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1. Killer immunoglobulin‐like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment‐free remission

Author

Pierre‐Yves Dumas, Emilie Bérard, Claire Bréal, Stéphanie Dulucq, Delphine Réa, Franck Nicolini, Edouard Forcade, Melody Dufossée, Jean‐Max Pasquet, Béatrice Turcq, Audrey Bidet, Noel Milpied, Julie Déchanet‐Merville, Xavier Lafarge, Gabriel Etienne, François‐Xavier Mahon, French Intergroup in Chronic Myeloid Leukemia, Service d’Hématologie Clinique et Thérapie Cellulaire, CHU Bordeaux, CHU Bordeaux [Bordeaux], Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Embodiment, social ineQualities, lifecoUrse epidemiology, cancer and chronIc diseases, intervenTions, methodologY (Equipe 5 - EQUITY), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Dpt hématologie [CHU Bordeaux], Service d’Hématologie, Hôpital Saint Louis, Paris, 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 [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), ImmunoConcEpT, UMR 5164, Bordeaux, Centre National de la Recherche Scientifique (CNRS), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Turcq, Beatrice, 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), Immunology from Concept and Experiments to Translation (ImmunoConcept), and Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Male, Cancer Research, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Receptors, KIR, Genotype, Cytotoxic T cell, Medicine, Receptor, Original Research, Innate lymphoid cell, Remission Induction, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, treatment‐free remission, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, [SDV] Life Sciences [q-bio], Killer Cells, Natural, Receptors, KIR2DL5, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Imatinib Mesylate, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tyrosine kinase, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, lcsh:RC254-282, Immunophenotyping, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, chronic myeloid leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, Radiology, Nuclear Medicine and imaging, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, killer immunoglobulin‐like receptors, Protein Kinase Inhibitors, Aged, business.industry, Clinical Cancer Research, Genetic Variation, Imatinib, natural killer, Discontinuation, 030104 developmental biology, imatinib, Haplotypes, Withholding Treatment, Cancer research, business, Biomarkers
Abstract

International audience; Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin‐like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells. Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2. Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B‐positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32‐0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment‐free remission rates. Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte‐mediated control of leukemic residual disease control in patient with CML relapse.

Published
2019
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2. LSC17 Score Is Complementary with Minimal Residual Disease to Stratify NPM1 -Mutated Acute Myeloid Leukemia:An ALFA Study

Author

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)

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

International audience

Published
2022
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3. Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

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)

Subjects
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.

Published
2022
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4. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells

Author

Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, Jean-Max Pasquet, 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 Biologique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Etablissement Français du Sang Nouvelle Aquitaine [Bordeaux] (EFS Bordeaux Nouvelle Aquitaine), and Vigon, Isabelle

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, autophagy, FLT3-ITD, leukemic initiating cells, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, persistence, acute myeloid leukemia, Article, Oncology, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, hemic and lymphatic diseases, tyrosine kinase inhibitors, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, RC254-282
Abstract

Simple Summary One of the most frequent molecular anomalies in acute myeloid leukemia (AML) is the mutation of the fms-like receptor tyrosine kinase 3 through internal tandem duplications, giving rise to a constitutive proliferative signaling. Even though clinical trials have shown that targeting this mutated kinase is of interest and well tolerated, there is still a high frequency of relapse. The emergence of AML cells upon treatment is linked to their maintenance through resistance and persistence mechanisms. Because FLT3-ITD AML cells require autophagy, we explored the consequence of autophagy inhibition by blocking the PI3-kinase class III, Vps34, when AML cells were committed. Results in vitro, ex vivo and in vivo suggest that remission with low minimal residual disease in FLT3-ITD AML offers a promising therapeutic window to target persistent leukemic cells. Abstract Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

Published
2021
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5. In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study

Author

Alice Garnier, Gaelle Guillerm, Anne Bouvier, Patrice Ceballos, Marie C. Béné, Yosr Hicheri, Arnaud Pigneux, Christian Recher, Mathilde Hunault-Berger, Sarah Guenounou, Raynier Devillier, Patrice Chevallier, Anne Huynh, Edouard Forcade, Pierre-Yves Dumas, Sylvain Thepot, Didier Blaise, Pierre Peterlin, Norbert Vey, 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), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Association internationale pour le développement de l’agroenvironnement (AIDA), 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 Régional Universitaire de Brest (CHRU Brest), Hôpital Lapeyronie [Montpellier] (CHU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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], Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département d’Oncologie Médicale [IPC, Marseille], and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, medicine.medical_specialty, Multivariate analysis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Allo hsct, Hematopoietic stem cell transplantation, European LeukemiaNet, Recurrence, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Aged, Proportional Hazards Models, business.industry, Hazard ratio, Remission Induction, Complete remission, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Hematology, Middle Aged, medicine.disease, Leukemia, Leukemia, Myeloid, Acute, Receptors, Complement 3b, business
Abstract

The benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (

Published
2021
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6. The Expression of Myeloproliferative Neoplasm-Associated Calreticulin Variants Depends on the Functionality of ER-Associated Degradation

Author

Gwénaële Jégou, Eric Lippert, Francois-Xavier Mahon, Béatrice Turcq, Olivier Mansier, Eric Chevet, Konstantinos Voutetakis, Diana Pelizzari Raymundo, Pierre-Yves Dumas, Kim Barroso, Chloé James, Vincent Praloran, Valérie Lagarde, Valérie Prouzet-Mauléon, Aristotelis Chatziioannou, Jean-François Viallard, Jean-Max Pasquet, Aurélie Chauveau, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Biologie des maladies cardiovasculaires = Biology of Cardiovascular Diseases, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Service d'Hématologie [Bordeaux], CHU Bordeaux [Bordeaux], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Centre National de la Recherche Scientifique (CNRS), Service de Médecine Interne [CHU de Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU de Bordeaux], Institute of Chemical Biology [Athens, Greece], National Hellenic Research Foundation [Athens], Department of Biochemistry and Biotechnology [Larissa, Greece], University of Thessaly [Volos] (UTH), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Jonchère, Laurent

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Cancer Research, XBP1, MPN, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endoplasmic-reticulum-associated protein degradation, Protein degradation, Article, calreticulin, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], biology, Chemistry, Endoplasmic reticulum, food and beverages, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, ERAD, 3. Good health, Cell biology, endoplasmic reticulum, 030104 developmental biology, Oncology, Article RECHERCHE, 030220 oncology & carcinogenesis, biology.protein, Unfolded protein response, STAT protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Janus kinase, Calreticulin
Abstract

Background: Mutations in CALR observed in myeloproliferative neoplasms (MPN) were recently shown to be pathogenic via their interaction with MPL and the subsequent activation of the Janus Kinase &ndash, Signal Transducer and Activator of Transcription (JAK-STAT) pathway. However, little is known on the impact of those variant CALR proteins on endoplasmic reticulum (ER) homeostasis. Methods: The impact of the expression of Wild Type (WT) or mutant CALR on ER homeostasis was assessed by quantifying the expression level of Unfolded Protein Response (UPR) target genes, splicing of X-box Binding Protein 1 (XBP1), and the expression level of endogenous lectins. Pharmacological and molecular (siRNA) screens were used to identify mechanisms involved in CALR mutant proteins degradation. Coimmunoprecipitations were performed to define more precisely actors involved in CALR proteins disposal. Results: We showed that the expression of CALR mutants alters neither ER homeostasis nor the sensitivity of hematopoietic cells towards ER stress-induced apoptosis. In contrast, the expression of CALR variants is generally low because of a combination of secretion and protein degradation mechanisms mostly mediated through the ER-Associated Degradation (ERAD)-proteasome pathway. Moreover, we identified a specific ERAD network involved in the degradation of CALR variants. Conclusions: We propose that this ERAD network could be considered as a potential therapeutic target for selectively inhibiting CALR mutant-dependent proliferation associated with MPN, and therefore attenuate the associated pathogenic outcomes.

Published
2019
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7. Testing for minimal residual disease in adults with acute lymphoblastic leukemia in Europe: a clinician survey

Author

Pau Montesinos, J McKendrick, Arnaud Pigneux, Heather Wieffer, Monika Brüggemann, Anja K. Pownell, Ze Cong, Xinke Zhang, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Hospital Universitari i Politècnic La Fe = University and Polytechnic Hospital La Fe, Instituto de Salud Carlos III [Madrid] (ISC), Amgen Inc, PRMA Consulting [Hampshire, UK] (Linea House), University of Technology Sydney (UTS), Universitätsklinikum Schleswig-Holstein, Amgen Inc., Bodescot, Myriam, and Hospital Universitario La Fe, Valencia

Subjects
Adult, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Neoplasm, Residual, Subsequent Relapse, Cross-sectional study, Lymphoblastic Leukemia, Clinical Decision-Making, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Induction therapy, hemic and lymphatic diseases, MRD testing, Genetics, Medicine, Humans, In patient, Oncology & Carcinogenesis, Internet, business.industry, Minimal residual disease, Consolidation Chemotherapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Test (assessment), Europe, body regions, Cross-Sectional Studies, Oncology, 030220 oncology & carcinogenesis, Health Care Surveys, Cross-sectional survey, Female, business, ALL, 030215 immunology, Research Article
Abstract

Background In acute lymphoblastic leukemia (ALL), the presence of minimal residual disease (MRD) after induction/consolidation chemotherapy is a strong prognostic factor for subsequent relapse and mortality. Accordingly, European clinical guidelines and protocols recommend testing patients who achieve a complete hematological remission (CR) for MRD for the purpose of risk stratification. The aim of this study was to provide quantitative information regarding real-world clinical practice for MRD testing in five European countries. Methods A web-based survey was conducted in March/April 2017 in France, Germany, Italy, Spain, and the UK. The survey was developed after consultation with specialist clinicians and a review of published literature. Eligible clinicians (20 per country; 23 in Spain) were board-certified in hemato-oncology or hematology, had at least five years’ experience in their current role after training, had treated at least two patients with B-cell precursor ALL in the 12 months before the survey or at least five patients in the last five years, and had experience of testing for MRD in clinical practice. Results MRD testing is now standard practice in the treatment of adult ALL across the five European countries, with common use of recent treatment protocols which specify testing. Respondents estimated that, among clinicians in their country who conduct MRD testing, 73% of patients in first CR (CR1) and 63% of patients in second or later CR (CR2+) are tested for MRD. The median time point reported as most commonly used for the first MRD test, to establish risk status and to determine a treatment plan was four weeks after the start of induction therapy. The timing and frequency of tests is similar across countries. An average of four or five post-CR1 tests per patient in the 12 months after the first MRD test were reported across countries. Conclusions This comprehensive study of MRD testing patterns shows consistent practice across France, Germany, Italy, Spain, and the UK with respect to the timing and frequency of MRD testing, aligning with use of national protocols. MRD testing is used in clinical practice also in patients who reach CR2 + . Electronic supplementary material The online version of this article (10.1186/s12885-018-5002-5) contains supplementary material, which is available to authorized users.

Published
2018
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8. Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial

Author

Julien Asselineau, Anne Banos, Caroline Bonmati, Romain Guieze, Mario Ojeda-Uribe, Eric Jourdan, Ariane C Mineur, Norbert Ifrah, Arnaud Pigneux, Hacene Zerazhi, Marie C. Béné, Louis-Rachid Salmi, Norbert Vey, Pascale Cornillet-Lefebvre, Marc Bernard, Christian Recher, Eric Delabesse, Jean-Christophe Ianotto, Jean-Yves Cahn, Isabelle Luquet, Roselyne Delepine, Jacques Delaunay, Pierre-Yves Dumas, Yosr Hishri, Luc Fornecker, Mathilde Hunault, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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], Service d'Hématologie Clinique [Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Société d'Hématologie du Confluent [Nantes], Société D'hematologie Du Confluent - Nantes, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), 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), Laboratoire d'hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), 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), CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital de Bayonne, Centre Hospitalier de la Côte Basque (CHCB), Laboratoire de Spectrométrie de Masse BioOrganique [Strasbourg] (LSMBO), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Département d'Hématologie [CHU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), 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), Médecine Interne Onco-hématologie, Centre Hospitalier Général, Centre Hospitalier Henri Duffaut (Avignon), Unité de Soutien Méthodologique à la Recherche Clinique (USMR), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Thérapeutique Recombinante Expérimentale (TIMC-IMAG-TheREx), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-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), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), CH de la Côte Basque, Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut Pluridisciplinaire Hubert Curien (IPHC), and Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 03 medical and health sciences, Myelogenous, 0302 clinical medicine, Internal medicine, medicine, Idarubicin, Cumulative incidence, Chemotherapy, business.industry, Lomustine, medicine.disease, 3. Good health, Regimen, Leukemia, 030104 developmental biology, 030220 oncology & carcinogenesis, Cytarabine, business, medicine.drug
Abstract

Purpose Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin. Patients and Methods Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety. Results From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( P = .01). The proportional hazards assumption was rejected for OS ( P = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( P = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( P = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( P = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( P = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( P = .04), and fewer patients required a second treatment after ICL. Conclusion Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.

Published
2018
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9. Higher survival following transplantation with a mismatched unrelated donor with posttransplant cyclophosphamide-based graft-versus-host disease prophylaxis than with double unit umbilical cord blood in patients with acute myeloid leukemia in first complete remission: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Author

Baron F, Labopin M, Versluis J, Vydra J, von dem Borne PA, Nicholson E, Blaise D, Protheroe R, Kulagin A, Bulabois CE, Rovira M, Chevallier P, Forcade E, Byrne J, Sanz J, Ruggeri A, Mohty M, and Ciceri F

Subjects
Humans, Middle Aged, Male, Female, Adult, Retrospective Studies, Aged, Remission Induction, Adolescent, Young Adult, Registries, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease prevention & control, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality, Cyclophosphamide therapeutic use, Cyclophosphamide administration & dosage, Unrelated Donors, Cord Blood Stem Cell Transplantation
Abstract

The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained intensively debated. We herein report the results of a large retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between double-unit umbilical cord blood transplantation (dCBT, n = 209) versus 9/10 HLA-matched unrelated donor (UD) with posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis (UD 9/10, n = 270) in patients with AML in first complete remission (CR1). Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT without PTCy, transplantation between 2013 and 2021, and no in vivo T-cell depletion. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (p = .001). After adjustment for covariates, dCBT recipients had a higher non-relapse mortality (HR = 2.35, 95% CI: 1.23-4.48; p = .01), comparable relapse incidence (HR = 1.12, 95% CI: 0.67-1.86; p = .66), lower leukemia-free survival (HR = 1.5, 95% CI: 1.01-2.23; p = .047), and lower overall survival (HR = 1.66, 95% CI: 1.08-2.55; p = .02) compared with patients receiving UD 9/10 HCT. In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis over dCBT in AML patients lacking an HLA-matched donor., (© 2024 Wiley Periodicals LLC.)

Published
2024
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10. Correction: Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

Author

Robin M, Iacobelli S, Koster L, Passweg J, Avenoso D, Wilson KMO, Salmenniemi U, Dreger P, von dem Borne P, Snowden JA, Robinson S, Finazzi MC, Schroeder T, Collin M, Eder M, Forcade E, Loschi M, Bramanti S, Pérez-Simón JA, Czerw T, Polverelli N, Drozd-Sokolowska J, Raj K, Hernández-Boluda JC, and McLornan DP

Published
2024
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11. Hematopoietic stem cell transplantation for DLBCL: a report from the European Society for Blood and Marrow Transplantation on more than 40,000 patients over 32 years.

Author

Berning P, Fekom M, Ngoya M, Goldstone AH, Dreger P, Montoto S, Finel H, Shumilov E, Chevallier P, Blaise D, Strüssmann T, Carpenter B, Forcade E, Castilla-Llorente C, Trneny M, Ghesquieres H, Capria S, Thieblemont C, Blau IW, Meijer E, Broers AEC, Huynh A, Caillot D, Rösler W, Nguyen Quoc S, Bittenbring J, Nagler A, Galimard JE, Glass B, Sureda A, and Schmitz N

Subjects
Humans, Middle Aged, Male, Female, Adult, Aged, Europe epidemiology, Adolescent, Young Adult, Transplantation Conditioning methods, Transplantation, Homologous, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation methods, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse mortality
Abstract

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies., (© 2024. The Author(s).)

Published
2024
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12. Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

Author

Robin M, Iacobelli S, Koster L, Passweg J, Avenoso D, Wilson KMO, Salmenniemi U, Dreger P, von dem Borne P, Snowden JA, Robinson S, Finazzi MC, Schroeder T, Collin M, Eder M, Forcade E, Loschi M, Bramanti S, Pérez-Simón JA, Czerw T, Polverelli N, Drozd-Sokolowska J, Raj K, Hernández-Boluda JC, and McLornan DP

Subjects
Humans, Middle Aged, Male, Female, Adult, Aged, Transplantation Conditioning methods, Transplantation, Homologous methods, Graft vs Host Disease mortality, Busulfan analogs & derivatives, Busulfan therapeutic use, Primary Myelofibrosis therapy, Primary Myelofibrosis mortality, Hematopoietic Stem Cell Transplantation methods, Registries
Abstract

We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2024
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13. Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

Author

Moukalled N, Labopin M, Versluis J, Socié G, Blaise D, Salmenniemi U, Rambaldi A, Gedde-Dahl T, Tholouli E, Kröger N, Bourhis JH, Von Dem Borne P, Daguindau E, Forcade E, Nagler A, Esteve J, Ciceri F, Bazarbachi A, and Mohty M

Subjects
Adult, Humans, Nucleophosmin, Bone Marrow, Mutation, Chromosome Aberrations, Abnormal Karyotype, Karyotype, Neoplasm, Residual, Prognosis, fms-Like Tyrosine Kinase 3 genetics, Retrospective Studies, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Hematopoietic Stem Cell Transplantation
Abstract

In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival., (© 2024 Wiley Periodicals LLC.)

Published
2024
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14. Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

Author

Baron F, Nagler A, Galimard JE, Sanz J, Versluis J, Forcade E, Chevallier P, Sirvent A, Anthias C, Kuball J, Furst S, Rambaldi A, Sierra J, von dem Borne PA, Gallego Hernanz MP, Cluzeau T, Robinson S, Raiola AM, Labussière-Wallet H, Byrne JL, Malfuson JV, Ruggeri A, Mohty M, and Ciceri F

Subjects
Adult, Humans, Retrospective Studies, Neoplasm Recurrence, Local etiology, Transplantation Conditioning methods, Receptors, Complement 3b, Cord Blood Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute complications, Hematopoietic Stem Cell Transplantation methods, Neoplasms, Second Primary etiology, Graft vs Host Disease etiology
Abstract

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Published
2024
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15. Improved Posttransplant Outcomes in Recent Years for AML Patients with FLT3-ITD and Wild-type NPM1: A Report from the EBMT Acute Leukemia Working Party.

Author

Bazarbachi A, Labopin M, Gedde-Dahl T, Remenyi P, Forcade E, Kröger N, Socié G, Craddock C, Bourhis JH, Versluis J, Yakoub-Agha I, Salmenniemi U, El-Cheikh J, Bug G, Esteve J, Nagler A, Ciceri F, and Mohty M

Subjects
Adult, Humans, Adolescent, Young Adult, Middle Aged, Nuclear Proteins genetics, Nucleophosmin, fms-Like Tyrosine Kinase 3 genetics, Mutation, Prognosis, Retrospective Studies, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
Abstract

Purpose: Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1) in patients with acute myeloid leukemia (AML) harboring FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD). We assessed changes over time in transplant characteristics and outcomes in patients with AML age 60 years and younger with a FLT3-ITD., Experimental Design: We identified 1,827 adult patients with AML (median age 49 years, range 18-60) with FLT3-ITD and intermediate karyotype, allografted between 2012 and 2021 in CR1., Results: NPM1 was mutated in 72% of patients. We compared changes over time in 688 patients transplanted between 2012 and 2016, and 1,139 patients transplanted between 2017 and 2021. For patients with wild-type NPM1, the 2-year leukemia-free survival (LFS) and overall survival (OS) significantly improved over time from 54% to 64% (HR = 0.67; P = 0.011) and from 63% to 71% (HR = 0.66; P = 0.021), respectively. Allo-HCT in recent years significantly reduced the cumulative incidence of relapse (CIR). For patients with NPM1 mutation, no significant changes over time were noted., Conclusions: In patients with AML with FLT3-ITD and wild-type NPM1, we noticed a significant decrease over time in the CIR and improvement of LFS and OS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as posttransplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in outcomes of patients harboring a FLT3 and NPM1 mutation., (©2023 American Association for Cancer Research.)

Published
2023
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16. Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT.

Author

Baron F, Ruggeri A, Peczynski C, Labopin M, Bourhis JH, Michallet M, Chevallier P, Sanz J, Forcade E, Saccardi R, Potter V, Gluckman E, Nagler A, and Mohty M

Subjects
Humans, Adolescent, Retrospective Studies, Acute Disease, Recurrence, Transplantation Conditioning adverse effects, Cord Blood Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Leukemia, Myeloid, Acute complications, Graft vs Host Disease etiology
Abstract

Graft failure has remained a limitation of umbilical cord blood transplantation (CBT). Here, we assessed the outcomes of patients who experienced graft failure after CBT. Inclusion criteria were patients (age ≥ 18 years) experiencing graft failure after unrelated CBT (single or double) between 2005 and 2016, for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), no prior allogeneic or autologous transplantation, no other stem cell product. The study included 87 patients. At 1-year, cumulative incidence of relapse and nonrelapse mortality (NRM) was 35% and 37%, respectively. One-year overall survival (OS) and progression-free survival (PFS) was 40% and 29%, respectively. Forty-six patients underwent a salvage second transplantation with 1-year and 2-year OS and PFS from second transplantation 41% and 34% for OS, and 37% and 34% for PFS, respectively. In multivariate analysis, complete remission (CR) at CBT (HR = 0.45, 95% CI 0.25-0.83, P = 0.01) and reduced-intensity conditioning (HR = 0.51, 95% CI 0.29-0.91, P = 0.023) were associated with better OS. In conclusion, in this retrospective study, we observed that approximately one-quarter of patients experiencing graft failure after CBT remained alive without relapse 2 years later., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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17. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML.

Author

de Botton S, Fenaux P, Yee K, Récher C, Wei AH, Montesinos P, Taussig DC, Pigneux A, Braun T, Curti A, Grove C, Jonas BA, Khwaja A, Legrand O, Peterlin P, Arnan M, Blum W, Cilloni D, Hiwase DK, Jurcic JG, Krauter J, Thomas X, Watts JM, Yang J, Polyanskaya O, Brevard J, Sweeney J, Barrett E, and Cortes J

Subjects
Humans, Adult, Middle Aged, Aged, Aged, 80 and over, Pyridines, Prognosis, Isocitrate Dehydrogenase genetics, Quinolines therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute chemically induced
Abstract

Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). Overall, 153 IDH1 inhibitor-naive patients with mIDH1R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) received olutasidenib monotherapy 150 mg twice daily in the pivotal cohort of this study. The median age of participants was 71 years (range, 32-87 years) and the median number of prior regimens received by patients was 2 (1-7). The rate of complete remission (CR) plus CR with partial hematologic recovery (CRh) was 35%, and the overall response rate was 48%. Response rates were similar in patients who had, and who had not, received prior venetoclax. With 55% of patients censored at the time of data cut-off, the median duration of CR/CRh was 25.9 months. The median duration of overall response was 11.7 months, and the median overall survival was 11.6 months. Of 86 patients who were transfusion dependent at baseline, a 56-day transfusion independence was achieved in 29 (34%), which included patients in all response groups. Grade 3 or 4 treatment-emergent adverse events (≥10%) were febrile neutropenia and anemia (n = 31; 20% each), thrombocytopenia (n = 25; 16%), and neutropenia (n = 20; 13%). Differentiation syndrome adverse events of special interest occurred in 22 (14%) patients, with 14 (9%) grade ≥3 and 1 fatal case reported. Overall, olutasidenib induced durable remissions and transfusion independence with a well-characterized and manageable side effect profile. The observed efficacy represents a therapeutic advance in this molecularly defined, poor-prognostic population of patients with mIDH1 R/R AML. This trial was registered at www.clinicaltrials.gov as #NCT02719574., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2023
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18. Significance of Degree of HLA Disparity Using T-cell Replete Peripheral Blood Stem Cells From Haploidentical Donors With Posttransplantation Cyclophosphamide in AML in First Complete Hematologic Remission: A Study of the Acute Leukemia Working Party of the EBMT.

Author

Kharfan-Dabaja MA, Labopin M, Ayala E, Bazarbachi A, Blaise D, Vydra J, Bramanti S, Itälä-Remes M, Schmid C, Busca A, Forcade E, Rabitsch W, Zecca M, Kröger N, Bulabois CE, Grillo G, Rambaldi A, Fanin R, Zallio F, Di Renzo N, Koc Y, Novis Y, McDonald A, Herrera Arroyo C, Sanz J, Nagler A, Ciceri F, and Mohty M

Abstract

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2-3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2-3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2-3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2-4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2-3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Published
2023
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19. Combining blinatumomab and donor lymphocyte infusion in B-ALL patients relapsing after allogeneic hematopoietic cell transplantation: a study of the SFGM-TC.

Author

Chauvet P, Paviglianiti A, Labopin M, Labussière H, Boissel N, Robin M, Maillard N, Ouachée-Chardin M, Forcade E, Poiré X, Chantepie S, Huynh A, Bulabois CE, Leclerc M, Maury S, Chevallier P, Cluzeau T, Mear JB, Cornillon J, Bilger K, Simand C, Beguin Y, Rubio MT, Yakoub-Agha I, and Brissot E

Subjects
Humans, Retrospective Studies, Transplantation, Homologous, Recurrence, Lymphocytes, Lymphocyte Transfusion, Hematopoietic Stem Cell Transplantation
Abstract

Relapsed B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic stem cell transplantation (allo-HCT) still represents a major concern with poor outcomes. The aim of this study is to compare the efficacy and safety of blinatumomab and donor lymphocyte infusion (DLI) versus blinatumomab alone in this setting. This is a multicenter retrospective study from centers of SFGM-TC. All transplanted patients who received blinatumomab salvage therapy were included. Patients who received DLI from 1 month before to 100 days after the starting of blinatumomab were included in the blina-DLI group. Seventy-two patients were included. Medium follow-up was 38 months. Fifty received blinatumomab alone and 22 the association blinatumomab-DLI. Two-year overall survival (OS) was 31% in the blinatumomab group and 43% in the blinatumomab-DLI group (p = 0.31). Studying DLI as a time dependent variable, PFS did not significantly differ between the 2 groups (HR:0.7, 95% CI: 0.4-1.5). In multivariate analysis, DLI was not a prognostic factor for OS, progression-free survival and progression/relapse incidence. Adverse events and graft-versus-disease rates were comparable in the 2 groups. In conclusion, adding DLI between 1 month before and 100 days after start of blinatumomab is safe and does not seem to improve outcomes in B-ALL patients who relapsed after allo-HCT., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2023
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20. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia.

Author

Baron F, Labopin M, Tischer J, Ciceri F, Raiola AM, Blaise D, Sica S, Vydra J, Fanin R, Diez-Martin JL, Bulabois CE, Stölzel F, Busca A, Jindra P, Koc Y, Chevallier P, Forcade E, Rösler W, Passweg J, Kulagin A, Carella AM, Simand C, Bazarbachi A, Pioltelli P, Nagler A, and Mohty M

Subjects
Adult, Humans, Transplantation, Haploidentical adverse effects, Unrelated Donors, Transplantation Conditioning methods, Retrospective Studies, Cyclophosphamide therapeutic use, Graft vs Host Disease etiology, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute drug therapy
Abstract

HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) is frequently used as treatment for patients with active acute myeloid leukemia (AML). Here, we investigated whether 9/10 HLA-mismatched unrelated donor transplantation (MMUD-HCT) with post-transplant cyclophosphamide (PTCy) is an adequate alternative. Inclusion criteria in this retrospective registry study consisted of adult patients, first HCT with a Haplo donor or MMUD between 2010 and 2020 using PTCy as graft-versus-host disease (GVHD) prophylaxis, and primary refractory or relapsed disease. MMUD patients were pair-matched 1 to 2 with Haplo-recipients. A total of 73 MMUD patients met the inclusion criteria. Their data were compared to those of 146 Haplo patients in a matched-pair analysis. Median follow-up was 27 months in MMUD patients and 36 months in Haplo recipients. Two-year incidences of relapse and non-relapse mortality (NRM) were 40% and 18% in MMUD patients, respectively, versus 50% (P = 0.23) and 24% (P = 0.18) in Haplo recipients. Two-year leukemia-free survival (LFS) and overall survival (OS) was 42% and 46% in MMUD recipients, respectively, versus 26% (P = 0.1) and 28% (P = 0.061) in Haplo-patients. In conclusions, in AML patients with active disease at transplantation, MMUD-HCT results in at least comparable outcomes to Haplo-HCT when PTCy is applied., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2022
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21. Correction: Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia.

Author

Baron F, Labopin M, Tischer J, Ciceri F, Raiola AM, Blaise D, Sica S, Vydra J, Fanin R, Diez-Martin JL, Bulabois CE, Stölzel F, Busca A, Jindra P, Koc Y, Chevallier P, Forcade E, Rösler W, Passweg J, Kulagin A, Carella AM, Simand C, Bazarbachi A, Pioltelli P, Nagler A, and Mohty M

Published
2022
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22. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.

Author

Dupont M, Huart M, Lauvinerie C, Bidet A, Guitart AV, Villacreces A, Vigon I, Desplat V, El Habhab A, Pigneux A, Ivanovic Z, Brunet De la Grange P, Dumas PY, and Pasquet JM

Abstract

Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

Published
2022
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23. Clinical and biological characteristics of leukemia cutis in chronic lymphocytic leukemia: A study of the French innovative leukemia organization (FILO).

Author

Lazarian G, Munger M, Quinquenel A, Dilhuydy MS, Veronese L, Luque Paz D, Guièze R, Ledoux-Pilon A, Paillassa J, Merabet F, Vial JP, Bidet A, Waultier Rascalou A, Broseus J, Roos-Weil D, Lavaud A, Molina L, Laribi K, Hivert B, Friedrich C, Carpentier B, Ysebaert L, Van Den Neste E, Willems L, Corby A, Poulain S, Eclache V, Maubec E, Martin A, Feugier P, Delmer A, Baran-Marszak F, Leprêtre S, and Cymbalista F

Subjects
Adult, Aged, Aged, 80 and over, B-Lymphocytes pathology, Female, France epidemiology, Humans, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Male, Middle Aged, Mutation, Skin Neoplasms epidemiology, Skin Neoplasms genetics, Treatment Outcome, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Skin pathology, Skin Neoplasms pathology
Published
2021
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24. Better leukemia-free survival with allogeneic than with autologous HCT in AML patients with isolated trisomy 8: a study from the ALWP of the EBMT.

Author

Baron F, Labopin M, Blaise D, Itälä-Remes M, Socié G, Forcade E, Yakoub-Agha I, Gorin NC, Esteve J, Nagler A, and Mohty M

Subjects
Adult, Chromosomes, Human, Pair 8, Humans, Neoplasm Recurrence, Local, Retrospective Studies, Transplantation Conditioning, Trisomy, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
Abstract

The indication for performing an allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with isolated trisomy 8 AML in first complete remission (CR) is still debated. Here, we compared outcomes of such patients given either allo-HCT or autologous (auto)-HCT. Inclusion criteria consisted of adult patients with de novo AML, isolated trisomy 8, first HCT between 2000 and 2018, CR1 at transplantation, and either auto-HCT or allo-HCT with a HLA-identical sibling donor (MSD) or a 10/10 HLA-matched unrelated donor (UD 10/10). A total of 401 patients met the inclusion criteria. They underwent an auto-HCT (n = 81), allo-HCT with a MSD (n = 186) or allo-HCT with a 10/10 UD (n = 134). At 3 years, relapse incidence, nonrelapse mortality and leukemia-free survival (LFS) were 59%, 5%, and 37%, respectively, in auto-HCT recipients; 31% (P < 0.001), 14% (P = 0.04), and 55% (P = 0.033), respectively, in MSD recipients and 29% (P < 0.001), 13% (P = 0.15), and 59% (P = 0.03), respectively, in UD 10/10 recipients. In multivariate analysis, in comparison to auto-HCT, MSD and UD 10/10 were associated with a lower risk of relapse (HR = 0.47, P < 0.001 and HR = 0.40, P < 0.001, respectively) translating to better LFS (HR = 0.69, P = 0.04 and HR = 0.60, P = 0.03, respectively). There was also a similar trend for overall survival (HR = 0.73, P = 0.12 and HR = 0.65, P = 0.08).

Published
2021
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25. [Health crisis and reflexive crisis: The medical perspective in times of epidemic].

Author

Galtier J and Rivière E

Subjects
Attitude of Health Personnel, COVID-19 epidemiology, COVID-19 psychology, COVID-19 therapy, Civil Defense history, Civil Defense organization & administration, Civil Defense standards, Cost of Illness, History, 19th Century, History, 20th Century, History, 21st Century, Humans, Pandemics, Perception physiology, Politics, Public Health history, Public Health standards, Public Policy history, Social Media history, Social Media organization & administration, Social Media standards, Time Factors, Attitude to Health, Delivery of Health Care history, Delivery of Health Care organization & administration, Delivery of Health Care standards, Emotions, Epidemics history, Mental Health standards
Published
2020
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26. Allogeneic stem cell transplantation for peripheral T cell lymphomas: a retrospective study in 285 patients from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Author

Mamez AC, Dupont A, Blaise D, Chevallier P, Forcade E, Ceballos P, Mohty M, Suarez F, Beguin Y, Peffault De Latour R, Rubio MT, Tournilhac O, and Nguyen S

Subjects
Adolescent, Adult, Aged, Allografts, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Humans, Immunosuppressive Agents therapeutic use, Incidence, Infections mortality, Kaplan-Meier Estimate, Lymphoma, Large-Cell, Anaplastic mortality, Lymphoma, Large-Cell, Anaplastic therapy, Lymphoma, T-Cell, Peripheral mortality, Middle Aged, Prognosis, Progression-Free Survival, Radiotherapy, Adjuvant, Recurrence, Remission Induction, Retrospective Studies, Salvage Therapy, Transplantation Conditioning methods, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation mortality, Hematopoietic Stem Cell Transplantation statistics & numerical data, Lymphoma, T-Cell, Peripheral therapy
Abstract

Background: Peripheral T cell lymphomas form a heterogeneous group with a usually dismal prognostic. The place of allogeneic stem cell transplantation to treat PTCL is debated., Methods: We retrospectively analyzed the overall survival (OS), event-free survival (EFS), relapse, and transplant-related mortality (TRM) and associated variables in 285 adults with non-primary cutaneous PTCL (PCTL-NOS (39%), angioimmunoblastic T cell lymphomas (29%), anaplastic T cell lymphomas (15%), and other subtypes (17%)), who received alloSCT in 34 centers between 2006 and 2014., Results: AlloSCT was given as part of front-line therapy (n = 138) to 93 patients in first complete response (CR) and 45 in first partial response (PR), and of salvage therapy (n = 147) to 116 patients for second or more CR/PR and 31 for progressive disease. Reduced-intensity conditioning (RIC) was given to 172 patients (62%), while 107 (38%) received myeloablative conditioning (MAC). The median follow-up was 72.4 months. The 2- and 4-year OS were 65% and 59%, respectively, and the cumulative incidence of relapse was 18% after 1 year and 19% after 2 years. TRM was 21% at 1 year, 24% after 2 years, and 28% after 4 years. In multivariate analysis, grade III-IV acute GvHD (HR = 2.57, 95% CI 1.53-4.31; p = 0.00036), low Karnofsky score < 80% (HR = 5.14, 95% CI 2.02-13.06; p = 0.00058), and progressive disease status before transplant (HR = 2.21, 95% CI 1.25-3.89; p = 0.0062) were significantly associated with a reduced OS., Conclusions: The data demonstrate in the largest retrospective cohort of non-cutaneous PTCL so far reported that alloSCT after RIC or MAC is an effective strategy, even in chemoresistant patients.

Published
2020
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27. Killer immunoglobulin-like receptor genotypes and chronic myeloid leukemia outcomes after imatinib cessation for treatment-free remission.

Author

Dumas PY, Bérard E, Bréal C, Dulucq S, Réa D, Nicolini F, Forcade E, Dufossée M, Pasquet JM, Turcq B, Bidet A, Milpied N, Déchanet-Merville J, Lafarge X, Etienne G, and Mahon FX

Subjects
Aged, Antineoplastic Agents therapeutic use, Biomarkers, Female, Haplotypes, Humans, Imatinib Mesylate therapeutic use, Immunophenotyping, Killer Cells, Natural drug effects, Killer Cells, Natural metabolism, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Middle Aged, Protein Kinase Inhibitors therapeutic use, Receptors, KIR metabolism, Receptors, KIR2DL5 genetics, Remission Induction, Treatment Outcome, Withholding Treatment, Genetic Variation, Genotype, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Receptors, KIR genetics
Abstract

Background: Natural Killer (NK) cells are innate lymphoid cells that can be cytotoxic toward a large panel of solid tumors and hematological malignancies including chronic myeloid leukemia (CML). Such a cytotoxicity depends on various receptors. Killer immunoglobulin-like receptors (KIR) belong to these receptors and are involved in maturation process, then in the activation abilities of NK cells., Methods: We investigated the prognostic impact of the KIR2DL5B genotype in 240 CML patients included in two clinical trials investigating tyrosine kinase inhibitors (TKI) discontinuation: STIM and STIM2., Results: After adjustment for standard risk factors in CML, we found that the inhibitory receptor KIR2DL5B-positive genotype was independently related to a delayed second deep molecular remission (HR 0.54, 95% CI [0.32-0.91], P = 0.02) after TKI rechallenge but not to time to first deep molecular remission or treatment-free remission rates., Conclusion: These results suggest that KIR2DL5B could carry a role in lymphocyte-mediated control of leukemic residual disease control in patient with CML relapse., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Published
2019
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28. Management of Myelodysplastic Syndrome Relapsing after Allogeneic Hematopoietic Stem Cell Transplantation: A Study by the French Society of Bone Marrow Transplantation and Cell Therapies.

Author

Guièze R, Damaj G, Pereira B, Robin M, Chevallier P, Michallet M, Vigouroux S, Beguin Y, Blaise D, El Cheikh J, Roos-Weil D, Thiebaut A, Rohrlich PS, Huynh A, Cornillon J, Contentin N, Suarez F, Lioure B, Mohty M, Maillard N, Clement L, François S, Guillerm G, and Yakoub-Agha I

Subjects
Adolescent, Adult, Aged, Female, Humans, Lymphocyte Transfusion, Male, Middle Aged, Prognosis, Recurrence, Tissue Donors, Young Adult, Bone Marrow Transplantation methods, Cell- and Tissue-Based Therapy methods, Hematopoietic Stem Cell Transplantation methods, Myelodysplastic Syndromes therapy, Transplantation Conditioning methods, Transplantation, Homologous methods
Abstract

To find out prognostic factors and to investigate different therapeutic approaches, we report on 147 consecutive patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS). Sixty-two patients underwent immunotherapy (IT group, second allo-HSCT or donor lymphocyte infusion), 39 received cytoreductive treatment alone (CRT group) and 46 were managed with palliative/supportive cares (PSC group). Two-year rates of overall survival (OS) were 32%, 6%, and 2% in the IT, CRT, and PSC groups, respectively (P < .001). In multivariate analysis, 4 factors adversely influenced 2-year rates of OS: history of acute graft-versus-host disease (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.26 to 2.67; P = .002), relapse within 6 months (HR, 2.69; 95% CI, .82 to 3.98; P < .001), progression to acute myeloid leukemia (HR, 2.59; 95% CI, 1.75 to 3.83; P < .001), and platelet count < 50 G/L at relapse (HR, 1.68; 95% CI, 1.15 to 2.44; P = .007). A prognostic score based on those factors discriminated 2 risk groups with median OSs of 13.2 versus 2.4 months, respectively (P < .001). When propensity score, prognostic score, and treatment strategy were included in Cox model, immunotherapy was found to be an independent factor that favorably impacts OS (HR, .40; 95% CI, .26 to .63; P < .001). In conclusion, immunotherapy should be considered when possible for MDS patients relapsing after allo-HSCT., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Published
2016
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