64 results on '"Emilie Lemasle"'
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2. Successful treatment of severe post hematopoietic stem cell transplantation bronchiolitis obliterans syndrome with lung transplantation in a patient with multi‐organ chronic graft‐versus‐host disease
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Juliette Pénichoux, Florian Bouclet, Mustafa Alani, Nathalie Contentin, Anne‐Lise Ménard, Stéphane Leprêtre, Pascal Lenain, Aspasia Stamatoullas, Elodie Lhuillier, Hélène Lanic, Emilie Lemasle, Sydney Dubois, Jean‐Henri Bourhis, Hervé Mal, Fabrice Jardin, and Vincent Camus
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allogeneic hematopoietic stem cell transplantation ,bronchiolitis obliterans syndrome ,graft‐versus‐host disease ,Medicine ,Medicine (General) ,R5-920 - Abstract
Abstract Allogeneic stem cell transplant and chronic graft‐versus‐host disease may lead to severe non‐infectious pulmonary disease in 6% of patients at 5 years. We report the case of a young patient with acute myeloid leukemia who successfully received bilateral lung transplantation for severe bronchiolitis obliterans syndrome.
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- 2022
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3. Dissociated humoral and cellular immune responses after a three-dose schema of BNT162b2 vaccine in patients receiving anti-CD20 monoclonal antibody maintenance treatment for B-cell lymphomas
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Sophie Candon, Veronique Lemee, Emilie Leveque, Pascaline Etancelin, Cedric Paquin, Marion Carette, Nathalie Contentin, Victor Bobee, Mustafa Alani, Nathalie Cardinael, Stephane Lepretre, Vincent Camus, Florian Bouclet, Edwige Boulet, Anne-Lise Menard, Helene Lanic, Aspasia Stamatoullas, Emilie Lemasle, Louis-Ferdinand Pepin, Doriane Richard, Sydney Dubois, Herve Tilly, Alain Dalleac, Jean-Christophe Plantier, Manuel Etienne, and Fabrice Jardin
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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4. Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: a prospective study
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Vincent Camus, Mathieu Viennot, Justine Lequesne, Pierre-Julien Viailly, Elodie Bohers, Lucile Bessi, Bénédicte Marcq, Pascaline Etancelin, Sydney Dubois, Jean-Michel Picquenot, Elena-Liana Veresezan, Marie Cornic, Lucie Burel, Justine Loret, Stéphanie Becker, Pierre Decazes, Pascal Lenain, Stéphane Lepretre, Emilie Lemasle, Hélène Lanic, Anne-Lise Ménard, Nathalie Contentin, Hervé Tilly, Aspasia Stamatoullas, and Fabrice Jardin
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients] were assessed in this non-interventional study. Median age of the patients was 33.5 years (range 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype are correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, NA=6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). Mean of DeltaSUVmax after C2 was -78.8%. We analyzed ctDNA after C2 for 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.
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- 2020
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5. Cardiovascular outcomes of patients treated for non-Hodgkin lymphoma with first-line doxorubicin-based chemotherapy
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Alexandra, Zduniak, Emilie, Lévêque, Anne, Perdrix, Pascaline, Etancelin, Anne-Lise, Ménard, Pascal, Lenain, Nathalie, Contentin, Louis-Ferdinand, Pépin, Stéphane, Leprêtre, Emilie, Lemasle, Hélène, Lanic, Aspasia, Stamatoullas-Bastard, Leila, Kammoun-Quique, Hervé, Tilly, Fabrice, Bauer, Fabrice, Jardin, and Vincent, Camus
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Cancer Research ,Oncology ,Hematology - Abstract
We conducted a single-center retrospective study to assess cardiovascular (CV) toxicity and treatment discontinuation for CV toxicity in diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) patients treated with immunochemotherapy (R-CHOP-like). Between 2006 and 2017, 433 patients were included (DLBCL
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- 2022
6. Prognostic relevance of sarcopenia, geriatric, and nutritional assessments in older patients with diffuse large B-cell lymphoma: results of a multicentric prospective cohort study
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Juliette, Pénichoux, primary, Hélène, Lanic, additional, Caroline, Thill, additional, Anne-Lise, Ménard, additional, Vincent, Camus, additional, Aspasia, Stamatoullas, additional, Emilie, Lemasle, additional, Stéphane, Leprêtre, additional, Pascal, Lenain, additional, Nathalie, Contentin, additional, Jerôme, Kraut-Tauzia, additional, Christophe, Fruchart, additional, Leila, Kammoun, additional, Gandhi, Damaj, additional, Agathe, Farge, additional, Caroline, Delette, additional, Romain, Modzelewski, additional, Sandrine, Vaudaux, additional, Louis-Ferdinand, Pépin, additional, Hervé, Tilly, additional, and Fabrice, Jardin, additional
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- 2023
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7. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study
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Loic Vasseur, Laurène Fenwarth, Jérôme Lambert, Stéphane de Botton, Martin Figeac, Céline Villenet, Maël Heiblig, Pierre-yves Dumas, Christian Récher, Celine Berthon, Emilie Lemasle, Delphine Lebon, Juliette Lambert, Christine Terré, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Meyling H Cheok, Raphaël A. Itzykson, Nicolas Duployez, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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 d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Claude Huriez [Lille], CHU Lille, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Département de Génétique [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), 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), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), and Service de pathologie [CHU Lille]
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[SDV]Life Sciences [q-bio] ,Hematology - Abstract
International audience; Whether the LSC17 gene expression can improve risk stratification in the context of NGS-based risk stratification and measurable residual disease (MRD) in AML patients treated intensively has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. Multiple (cyto)genetic alterations were associated with changes in LSC17, such as higher LSC17 in patients with RUNX1 or TP53 mutations, and lower scores in those with CEBPA and NPM1 mutations. LSC17-high patients had a lower rate of complete response (CR) or CR with incomplete platelet recovery (CRp) after one induction course in a multivariable analysis (OR=0.41, p=0.0007) accounting for European LeukemiaNet 2022 (ELN22) risk groups, age, and white blood cell (WBC) count. The LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% versus 52.7% in LSC17-low patients, p
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- 2023
8. Supplementary Figure 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).
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- 2023
9. Supplementary Figure 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.
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- 2023
10. Supplementary Figure 4 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.
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- 2023
11. Supplementary Table 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.
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- 2023
12. Supplementary Figure 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Flow chart of the study displaying the three cohorts.
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- 2023
13. Supplementary Table 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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TP53 mutations characteristics among t-MN PARPi national cohort.
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- 2023
14. Supplementary Table 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.
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- 2023
15. Data from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset
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Purpose:To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi).Experimental Design:In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort.Results:From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS.Conclusions:In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
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- 2023
16. 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
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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
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[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
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- 2022
17. LSC17 Score Is Complementary with Minimal Residual Disease to Stratify NPM1 -Mutated Acute Myeloid Leukemia:An ALFA Study
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Loïc Vasseur, Laurène Fenwarth, Xavier Thomas, Jérôme Lambert, Stéphane de Botton, Martin Figeac, Céline Villenet, Pierre-Yves Dumas, Christian Recher, Céline Berthon, Emilie Lemasle, Delphine Lebon, Juliette Lambert, Christine Terré, Karine Celli-Lebras, Hervé Dombret, Claude Preudhomme, Meyling Cheok, Raphael Itzykson, Nicolas Duployez, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Centre Hospitalier Lyon Sud [CHU - HCL] [CHLS], Hopital Saint-Louis [AP-HP] [AP-HP], Institut Gustave Roussy [IGR], Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS], BoRdeaux Institute in onCology [Inserm U1312 - BRIC], Institut National de la Santé et de la Recherche Médicale [INSERM], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen [CLCC Henri Becquerel], CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 [HEMATIM], Centre Hospitalier de Versailles André Mignot [CHV], Service d'Hémato-oncologie [CHU Saint-Louis], Institut pour la recherche sur le cancer de Lille [Lille] [IRCL], Génomes, biologie cellulaire et thérapeutiques [GenCellDi (U944 / UMR7212)], Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Université de Lille, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Versailles André Mignot (CHV), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
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Immunology ,Cell Biology ,Hematology ,Biochemistry ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience
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- 2022
18. Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy
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P. Rousselot, Lionel Ades, Hubert Serve, Sylvain Chantepie, Xavier Thomas, Delphine Lebon, Kevin-James Wattebled, Raphael Itzykson, Cécile Pautas, Hervé Dombret, Karine Celli-Lebras, Olivier Nibourel, Thorsten Braun, Elise Fournier, Nicolas Boissel, Thomas Cluzeau, Emilie Lemasle, Christine Terré, Lauris Gastaud, Nicolas Duployez, Claude Gardin, Alice Marceau-Renaut, Christian Thiede, Jean-Baptiste Micol, Emmanuel Raffoux, Christoph Röllig, Céline Berthon, Jean-Valère Malfuson, Laure Goursaud, Claude Preudhomme, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Claude Huriez [Lille], CHU Lille, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Transfusion Sanguine des Armées (CTSA), Service de Santé des Armées, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Etablissement français du sang [Rennes] (EFS Bretagne), CH Dunkerque, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), 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, XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Frankfurt am Main [Germany], Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), and Hôpital Avicenne [AP-HP]
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Male ,Neuroblastoma RAS viral oncogene homolog ,Oncology ,NPM1 ,medicine.medical_specialty ,Standard of care ,[SDV]Life Sciences [q-bio] ,Immunology ,Intensive chemotherapy ,medicine.disease_cause ,Biochemistry ,Disease-Free Survival ,Cytogenetics ,Internal medicine ,Long term survival ,Humans ,Medicine ,Aged ,Aged, 80 and over ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Neoplasm Proteins ,Survival Rate ,Leukemia, Myeloid, Acute ,Mutation ,Prognostic model ,Female ,KRAS ,business ,Follow-Up Studies - Abstract
To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) ≥60 years of age treated with 7 + 3, we sequenced 37 genes in 471 patients from the ALFA1200 (Acute Leukemia French Association) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patients with good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10−4) allelic ratio, DNMT3A (HR, 1.86; P < 10−4), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P = .0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a “go-go” tier with a 2-year OS of 66.1%, 7.6% to the “no-go” group (2-year OS 2.8%), and 3.3% of to the “slow-go” group (2-year OS of 39.1%; P < 10−5). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences in OS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; and SAL [Study Alliance Leukemia], n = 46; AMLSG [AML Study Group], n = 223, both P < 10−5). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients ≥60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7 + 3 standard of care with less intensive regimens.
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- 2021
19. Prognostic relevance of lymphocyte-to-monocyte ratio in primary myelodysplastic syndromes: a single center experience
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Sylvie Daliphard, Aspasia Stamatoullas, Juliette Pénichoux, Gérard Buchonnet, Hervé Tilly, Vincent Camus, Daphné Krzisch, Emilie Lemasle, Sydney Dubois, Fabrice Jardin, Dominique Penther, Christian Bastard, Anne-Lise Menard, Hélène Lanic, Nathalie Contentin, Pascal Lenain, and Stéphane Leprêtre
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Oncology ,Cancer Research ,medicine.medical_specialty ,Lymphocyte ,Disease ,Single Center ,Monocytes ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Lymphocytes ,Retrospective Studies ,Acute leukemia ,business.industry ,Myelodysplastic syndromes ,Monocyte ,Hematology ,Prognosis ,medicine.disease ,medicine.anatomical_structure ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
In myelodysplastic syndromes (MDS), the prognosis of the disease is related partly to the complications of blood cytopenias, and partly to the risk of transformation, over time, into acute leukemia...
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- 2021
20. Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience
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Vincent Marmouset, Justine Decroocq, Sylvain Garciaz, Gabriel Etienne, Amine Belhabri, Sarah Bertoli, Lauris Gastaud, Celestine Simand, Sylvain Chantepie, Madalina Uzunov, Alexis Genthon, Celine Berthon, Edmond Chiche, Pierre-Yves Dumas, Jacques Vargaftig, Géraldine Salmeron, Emilie Lemasle, Emmanuelle Tavernier, Jeremy Delage, Marion Loirat, Nadine Morineau, Felix Blanc-Durand, Patricia Pautier, Veronique Vergé, Nathalie Auger, Myrtille Thomas, Laetitia Stefani, Marion Lepelley, Thomas Boyer, Sylvain Thepot, Marie-Pierre Gourin, Pascal Bourquard, Matthieu Duchmann, Pierre Morice, Mauricette Michallet, Lionel Ades, Pierre Fenaux, Christian Recher, Hervé Dombret, Arnaud Pages, Christophe Marzac, Alexandra Leary, Jean-Baptiste Micol, Université de Picardie Jules Verne (UPJV), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aix Marseille Université (AMU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Bergonié [Bordeaux], UNICANCER, Centre Léon Bérard [Lyon], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], CHU Lille, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CH de Saint-Nazaire, CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Ovarian Neoplasms ,Cancer Research ,Immunology ,Neoplasms, Second Primary ,Cell Biology ,Hematology ,Poly(ADP-ribose) Polymerase Inhibitors ,Carcinoma, Ovarian Epithelial ,Biochemistry ,Oncology ,Mutation ,Humans ,Female ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Germ-Line Mutation - Abstract
Purpose: To provide insights into the diagnosis and management of therapy-related myeloid neoplasms (t-MN) following PARP inhibitors (PARPi). Experimental Design: In a French cancer center, we identified and described the profiles of 13 t-MN diagnosed among 37 patients with ovarian cancer referred to hematology consultation for cytopenia under PARPi. Next, we described these 13 t-MN post-PARPi among 37 t-MN post ovarian cancer according to PARPi exposure. Finally, we described 69 t-MN post-PARPi in a national cohort. Results: From 2016 to 2021, cumulative incidence of t-MN was 3.5% (13/373) among patients with ovarian cancer treated with PARPi. At time of hematologic consultation, patients with t-MN had a longer PARPi exposure (9 vs. 3 months, P = 0.01), lower platelet count (74 vs. 173 G/L, P = 0.0005), and more cytopenias (2 vs. 1, P = 0.0005). Compared with t-MN not exposed to PARPi, patients with t-MN-PARPi had more BRCA1/2 germline mutation (61.5% vs. 0%, P = 0.03) but similar overall survival (OS). In the national cohort, most t-MN post-PARPi had a complex karyotype (61%) associated with a high rate of TP53 mutation (71%). Median OS was 9.6 months (interquartile range, 4–14.6). In multivariate analysis, a longer time between end of PARPi and t-MN (HR, 1.046; P = 0.02), olaparib compared with other PARPi (HR, 5.82; P = 0.003) and acute myeloid leukemia (HR, 2.485; P = 0.01) were associated with shorter OS. Conclusions: In a large series, we described a high incidence of t-MN post-PARPi associated with unfavorable cytogenetic and molecular abnormalities leading to poor OS. Early detection is crucial, particularly in cases of delayed cytopenia.
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- 2022
21. Targeted genotyping of circulating tumor DNA for classical Hodgkin lymphoma monitoring: a prospective study
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J. Lequesne, Marie Cornic, Stéphane Leprêtre, Lucile Bessi, Elena-Liana Veresezan, Elodie Bohers, Justine Loret, Anne-Lise Menard, Hervé Tilly, Nathalie Contentin, Pierre-Julien Viailly, Aspasia Stamatoullas, Vincent Camus, Stéphanie Becker, Jean-Michel Picquenot, Hélène Lanic, Pierre Decazes, Sydney Dubois, Pascaline Etancelin, Pascal Lenain, Mathieu Viennot, Bénédicte Marcq, Fabrice Jardin, Emilie Lemasle, Lucie Burel, 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), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Normandie Université (NU), Service de médecine nucléaire [Rouen], and CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
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Adult ,Oncology ,medicine.medical_specialty ,Genotype ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Vinblastine ,Article ,Circulating Tumor DNA ,Bleomycin ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Medicine ,Hodgkin's Lymphoma ,Prospective Studies ,Liquid biopsy ,Prospective cohort study ,Genotyping ,Aged ,Retrospective Studies ,Aged, 80 and over ,Minimal Residual Disease ,Chemotherapy ,Cytogenetics and Molecular Genetics ,business.industry ,Editorials ,Retrospective cohort study ,Hematology ,Middle Aged ,Hodgkin's lymphoma ,medicine.disease ,Hodgkin Disease ,Minimal residual disease ,3. Good health ,Dacarbazine ,ABVD ,Doxorubicin ,030220 oncology & carcinogenesis ,Mutation ,business ,030215 immunology ,medicine.drug - Abstract
The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed in a prospective setting. We developed a targeted Next-Generation sequencing (NGS) panel for fast analysis (AmpliSeq® technology) of nine commonly mutated genes in biopies and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow-up at diagnosis and after two cycles (C2) of chemotherapy. Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD-like [73.5%] and other regimens [5.2%, for elderly patients]) were assessed in this noninterventional study. The median age of the patients was 33.5 years (range: 20-86). Variants were identified in 42 (70%) patients. Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1 were found in 13.3%, 31.7%, 23.3%, 5%, 33.3%, 10%, 23.3%, 13.3% and 50% of patients, respectively. ctDNA concentration and genotype were correlated with clinical characteristics and presentation. Regarding early therapeutic response, 45 patients (83%, not available [NA] =6) had a negative positron emission tomography (PET) after C2 (Deauville Score 1-3). The mean of DeltaSUVmax after C2 was -78.8%. ctDNA after C2 was analysed in 54 patients (90%). ctDNA became rapidly undetectable in all cases after C2. Variant detection in ctDNA is suitable to depict the genetic features of cHL at diagnosis and may help to assess early treatment response, in association with PET. Clinical Trial reference: NCT02815137.
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- 2020
22. High Prevalence of Pre-Existing Sarcopenia in Critically Ill Patients with Hematologic Malignancies Admitted to the Intensive Care Unit for Sepsis or Septic Shock
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Antoine Herault, Emilie Lévêque, Simon Draye-Carbonnier, Pierre Decazes, Alexandra Zduniak, Romain Modzelewski, Julie Libraire, Najate Achamrah, Anne-Lise Ménard, Pascal Lenain, Nathalie Contentin, Maximilien Grall, Stéphane Leprêtre, Emilie Lemasle, Hélène Lanic, Mustafa Alani, Aspasia Stamatoullas-Bastard, Hervé Tilly, Fabrice Jardin, Fabienne Tamion, and Vincent Camus
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History ,Nutrition and Dietetics ,Polymers and Plastics ,Endocrinology, Diabetes and Metabolism ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
23. Dissociated humoral and cellular immune responses after a three-dose schema of BNT162b2 vaccine in patients receiving anti-CD20 monoclonal antibody maintenance treatment for B-cell lymphomas
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Sydney Dubois, Doriane Richard, Louis-Ferdinand Pepin, Marion Carette, Sophie Candon, Nathalie Contentin, Stéphane Leprêtre, Emilie Leveque, Aspasia Stamatoullas, Florian Bouclet, Jean-Christophe Plantier, Alain Dalleac, Edwige Boulet, Veronique Lemee, Pascaline Etancelin, Anne-Lise Menard, Cedric Paquin, Hélène Lanic, Manuel Etienne, Hervé Tilly, Victor Bobée, Fabrice Jardin, Vincent Camus, Nathalie Cardinael, Mustafa Alani, and Emilie Lemasle
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Immunity, Cellular ,Vaccines ,Lymphoma, B-Cell ,medicine.drug_class ,business.industry ,Antibodies, Monoclonal ,Hematology ,Monoclonal antibody ,Antibodies, Viral ,Schema (genetic algorithms) ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Humans ,In patient ,Anti cd20 ,business ,B cell ,BNT162 Vaccine - Published
- 2021
24. Prognostic significance of concurrent gene mutations i n intensively treated patients with IDH-mutated AML: an ALFA study
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Céline Berthon, Lionel Ades, Nicolas Boissel, Emilie Lemasle, Christian Recher, Xavier Thomas, Nicolas Duployez, Norbert Vey, Raphael Itzykson, Sylvain Chantepie, Karine Celli-Lebras, Arnaud Pigneux, Pascal Turlure, Stéphane de Botton, Claude Preudhomme, Claude Gardin, Denis Caillot, Jean-Pierre Marolleau, Christine Terré, Jean-Baptiste Micol, Hervé Dombret, Thorsten Braun, Juliette Lambert, Emmanuel Raffoux, Jean-Valère Malfuson, Matthieu Duchmann, Cécile Pautas, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Université Paris-Saclay, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Hôpital Avicenne [AP-HP], Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital Henri Mondor, Centre Hospitalier de Versailles André Mignot (CHV), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Centre de Transfusion Sanguine des Armées (CTSA), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Universitaire d'Hématologie (IUH), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], and DESSAIVRE, Louise
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Male ,Oncology ,medicine.medical_specialty ,NPM1 ,IDH1 ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Immunology ,Abnormal Karyotype ,Hematopoietic stem cell transplantation ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Disease-Free Survival ,DNA Methyltransferase 3A ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Point Mutation ,Medicine ,Prospective Studies ,In Situ Hybridization, Fluorescence ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Chromosome Aberrations ,Clinical Trials as Topic ,Mutation ,Acute leukemia ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,[SDV] Life Sciences [q-bio] ,Leukemia, Myeloid, Acute ,Isocitrate dehydrogenase ,Female ,France ,business ,Nucleophosmin - Abstract
International audience; In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P< .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.
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- 2021
25. A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia
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Norbert Vey, Mauricette Michallet, Sylvain Chantepie, Xavier Thomas, Paul-Arthur Meslin, Delphine Lebon, Christine Terré, Sylvie Chevret, Claude Preudhomme, Pascal Turlure, Emilie Lemasle, Sébastien Maury, Emmanuel Raffoux, Karine Celli-Lebras, Nicolas Duployez, Pierre-Yves Dumas, Raphael Itzykson, Céline Berthon, Jean-Valère Malfuson, Denis Caillot, Arnaud Pigneux, Ibrahim Yakoub-Agha, Juliette Lambert, Auriane Lesieur, Christian Recher, Claude Gardin, Pierre Sujobert, Cécile Pautas, Benoît Ducourneau, Gérard Socié, Gael Fortin, Stéphanie Nguyen, Laurène Fenwarth, Stéphane de Botton, Hervé Dombret, Nicolas Boissel, Jean-Henri Bourhis, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), 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, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hôpital Avicenne [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Transfusion Sanguine des Armées (CTSA), Service de Santé des Armées, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Henri Mondor [Créteil], Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), DESSAIVRE, Louise, Centre International des greffes [CHU Saint-Antoine] (EBMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Henri Mondor, Service d'Hématologie [CHU Toulouse], and CHU Toulouse [Toulouse]
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Oncology ,Male ,Myeloid ,Neoplasm, Residual ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Datasets as Topic ,Hematopoietic stem cell transplantation ,Biochemistry ,European LeukemiaNet ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Multicenter Studies as Topic ,Precision Medicine ,Randomized Controlled Trials as Topic ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Nuclear Proteins ,Hematology ,Middle Aged ,Prognosis ,Combined Modality Therapy ,[SDV] Life Sciences [q-bio] ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,surgical procedures, operative ,Female ,Nucleophosmin ,Algorithms ,Adult ,medicine.medical_specialty ,NPM1 ,Adolescent ,Immunology ,Clinical Decision-Making ,Risk Assessment ,Young Adult ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,business.industry ,Cell Biology ,Models, Theoretical ,medicine.disease ,Minimal residual disease ,Transplantation ,business - Abstract
A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.
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- 2021
26. Outcomes after intensive care unit admission in newly diagnosed diffuse large B-cell lymphoma patients: A real-life study
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J. Lequesne, Aspasia Stamatoullas-Bastard, Louis-Ferdinand Pepin, Anne-Lise Menard, Vincent Camus, Emilie Lemasle, Alexandra Zduniak, Hervé Tilly, Fabienne Tamion, Fabrice Jardin, Nathalie Contentin, Sorina-Dana Mihailescu, Pascal Lenain, Hélène Lanic, and Stéphane Leprêtre
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Male ,medicine.medical_specialty ,health care facilities, manpower, and services ,Disease-Free Survival ,law.invention ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Patient Admission ,law ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Hospital Mortality ,Cyclophosphamide ,Aged ,Retrospective Studies ,Septic shock ,business.industry ,Retrospective cohort study ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Intensive care unit ,Survival Rate ,Regimen ,Intensive Care Units ,Respiratory failure ,Doxorubicin ,Vincristine ,030220 oncology & carcinogenesis ,Cohort ,Prednisone ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Rituximab ,Diffuse large B-cell lymphoma ,030215 immunology - Abstract
We conducted a retrospective study to analyze the prognostic factors impacting the overall survival (OS) and progression-free survival (PFS) of diffuse large B-cell lymphoma (DLBCL) patients undergoing first-line therapy and admitted to intensive care unit (ICU) compared to a control cohort who did not required ICU admission. Between January 1, 2008, and December 31, 2018, 828 patients were diagnosed with DLBCL at our institution, including 72 patients who were required ICU admission during disease course. Among them, forty-five patients undergoing homogeneous first-line therapy with /R-CHOP-like regimen and ICU-admitted were selected for the present analysis. Control "non-ICU" DLBCL patients were matched by age, IPI score and treatment received. The median age at ICU admission was 65 years, 97.8% of patients displayed advanced-stage disease (III/IV), and 84.4% had a high IPI score (3-5). The main reasons for ICU admission were acute respiratory failure (40.0%) and septic shock (33.3%). The ICU mortality rate was 33.3%. The 2-year PFS was lower in ICU survivors patients than in non-ICU patients: 31.7% (95% CI 18.5-54.1) vs 60.8% (95% CI 51.2-72.1, P = .00049). Admission to the ICU is an event that clearly impacts the outcomes of patients with DLBCL, until 2 years after the event. ICU prognosis seems mainly related to critical patient severity at admission rather than lymphoma-related prognostic factors (IPIs), suggesting that ICU admission criteria should not be based only on the lymphoma prognosis.
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- 2020
27. Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results
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Mauricette Michallet, Emilie Lemasle, Claude Preudhomme, Lauris Gastaud, Nicolas Boissel, Karine Celli-Lebras, Christine Terré, Thorsten Braun, Régis Peffault de Latour, Juliette Lambert, Nicolas Duployez, Elise Fournier, Claude Gardin, Raphael Itzykson, Hervé Dombret, Stéphane de Botton, Lionel Ades, Cécile Pautas, Céline Berthon, Jean-Henri Bourhis, Emmanuel Raffoux, Jean-Pierre Marolleau, Jean-Valère Malfuson, Sylvain Chantepie, Thomas Cluzeau, Xavier Thomas, Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Henri Mondor, Hôpital Claude Huriez [Lille], CHU Lille, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], CHU Amiens-Picardie, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre Léon Bérard [Lyon], Laboratoire d'Hématologie Biologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Hopital Saint-Louis [AP-HP] (AP-HP)
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Oncology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Gene mutation ,03 medical and health sciences ,European LeukemiaNet ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030304 developmental biology ,Aged ,0303 health sciences ,Acute leukemia ,Myeloid Neoplasia ,business.industry ,Myelodysplastic syndromes ,Hazard ratio ,Neoplasms, Second Primary ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Chemotherapy regimen ,3. Good health ,Transplantation ,Leukemia ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Mutation ,business - Abstract
In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497.
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- 2019
28. Non-invasive monitoring of diffuse large B-cell lymphoma by cell-free DNA high-throughput targeted sequencing: analysis of a prospective cohort
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Hélène Lanic, Pierre-Julien Viailly, Philippe Bertrand, Philippe Ruminy, Stéphanie Becker, Louis-Ferdinand Pepin, Vincent Camus, Emilie Lemasle, Julie Libraire, Elodie Bohers, Stéphane Leprêtre, Vinciane Marchand, Sandrine Vaudaux, Catherine Maingonnat, Pascaline Etancelin, Pascal Lenain, Jean-Michel Picquenot, Anne-Lise Menard, Fabrice Jardin, Pierre Vera, Aspasia Stamatoullas, Nathalie Contentin, Hervé Tilly, 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), Service de médecine nucléaire [Rouen], CRLCC Haute Normandie-CRLCC Henri Becquerel, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'Hématologie, CRLCC Henri Becquerel, Service d'hématologie, Unité de recherche clinique, Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), CRLCC Haute Normandie-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Unité de recherche clinique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), This research was supported by grants from the Cancéropole Nord-Ouest, the Ligue Contre le Cancer, and Henri Becquerel Center., and Breton, Céline
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Male ,0301 basic medicine ,Oncology ,0302 clinical medicine ,Positron Emission Tomography Computed Tomography ,Antineoplastic Combined Chemotherapy Protocols ,Prospective Studies ,Prospective cohort study ,ComputingMilieux_MISCELLANEOUS ,Aged, 80 and over ,medicine.diagnostic_test ,High-Throughput Nucleotide Sequencing ,DNA, Neoplasm ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell-free fetal DNA ,030220 oncology & carcinogenesis ,Female ,Lymphoma, Large B-Cell, Diffuse ,Cell-Free Nucleic Acids ,Adult ,medicine.medical_specialty ,DNA Copy Number Variations ,Genotype ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Context (language use) ,lcsh:RC254-282 ,Article ,Young Adult ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,Biopsy ,Biomarkers, Tumor ,medicine ,Humans ,Clinical significance ,Liquid biopsy ,Alleles ,Aged ,business.industry ,Liquid Biopsy ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Lymphoma ,030104 developmental biology ,business ,Diffuse large B-cell lymphoma - Abstract
From a liquid biopsy, cell-free DNA (cfDNA) can provide information regarding basal tumoral genetic patterns and changes upon treatment. In a prospective cohort of 30 diffuse large B-cell lymphomas (DLBCL), we determined the clinical relevance of cfDNA using targeted next-generation sequencing and its correlation with PET scan imaging at the time of diagnosis and during treatment. Using a dedicated DLBCL panel, mutations were identified at baseline for 19 cfDNAs and profiles were consistent with expected DLBCL patterns. Tumor burden-related clinical and PET scan features (LDH, IPI, and metabolic tumor volume) were significantly correlated with the quantity of tumoral cfDNA. Among the four patients presenting additional mutations in their cfDNAs, three had high metabolic tumor volumes, suggesting that cfDNA more accurately reflects tumor heterogeneity than tissues biopsy itself. Mid-treatment, four patients still had basal mutations in their cfDNAs, including three in partial response according to their Deauville scores. Our study highlights the major interests in liquid biopsy, in particular in the context of bulky tumors where cfDNA allows capturing the entire tumoral mutation profile. Therefore, cfDNA analysis in DLBCL represents a complementary approach to PET scan imaging.
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- 2018
29. Replacing the Anthracycline By Gemtuzumab Ozogamicin in Older Patients with De Novo Standard-Risk Acute Myeloid Leukemia Treated Intensively - Results of the Randomized ALFA1401-Mylofrance 4 Study
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Philippe Rousselot, Sylvie Castaigne, Cécile Pautas, Diana Carp, Nicolas Duployez, Claude Gardin, Xavier Thomas, Emmanuelle Tavernier, Lauris Gastaud, Christine Terré, Magalie Joris, Jean Valère Malfuson, Céline Berthon, Olivier Legrand, Denis Caillot, Emilie Lemasle, Claude Preudhomme, Karine Celli-Lebras, Jérôme Lambert, Hervé Dombret, Juliette Lambert, Iona Vaida, Pascal Turlure, Sarah Barbieux, Ambroise Marçais, and Sylvain Chantepie
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Oncology ,medicine.medical_specialty ,Anthracycline ,business.industry ,Gemtuzumab ozogamicin ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Older patients ,Standard Risk ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Introduction Based on the results of the ALFA-0701 trial (Castaigne et al. Lancet 2012), the addition of fractionated doses of the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin (GO, Mylotarg®) to conventional chemotherapy has been approved in 2017 for frontline treatment of adults with CD33-positive acute myeloid leukemia (AML). Prolonged event-free survival (EFS) was observed in patients with AML of favorable or intermediate risk, while not in those with adverse cytogenetics. Nevertheless, more frequent added toxicities could make the addition of GO a questionable option in patients over 60-65 years of age. In this ALFA-1401/Mylofrance 4 trial (NCT02473146), we investigated if the replacement of the anthracycline by GO might also improve EFS in older patients. Methods Between January 2016 and March 2019, 225 patients were randomized 2:1 to receive an experimental GO-cytarabine combination (154 patients) or a standard anthracycline-cytarabine treatment (71 patients). Patients aged 65 to 80 years old (later extended to patients aged 60-64 years old), with previously untreated de novo AML of favorable or intermediate cytogenetics were eligible for the trial. Standard treatment arm consisted in a 7+3 using idarubicin at 12 mg/m 2/d on day 1 to 3 and cytarabine 200 mg/m 2/d on day 1 to 7. Experimental arm (GO arm) consisted of two doses of GO 3 mg/m 2/d on day 1 and 4 and cytarabine 200 mg/m 2/d on day 1 to 7. Post-remission therapy comprised two courses of intermediate-dose cytarabine (IDAC) at 1.5 g/m 2/12h on day 1, 3 and 5. In the GO arm, a third dose of 3mg/m 2/d GO was administered on day 1 of the first IDAC course. The first IDAC course could serve as second induction in patients not responding to the first one. The decision to perform allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission was left to the discretion of the physician. The efficacy analysis was conducted in the modified intent-to-treat (mITT) population excluding patients who did not meet the cytogenetic eligibility criteria. The primary study endpoint was EFS. Secondary endpoints were response rate defined by complete remission (CR), CR with incomplete platelets recovery (CRp) and CR with incomplete hematological recovery (CRi), early mortality, relapse incidence, overall survival (OS) and safety. Results Among the 225 randomized patients, 214 (71 standard arm, 143 GO arm) were included in the mITT population. There were 126 men and 88 women. Median age was 70 years (61-80). Cytogenetics was of favorable and intermediate risk in 14 and 200 patients, respectively. One hundred and eighty-one patients reached CR/CRp/CRi, 64 (90%) in standard arm and 117 (82%) in GO arm (p=0.17). Median follow-up time was 38 months. At 2 years, estimated EFS was 38% [95% CI, 28-51] in the standard arm vs. 29% [22-37] in the GO arm (Hazard Ratio (HR), 1.37 [0.98-1.93]; p= 0.067) (Figure 1A). Overall, 118 patients relapsed, 36 (51%) in standard arm and 82 (57%) in GO arm. At 2 years, estimated cumulative incidence of relapse was 48% [36-61] in standard arm vs. 61% [52-70] in GO arm (csHR, 1.32 [0.90-1.93]; p= 0.078). Overall, 122 patients died, 38 (54%) in standard arm, 84 (59%) in GO arm. Sixty-day mortality was 4% in standard arm vs. 10% in GO arm (p=0.13). At 2 years, estimated OS was 65% [55-77] in standard arm vs. 52% [45-61] in GO arm (HR, 1.27 [0.86-1.87]; p= 0.23). In subgroup analysis for EFS (Figure 1B), we found a significant interaction with gender, GO having a detrimental effect in women which persisted after adjustment on known prognostic factors. A total of 33 patients received allo-HSCT in first remission, 19 (30%) in standard arm and 14 (12%) in GO arm (p=0.006). When censoring these patients at transplant time, HR of GO on EFS was 1.27 ([0.88-1.83]; p=0.19). Regarding safety, 76% and 80% of patients had at least one grade 3 to 5 adverse event (p=0.81), including infection in 30% vs. 21% and bleeding in 7% vs. 29% in standard arm and GO arm respectively. Serious adverse events were reported in 34% of patients in standard arm vs. 49% in GO arm (p=0.031). Sinusoidal obstruction syndrome occurred in 2 patients in the GO arm. Conclusion Frontline use of GO instead of idarubicin, when combined to cytarabine, does not benefit older patients with de novo standard-risk AML. At the reduced dose schedule used in this study, GO remains associated with significant toxicities while non-significant higher relapse incidence, shorter EFS and shorter OS were observed. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: ABBVIE: Consultancy; PFIZER: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Barbieux: ASTRA-ZENECCA: Consultancy. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; Daiichi Sankyo: Honoraria; BMS-Celgene: Honoraria.
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- 2021
30. Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group
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Norbert Vey, Claude Preudhomme, Marie Balsat, Christine Terré, Jean-Pierre Marolleau, Thorsten Braun, Sandrine Hayette, Xavier Thomas, Emmanuel Raffoux, Céline Rodriguez, Olivier Nibourel, Céline Berthon, Karine Celli-Lebras, Arnaud Pigneux, Hervé Dombret, Marie Magdeleine Coudé, Aline Renneville, Alice Marceau, Emilie Lemasle, Jean-Michel Cayuela, Denis Caillot, Nicolas Boissel, Stéphane de Botton, Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Amiens-Picardie, Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], ERAMET RESEARCH, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), and Hopital Saint-Louis [AP-HP] (AP-HP)
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Myeloid ,[SDV]Life Sciences [q-bio] ,Context (language use) ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Acute leukemia ,business.industry ,Remission Induction ,Nuclear Proteins ,Myeloid leukemia ,Middle Aged ,Prognosis ,medicine.disease ,Minimal residual disease ,body regions ,Transplantation ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Mutation ,Immunology ,Female ,business ,Nucleophosmin ,Stem Cell Transplantation ,030215 immunology - Abstract
Purpose This study assessed the prognostic impact of postinduction NPM1-mutated ( NPM1m) minimal residual disease (MRD) in young adult patients (age, 18 to 60 years) with acute myeloid leukemia, and addressed the question of whether NPM1m MRD may be used as a predictive factor of allogeneic stem cell transplantation (ASCT) benefit. Patients and Methods Among 229 patients with NPM1m who were treated in the Acute Leukemia French Association 0702 (ALFA-0702) trial, MRD evaluation was available in 152 patients in first remission. Patients with nonfavorable AML according to the European LeukemiaNet (ELN) classification were eligible for ASCT in first remission. Results After induction therapy, patients who did not achieve a 4-log reduction in NPM1m peripheral blood-MRD (PB-MRD) had a higher cumulative incidence of relapse (subhazard ratio [SHR], 5.83; P < .001) and a shorter overall survival (OS; hazard ratio [HR], 10.99; P < .001). In multivariable analysis, an abnormal karyotype, the presence of FLT3-internal tandem duplication (ITD), and a < 4-log reduction in PB-MRD were significantly associated with a higher relapse incidence and shorter OS. In the subset of patients with FLT3-ITD, only age, white blood cell count, and < 4-log reduction in PB-MRD, but not FLT3-ITD allelic ratio, remained of significant prognostic value. In these patients with nonfavorable AML according to European LeukemiaNet, disease-free survival and OS were significantly improved by ASCT in those with a < 4-log reduction in PB-MRD. This benefit was not observed in those with a > 4-log reduction in PB-MRD, with a significant interaction between ASCT effect and PB-MRD response ( P = .024 and .027 for disease-free survival and OS, respectively). Conclusion Our study supports the strong prognostic significance of early NPM1m PB-MRD, independent of the cytogenetic and molecular context. Moreover, NPM1m PB-MRD may be used as a predictive factor for ASCT indication.
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- 2017
31. Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup
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Xavier Thomas, Chantal Himberlin, Anne Banos, Clémence Loiseau, Emmanuel Raffoux, Corentin Orvain, Amine Belhabri, Isabelle Luquet, Christian Recher, Mathilde Hunault, Norbert Vey, Pierre Peterlin, Sylvain Chantepie, Christine Terré, Claude Gardin, Ariane C Mineur, Eric Delabesse, Cécile Pautas, Claude Preudhomme, Romain Guieze, Jean Francois Hamel, Emilie Lemasle, Martin Carre, Karine Celli-Lebras, Arnaud Pigneux, Hervé Dombret, Jean-Francois Brasme, and Marc Bernard
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Complete remission ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Vosaroxin ,Consolidation therapy ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Cytarabine ,Intermediate risk ,business ,medicine.drug - Abstract
In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.
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- 2020
32. Mutational profile and benefit of gemtuzumab ozogamicin in acute myeloid leukemia
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Sylvain Chantepie, Alice Marceau-Renaut, Nicolas Duployez, Claude Preudhomme, Pascal Turlure, Karine Celli-Lebras, Xavier Thomas, Estelle Guérin, Jean-Valère Malfuson, Juliette Lambert, Christine Terré, Hervé Dombret, Elise Fournier, Meyling Cheok, Benoît Ducourneau, Emmanuel Raffoux, Emilie Lemasle, Sylvie Castaigne, Cécile Pautas, Nicolas Boissel, and Denis Caillot
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Oncology ,medicine.medical_specialty ,Myeloid ,Gemtuzumab ozogamicin ,Immunology ,CD33 ,Sialic Acid Binding Ig-like Lectin 3 ,Biochemistry ,Antineoplastic Agents, Immunological ,Internal medicine ,medicine ,Humans ,Aged ,Proportional Hazards Models ,Proportional hazards model ,business.industry ,Gene Expression Regulation, Leukemic ,Hazard ratio ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Gemtuzumab ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Mutation ,business ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is a highly heterogeneous disease both in terms of genetic background and response to chemotherapy. Although molecular aberrations are routinely used to stratify AML patients into prognostic subgroups when receiving standard chemotherapy, the predictive value of the genetic background and co-occurring mutations remains to be assessed when using newly approved antileukemic drugs. In the present study, we retrospectively addressed the question of the predictive value of molecular events on the benefit of the addition of gemtuzumab ozogamicin (GO) to standard front-line chemotherapy. Using the more recent European LeukemiaNet (ELN) 2017 risk classification, we confirmed that the benefit of GO was restricted to the favorable (hazard ratio [HR], 0.54, 95% confidence interval [CI], 0.30-0.98) and intermediate (HR, 0.57; 95% CI, 0.33-1.00) risk categories, whereas it did not influence the outcome of patients within the adverse risk subgroup (HR, 0.93; 95% CI, 0.61-1.43). Interestingly, the benefit of GO was significant for patients with activating signaling mutations (HR, 0.43; 95% CI, 0.28-0.65), which correlated with higher CD33 expression levels. These results suggest that molecular aberrations could be critical for future differentially tailored treatments based on integrated genetic profiles that are able to predict the benefit of GO on outcome.
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- 2019
33. TARGETED GENOTYPING OF CIRCULATING TUMOR DNA FOR CLASSICAL HODGKIN LYMPHOMA MONITORING: A PROSPECTIVE STUDY
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Vincent Camus, Hélène Lanic, Emilie Lemasle, Fabrice Jardin, Jean-Michel Picquenot, Hervé Tilly, Pascaline Etancelin, Elodie Bohers, Stéphanie Becker, Aspasia Stamatoullas, B. Marcq, Mathieu Viennot, L. Burel, Stéphane Leprêtre, Anne-Lise Menard, Pascal Lenain, Marie Cornic, L. Bessi, Nathalie Contentin, Pierre-Julien Viailly, J. Loret, 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), and Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
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0303 health sciences ,Cancer Research ,business.industry ,[SDV]Life Sciences [q-bio] ,Hematology ,General Medicine ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Circulating tumor DNA ,030220 oncology & carcinogenesis ,Cancer research ,Classical Hodgkin lymphoma ,Medicine ,business ,Prospective cohort study ,Genotyping ,030304 developmental biology - Abstract
International audience; About Related Information ePDFPDF Request permission Export citation Add to favorites Track citationShare a linkShare on Email Facebook Twitter LinkedIn RedditIntroduction: The relevance of circulating tumor DNA (ctDNA) analysis as a liquid biopsy and minimal residual disease tool in the management of classical Hodgkin Lymphoma (cHL) patients was demonstrated in retrospective settings and remains to be confirmed.Methods: We developed a targeted Next‐Generation sequencing (NGS) panel for fast analysis (AmpliSeq® technology) of nine commonly mutated genes in biopsy and ctDNA of cHL patients. We then conducted a prospective trial to assess ctDNA follow up at diagnosis and after 2 cycles of chemotherapy (C2). A dedicated bioinformatics pipeline to optimize detections of variants with low rates and minimize artefactual misinterpretations was built. Sixty cHL patients treated by first line conventional chemotherapy (BEACOPPescalated [21.3%], ABVD/ABVD‐like [73.5%] and other regimens [5.2%, for elderly patients] were included in this non‐interventional study (NCT02815137).Results: Median age of the patients was 33.5 years (range 20‐86) with a predominance of male patients, scleronodular subtype and ECOG 0‐1 (53.3%, 70% and 88.3%, respectively). Variants were identified in 33 (55%) patients, precisely in 16/30 (53.3%) and 30/60 (50%) of available biopsy and ctDNA samples respectively. Concordance between genetic profiles of biopsy and ctDNA was accurate for 22/30 patients (73.3%). Mutations of NFKBIE, TNFAIP3, STAT6, PTPN1, B2M, XPO1, ITPKB, GNA13 and SOCS1were found in 11.7% (mean number of variants by sample [range]: 1 [0‐1]), 25% (1.1 [0‐2]), 21.7% (1.4 [0‐2]), 1.7% (1 [0‐1]), 25% (1.3 [0‐3]), 6.7% (1 [0‐1]), 15% (1.4 [0‐3]), 5% (1.3 [0‐2]) and 31.7% (1.8 [0‐7]) of all patients, respectively. Unsupervised hierarchical clustering was performed among the 9 genes to represent the association of alterations (See Figure 1).Higher level of [ctDNA] at diagnosis was associated with adverse characteristics: age ≥45 years, presence of anemia (hemoglobin
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- 2019
34. Prognostic Significance of Concurrent Gene Mutations in Intensively Treated Patients with IDH1/2 Mutated AML
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Raphael Itzykson, Lionel Ades, Hervé Dombret, Jean Valère Malfuson, Juliette Lambert, Céline Berthon, Claude Preudhomme, Christine Terré, Emmanuel Raffoux, Cécile Pautas, Jean-Baptiste Micol, Matthieu Duchmann, Jean-Pierre Marolleau, Nicolas Duployez, Emilie Lemasle, Karine Celli-Lebras, Arnaud Pigneux, Claude Gardin, Christian Recher, Xavier Thomas, Pascal Turlure, Nicolas Boissel, Stéphane de Botton, Thorsten Braun, Denis Caillot, Norbert Vey, Sylvain Chantepie, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Service d'Hématologie Biologique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Service d'Hématologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie cellulaire, F-33000, Bordeaux., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Génétique [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service clinique des Maladies du Sang, CHU Amiens-Picardie, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), DESSAIVRE, Louise, and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Mutation ,IDH1 ,business.industry ,Point mutation ,[SDV]Life Sciences [q-bio] ,Immunology ,DNMT3A Gene ,Cell Biology ,Hematology ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Chemotherapy regimen ,[SDV] Life Sciences [q-bio] ,Isocitrate dehydrogenase ,Cancer research ,Medicine ,business ,Gene - Abstract
Background : Point mutations in isocitrate dehydrogenase (IDH) genes are seen in 20% of adult patients (pts) with acute myeloid leukemia (AML). Prognostic significance of each IDH1/2 mutation (mut) analyzed with co-occurring mutations treated with intensive chemotherapy (IC) remains inconsistent, particularly with the advent of IDH inhibitors. Furthermore, the role of allogeneic stem cell transplantation (SCT) in IDH-mutated without favorable-risk features is not known. Patients & Methods: Between 2009 and 2016, 262 pts with IDH1/2 mutated AML (101 IDH1mut, 115 IDH2R140Qmutand 46 IDH2R172mut) were treated with IC in younger ALFA-0702 (NCT00932412, n = 133) and older ALFA-1200 (NCT01966497, n = 129) prospective trials. Median age was 50 [42-54] and 67 y [64-71], respectively (resp). Targeted 37-gene next-generation sequencing (NGS) information was available for all pts. According to ELN 2010 classification, non-favorable CR/CRp pts were eligible for SCT if they had a sibling or matched unrelated donor. Correlation between IDHmutand covariates was realized by Pearson correlation coefficient and point biserial correlation for continuous and dichotomic variables, resp. Impact on response and survival was assessed for all covariates present in at least 10% of patients. SCT was considered as a time-dependent variable. Informative variables selected by LASSO were included in multivariate logistic regression for response and multivariate Cox model for survival. All analyses were stratified on the clinical trial. Results: IDH1 mut was significantly associated with NPM1mut(p=0.025), DNMT3Amut(p=0.009) and mutually exclusive with TET2mut(p=0.009). 80% (81/101) of IDH1 mutated pts achieved CR/CRp [96 % (46/48) if concomitant NPM1mut vs 66% (35/53) if not (p=0.0009)]. With a median FU of 39 months, overall median OS was not reached and median EFS was 15 months (Fig 1A). Presence of NPM1mutwas the only variable associated with longer OS (HR=0.33, p=0.001) and EFS (HR = 0.4, p = 0.001) in multivariate analysis. At 5 years, OS was estimated at 68% and 35% and EFS at 55% and 26%, resp (Fig 1B). Effect of concomitant NPM1mutwas reinforced in the absence of DNMT3Amut(HR=0.14, p=0.0006 and HR=0.16, p IDH2R140Q mut was significantly associated with NPM1mut(p=0.0004) and SRSF2mut(p IDH2R172K mut was significantly associated with DNMT3Amut(p=0.0004) and BCORmut(p Finally, in non-favorable ELN 2010 pts (74, 74 and 46 with IDH1mut, IDH2R140Qmutand IDH2R172Kmut, resp), SCT in first CR only benefited to pts with IDH1mut(p=0.004 for OS) or with IDH2R172Kmut(p=0.03 for EFS). Conclusion: In a large prospective series, NPM1mutis the main better risk factor in the IDH1mutand IDH2R140Qmutsubgroups and may be used as stratification factor in clinical trials testing frontline specific IDH inhibitors with IC. Allogeneic SCT in first CR appears to improve the outcome of pts with non-favorable IDH1 or IDH2R172K mutated AML. Figure 1 Disclosures Micol: Jazz Pharmaceuticals: Consultancy; AbbVie: Consultancy. Thomas:ABBVIE: Honoraria; DAICHI: Honoraria; INCYTE: Honoraria; PFIZER: Honoraria. Braun:Institut de Recherches Internationales Servier (IRIS): Research Funding. Ades:Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Boissel:NOVARTIS: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Pigneux:Astellas: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Jazz: Honoraria; Abbvie: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Daichi: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding. De Botton:Daiichi: Consultancy; Janssen: Consultancy; Agios: Consultancy, Research Funding; Astellas: Consultancy; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Forma: Consultancy, Research Funding; Syros: Consultancy; AbbVie: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Bayer: Consultancy.
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- 2019
35. Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma
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Christer Sundström, Noel Milpied, Christian Argueta, Jean-Philippe Jais, Alexandra Traverse-Glehen, Christiane Copie-Bergman, Sydney Dubois, Vincent Camus, Emilie Lemasle, Laura Pelletier, Catherine Maingonnat, Hervé Tilly, Richard Delarue, Fabrice Jardin, Corinne Haioun, Anais Pujals, Pierre-Julien Viailly, Gilles Salles, François Lemonnier, Marie Cornic, Thierry Fest, Thierry Jo Molina, Christian Bastard, Elodie Bohers, Martin Figeac, Philippe Gaulard, Diane Damotte, Sylvain Mareschal, Peter Moeller, Karen Leroy, Jean Michel Picquenot, Marlene Ochmann, Brigitte Sola, Martin J. S. Dyer, Aspasia Stamatoullas, Yosef Landesman, and Philippe Bertrand
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0301 basic medicine ,Mutation ,Mutant ,Wild type ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Molecular biology ,3. Good health ,Lymphoma ,Gene expression profiling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,International Prognostic Index ,030220 oncology & carcinogenesis ,medicine ,Cancer research ,Primary mediastinal B-cell lymphoma ,Allele - Abstract
Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein.
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- 2016
36. Cyberlindnera jadinii (teleomorph Candida utilis) candidaemia in a patient with aplastic anaemia: a case report
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Hélène Lanic, Vincent Camus, Stéphane Leprêtre, Gilles Gargala, Emilie Lemasle, Aspasia Stamatoullas, Marion David, Nathalie Contentin, Pascal Lenain, Hervé Tilly, Pauline Treguier, Anne-Lise Menard, Fabrice Jardin, 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), Service d'hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Rouen, Normandie Université (NU), Epidémiosurveillance de protozooses à transmission alimentaire et vectorielle (ESCAPE), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Reims Champagne-Ardenne (URCA), VILLIER, Venceslas, Université de Reims Champagne-Ardenne (URCA)-Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)
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[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,Microbiology (medical) ,Antifungal ,medicine.medical_specialty ,medicine.drug_class ,Case Report ,Case presentation ,Microbiology ,Cyberlindnera ,03 medical and health sciences ,0302 clinical medicine ,medullary aplasia ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Internal medicine ,Medicine ,candidaemia ,Cyberlindnera jadinii ,Pichia ,Torulopsis utilis ,biology ,Adult patients ,business.industry ,Septic shock ,Blood/heart and Lymphatics ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,medicine.disease ,biology.organism_classification ,3. Good health ,Transplantation ,030220 oncology & carcinogenesis ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,business ,030215 immunology - Abstract
International audience; Introduction. We present what is believed to be the first report of candidaemia caused by Cyberlindnera (Pichia) jadinii (teleomorph of Candida utilis) in a patient with an aplastic anaemia.Case presentation. The patient, a 21-year-old male, presented with hepatic cytolysis, cutaneous and pulmonary involvement, and septic shock. Cyberlindnera jadinii was identified by aerobic blood culture and MS. The patient initially received multiple and combined antifungal therapy, but continued to have persistent skin lesions and fever. He was successfully treated by emergency haploidentical haematopoietic stem cell transplantation, combined with triple antifungal therapy and supportive care.Conclusion. Cyberlindnera jadinii, teleomorph of Candida utilis, which is not usually invasive, can lead to an opportunistic invasive infection in unhealthy adult patients. For treatment of the invasive candida infection, it is necessary to combine antifungal therapy and supportive care.
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- 2018
37. Oncogenic Predictors of Outcome in Older AML Patients Treated Intensively. Analysis of the ALFA-1200 Trial
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Lauris Gastaud, Sylvain Chantepie, Olivier Nibourel, Karine Celli-Lebras, Christine Terré, Nicolas Boissel, Hervé Dombret, Lionel Ades, Jean-Baptiste Micol, Benjamin Papoular, Raphael Itzykson, Cécile Pautas, Nicolas Duployez, Elise Fournier, Claude Gardin, Céline Berthon, Emilie Lemasle, Thomas Cluzeau, Thorsten Braun, Xavier Thomas, Alice Marceau-Renaut, Emmanuel Raffoux, Jean Valère Malfuson, Philippe Rousselot, Claude Preudhomme, Jean-Pierre Marolleau, Hématopoïèse normale et pathologique, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Claude Huriez [Lille], CHU Lille, Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service de pathologie [CHU Lille], Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service clinique des Maladies du Sang, CHU Amiens-Picardie, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), 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, Mathématiques & Sécurité de l'information (XLIM-MATHIS), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de Génétique [CH Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Service d'Hématologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], and DESSAIVRE, Louise
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0301 basic medicine ,Oncology ,Neuroblastoma RAS viral oncogene homolog ,medicine.medical_specialty ,Univariate analysis ,business.industry ,[SDV]Life Sciences [q-bio] ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Odds ratio ,Gene mutation ,medicine.disease_cause ,Biochemistry ,[SDV] Life Sciences [q-bio] ,Transplantation ,03 medical and health sciences ,030104 developmental biology ,Gene interaction ,Internal medicine ,medicine ,KRAS ,business - Abstract
Context. The prognostic value of gene mutations in older AML patients (pts) treated intensively remains unclear. Only one study has explored the role of mutation patterns determined by NGS in older AML pts prospectively treated with various chemotherapies in years 2000-2010 (Eisfeld Leukemia 2018). Methods. Pts older than 60y enrolled in the ALFA-1200 trial (NCT01966497) between 09/2012 and 06/2016 were sequenced with a 37-gene myeloid panel. Pts received one 7+3 course followed by 2 intermediate-dose cytarabine courses. Pts with non-favorable risk were eligible for allogeneic stem cell transplantation (SCT). Variable selection for multivariate analyses was performed by lasso penalized regression including age, gender and log(WBC) as covariates. Results. Sequencing was done in 471 (93%) of the 509 enrolled pts. Median age and WBC count were 68y and 5.3x109/L, respectively (resp). CR (including CRp) was achieved in 341 (72%) pts and 90 underwent RIC-SCT in first CR. With a median follow-up of 25.4 months, median OS was 20.7 months. Pts had a median of 3 mutations (range 1-10). The 17 mostly frequently mutated genes (≥5% of pts, by decreasing frequency: DNMT3A, NPM1, TET2, ASXL1, FLT3, SRSF2, IDH2, RUNX1, NRAS, IDH1, STAG2, BCOR, TP53, PTPN11, U2AF1, EZH2 and KRAS) were retained for prognostic analyses. Genes belonging to a common pathway (eg. NRAS and KRAS) may have divergent prognostic values, preventing biology-informed grouping of mutations. Cytogenetic risk (derived from ELN 2017, Döhner Blood 2017, not considering gene mutations) was favorable (fav), intermediate (int), adverse (adv) and missing in 3%, 72%, 18% and 7% resp. Because of the few pts with fav cytogenetics in our cohort, pts were further grouped into non-adv and adv cytogenetics. CR rates and median OS were 75.6% vs 56.6% and 24.8 vs 9.5 months in pts with non-adv and adv cytogenetics, resp (both p In the 388 pts with non-adv cytogenetics, NPM1 mutations independently predicted improved CR rate (Odds Ratio [OR]=2.3, p=0.014), while mutations in ASXL1 (OR=0.46, p=0.012), RUNX1 (OR=0.46, p=0.013) and NRAS (OR=0.49, p=0.04) had independent adverse predictive value. In univariate analysis the shorter OS of FLT3-ITD pts was confined to allele ratios≥ 0.5 (FLT3-ITDhigh, p=0.02). In a multivariate analysis accounting for clinical covariates, mutations in NPM1 (Hazard Ratio [HR]=0.45, p In the 83 pts with adv cytogenetics, TP53 mutations predicted shorter OS (p=0.004). Among pts with adv cytogenetics, those without TP53 mutation had a median OS of 12.6 months and were thus classified as high risk while the median OS of the 30 pts with adv cytogenetics and TP53 mutations was only 5.4 months, defining very high risk disease. This stratification resulted in improved OS prediction compared to the full molecular ELN 2017 (C-index 0.63 vs 0.58, resp). This stratification also predicted Relapse-Free Survival (RFS, Figure, p Conclusion. In AML patients older than 60y treated intensively, mutations in 7 genes (NPM1, SRSF2, FLT3, DNMT3A, ASLX1, NRAS and TP53) can refine the prognosis of cytogenetic sub-groups. Figure Figure. Disclosures Cluzeau: MENARINI: Consultancy; CELGENE: Consultancy; JAZZ PHARMA: Consultancy.
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- 2018
38. Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission
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Olivier Hermine, Denis Caillot, Karine Celli-Lebras, Céline Berthon, Arnaud Pigneux, Emmanuel Raffoux, Sylvie Chevret, Jean-Pierre Marolleau, Oumedaly Reman, Emilie Lemasle, Hervé Dombret, Norbert Vey, Stéphane de Botton, Xavier Thomas, Jean-Yves Cahn, Marc A. Simon, Claude Preudhomme, Norbert Ifrah, Christian Recher, Sylvie Castaigne, Christine Terré, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Amiens-Picardie, Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Georges Clémenceau, CH de Valenciennes, 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 [Grenoble] (CHU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CRLCC Henri Becquerel, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux]-Université Sciences et Technologies - Bordeaux 1, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Versailles (CHV), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, CHU Versailles, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], 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
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Male ,Cancer Research ,Survival ,medicine.medical_treatment ,Phases of clinical research ,Hematopoietic stem cell transplantation ,Older Patients ,Gastroenterology ,Trial ,0302 clinical medicine ,Adenine nucleotide ,Antineoplastic Combined Chemotherapy Protocols ,Granulocyte Colony-Stimulating Factor ,Repetitive Cycles ,Clofarabine ,Cumulative incidence ,Adenine Nucleotides ,Hazard ratio ,Colony-Stimulating Factor ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Acute Myelogenous Leukemia ,Middle Aged ,3. Good health ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,High-Dose Cytarabine ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Chemotherapy ,Group-B ,business.industry ,Induction Therapy ,Surgery ,Transplantation ,Consolidation Chemotherapy ,Arabinonucleosides ,business ,030215 immunology - Abstract
Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.
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- 2017
39. Integrating ELN Criteria and a 'Knowledge Bank' Approach to Guide Allogeneic Stem Cell Transplantation (SCT) Indication in Younger Adults with Acute Myeloid Leukemia (AML): An Acute Leukemia French Association Study
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Sylvie Chevret, Hervé Dombret, Claude Preudhomme, Pascal Turlure, Xavier Thomas, Nicolas Duployez, Pierre Sujobert, Céline Berthon, Benoît Ducourneau, Raphael Itzykson, Cécile Pautas, Norbert Vey, Christian Recher, Sylvain Chantepie, Christine Terré, Emmanuel Raffoux, Karine Celli-Lebras, Juliette Lambert, Arnaud Pigneux, Emilie Lemasle, Stéphane de Botton, Denis Caillot, and Laurène Fenwarth
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Oncology ,medicine.medical_specialty ,Acute leukemia ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Immune reconstitution inflammatory syndrome ,Younger adults ,Internal medicine ,Disease remission ,medicine ,Stem cell ,business - Abstract
Background High-resolution sequencing has improved prognostication of AML. A multistage model (MM), based on a knowledge bank (KB) of 1540 patients (pts) treated between 2004 and 2010, has been set up to improve outcome prediction and tailor therapeutic decision, including SCT (Gerstung, Nat Genet 2017). Validation of overall survival (OS) predictions by this KB has been reported (Huet, Blood 2018). Given progresses of SCT over the last decades, whether such a KB approach can be harnessed to personalize SCT decision in first remission (CR1) remains unclear. We addressed this question in younger AML pts treated intensively. Methods From 03/2009 to 09/2013, the multicentric ALFA-0702 study (NCT00932412) enrolled 713 pts with de novo AML aged 18-60 years old, excluding APL and CBF AML. Pts with protocol-defined non-favorable risk AML were eligible for SCT from a matched donor (Thomas, J Clin Oncol 2017). High throughput sequencing of 41 genes and ligation-dependent RT-PCR was done in 656 pts (92%). Risk stratification was assessed according to ELN 2017 (Döhner, Blood 2017). Of the 100 variables used by the MM, 3 clinical (splenomegaly, LDH and Hb levels) and 24 genetic variables (genes mutated in at most 5.3% in the KB) were unavailable. After imputation of missing data based on the KB, individualized 5y-OS predictions were done for each patient in 3 scenarios: no SCT, SCT in CR1 or SCT after first relapse, as previously described (Gerstung, Nat Genet 2017). Results Median age at diagnosis was 46 years. Median follow-up was 4.2 years. Overall, 302, 282 and 72 pts were never transplanted, transplanted in CR1 or after relapse, respectively (resp). ELN 2017 risk was favorable (Fav), intermediate (Int) and adverse (Adv) in 31%, 31% and 38% of the 647 evaluable pts, resp. 5y-OS was 77.7%, 58.3% and 42.2% in Fav, Int and Adv pts, resp (Fav versus [vs] Int P Considering SCT in CR1 as a time-dependent variable, there was a significant interaction between ELN 2017 risk and SCT in CR1 (P We investigated the ability of the KB approach to determine the subset of patients that may benefit from SCT in CR1 rather than at relapse (per Gerstung, Nat Genet 2017). An estimated 128 patients (ELN 2017 Fav/Int/Adv in 34.6%, 45.7% and 19.7%) would have a 10% improvement in 5y-OS if allografted in CR1. However, in these 128 pts, the effect of SCT in CR1 on OS did not differ from that in the other 528 pts (interaction test P=0.31). We therefore sought alternative ways to inform SCT decision based on KB predictions. The KB approach predicted a 5y-OS We next combined ELN 2017 risk and KB-predicted OS into a single rule to guide SCT decision. Only pts with both ELN 2017 Int/Adv risk and a KB-predicted 5y-OS Conclusion The Knowledge bank approach predicts OS of younger adults with AML more accurately than ELN 2017. ELN 2017 and KB risk predictions may be combined to optimize indications of SCT in CR1. Figure Disclosures Berthon: JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; PFIZER: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD. Pigneux:Jazz: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Pfizer: Honoraria. Recher:Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Thomas:ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria. Dombret:Institut de Recherches Internationales Servier (IRIS): Research Funding; CELGENE: Consultancy, Honoraria; AGIOS: Honoraria.
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- 2019
40. Hypoalbuminemia and hypergammaglobulinemia are associated with an increased infection risk in patients with myeloid malignancies treated with azacitidine. A 3-year monocentric retrospective study
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Pascal Lenain, Stéphane Leprêtre, Marion David, Nathalie Contentin, Hélène Lanic, Dominique Penther, Christian Bastard, Fabrice Jardin, Sylvain Mareschal, Emilie Lemasle, Hervé Tilly, Imene Rezine, Sylvie Daliphard, Ophélie Cassuto, Anne Lise Menard, Aspasia Stamatoullas, Service d'hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service d'Hématologie, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Département d'Oncologie Génétique [Rouen] (CLCC Henri Becquerel), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), and Normandie Université (NU)-Normandie Université (NU)
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Risk ,Antimetabolites, Antineoplastic ,Cancer Research ,medicine.medical_specialty ,Myeloid ,[SDV]Life Sciences [q-bio] ,Azacitidine ,Infections ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Hypergammaglobulinemia ,Internal medicine ,Humans ,Medicine ,In patient ,Hypoalbuminemia ,Antibiotic prophylaxis ,ComputingMilieux_MISCELLANEOUS ,Retrospective Studies ,business.industry ,Myelodysplastic syndromes ,Retrospective cohort study ,Hematology ,Antibiotic Prophylaxis ,medicine.disease ,3. Good health ,Surgery ,medicine.anatomical_structure ,Oncology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
International audience
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- 2015
41. Human herpesvirus-6 acute limbic encephalitis after unrelated umbilical cord blood transplantation successfully treated with ganciclovir
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P Ahtoy, Fabrice Jardin, Stéphane Leprêtre, O. Cassuto, Ali N. Chamseddine, Hervé Tilly, Aspasia Stamatoullas, Vincent Camus, Emilie Lemasle, Nathalie Contentin, Sydney Dubois, J-P Bouwyn, Hélène Lanic, and Pascal Lenain
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Ganciclovir ,Transplantation ,biology ,business.industry ,Umbilical Cord Blood Transplantation ,viruses ,Limbic encephalitis ,virus diseases ,Hematology ,biology.organism_classification ,medicine.disease ,surgical procedures, operative ,Graft-versus-host disease ,stomatognathic system ,nervous system ,Immunology ,medicine ,Human herpesvirus 6 ,Progenitor cell ,Stem cell ,business ,medicine.drug - Abstract
Human herpesvirus-6 acute limbic encephalitis after unrelated umbilical cord blood transplantation successfully treated with ganciclovir
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- 2015
42. Multiplexed targeted sequencing of recurrent fusion genes in acute leukaemia
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Emilie Lemasle, Marie Cornic, Vannier Jp, Pierre-Julien Viailly, Dominique Penther, Sydney Dubois, Stéphane Leprêtre, N. Buchbinder, Camus, Fabrice Jardin, Girod C, Philippe Ruminy, Philippe Bertrand, Sylvain Mareschal, Jean-Michel Picquenot, Pascale Schneider, Larson T, G Buchonnet, David Rizzo, Joly B, Pascaline Etancelin, Angot E, Christian Bastard, Elodie Bohers, Marchand, Hervé Tilly, Florian Clatot, Mathieu Viennot, Groupe d'étude des proliférations lymphoïdes (GPL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), 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 Rouen, Normandie Université (NU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Argelander-Institut für Astronomie (AlfA), and Rheinische Friedrich-Wilhelms-Universität Bonn
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0301 basic medicine ,Cancer Research ,Oncogene Proteins ,Oncogene Proteins, Fusion ,Chromosomes, Human, Pair 21 ,[SDV]Life Sciences [q-bio] ,Molecular Sequence Data ,Chromosomal translocation ,Biology ,Translocation, Genetic ,Fusion gene ,03 medical and health sciences ,Text mining ,Humans ,Base sequence ,ComputingMilieux_MISCELLANEOUS ,Retrospective Studies ,Genetics ,Chromosomes, Human, Pair 15 ,Leukemia ,Base Sequence ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,High-Throughput Nucleotide Sequencing ,Hematology ,030104 developmental biology ,Oncology ,Acute Disease ,Cytogenetic Analysis ,Biological Assay ,business ,Oligonucleotide Probes ,Chromosomes, Human, Pair 17 - Abstract
International audience
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- 2016
43. Digital PCR for quantification of recurrent and potentially actionable somatic mutations in circulating free DNA from patients with diffuse large B-cell lymphoma
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Pierre-Julien Viailly, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, Emilie Lemasle, Ludivine Beaussire, Sylvain Mareschal, Aspasia Stamatoullas, Christian Bastard, Hervé Tilly, Nasrin Sarafan-Vasseur, Fabrice Jardin, Thierry Frebourg, Marie Cornic, Sydney Dubois, Jean-Michel Picquenot, Vincent Camus, Elodie Bohers, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Génétique du cancer et des maladies neuropsychiatriques (GMFC), and Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)
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0301 basic medicine ,Adult ,Male ,Cancer Research ,Somatic cell ,[SDV]Life Sciences [q-bio] ,Receptors, Cytoplasmic and Nuclear ,Biology ,Karyopherins ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Biomarkers, Tumor ,Humans ,Digital polymerase chain reaction ,Liquid biopsy ,ComputingMilieux_MISCELLANEOUS ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Mutation ,Liquid Biopsy ,High-Throughput Nucleotide Sequencing ,Hematology ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,3. Good health ,Lymphoma ,030104 developmental biology ,Real-time polymerase chain reaction ,Oncology ,030220 oncology & carcinogenesis ,Positron-Emission Tomography ,Myeloid Differentiation Factor 88 ,Cancer research ,Female ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma - Abstract
Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogeneous malignancy harboring frequent targetable activating somatic mutations. Emerging evidence suggests that circulating cell-free DNA (cfDNA) can be used to detect somatic variants in DLBCL using Next-Generation Sequencing (NGS) experiments. In this proof-of-concept study, we chose to develop simple and valuable digital PCR (dPCR) assays for the detection of recurrent exportin-1 (XPO1) E571K, EZH2 Y641N, and MYD88 L265P mutations in DLBCL patients, thereby identifying patients most likely to potentially benefit from targeted therapies. We demonstrated that our dPCR assays were sufficiently sensitive to detect rare XPO1, EZH2, and MYD88 mutations in plasma cfDNA, with a sensitivity of 0.05%. cfDNA somatic mutation detection by dPCR seems to be a promising technique in the management of DLBCL, in addition to NGS experiments.
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- 2015
44. Recurrent Mutations of the Exportin 1 Gene (XPO1) in Primary Mediastinal B-Cell Lymphoma: A Lysa Study
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Diane Damotte, Corinne Haioun, Pierre-Julien Viailly, Alexandra Traverse-Glehen, Christian Argueta, Sylvain Mareschal, Aspasia Stamatoullas, Martin Figeac, Karen Leroy, Fabrice Jardin, Catherine Maingonnat, Peter Moeller, Philippe Gaulard, Hervé Tilly, Christer Sundström, Elodie Bohers, Thierry Jo Molina, Laura Pelletier, Philippe Bertrand, Sydney Dubois, Vincent Camus, Emilie Lemasle, Thierry Fest, Christian Bastard, Gilles Salles, Noel Milpied, Jean-Michel Picquenot, Jean-Philippe Jais, François Lemonnier, Marie Cornic, Anaïs Pujals, Christiane Copie-Bergman, Marlene Ochman, Richard Delarue, William Senapedis, Martin J. S. Dyer, Yosef Landesman, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Microenvironnement et cancer (MiCa), 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 ), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique, Hospices Civils de Lyon (HCL), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Pharmacie Pathologie, Sorbonne Paris Cité-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie clinique, Service d'informatique médicale et biostatistiques [CHU Necker], Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, INSERM U955, équipe 9, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Anatomo-Pathologie, service d'anatomo-pathologie, Service d'Hématologie et Thérapie Cellulaire, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Pathology, Uppsala University Hospital, Service de Pathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), 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 Biologique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Henri Mondor, Karyopharm Therapeutics Inc., Newton, MA, U918, CHU Necker - Enfants Malades [AP-HP], Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Universitätsklinikum Ulm - University Hospital of Ulm, Department of Cancer Studies and Molecular Medicine, University of Leicester, Service de génétique oncologique, Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, 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 ), Laboratoire de Biologie Moléculaire de la Cellule ( LBMC ), École normale supérieure - Lyon ( ENS 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Sorbonne Paris Cité-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Université de Lille, Droit et Santé, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Assistance publique - Hôpitaux de Paris (AP-HP), CRLCC Henri Becquerel, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Paris Cité-CHU Cochin [AP-HP]-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut Mondor de Recherche Biomédicale (IMRB), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bohers, Elodie, Jonchère, Laurent, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Henri Mondor [Créteil], and Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
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Mutation ,[ SDV ] Life Sciences [q-bio] ,[SDV]Life Sciences [q-bio] ,Immunology ,Mutant ,Wild type ,Cell Biology ,Hematology ,Biology ,medicine.disease ,medicine.disease_cause ,Biochemistry ,3. Good health ,Lymphoma ,[SDV] Life Sciences [q-bio] ,International Prognostic Index ,medicine ,Cancer research ,Missense mutation ,Primary mediastinal B-cell lymphoma ,Nuclear export signal ,ComputingMilieux_MISCELLANEOUS - Abstract
Background and aim of the study Primary mediastinal B-cell lymphoma (PMBL) is an entity of aggressive B-cell lymphoma that is clinically and biologically distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We recently detected by Whole exome sequencing a recurrent point mutation in the XPO1 (exportin 1) gene (also referred to as chromosome region maintenance 1; CRM1), which resulted in the Glu571Lys (p.E571K) missense substitution in 2 refractory/relapsed PMBL (Dubois et al., ICML 2015; Mareschal et al. AACR 2015). XPO1 is a member of the Karyopherin-b superfamily of nuclear transport proteins. XPO1 mediates the nuclear export of numerous RNAs and cellular regulatory proteins, including tumor suppressor proteins. This mutation is in the hydrophobic groove of XPO1 that binds to the leucine-rich nuclear export signal (NES) of cargo proteins. In this study, we investigated the prevalence, specificity, and biological / clinical relevance of XPO1 mutations in PMBL. Patients and methods High-throughput targeted or Sanger sequencing of 117 PMBL patients and 3 PMBL cell lines were performed. PMBL cases were defined either molecularly by gene expression profile (mPMBL cohort) or by standard histological method (hPMBL cohort) and enrolled in various LYSA (LYmphoma Study Association) clinical trials. To assess the frequency and specificity of XPO1 mutations, cases of classical Hodgkin lymphoma (cHL) and primary mediastinal grey zone lymphoma (MGZL) were analysed. Cell experiments were performed to assess the impact of the E571 mutation on the activity of selective inhibitor of nuclear export (SINE) molecules. Results XPO1 mutations were present in 28/117 (24%) PMBL cases but were rare in cHL cases (1/19, 5%) and absent from MGZL cases (0/20). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in PMBL cases defined by gene expression profiling (n = 32), as compared to hPMBL cases (n = 85, 13%). No difference in age, International Prognostic Index (IPI) or bulky mass was observed between the PMBL patients harboring mutant and wild-type XPO1 in the overall cohort whereas a female predominance was noticed in the mPMBL cohort. Based on a median follow-up duration of 42 months, XPO1 mutant patients exhibited significantly decreased PFS (3y PFS = 74% [CI95% 55-100]) compared to wild-type patients (3y PFS = 94% [CI95% 83-100], p=0.049) in the mPMBL cohort. In 4/4 tested cases, the E571K variant was also detected in cell-free circulating plasmatic DNA, suggesting that the mutation can be used as a biomarker at the time of diagnosis and during follow-up. Importantly, the E571K variant was detected as a heterozygous mutation in MedB-1, a PMBL-derived cell line, whereas the two other PMBL cell lines tested, Karpas1106 and U-2940, did not display any variants in XPO1 exon 15. KPT-185, the SINE compound that blocks XPO1-dependent nuclear export, induced a dose-dependent decrease in cell proliferation and increased cell death in the PMBL cell lines harbouring wild type or mutated alleles. To test directly if XPO1 mutation from E571 to E571K alters XPO1 inhibition by SINE compounds, the mutated protein was tested in vitro. The E571XPO1 mutated allele was transiently transfected into osteosarcoma U2OS cells which stably express the fluorescently labelled XPO1 cargo REV. Cells were treated with the clinical SINE compound selinexor, which is currently in phase I/II clinical trials and nuclear localization of REV-GFP was analysed in red transfected cells. The results showed that the nuclear export of the mutated XPO1 protein was inhibited by selinexor similarly to the wild-type XPO1 protein (Figure 1). Conclusion Although the oncogenic properties of XPO1 mutations remain to be determined, their recurrent selection in PMBL strongly supports their involvement in the pathogenesis of this curable aggressive B-cell lymphoma. XPO1 mutations were primarily observed in young female patients who displayed a typical PMBL molecular signature. The E571K XPO1 mutation represents a novel hallmark of PMBL but does not seem to interfere with SINE activity. Rev-GFP (green fluorescent) expressing U2OS cells were transfected with wild type XPO1-RFP (red fluorescent protein), XPO1-C528S-RFP, XPO1-E571K-mCherry, and XPO1-E571G-mCherry. The cells were then treated with 1µM KPT-330 for 8 hours. Figure 1. Rev-GFP expressing U2OS cells transfected with XPO1 variants. Figure 1. Rev-GFP expressing U2OS cells transfected with XPO1 variants. Disclosures Landesman: Karyopharm Therapeutics: Employment. Senapedis:Karyopharm Therapeutics, Inc.: Employment, Patents & Royalties. Argueta:Karyopharm Therapeutics: Employment. Milpied:Celgene: Honoraria, Research Funding.
- Published
- 2015
45. Impact of Cytogenetics on Outcome after Allogeneic Transplantation for Myelodysplastic Syndrome or Post MDS Secundary Myeloid Leukemia
- Author
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P. Etancelin, B. Marcq, Hervé Tilly, Hélène Lanic, Pascal Lenain, Aspasia Stamatoullas, Anne-Lise Menard, Dominique Penther, Christian Bastard, Stéphane Leprêtre, P. Lebreton, Emilie Lemasle, I. Rezine, Nathalie Contentin, and Fabrice Jardin
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Allogeneic transplantation ,business.industry ,Internal medicine ,medicine ,Cytogenetics ,Myeloid leukemia ,Hematology ,business - Published
- 2017
46. Spontaneous remission in three cases of AML M5 with NPM1 mutation
- Author
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Pascaline Etancelin, Fabrice Jardin, Gérard Buchonnet, Dominique Penther, Christian Bastard, Vincent Camus, Emilie Lemasle, Pascal Lenain, Aspasia Stamatoullas, Hélène Lanic, Sylvie Daliphard, Sydney Dubois, Hervé Tilly, Nathalie Contentin, Stéphane Leprêtre, Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'Hématologie, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Département d'Oncologie Génétique [Rouen] (CLCC Henri Becquerel), and Service d'hématologie
- Subjects
Oncology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Spontaneous remission ,Case Reports ,Favorable prognosis ,acute myeloid leukemia ,monocytic leukemia ,Text mining ,Internal medicine ,hemic and lymphatic diseases ,Genotype ,medicine ,neoplasms ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Standard treatment ,spontaneous remission ,General Medicine ,medicine.disease ,3. Good health ,Leukemia ,NPM1 Mutation ,Immunology ,NPM1 mutation ,Monocytic leukemia ,business - Abstract
Key Clinical Message Patients with NPM1-mutated AML M5 who develop spontaneous remission (SR) after antibiotic therapy at diagnosis seem to form a favorable prognosis and chemo sensitive subtype. We report three cases of AML M5 patients with the same genotype that experienced transient SR and are now leukemia free after standard treatment.
- Published
- 2015
47. Prognostic Value of Lymphocyte-Monocyte Ratio in Primary Myelodysplastic Syndrome
- Author
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S. Daliphard, Emilie Lemasle, D. Krzisch, A. Curie, Dominique Penther, B. Marcq, Pierre-Julien Viailly, Aspasia Stamatoullas, Fabrice Jardin, Hélène Lanic, Nathalie Contentin, Hervé Tilly, Pascal Lenain, Stéphane Leprêtre, and Christian Bastard
- Subjects
Cancer Research ,medicine.anatomical_structure ,Oncology ,business.industry ,Monocyte ,Lymphocyte ,Immunology ,medicine ,Hematology ,business ,Value (mathematics) - Published
- 2017
48. Invasive aspergillosis in neutropenic patients during hospital renovation: effectiveness of mechanical preventive measures in a prospective cohort of 438 patients
- Author
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Marion David, Hervé Tilly, Marie-France Bagatha, Michael Loschi, Caroline Thill, Hélène Lanic, Nathalie Contentin, Emilie Lemasle, Christian Gray, Aspasia Stamatoullas, Fabrice Jardin, Pascal Lenain, Ali N. Chamseddine, and Stéphane Leprêtre
- Subjects
Adult ,Male ,medicine.medical_specialty ,Neutropenia ,Adolescent ,Veterinary (miscellaneous) ,Air Microbiology ,Aspergillosis ,Applied Microbiology and Biotechnology ,Microbiology ,Cohort Studies ,Young Adult ,Medical microbiology ,medicine ,Humans ,Hospital Design and Construction ,Prospective Studies ,Young adult ,Intensive care medicine ,Prospective cohort study ,Aged ,Aged, 80 and over ,Invasive Pulmonary Aspergillosis ,Infection Control ,business.industry ,Incidence (epidemiology) ,Incidence ,Outbreak ,Middle Aged ,medicine.disease ,Aspergillus ,Female ,business ,Agronomy and Crop Science ,Cohort study - Abstract
Aspergillus species are the main cause of invasive fungal disease for patients with severe and prolonged neutropenia. Building or renovation works have been shown as one of the major causes of outbreaks of aspergillosis.This study aimed to assess the effectiveness of introduction and adaptation by air sampling of mechanical preventive measures on the incidence of invasive pulmonary aspergillosis in neutropenic patients during hospital renovation.All of the patients admitted for prolonged and severe neutropenia during a renovation period from 2003 to 2008 were prospectively enrolled. Invasive pulmonary aspergillosis (IPA) cases were classified as possible, probable, and proven, according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group criteria. The effectiveness of preventive measures was determined by air sampling.We recorded 705 hospitalizations for neutropenia concerning 438 patients. The majority of hospitalized neutropenic patients was treated for acute leukemia (38.3 %), followed by patients suffering from non-Hodgkin and Hodgkin lymphomas (33 %). The total cumulative incidence of probable and proven IPA was 4.1 %. Risk factors for developing IPA were underlying disease, treatment course at the time of hospitalization, and the mean duration of hospitalization and of neutropenia.In this prospective study, the incidence of invasive pulmonary aspergillosis did not increase in neutropenic patients during a renovation period because of efficient mechanical preventive measures systematically adjusted using the results of air sampling.
- Published
- 2014
49. Prognostic impact of fat tissue loss and cachexia assessed by computed tomography scan in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy
- Author
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Hervé Tilly, Stéphane Leprêtre, Jerome Kraut, Fabrice Jardin, Marie-Laure Fontoura, Romain Modzelewski, Aspasia Stamatoullas, Jean Michel Picquenot, Oana Brehar, Carole Fronville, Vincent Camus, Ali N. Chamseddine, Luminata Groza, Pascal Lenain, Hélène Lanic, Nathalie Cardinael, Emilie Lemasle, Nathalie Contentin, Florian Clatot, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Psychiatrique Universitaire [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Groupe d'étude des proliférations lymphoïdes (GPL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Centre de Recherche en Automatique de Nancy (CRAN), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Breton, Céline, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,MESH: Combined Modality Therapy ,Cachexia ,MESH: Immunotherapy ,[SDV]Life Sciences [q-bio] ,Gastroenterology ,MESH: Aged, 80 and over ,0302 clinical medicine ,International Prognostic Index ,Medicine ,MESH: Aged ,2. Zero hunger ,Aged, 80 and over ,0303 health sciences ,Hazard ratio ,Hematology ,General Medicine ,Prognosis ,Combined Modality Therapy ,3. Good health ,[SDV] Life Sciences [q-bio] ,Adipose Tissue ,030220 oncology & carcinogenesis ,Rituximab ,Female ,Immunotherapy ,Lymphoma, Large B-Cell, Diffuse ,MESH: Tomography, X-Ray Computed ,MESH: Adipose Tissue ,medicine.drug ,medicine.medical_specialty ,MESH: Prognosis ,03 medical and health sciences ,Internal medicine ,Humans ,030304 developmental biology ,Aged ,Retrospective Studies ,MESH: Humans ,business.industry ,MESH: Retrospective Studies ,medicine.disease ,MESH: Male ,Confidence interval ,Surgery ,MESH: Cachexia ,Sarcopenia ,MESH: Lymphoma, Large B-Cell, Diffuse ,business ,Tomography, X-Ray Computed ,MESH: Female ,Body mass index ,Diffuse large B-cell lymphoma - Abstract
Objectives Approximately 30% of DLBCL patients are older than 70 yr. This study evaluated the prognostic impact of a cachexia score (CS) including fat tissue loss (adipopenia) and sarcopenia as assessed by computed tomography (CT scan) in elderly DLBCL patients treated with chemotherapy and rituximab (R). Methods This retrospective analysis included 80 DLBCL patients older than 70 yr treated with R-CHOP or R-miniCHOP. Skeletal muscle (SM) and visceral (V) and subcutaneous (S) adipose (A) tissues were measured by analysing CT images at the third lumbar (L3) level. Results The median age of the patients was 78 yr. Forty-four and 46 patients were considered sarcopenic and adipopenic, respectively. The median progression-free survival (PFS) was 13.6 months in the adipopenic group and 49.4 months in the non-adipopenic group [hazard ratio (HR) = 2.27; 95% confidence interval (CI): 1.3–4; P = 0.0042]. The median overall survival (OS) was 25.7 months in the adipopenic group and 57.1 months in the non-adipopenic group (HR = 1.93; 95% CI: 1.05–3.55; P = 0.0342). A two-point CS including adipopenia and sarcopenia was created and defined two distinct risk groups with differences in outcomes that were highly significant. The CS was predictive of the prognosis in a multivariate analysis including body mass index (BMI) (< or ≥25 kg/m2), age (< or ≥80 yr), international prognostic index (IPI) and albuminaemia (HR = 3.67; 95% CI = 1.93–6.97; P
- Published
- 2014
50. Miescher cheilitis and myelomonocytic leukemia: a fortuitous association or a rare paraneoplastic syndrome?
- Author
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Emilie Lemasle, G Buchonnet, Fabrice Jardin, Aspasia Stamatoullas, Anne Benedicte Duval, Philippe Courville, Hervé Tilly, and Marie Paule Callat
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Cancer Research ,medicine.medical_specialty ,Myelomonocytic leukemia ,business.industry ,Chronic myelomonocytic leukemia ,Hematology ,medicine.disease ,Dermatology ,World health ,Hematopoietic malignancy ,Oncology ,hemic and lymphatic diseases ,Medicine ,business ,Myeloproliferative neoplasm - Abstract
Chronic myelomonocytic leukemia (CMML) is a rare clonal hematopoietic malignancy that has been classified as a myelodysplastic/myeloproliferative neoplasm by the 2008 World Health Organization clas...
- Published
- 2010
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