine.anatomical_structure, Median follow-up, Erythrocyte sedimentation rate, Tonsil, medicine, Stage (cooking), Nuclear medicine, business, Head and neck
Abstract

From November 1984 till April 1996 135 patients (67% M, 33% F) presenting a NHL of the head and neck were treated by the GOELAMS 02 trial (3 VCAP + 40 Gy locoregional irradiation). The median age was 48.5 years (17–69) with 36 patients being 60 or over. The main localization was Waldeyer’s ring (57) including tonsil (35), nasopharynx (14), whole Waldeyer (8), neck (49), nasal cavities (14), thyroid (8) salivary gland (5), mandibular bone (2). According to the WFC, histological subtype were as F (21%), G (57%) and H (20%) and unclassified (2%). Ann Harbor classification included 80 stage 1 and 55 stage II. The IPI score was 0 (49.7%), 1 (22.3%), 2 (10.4%), 3 (2.3%) undetermined (16,3%). PS>2 and bulk (= 5 cm) were observed in 7.5% and 43% of patients respectively. 94% achieved CR. 2 patients died during treatment. Relapses occurred in 23/127 (18.1%) at a median time of 31 months (5.5 – 80). 16 of these relapses occurred before 3 years of CR, 5 between 3 and 6 years and 2 after 6 years of CR. With a median follow up of 65 month (7 – 146) OS and EFS were 81.5% and 77% respectively. In univariate analysis age = 60, extension, PS >2, Bulk = 5 cm, erythrocyte sedimentation rate > 40 and high serum LDH significantly decrease EFS (P= 0.01, 0.047, 0.028, 0.0001, 0.004 and 0.03 respectively). In multivariate analysis only the bulk = 5 cm and the localization to salivary gland significantly decrease EFS( P=0.003 and 0.039 respectively). Even if larger studies are needed to confirm these findings, NHL of the head and neck localized to the salivary gland or having a bulk = 5 cm should already be included in new therapeutic trials in order to improve their outcome.

Published
2005

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