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23 results on '"Cedric Pastoret"'

1. Blinatumomab during Consolidation in High-Risk Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL) Adult Patients: A Two-Cohort Comparison within the Graall-2014/B Study

Author

Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Mathilde Hunault, Rathana KIM, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Sébastien Maury, Anne Thiebaut-Bertrand, Florence Van Obbergh, Thomas Cluzeau, Martine Escoffre-Barbe, Nicole Straetmans, Johanna Konopacki, Amine Belhabri, Alban Villate, Florence Pasquier, Ioana Vaida, Laurence Sanhes, Magda Alexis, Cedric Pastoret, Mathlide Lamarque, Laure Farnault, Nathalie Grardel, Celine Berthon, Eric Delabesse, Veronique Lheritier, Norbert Ifrah, Carlos Graux, Yves Chalandon, Emmanuelle Clappier, and Herve Dombret

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

2. In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial

Author

Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Hunault-Berger Mathilde, Carlos Graux, Yves Chalandon, Eric Delabesse, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Cedric Pastoret, Martine Escoffre-Barbe, Florence Pasquier, Jean-Pierre Marolleau, Anne Thiebaut-Bertrand, Anne Huynh, Nathalie Dhedin, Emilie Lemasle, Caroline Bonmati, Sébastien Maury, Gaëlle Guillerm, Anna Berceanu, Urs Schanz, Thomas Cluzeau, Pascal Turlure, Philippe Rousselot, Bernard J.M. De Prijck, Nathalie Grardel, Marie C Bene, Marine Lafage, Norbert Ifrah, Veronique Lheritier, Vahid Asnafi, Emmanuelle Clappier, Herve Dombret, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU UCL Namur, Hôpitaux Universitaires de Genève (HUG), 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], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), CHU Amiens-Picardie, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Henri Mondor, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University hospital of Zurich [Zurich], Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CHU Limoges, Centre Hospitalier de Versailles André Mignot (CHV), CHU Sart Tilman [Liege, Belgium], CHU Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), CHU d'Angers [Département Urgences], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Coordination du Groupe GRAALL [CH Lyon-Sud], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], 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 DESSAIVRE, Louise

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

International audience; Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p

Published
2022

3. A reduced panel of eight genes ( ATM , SF3B1 , NOTCH1 , BIRC3 , XPO1 , MYD88 , TNFAIP3 , and TP53 ) as an estimator of the tumor mutational burden in chronic lymphocytic leukemia

Author

Cedric Pastoret, Lucie Donaty, David Rizzo, Nathalie Gachard, Jean Feuillard, Jasmine Chauzeix, and Thierry Fest

Subjects
Chronic lymphocytic leukemia, Biochemistry (medical), Clinical Biochemistry, Karyotype, Hematology, General Medicine, Computational biology, 030204 cardiovascular system & hematology, Biology, medicine.disease, TNFAIP3, Genome, DNA sequencing, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine, Stage (cooking), Gene, Exome, 030215 immunology
Abstract

Introduction: Mutational complexity or tumor mutational burden (TMB) influences the course of chronic lymphocytic leukemia (CLL). However, this information is not routinely used because TMB is usually obtained from whole genome or exome, or from large gene panel high‐throughput sequencing. Methods: Here, we used the C‐Harrel concordance index to determine the minimum panel of genes for which mutations predict treatment‐free survival (TFS) as well as large resequencing panels. Results: An eight gene estimator was defined encompassing ATM, SF3B1, NOTCH1, BIRC3, XPO1, MYD88, TNFAIP3, and TP53. TMB estimated from either a large panel of genes or the eight gene estimator was increased in treated patients or in those with a short TFS ( 6 months). Strikingly, the eight gene estimator was also highly informative for patients with Binet stage A CLL or with a good prognosis karyotype. Conclusion: These results suggest that the eight gene estimator, that is easily achievable by high‐throughput resequencing, brings robust and valuable information that predicts evolution of untreated patients at diagnosis better than any other parameter.

Published
2020

4. Thrombosis with Non-Proliferative Complete Blood Count Indicative of Underlying Myeloproliferative Neoplasm, Sythrom, a Study on Behalf of the FIM Group

Author

Yannick LE Bris, Jean Galtier, Dina Naguib, Mathieu Wemeau, Jean Claude Chomel, Laurence Legros, Yan Beauverd, Lise Willems, Guillaume Denis, Françoise Boyer perrard, Damien Luque-Paz, Kamel Laribi, Mélanie Mercier, Pascale Cony-Makhoul, Olivier Herault, Lydia Roy, Pierre Sujobert, Lenaig Le Clech, Sylvie Tondeur, Gaelle Laboure, Jerome Rey, Guillou Sophie, Cedric Pastoret, Pascaline Etancelin, Suzanne Tavitian, Charles Bescond, Francois Girodon, Shanti Amé, Viviane Dubruille, Eric Lippert, Chloe James, Barbara Burroni, Marc Fouassier, Marie C Béné, and Jean Christophe Ianotto

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

5. Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Author

Rathana Kim, Nicolas Boissel, Hervé Dombret, Florence Van Obbergh, Sébastien Maury, Carlos Graux, Yosr Hicheri, Laure Farnault, Yves Chalandon, Thibaut Leguay, Thomas Cluzeau, Cedric Pastoret, Alban Villate, Emmanuelle Clappier, Françoise Huguet, Philippe Rousselot, Martine Escoffre-Barbe, Florence Pasquier, Marie Balsat, Anne Thiebaut-Bertrand, Mathilde Hunault, Eric Delabesse, Patrice Chevallier, Véronique Lhéritier, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université 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), Université Catholique de Louvain = Catholic University of Louvain (UCL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Henri Mondor [Créteil], CHU Pontchaillou [Rennes], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier de Versailles André Mignot (CHV), Hôpitaux Universitaires de Genève (HUG), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), and Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Philadelphia negative, medicine.medical_specialty, Adult patients, Consolidation (soil), business.industry, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Biochemistry, Early results, Internal medicine, Medicine, Blinatumomab, business, medicine.drug
Abstract

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

Published
2021

6. High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL

Author

Aurelie Cabannes-Hamy, Eolia Brissot, Thibaut Leguay, Francoise Huguet, Patrice Chevallier, Mathilde Hunault, Martine Escoffre-Barbe, Thomas Cluzeau, Marie Balsat, Stephanie Nguyen, Florence Pasquier, Magda Alexis, Veronique Lheritier, Cedric Pastoret, Eric Delabesse, Emmanuelle Clappier, Herve Dombret, and Nicolas Boissel

Subjects
Adult, Lymphoma, B-Cell, Neoplasm, Residual, Antineoplastic Agents, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Burkitt Lymphoma, Tumor Burden, body regions, Recurrence, hemic and lymphatic diseases, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Antibodies, Bispecific, Humans, Retrospective Studies
Abstract

Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and

Published
2021

7. Ruxolitinib for refractory large granular lymphocyte leukemia

Author

Paul Coppo, Guillaume Cartron, Thierry Lamy, Cedric Pastoret, Aline Moignet, CHU Pontchaillou [Rennes], 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 ), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), 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 Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), and Jonchère, Laurent

Subjects
0303 health sciences, Ruxolitinib, business.industry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Refractory, 030220 oncology & carcinogenesis, medicine, Cancer research, business, Large Granular Lymphocyte Leukemia, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, medicine.drug
Abstract

International audience

Published
2021

8. Reliable IGHV status assessment by next generation sequencing in routine practice for chronic lymphocytic leukemia

Author

Thierry Lamy, Sophie de Guibert, Samuel Vic, Michel Ganard, Cedric Pastoret, Florian Thonier, Marie-Laure Boulland, Thierry Fest, Service d’Hématologie Clinique [Rennes], CHU Pontchaillou [Rennes], 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 ), Institut National de Recherche en Informatique et en Automatique (Inria), 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 ), and Inria Rennes – Bretagne Atlantique

Subjects
Cancer Research, Chronic lymphocytic leukemia, Immunoglobulin Variable Region, [SDV.CAN]Life Sciences [q-bio]/Cancer, Routine practice, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, Humans, ComputingMilieux_MISCELLANEOUS, business.industry, High-Throughput Nucleotide Sequencing, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, Status assessment, Oncology, 030220 oncology & carcinogenesis, Immunology, Mutation, Immunoglobulin heavy chain, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], IGHV@, business, Immunoglobulin Heavy Chains, 030215 immunology
Abstract

The level of somatic mutations within the variable region of the immunoglobulin heavy chain (IGVH) is considered as one of the most important prognostic markers in chronic lymphocytic leukemia (CLL...

Published
2021

9. PAX5 P80R mutation identifies a novel subtype of B-cell precursor acute lymphoblastic leukemia with favorable outcome

Author

Yves Chalandon, Véronique Lhéritier, Hervé Dombret, Johanna Konopacki, Eric Delabesse, Nicolas Boissel, Carlos Graux, Marie Passet, Colombe Saillard, Vahid Asnafi, Nathalie Grardel, Jean Soulier, Mario Bargetzi, Thibaut Leguay, Samuel Quentin, Emmanuelle Clappier, Ibrahima Ba, Marina Lafage-Pochitaloff, Xavier Thomas, Cedric Pastoret, François Sigaux, and Etienne Lengliné

Subjects
Adult, Homologous, 0301 basic medicine, Immunology, Chromosomal translocation, Malignancy, medicine.disease_cause, PAX5 Transcription Factor/genetics, Biochemistry, Cohort Studies, Fusion gene, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Acute lymphocytic leukemia, Local/genetics/pathology/therapy, medicine, Humans, B cell, ddc:616, Transplantation, Mutation, business.industry, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/classification/genetics/pathology/therapy, Cell Biology, Hematology, Prognosis, medicine.disease, Survival Rate, Neoplasm Recurrence, 030104 developmental biology, medicine.anatomical_structure, Cancer research, PAX5, business, Follow-Up Studies, Stem Cell Transplantation, 030215 immunology
Abstract

TO THE EDITOR: B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a rare aggressive malignancy in adults. BCP-ALL is frequently characterized by recurrent chromosomal translocations that deregulate proto-oncogenes or result in fusion genes encoding chimeric oncoproteins.[1][1] Gene

Published
2019

10. Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells

Author

Thierry Fest, Mikael Roussel, Cedric Pastoret, Fabienne Desmots, Véronique Salaun, Anne-Violaine Doncker, Gandhi Damaj, Aline Moignet, Marie-Laure Boulland, Gaëlle Drillet, Céline Pangault, Simon Le Gallou, Alexia Thannberger, Thierry Lamy, Richard Veyrat-Masson, Olivier Tournilhac, 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 ), CHU Pontchaillou [Rennes], CH de Saint-Malo [Broussais], Hopital Privé Sévigné [Cesson-Sévigné, France], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), 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, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, CIC Clermont Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-Centre de Pharmacologie Clinique, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Hematology Laboratory at Rennes University Medical Center, Association pour le développement de l’Hématologie Oncologie (ADHO), Chard-Hutchinson, Xavier, 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 ), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Myeloid, [SDV]Life Sciences [q-bio], Immunology, Lymphoproliferative disorders, [SDV.CAN]Life Sciences [q-bio]/Cancer, NK cells, Biology, medicine.disease_cause, Biochemistry, Transcriptome, Pathogenesis, STAT3, large granular lymphocyte leukemia, 03 medical and health sciences, 0302 clinical medicine, chronic lymphoproliferative disorders of NK cells, [SDV.CAN] Life Sciences [q-bio]/Cancer, KIR phenotype, medicine, 030304 developmental biology, 0303 health sciences, Mutation, TET2, Cell Biology, Hematology, medicine.disease, Phenotype, 3. Good health, Lymphoma, [SDV] Life Sciences [q-bio], Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research
Abstract

Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities.

Published
2021

11. Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation

Author

Cedric Pastoret, Yves Delneste, Sylvain Thepot, Marie-Christine Rousselet, Damien Luque Paz, Jean-Marie Chrétien, Maxime Renard, Jean-Christophe Ianotto, Odile Blanchet, Mathilde Hunault-Berger, Jean-Claude Chomel, Anne Murati, Norbert Ifrah, Maria-Pilar Gallego-Hernanz, Isabelle Quintin-Roué, Laurane Cottin, Aurélie Chauveau, Jérémie Riou, Frédéric Courtier, Françoise Boyer, Corentin Orvain, Valérie Ugo, Emilie Cayssials, Rébecca Jouanneau-Courville, Eric Lippert, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service des maladies du sang [CHU Angers], Laboratoire d'hématologie (Labo Hémato - BREST), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Service de Cancérologie Biologique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d’Oncologie Hématologique et Thérapie Cellulaire [CHU Poitiers], Laboratoire d'Hematologie [CHU Pontchaillou, Rennes] (Pôle de Biologie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Laboratoire d'Hématologie et Laboratoire d'Oncologie Moléculaire, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département de Pathologie Cellulaire et Tissulaire, Cellule de Gestion des Données et Evaluation (DRCI), Centre de Ressources Biologiques [CHU Angers], Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], and Bernardo, Elizabeth

Subjects
Neuroblastoma RAS viral oncogene homolog, IDH1, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Polycythemia vera, Myeloproliferative Disorders, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Allele, Polycythemia Vera, Gene, 030304 developmental biology, 0303 health sciences, Mutation, Myeloid Neoplasia, Essential thrombocythemia, Genomics, Hematology, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Cancer research, Erratum, Thrombocythemia, Essential
Abstract

Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.

Published
2020

12. The Broad Spectrum of TP53 Variants in CLL: NGS Analysis of 573 Pathogenic TP53 Variants

Author

Laurence Lodé, Veronique Leblond, Nathalie Nadal, Cedric Pastoret, Rémi Letestu, Stéphanie Poulain, Gregory Lazarian, Audrey Bidet, Pierre Sujobert, Frederic Davi, Florence Nguyen-Khac, Sophie Raynaud, Laurent Miguet, Eric Delabesse, Florence Cymbalista, Pascaline Etancelin, Stéphane Giraudier, Marie-Hélène Estienne, Myriam Hormi, Fanny Baran-Marszak, Thierry Soussi, Lauren Veronese, Olivier Kosmider, Pascale Cornillet-Lefebvre, Floriane Theves, Virginie Eclache, Dina Naguib, Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, and Baran-Marszak, Fanny

Subjects
Genetics, Mutation, [SDV]Life Sciences [q-bio], Immunology, Locus (genetics), Cell Biology, Hematology, Biology, medicine.disease_cause, Biochemistry, Null allele, [SDV] Life Sciences [q-bio], Gene duplication, medicine, Allele, IGHV@, Allele frequency, SNP array
Abstract

TP53 aberrations, including somatic mutations of TP53 gene or 17p deletion leading to the loss of the TP53 locus, are a major predictive factor of resistance to fludarabin based chemotherapy in chronic lymphocytic leukemia (CLL) and remain an adverse prognostic factor in the chemofree era. Therefore, detection of TP53 alteration before each new line of treatment is required for theranostic stratification. In order to better characterize the distribution and combination of the TP53 variants in CLL, we collected the TP53 sequencing data of 343 patients harboring TP53 mutations from centers of the French Innovative Leukemia Organization-CLL (FILO) and established a large data base of 573 TP53 mutations. Mutations were identified through NGS sequencing (covering exon 2 to 11) allowing the detection of low frequency variants down to 1% VAF. Several distinct low VAF mutations were orthogonally confirmed by digital PCR. TP53 variants were analyzed through UMD_TP53 data gathering 90 000 TP53 mutations from all type of cancers. IGHV mutational status and FISH analysis were available for 224 and 176 patients respectively. Using ACMG criteria from the UMD_TP53 database, we confirmed that 523 could be classified as pathogenic, 42 were likely pathogenic and 8 were VUS (Variants of Unknown Significance). As expected, the mutation distribution along the p53 protein exhibited a clustering of variants in the DNA binding domain of the protein. We also confirmed the presence of a specific hotspot at codon 234 (6%) which is noticeable in other CLL cohorts but absent in solid tumors. 431 TP53 variants led to the expression of a mutant protein whereas the remaining 142 led a TP53 null phenotype. For 8 patients without 17p deletion and a mutation VAF larger than 50%, SNP analysis indicate that these tumors had a copy number neutral loss of heterozygosis at 17p with a duplication of the mutant allele leading to homozygous mutations of TP53. When focusing on the allele burden of TP53 mutations, 264/573 (46%) variants had an allele frequency Among the 343 patients, 113 (33%) were poly-mutated and harbored more than one pathogenic TP53 variants (2 to 11 variants per patient): 57 (16,7 %) had 2 variants, 32 (9,3%) had 3, 10 had 4 (3%) and 14 patients (4%) had 5 to 11 variants. Using both long range sequencing and in silico analysis, we could show that all these variants were distributed in different alleles supporting an important intratumoral heterogeneity and a strong selection for TP53 loss of function during tumor progression in these patients. Null variants were rarely found as single alteration: only 46 patients (13,4%) patients harbored a single null mutation. Null mutations were predominantly found in patients with multiclonal mutations (87% with 4 or more). Median size of variants significantly decreased with the number of mutations and most of low VAF (less than 10%) variants were found in multiclonal combinations. Multiclonal mutations were predominantly found in previously treated patients (41% treated versus 10 % untreated) but whether all these variants preceded treatment and were further selected is currently unknown. We observed that 71,5 % of patients were IGHV unmutated and multiclonal mutations were surprisingly more frequent in mutated IGHV cases than in unmutated ones. Only 50% of cases carried a 17p deletion, highlighting again the importance of testing for TP53 mutations in addition to FISH analysis. Presence or absence of 17p deletion was unrelated to the number of TP53 mutations. Taken together these observations suggest that the TP53 mutational landscape in CLL is very complex and can involve multiple mechanisms, converging to a total loss of TP53 function and tumor progression. NGS provides a powerful tool for detecting all these alterations including variants with low VAF and should become a standard for CLL screening prior to each line of treatment. Disclosures Leblond: Amgen: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Letestu:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Cymbalista:Abbvie: Honoraria; Roche: Research Funding; Sunesis: Research Funding; Gilead: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria.

Published
2019

13. Switches of tyrosine-kinase inhibitors in chronic phase of chronic myeloid leukemia in real life

Author

Olivier Allangba, Violaine Doncker, Thierry Lamy, Vincent Launay, Dominique Jacomy, Estelle M. Le Pabic, Philippe Moreau, Isabelle Grulois, Adrien Trebouet, Benoit Bareau, Mathilde Niault, Marie-Laure Boulland, Marie-Françoise Le Coz, Katell Le Du, James D. Norwood, Cedric Pastoret, Odile Luycx, Thierry Fest, Martine Escoffre-Barbe, and Catherine Henry

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, business.industry, Phase (matter), Cancer research, In real life, Medicine, Myeloid leukemia, Hematology, business, Tyrosine kinase
Published
2018

14. The Need for a Consensus Next-generation Sequencing Panel for Mature Lymphoid Malignancies

Author

Gilles Salles, Catherine Thieblemont, Vahid Asnafi, Yannick Le Bris, Elizabeth Macintyre, Audrey Gros, Pierre Sujobert, David Sibon, Sarah Huet, Cedric Pastoret, Jean-Philippe Merlio, Clémentine Sarkozy, Fabrice Jardin, Laurence de Leval, Claude Preudhomme, Frederic Davi, Philippe Gaulard, Mary Callanan, Jonchère, Laurent, Hospices Civils de Lyon (HCL), 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), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Division de cardiologie [CHU Vaudois] (CHUV), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 [2016-2019] (UGA [2016-2019]), Université Paris Diderot - Paris 7 (UPD7), Université Paris Descartes - Paris 5 (UPD5), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, CHU Henri Mondor, Université Paris-Est Marne-la-Vallée (UPEM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), CHU Henri Mondor [Créteil], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université 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 ), 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]), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille

Subjects
0303 health sciences, lcsh:RC633-647.5, business.industry, MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:Diseases of the blood and blood-forming organs, Computational biology, Hematology, DNA sequencing, 03 medical and health sciences, Text mining, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Perspective, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Medicine, business, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 030215 immunology
Abstract

International audience; Supplemental Digital Content is available in the text.

Published
2018

15. Detection of clonal heterogeneity and targetable mutations in myeloid sarcoma by high-throughput sequencing

Author

Thierry Lamy, Cedric Pastoret, Beatrice Ly-Sunnaram, Thierry Fest, Roch Houot, Mikael Roussel, Francisco Llamas-Gutierrez, Virginie Gandemer, Marie-Laure Boulland, Tony Marchand, Patrick Tas, Etablissement français du sang [Rennes] (EFS Bretagne), Laboratoire d'Hematologie, CHU Pontchaillou [Rennes], 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 clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de Biologie, CRLCC Eugène Marquis (CRLCC), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-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 ), Université de Rennes (UR)-Hôpital Pontchaillou, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Cancer Research, Myeloid, Adolescent, DNA Mutational Analysis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, DNA sequencing, Immunophenotyping, Genetic Heterogeneity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Biomarkers, Tumor, medicine, Myeloid sarcoma, Humans, Sarcoma, Myeloid, Child, ComputingMilieux_MISCELLANEOUS, Mutation, Genetic heterogeneity, Gene Expression Profiling, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Hematology, Middle Aged, Prognosis, medicine.disease, Molecular biology, 3. Good health, Gene expression profiling, medicine.anatomical_structure, Oncology, Child, Preschool, Karyotyping, 030220 oncology & carcinogenesis, Female, Sarcoma, 030215 immunology
Abstract

Myeloid sarcoma (MS) are extramedullary tumor masses consisting of a proliferation of myeloid immature cells that efface the underlying tissue architecture.[1] It may develop de novo or concurrentl...

Published
2016

16. Discordant Response of Systemic Mastocytosis Associated With Myelodysplastic Syndrome After Midostaurin and Allogeneic Hematopoietic Stem-cell Transplantation

Author

Cedric Pastoret, Francisco Llamas-Gutierrez, Thierry Fest, Thierry Lamy, Mikael Roussel, Roch Houot, Marie-Laure Boulland, and Marion Haas

Subjects
Oncology, medicine.medical_specialty, lcsh:RC633-647.5, business.industry, medicine.medical_treatment, Case Report, lcsh:Diseases of the blood and blood-forming organs, Hematology, Hematopoietic stem cell transplantation, medicine.disease, chemistry.chemical_compound, chemistry, Internal medicine, medicine, Midostaurin, Systemic mastocytosis, business
Published
2020

17. Pan-HDAC Inhibitors May Restore PRDM1 Expression in Follicular Lymphoma

Author

Eric Guiheneuf, Mikael Roussel, Fabienne Desmots-Loyer, Thierry Lamy, Francisco Llamas-Gutierrez, Valérie Camara-Clayette, Vincent Ribrag, Cedric Pastoret, Céline Pangault, Karin Tarte, Thierry Fest, 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, Institut Gustave Roussy (IGR), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Université Paris-Saclay, Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), 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, and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Immunology, Follicular lymphoma, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, hemic and lymphatic diseases, PRDM1, Plasma cell differentiation, Centroblasts, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, business.industry, Germinal center, Cell Biology, Hematology, medicine.disease, BCL6, 3. Good health, Cancer research, business, 030215 immunology
Abstract

Follicular lymphoma (FL) arises from a germinal center (GC) B cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). Besides BCL2 translocation hallmark, tumor B cells progressively acquire loss-of-function alterations within chromatin organization factor genes. Notably, frequent inactivating mutations in CREBBP acetyltransferase are found in B-cell lymphoma and drive deep epigenetic and transcriptional profile modifications. Our transcriptional analysis on highly purified cell fractions revealed that, conversely to normal GC B cells (centroblasts and centrocytes), primary FL B cells are unable to upregulate the transcription repressor PRDM1 that is required for plasma cell differentiation and maintenance. This defect happens although FL tumor environment is enriched in the potent inducer of PRDM1, IL-21 that we found highly produced by CD4+ Tfhs. In 20 different FLs perfectly characterized at clinical and genetic level, we analyzed their FL cells obtained after purification from the initial tumor. Globally, we found a significant lack of IL-21-mediated PRDM1 response while our control cell line showed a positive increase of PRDM1 expression. We analyzed some of these primary FL tumor cells by qPCR-ChIP to assess BCL6 protein binding at intron 3 of the PRDM1 gene. We found that the lack of PRDM1 response to IL-21 was associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1 gene. Our data indicated this was especially the case for FLs with nonfunctional CREBBP. We next explored 6 FLs, cells were treated in vitro with vorinostat, a pan-HDAC inhibitor. We found that for FL B cells carrying CREBBP loss-of-function mutations, vorinostat restored partially their PRDM1 response to IL-21 by lowering BCL6 bound to PRDM1. Finally, we wanted to assess this drug effect in the context of FL patients treated with a pan-HDACi. We found 4 patients involved in a phase I/II clinical at the Gustave Roussy Institute in Villejuif and treated with abexinostat, a new and off-label pan-HDAC inhibitor. All the patients presented a progressive FL disease, were heavily pretreated and their tumor were characterized by genomic DNA sequencing. One patient reached a stable complete remission, the drug was discontinued after 4 years of treatment. Among the three other patients, one had an objective 28-month response to the drug before relapse, one a stable disease for seven months while the last one did not response to the drug. For these 3 patients we've got fine needle tumor biopsy when patients re-progressed. Re-biopsies showed an increased expression of plasma cell-identity genes, mainly PRDM1 and XBP1, which underline the progression of FL B cells in the process of differentiation. Altogether, our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat FL patients. Disclosures Ribrag: BMS: Consultancy, Honoraria, Other: travel; argenX: Research Funding; Servier: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Amgen: Research Funding; Roche: Honoraria, Other: travel; Incyte Corporation: Consultancy; pharmamar: Other: travel; Infinity: Consultancy, Honoraria; MSD: Honoraria.

Published
2018

18. Definition of a minimal genes set for mature lymphoid blood diseases

Author

Yannick Le Bris, Claude Preudhomme, Elizabeth Macintyre, Pierre Sujobert, Mary Callanan, Frederic Davi, Sarah Huet, Gilles Salles, Clémentine Sarkozy, Cedric Pastoret, Laurence de Leval, Fabrice Jardin, Audrey Gros, Catherine Thieblemont, Philippe Gaulard, David Sibon, Vahid Asnafi, Jean-Philippe Merlio, 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), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), 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 ), Métabolisme et physiologie rénale (CRC - UMR_S 1138), 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)-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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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 [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), 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 National de la Recherche Scientifique (CNRS)-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)-École Pratique des Hautes Études (EPHE), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), CHU Henri Mondor [Créteil], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Hospitalier 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]), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, 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), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), École pratique des hautes études (EPHE)-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)-École pratique des hautes études (EPHE)-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), CHU Pitié-Salpêtrière [APHP], 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine

Subjects
Set (abstract data type), 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Computational biology, Biology, Gene, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

National audience

Published
2018

19. T-cell large granular lymphocytic leukemia

Author

Thierry Lamy, Cedric Pastoret, and Tony Marchand

Subjects
Chemistry, T-Cell Large Granular Lymphocytic Leukemia, chemical and pharmacologic phenomena, Hematology, Molecular biology
Abstract

Decrite pour la premiere fois en 1985, la leucemie a grands lymphocytes granuleux (LGL, pour large granular lymphocytes) est un syndrome lymphoproliferatif rare caracterise par une expansion clonale de lymphocytes T CD3+ cytotoxiques ou de cellules natural killer (NK) CD3- infiltrant la moelle osseuse, la rate et le foie, et frequemment associee a des maladies auto-immunes. La classification de l’Organisation mondiale de la sante (OMS) de 1999 inclut les leucemies LGL a cellules T [...]

Published
2015

20. STAT3 mutation impacts biological and clinical features of T-LGL leukemia

Author

Matteo Leoncin, Renato Zambello, Tamara Berno, Elena De March, Sara Teolato, Gregorio Barilà, Francesco Piazza, Elisa Pagnin, Livio Trentin, Antonella Teramo, Mikael Roussel, Gianpietro Semenzato, Elisa Boscaro, Giulia Calabretto, Chiara Ercolin, Cristina Gattazzo, Monica Facco, Thierry Lamy, Cedric Pastoret, Aline Moignet, and Anna Cabrelle

Subjects
0301 basic medicine, fas ligand, medicine.medical_specialty, chemical and pharmacologic phenomena, Neutropenia, Fas ligand, large granular lymphocyte leukemia, 03 medical and health sciences, 0302 clinical medicine, Immunophenotyping, STAT3 mutation, immunophenotype, neutropenia, Internal medicine, medicine, T-Cell Large Granular Lymphocyte Leukemia, Hematology, business.industry, medicine.disease, Molecular medicine, Leukemia, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, business, CD8, Research Paper
Abstract

// Antonella Teramo 1, 2, * , Gregorio Barila 1, 2, * , Giulia Calabretto 1, 2 , Chiara Ercolin 1, 2 , Thierry Lamy 3 , Aline Moignet 3 , Mikael Roussel 4 , Cedric Pastoret 4 , Matteo Leoncin 1 , Cristina Gattazzo 1, 2 , Anna Cabrelle 2 , Elisa Boscaro 1 , Sara Teolato 1 , Elisa Pagnin 1 , Tamara Berno 1 , Elena De March 1 , Monica Facco 1, 2 , Francesco Piazza 1, 2 , Livio Trentin 1, 2 , Gianpietro Semenzato 1, 2 and Renato Zambello 1, 2 1 Padua University School of Medicine, Department of Medicine, Hematology and Clinical Immunology Branch, Padua, Italy 2 Venetian Institute of Molecular Medicine (VIMM), Padua, Italy 3 Department of Clinical Hematology, University Hospital of Rennes, Rennes, France 4 Biology Department, University Hospital of Rennes, Rennes, France * These authors have contributed equally to this work Correspondence to: Renato Zambello, email: r.zambello@unipd.it Keywords: large granular lymphocyte leukemia, STAT3 mutation, immunophenotype, neutropenia, fas ligand Received: January 20, 2017 Accepted: May 22, 2017 Published: June 27, 2017 ABSTRACT STAT3 mutations have been described in 30-40% of T-large granular lymphocyte (T-LGL) leukemia patients, leading to STAT3 pathway activation. Considering the heterogeneity of the disease and the several immunophenotypes that LGL clone may express, the aim of this work was to evaluate whether STAT3 mutations might be associated with a distinctive LGL immunophenotype and/or might be indicative for specific clinical features. Our series of cases included a pilot cohort of 101 T-LGL leukemia patients (68 CD8+/CD4- and 33 CD4+/CD8±) from Padua Hematology Unit (Italy) and a validation cohort of additional 20 patients from Rennes Hematology Unit (France). Our results indicate that i) CD8+ T-LGL leukemia patients with CD16+/CD56- immunophenotype identify a subset of patients characterized by the presence of STAT3 mutations and neutropenia, ii) CD4+/CD8± T-LGL leukemia are devoid of STAT3 mutations but characterized by STAT5b mutations, and iii) a correlation exists between STAT3 activation and presence of Fas ligand, this molecule resulting highly expressed in CD8+/CD16+/CD56- patients. Experiments with stimulation and inhibition of STAT3 phosphorylation confirmed this relationship. In conclusion, our data show that T-LGL leukemia with specific molecular and phenotypic patterns is associated with discrete clinical features contributing to get insights into molecular bases accounting for the development of Fas ligand-mediated neutropenia.

Published
2017

21. Prospective, Multicentric Phase II Randomized Trial Comparing the Efficacy of Methotrexate or Cyclophosphamide in Large Granular Lymphocytic Leukemia: A French National Study. Report on the Interim Analysis

Author

Thierry Lamy, Roch Houot, Thierry Fest, Anne Lazareth, Jehan Dupuis, Eric Bellissant, Cedric Pastoret, P. Feugier, Gandhi Damaj, Sophie Rigaudeau, Alain Delmer, Emmanuel Gyan, Anne Banos, Bachra Choufi, Jean Valère Malfuson, Mathilde Hunault, Loic Ysebaert, Olivier Tournilhac, Jean-Pierre Marolleau, Stéphane Leprêtre, 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
Oncology, medicine.medical_specialty, Cyclophosphamide, Large granular lymphocytic leukemia, Immunology, Biochemistry, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Surrogate endpoint, business.industry, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, medicine.disease, Interim analysis, 3. Good health, Leukemia, 030220 oncology & carcinogenesis, Rheumatoid arthritis, Methotrexate, business, medicine.drug
Abstract

Introduction Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of CD3+ cytotoxic T or CD3- NK cells. Prominent clinical features include neutropenia, anemia and autoimmune-associated diseases such as rheumatoid arthritis (RA). Although the disease is usually chronic and indolent, some patients may be symptomatic and require treatment. No standard therapy has been established due to the absence of prospective clinical trials. So far, low dose methotrexate, oral cyclophosphamide, and cyclosporine represent the 3 main options for initial therapy. In 2014, we launched a prospective clinical trial comparing methotrexate to cyclophosphamide in previously-untreated patients with LGL leukemia in need of treatment. Patients and methods The study was designed as a multicentric, national, open label, randomized, controlled trial on two parallel groups, comparing methotrexate and cyclophosphamide. Patients were included if they had at least one of the following indications of treatment: isolated severe neutropenia (ANC 0.5x109/L or decrease of transfusion requirements). Treatment failure was defined as no response or any response which did not meet the above-mentioned criteria within four months after the beginning of treatment. To stop the trial as soon as sufficient information was collected, a sequential analysis was planned each time 20 patients were included and evaluated using the triangular test (Sébille V, Bellissant E. Fundam Clin Pharmacol. 2003;17(5):505-16). The primary endpoint was the hematological CR rate evaluated at M4 (binary endpoint). Secondary endpoints were overall response rate (ORR) at M4, M8 and M12, time to relapse. For non-responders at M4, cyclosporine was compared to the treatment which had not been administered during the first phase. Results From Nov 2013 to July 2019, 99 patients met inclusion criteria among which 96 were randomized. The baseline characteristics of these patients are shown in Table1. STAT3 mutation was observed 52% of cases. After the 4th sequential analysis performed on the first 80 patients evaluable for response at M4, the sample path remained in the continuation region of the triangular test. Thus, the trial has to be continued. At M4, 13 patients were in CR (16.3%) and 29 patients were in PR (36.3%), ORR was 52.6%, 36 patients were considered as refractory and underwent a second randomization: 18 patients received cyclosporine and 17 received methotrexate or cyclophosphamide. Conclusions This first prospective randomized clinical trial in LGL leukemia shows that the CR after first line therapy using either methotrexate or cyclophosphamide is relatively low (< 20%). Recruitment is still ongoing to assess if there is a difference in terms of response between the two drugs. Predictive biomarkers of response will be presented at the meeting. Regarding a 52% of incidence of Stat3 mutation (higher than that previously published), Jak/Stat targeted therapy should be prospectively evaluated in this disease. Disclosures Houot: Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria. Gyan:Pfizer: Honoraria. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

Published
2019

22. PF373 IMPACT OF ATM ALTERATIONS ON CHRONIC LYMPHOCYTIC LEUKEMIA IN GENERAL PRACTICE IN THE AREA OF NEXT GENERATION SEQUENCING

Author

Michel Ganard, S. De Guibert, O. Luycx, D. Jacomy, Cécile Henry, Marie-Laure Boulland, J. Norwood, I. Grulois, Vincent Launay, Thierry Fest, Roch Houot, Benoit Bareau, Cedric Pastoret, Thierry Lamy, Mikael Roussel, and M. De Tayrac

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, Chronic lymphocytic leukemia, General practice, Medicine, Hematology, business, medicine.disease, DNA sequencing
Published
2019

23. Diversity of TP53 Mutations in CLL: Retrospective Analysis of 450 Mutations from the French Innovative Leukemia Organization (FILO) Group

Author

Dina Naguib, Marc Muller, Cedric Pastoret, Pierre Sujobert, Eric Delabesse, Frederic Davi, Laurence Lodé, Audrey Bidet, Stéphanie Poulain, Sophy Laibe, Florence Nguyen-Khac, Marie-Hélène Estienne, Olivier Kosmider, Pascale Cornillet-Lefebvre, Stéphane Giraudier, Thierry Souci, Lauren Veronese, Florence Cymbalista, Fanny Baran-Marszak, and Myriam Hormi

Subjects
Cancer Research, medicine.medical_specialty, Pediatrics, business.industry, media_common.quotation_subject, Hematology, Tp53 mutation, medicine.disease, Leukemia, Oncology, Internal medicine, medicine, Retrospective analysis, business, Diversity (politics), media_common
Published
2017

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