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1. Multi-target measurable residual disease assessed by error-corrected sequencing in patients with acute myeloid leukemia: An ALFA study

Author

Pierre Hirsch, Jérôme Lambert, Maxime Bucci, Caroline Deswarte, Augustin Boudry, Juliette Lambert, Laurene Fenwarth, Jean-Baptiste Micol, Christine Terré, Karine Celli-Lebras, Xavier Thomas, Hervé Dombret, Nicolas Duployez, Claude Preudhomme, Raphael Itzykson, and Francois Delhommeau

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p

Published
2024
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3. French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes

Author

Matthieu Groh, Julien Rohmer, Nicolas Etienne, Wadih Abou Chahla, Antoine Baudet, Aurélie Chan Hew Wai, Cécile Chenivesse, Irena Clisson Rusek, Vincent Cottin, Matthieu Decamp, Pascal De Groote, Fanny Delahousse, Nicolas Duployez, Stanislas Faguer, Frédéric Gottrand, Florent Huang, Thierry Leblanc, Antoine Magnan, Thierry Martin, Geoffrey Mortuaire, Antoine Néel, Luc Paris, Arnaud Petit, Julien Rossignol, Nicolas Schleinitz, Juliette Soret-Dulphy, Delphine Staumont-Salle, Benjamin Terrier, Louis Terriou, Jean-François Viallard, Guillaume Lefèvre, and Jean-Emmanuel Kahn

Subjects
Hypereosinophilia, Hypereosinophilic syndromes, Recommendation, Management, Medicine
Abstract

Abstract Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients’ association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Published
2023
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4. Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia

Author

Eleanor L. Woodward, Minjun Yang, Larissa H. Moura-Castro, Hilda van den Bos, Rebeqa Gunnarsson, Linda Olsson-Arvidsson, Diana C. J. Spierings, Anders Castor, Nicolas Duployez, Marketa Zaliova, Jan Zuna, Bertil Johansson, Floris Foijer, and Kajsa Paulsson

Subjects
Science
Abstract

High hyperdiploid acute lymphoblastic leukaemia (HeH ALL) is driven by nonrandom chromosomal gains, which have been suggested to arise early - even before birth. Here, the authors use single-cell whole genome sequencing and in silico modelling to show that HeH ALL aneuploidies could originate early and follow punctuated evolution.

Published
2023
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5. Small myeloid subclones are present at diagnosis of multiple myeloma in patients who develop secondary myelodysplastic syndromes

Author

Guillaume Escure, Elise Fournier, Cynthia Saade, Lama Hasan Bou Issa, Inès Arib, Rémi Tilmont, Nicolas Gazeau, Binta M. Thiam, Morgane Chovet, Maxime Delforge, Nicolas Gower, Léa Fléchon, Doriane Cavalieri, Paul Chauvet, Morgane Nudel, Laure Goursaud, Céline Berthon, Bruno Quesnel, Thierry Facon, Claude Preudhomme, Nicolas Duployez, and Salomon Manier

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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6. Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r

Author

Augustin Boudry, Sasha Darmon, Nicolas Duployez, Martin Figeac, Sandrine Geffroy, Maxime Bucci, Karine Celli-Lebras, Matthieu Duchmann, Romane Joudinaud, Laurène Fenwarth, Olivier Nibourel, Laure Goursaud, Raphael Itzykson, Hervé Dombret, Mathilde Hunault, Claude Preudhomme, and Mikaël Salson

Subjects
Sequence analysis, High-throughput sequencing, Alignment-free, Cancer, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data. Results Our algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software. Conclusion FiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r . The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.

Published
2022
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7. Hematopoietic differentiation at single-cell resolution in NPM1-mutated AML

Author

Matthieu Duchmann, Romane Joudinaud, Augustin Boudry, Justine Pasanisi, Giuseppe Di Feo, Rathana Kim, Maxime Bucci, Clémentine Chauvel, Laureen Chat, Lise Larcher, Kim Pacchiardi, Stéphanie Mathis, Emmanuel Raffoux, Lionel Adès, Céline Berthon, Emmanuelle Clappier, Christophe Roumier, Alexandre Puissant, Claude Preudhomme, Nicolas Duployez, and Raphaël Itzykson

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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9. Somatic genetic alterations predict hematological progression in GATA2 deficiency

Author

Laetitia Largeaud, Matthew Collin, Nils Monselet, Francois Vergez, Vincent Fregona, Lise Larcher, Pierre Hirsch, Nicolas Duployez, Audrey Bidet, Isabelle Luquet, Jacinta Bustamante, Stephanie Dufrechou, Nais Prade, Marie Nolla, Camille Hamelle, Suzanne Tavitian, Christophe Habib, Mateo Meynier, Christine Bellanne-Chantelot, Jean Donadieu, Flore Sicre de Fontbrune, Claire Fieschi, Alina Ferster, Francois Delhommeau, Eric Delabesse, and Marlene Pasquet

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

Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.

Published
2023
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10. Publisher Correction: Frugal alignment-free identification of FLT3-internal tandem duplications with FiLT3r

Author

Augustin Boudry, Sasha Darmon, Nicolas Duployez, Martin Figeac, Sandrine Geffroy, Maxime Bucci, Karine Celli-Lebras, Matthieu Duchmann, Romane Joudinaud, Laurène Fenwarth, Olivier Nibourel, Laure Goursaud, Raphael Itzykson, Hervé Dombret, Mathilde Hunault, Claude Preudhomme, and Mikaël Salson

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Published
2022
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11. The RUNX1 database (RUNX1db): establishment of an expert curated RUNX1 registry and genomics database as a public resource for familial platelet disorder with myeloid malignancy

Author

Claire C. Homan, Sarah L. King-Smith, David M. Lawrence, Peer Arts, Jinghua Feng, James Andrews, Mark Armstrong, Thuong Ha, Julia Dobbins, Michael W. Drazer, Kai Yu, Csaba Bödör, Alan Cantor, Mario Cazzola, Erin Degelman, Courtney D. DiNardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Jude Fitzgibbon, Jeffery M. Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V. Morgan, Georges Natsoulis, Carolyn Owen, Keyur P. Patel, Claude Preudhomme, Hana Raslova, Hugh Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Velloso, Benedict Yan, Paul Liu, Lucy A. Godley, Andreas W. Schreiber, Christopher N. Hahn, Hamish S. Scott, and Anna L. Brown

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2021
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12. IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

Author

Bruno A. Lopes, Claus Meyer, Thayana C. Barbosa, Caroline P. Poubel, Marcela B. Mansur, Nicolas Duployez, Matthew Bashton, Christine J. Harrison, Udo zur Stadt, Martin Horstmann, Maria S. Pombo-de-Oliveira, Chiara Palmi, Gianni Cazzaniga, Nicola C. Venn, Rosemary Sutton, Cristina N. Alonso, Grigory Tsaur, Sanjeev K. Gupta, Sameer Bakhshi, Rolf Marschalek, and Mariana Emerenciano

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Published
2019
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14. Minimal residual disease monitoring in acute myeloid leukemia with non-A/B/D-NPM1 mutations by digital polymerase chain reaction: feasibility and clinical use

Author

Auriane Lesieur, Xavier Thomas, Olivier Nibourel, Nicolas Boissel, Laurène Fenwarth, Stéphane De Botton, Elise Fournier, Karine Celli-Lebras, Emmanuel Raffoux, Christian Recher, Juliette Lambert, Céline Berthon, Arnaud Pigneux, Raphael Itzykson, Pascal Turlure, Cécile Pautas, Jacques Vargaftig, Claude Preudhomme, Hervé Dombret, and Nicolas Duployez

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2020
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15. Germline pathogenic variants in transcription factors predisposing to pediatric acute myeloid leukemia: results from the French ELAM02 trial

Author

Laurène Fenwarth, Nicolas Duployez, Alice Marceau-Renaut, Wadih Abou Chahla, Stéphane Ducassou, Virginie Gandemer, Marlène Pasquet, Thierry Leblanc, Pascale Schneider, Carine Domenech, Paul Saultier, Guy Leverger, Hélène Lapillonne, Claude Preudhomme, and Arnaud Petit

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2020
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16. B-ALL With t(5;14)(q31;q32); IGH-IL3 Rearrangement and Eosinophilia: A Comprehensive Analysis of a Peculiar IGH-Rearranged B-ALL

Author

Benjamin Fournier, Estelle Balducci, Nicolas Duployez, Emmanuelle Clappier, Wendy Cuccuini, Chloé Arfeuille, Aurélie Caye-Eude, Eric Delabesse, Elodie Bottollier-Lemallaz Colomb, Karin Nebral, Marie-Lorraine Chrétien, Coralie Derrieux, Aurélie Cabannes-Hamy, Florent Dumezy, Pascaline Etancelin, Odile Fenneteau, Jamile Frayfer, Antoine Gourmel, Marie Loosveld, Gérard Michel, Nathalie Nadal, Dominique Penther, Isabelle Tigaud, Elise Fournier, Bettina Reismüller, Andishe Attarbaschi, Marina Lafage-Pochitaloff, and André Baruchel

Subjects
acute lymphoblastic leukemia, cytogenetics and molecular genetics, clinical and molecular epidemiology, eosinophilia, IKZF1 rearrangement, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: B-cell acute lymphoblastic leukemia associated with t(5;14)(q31;q32); IGH-IL3 is an exceptional cause of eosinophilia. The IGH enhancer on 14q32 is juxtaposed to the IL3 gene on 5q31, leading to interleukin-3 overproduction and release of mature eosinophils in the blood. Clinical, biological and outcome data are extremely scarce in the literature. Except for eosinophilia, no relevant common feature has been highlighted in these patients. However, it has been classified as a distinct entity in the World Health Organization classification.Cases Presentation: Eight patients with t(5;14)(q31;q32) treated by French or Austrian protocols were retrospectively enrolled. Array comparative genomic hybridization, multiplex ligation-dependent probe amplification or genomic PCR search for IKZF1 deletion were performed in 7. Sixteen patients found through an exhaustive search in the literature were also analyzed.For those 24 patients, median age at diagnosis is 14.3 years with a male predominance (male to female ratio = 5). Eosinophilia-related symptoms are common (neurologic in 26%, thromboembolic in 26% or pulmonary in 50%). Median white blood cells count is high (72 × 109/L) and linked to eosinophilia (median: 32 × 109/L). Peripheral blasts are present at a low level or absent (median: 0 × 109/L; range: 0–37 × 109/L). Bone marrow morphology is marked by a low blast infiltration (median: 42%). We found an IKZF1 deletion in 5 out of 7 analyzable patients Outcome data are available for 14 patients (median follow-up: 28 months): 8 died and 6 are alive in complete remission.Some of these features are concordant with those seen in patients with other IGH-rearranged B-cell acute lymphoblastic leukemias: young age at onset, male sex, low blast count, high incidence of IKZF1 deletion and intermediate prognosis.Conclusion: Based on shared epidemiological and biological features, B-cell acute lymphoblastic leukemia with t(5;14)(q31;q32) is a peculiar subset of IGH-rearranged B-cell acute lymphoblastic leukemia with an intermediate prognosis and particular clinical features related to eosinophilia.

Published
2019
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17. ASXL2 is essential for haematopoiesis and acts as a haploinsufficient tumour suppressor in leukemia

Author

Jean-Baptiste Micol, Alessandro Pastore, Daichi Inoue, Nicolas Duployez, Eunhee Kim, Stanley Chun-Wei Lee, Benjamin H. Durham, Young Rock Chung, Hana Cho, Xiao Jing Zhang, Akihide Yoshimi, Andrei Krivtsov, Richard Koche, Eric Solary, Amit Sinha, Claude Preudhomme, and Omar Abdel-Wahab

Subjects
Science
Abstract

While the role of ASLX1 in haematopoiesis and leukaemia has been heavily studied, the role of ASLX2 is unclear. Here the authors show that ASLX2 is required for normal haematopoietic stem cell self-renewal whereas Asxl2 loss promotes leukemogenesis, thus explaining the frequently observed mutations in AML patients

Published
2017
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18. Efficacy of Tyrosine Kinase Inhibitor Therapy in a Chemotherapy-refractory B-cell Precursor Acute Lymphoblastic Leukemia With ZC3HAV1-ABL2 Fusion

Author

Gauthier Decool, Carine Domenech, Nathalie Grardel, Adriana Plesa, Imelda Raczkiewicz, Benoit Ducourneau, Philippe Ruminy, Marie-Pierre Pages, Sandrine Girard, Laurène Fenwarth, Claude Preudhomme, Yves Bertrand, and Nicolas Duployez

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2019
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19. Germline RUNX1 Intragenic Deletion: Implications for Accurate Diagnosis of FPD/AML

Author

Nicolas Duployez, Jean-Edouard Martin, Sabine Khalife-Hachem, Ryane Benkhelil, Véronique Saada, Christophe Marzac, Nathalie Auger, Alice Marceau-Renaut, Rémi Favier, Paola Ballerini, Olivier Caron, André Baruchel, Stéphane de Botton, Claude Preudhomme, Jean-Baptiste Micol, Hana Raslova, and Iléana Antony-Debré

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2019
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21. Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment

Author

Laurène Fenwarth, Elise Fournier, Meyling Cheok, Thomas Boyer, Fanny Gonzales, Sylvie Castaigne, Nicolas Boissel, Juliette Lambert, Hervé Dombret, Claude Preudhomme, and Nicolas Duployez

Subjects
acute myeloid leukemia, gemtuzumab ozogamicin, biomarkers, CD33, FLT3, therapy, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Gemtuzumab ozogamicin (GO, Mylotarg®) consists of a humanized CD33-targeted antibody-drug conjugated to a calicheamicin derivative. Growing evidence of GO efficacy in acute myeloid leukemia (AML), demonstrated by improved outcomes in CD33-positive AML patients across phase I to III clinical trials, led to the Food and Drug Administration (FDA) approval on 1 September 2017 in CD33-positive AML patients aged 2 years and older. Discrepancies in GO recipients outcome have raised significant efforts to characterize biomarkers predictive of GO response and have refined the subset of patients that may strongly benefit from GO. Among them, CD33 expression levels, favorable cytogenetics (t(8;21), inv(16)/t(16;16), t(15;17)) and molecular alterations, such as NPM1, FLT3-internal tandem duplications and other signaling mutations, represent well-known candidates. Additionally, in depth analyses including minimal residual disease monitoring, stemness expression (LSC17 score), mutations or single nucleotide polymorphisms in GO pathway genes (CD33, ABCB1) and molecular-derived scores, such as the recently set up CD33_PGx6_Score, represent promising markers to enhance GO response prediction and improve patient management.

Published
2020
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22. Molecular Profiling Defines Distinct Prognostic Subgroups in Childhood AML: A Report From the French ELAM02 Study Group

Author

Alice Marceau-Renaut, Nicolas Duployez, Benoît Ducourneau, Myriam Labopin, Arnaud Petit, Alexandra Rousseau, Sandrine Geffroy, Maxime Bucci, Wendy Cuccuini, Odile Fenneteau, Philippe Ruminy, Brigitte Nelken, Stéphane Ducassou, Virginie Gandemer, Thierry Leblanc, Gérard Michel, Yves Bertrand, André Baruchel, Guy Leverger, Claude Preudhomme, and Hélène Lapillonne

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

Abstract. Despite major treatment improvements over the past decades, pediatric acute myeloid leukemia (AML) is still a life-threatening malignancy with relapse rates up to 30% and survival rates below 75%. A better description of the pattern of molecular aberrations in childhood AML is needed to refine prognostication in such patients. We report here the comprehensive molecular landscape using both high-throughput sequencing focused on 36 genes and ligation-dependent RT-PCR in 385 children with de novo AML enrolled in the prospective ELAM02 trial and we evaluated their prognostic significance. Seventy-six percent of patients had at least 1 mutation among the genes we screened. The most common class of mutations involved genes that control kinase signaling (61%) followed by transcription factors (16%), tumor suppressors (14%), chromatin modifiers (9%), DNA methylation controllers (8%), cohesin genes (5%), and spliceosome (3%). Moreover, a recurrent transcript fusion was detected in about a half of pediatric patients. Overall, CBF rearrangements, NPM1 and double CEBPA mutations represented 37% of the cohort and defined a favorable molecular subgroup (3 years OS: 92.1%) while NUP98 fusions, WT1, RUNX1, and PHF6 mutations (15% of the cohort) segregated into a poor molecular subgroup (3 years OS: 46.1%). KMT2A-rearrangements (21% of the cohort) were associated with an intermediate risk. Despite some overlaps, the spectrum of molecular aberrations and their prognostic significance differ between childhood and adult AML. These data have important implications to contribute in refining risk stratification of pediatric AML and show the need for further validations in independent pediatric cohorts.

Published
2018
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26. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study

Author

Nicolas Duployez, Laëtitia Largeaud, Matthieu Duchmann, Rathana Kim, Julie Rieunier, Juliette Lambert, Audrey Bidet, Lise Larcher, Jean Lemoine, François Delhommeau, Pierre Hirsch, Laurène Fenwarth, Olivier Kosmider, Justine Decroocq, Anne Bouvier, Yannick Le Bris, Marlène Ochmann, Alberto Santagostino, Lionel Adès, Pierre Fenaux, Xavier Thomas, Jean-Baptiste Micol, Claude Gardin, Raphael Itzykson, Jean Soulier, Emmanuelle Clappier, Christian Recher, Claude Preudhomme, Arnaud Pigneux, Hervé Dombret, Eric Delabesse, and Marie Sébert

Subjects
Male, Immunology, Hematopoietic Stem Cell Transplantation, Cell Biology, Hematology, Prognosis, Biochemistry, DEAD-box RNA Helicases, Leukemia, Myeloid, Acute, Humans, Female, Prospective Studies, Germ-Line Mutation, Retrospective Studies
Abstract

DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).

Published
2022

27. LSC17 score complements genetics and measurable residual disease in acute myeloid leukemia: an ALFA study

Author

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]

Subjects
[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

Published
2023

28. UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia

Author

Nicolas Duployez, Loïc Vasseur, Rathana Kim, Laëtitia Largeaud, Marie Passet, Anaïs L’Haridon, Pierre Lemaire, Laurène Fenwarth, Sandrine Geffroy, Nathalie Helevaut, Karine Celli‑Lebras, Lionel Adès, Delphine Lebon, Céline Berthon, Alice Marceau-Renaut, Meyling Cheok, Juliette Lambert, Christian Récher, Emmanuel Raffoux, Jean-Baptiste Micol, Arnaud Pigneux, Claude Gardin, Eric Delabesse, Jean Soulier, Mathilde Hunault, Hervé Dombret, Raphael Itzykson, Emmanuelle Clappier, Claude Preudhomme, Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT), Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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, 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), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL), Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service d'hématologie adulte [Hôpital de Saint Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Hôpital Haut-Lévêque, and Université Sciences et Technologies - Bordeaux 1 (UB)-CHU Bordeaux [Bordeaux]

Subjects
Cancer Research, Oncology, Hematology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

Published
2023

30. JAK inhibition for CD3− CD4+ lymphocytic-variant hypereosinophilic syndrome

Author

Stanislas Faguer, Matthieu Groh, François Vergez, Mathilde Hunault-Berger, Nicolas Duployez, Yves Renaudineau, Carle Paul, Guillaume Lefevre, Jean-Emmanuel Kahn, Institut des Maladies Métaboliques et Casdiovasculaires (UPS/Inserm U1297 - I2MC), 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 Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Foch [Suresnes], Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Université de Toulouse (UT), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), 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), Institut Fédératif de Biologie (IFB), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Institute of Chemistry for Life and Health Sciences (iCLeHS), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Hôpital Ambroise Paré [AP-HP]

Subjects
T-cell clone. Copyright © 2023. Published by Elsevier Inc, Ruxolitinib, [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy, Lymphocytic variant, Hypereosinophilic syndrome, JAK inhibition
Abstract

International audience; Alternatives are urgently needed in patients with CD3- CD4+ lymphocytic-variant hypereosinophilic syndrome (L-HES) requiring high-level steroids or who are unresponsive and/or intolerant to conventional alternative therapies. We report five L-HES patients (44-66 years) with cutaneous involvement (n = 5) and persistent eosinophilia (n = 3) despite conventional therapies, who successfully received JAK inhibitors (tofacitinib n = 1, ruxolitinib n = 4). JAKi led to complete clinical remission in the first 3 months in all (with prednisone withdrawal in four). Absolute eosinophil counts normalized in cases receiving ruxolitinib, while reduction was partial under tofacitinib. After switch from tofacitinib to ruxolitinib, complete clinical response persisted despite prednisone withdrawal. The clone size remained stable in all patients. After 3-13 months of follow-up, no adverse event was reported. Randomized controlled trials are now mandatory to optimize the use of JAKi in L-HES.

Published
2023

31. A randomised phase <scp>II</scp> study of azacitidine ( <scp>AZA</scp> ) alone or with Lenalidomide ( <scp>LEN</scp> ), Valproic acid ( <scp>VPA</scp> ) or Idarubicin ( <scp>IDA</scp> ) in <scp>higher‐Risk MDS</scp> or low blast <scp>AML</scp> : <scp>GFM</scp> 's 'pick a winner' trial, with the impact of somatic mutations

Author

Lionel Adès, Nicolas Duployez, Agnes Guerci‐Bresler, Kamel Laribi, Pierre Peterlin, Norbert Vey, Sylvain Thepot, Stefan Wickenhauser, Hacene Zerazhi, Aspassia Stamatoullas, Eric Wattel, Christian Recher, Andrea Toma, Sophie Dimicoli‐Salazar, Thorsten Braun, Odile Beyne‐Rauzy, Jean‐Pierre Marolleau, Stéphane Cheze, Sophie Park, Thomas Cluzeau, Stanislas Nimubona, Dominique Bordessoule, Riad Benramdane, Bruno Quesnel, Shanti Amé, Stéphane de Botton, Fathia Chermat, Claude Preudhomme, Sylvie Chevret, and Pierre Fenaux

Subjects
Hematology
Published
2022

32. Molecular heterogeneity and measurable residual disease of rare NPM1 mutations in acute myeloid leukemia: a nationwide experience from the GBMHM study group

Author

Elise Fournier, Maël Heiblig, Christine Lespinasse, Pascale Flandrin-Gresta, Antoine Geay, Laurent Miguet, Laurene Fenwarth, Laurent Vallat, Brigitte Soubeyrand, Alice Marceau-Renaut, Adriana Plesa, Claude Preudhomme, Pierre Sujobert, Sandrine Hayette, Nicolas Duployez, and Sarah Huet

Subjects
Leukemia, Myeloid, Acute, Cancer Research, Neoplasm, Residual, Oncology, Mutation, Humans, Nuclear Proteins, Hematology
Published
2022

33. Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a 2-center experience

Author

Elise Fournier, Pierre Sujobert, Ibrahim Yakoub-Agha, Eric Hachulla, Maël Heiblig, Ava Diarra, Fiorenza Barraco, Claude Preudhomme, David Launay, Nicolas Duployez, Leonardo Magro, Quentin Scanvion, Valérie Coiteux, Marie Balsat, Bruno Quesnel, and Louis Terriou

Subjects
Oncology, medicine.medical_specialty, business.industry, Somatic cell, medicine.medical_treatment, Hematopoietic Stem Cell Transplantation, Complete remission, Syndrome, Ubiquitin-Activating Enzymes, Hematology, Hematopoietic stem cell transplantation, Clinical trial, Refractory, Internal medicine, Mutation, Humans, Medicine, Treatment strategy, In patient, business, Retrospective Studies
Abstract

The recently described vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by somatic mutations in UBA1. Patients with VEXAS syndrome display late-onset autoinflammatory symptoms, usually refractory to treatment, and hematologic abnormalities. The identification of an easily-accessible specific marker (UBA1 mutations) is of particular interest as it allows the convergence of various inflammatory and hematological symptoms in a unique clinico-biological entity and gives the opportunity to design specific treatment strategies. Here we retrospectively identified 6 patients with VEXAS syndrome who underwent allogeneic hematopoietic stem cell transplantation (ASCT). To date, no treatment guidelines have been validated. In 4 patients, ASCT was guided by life-threatening autoinflammatory symptoms that were refractory to multiple therapies. Three patients are in durable complete remission 32, 38, and 37 months after ASCT. Two others are in complete remission response after 3 and 5 months. One unfortunately died post-ASCT. This report suggests that ASCT could be a curative option in patients with VEXAS syndrome and severe manifestations. Considering the complications and side effects of the procedure as well as the existence of other potential treatment, clinical trials are needed to define the subgroup of patients who will benefit from this strategy and its place in the therapeutic arsenal against VEXAS syndrome.

Published
2022

35. Early detection of WT1 measurable residual disease identifies high-risk patients, independent of transplantation in AML

Author

Hervé Dombret, Karine Celli-Lebras, Arnaud Pigneux, Sylvie Castaigne, Aline Renneville, Christine Terré, Alice Marceau-Renaut, Nicolas Boissel, Jean-Baptiste Micol, Sandrine Hayette, Claude Preudhomme, Céline Berthon, Philippe Rousselot, Jérôme Lambert, Juliette Lambert, Emmanuelle Clappier, Christian Recher, Nicolas Duployez, Xavier Thomas, Emmanuel Raffoux, 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), 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), 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), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), and HAL UVSQ, Équipe

Subjects
Adult, Oncology, medicine.medical_specialty, Neoplasm, Residual, Adolescent, [SDV]Life Sciences [q-bio], Population, Early detection, Disease, Young Adult, hemic and lymphatic diseases, Internal medicine, medicine, Humans, WT1 Proteins, education, education.field_of_study, High risk patients, business.industry, Hematopoietic Stem Cell Transplantation, Myeloid leukemia, Induction chemotherapy, Hematology, Middle Aged, Prognosis, [SDV] Life Sciences [q-bio], body regions, Transplantation, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Bone marrow, business
Abstract

WT1 overexpression is frequently identified in acute myeloid leukemia (AML) and has been reported to be a potential marker for monitoring measurable residual disease (MRD). We evaluated the use of postinduction WT1 MRD level as a prognostic factor, as well as the interaction between postinduction WT1 MRD response and the effect of allogeneic stem cell transplantation (allo-SCT) in the first complete remission (CR). In the ALFA-0702 trial, patients with AML, aged 18 to 59, had a prospective quantification of WT1 MRD. The occurrence of a WT1 MRD ratio >2.5% in bone marrow or >0.5% in peripheral blood was defined as MRDhigh, and ratios below these thresholds were defined as MRDlow. The prognostic value of MRD after induction chemotherapy was assessed in 314 patients in first CR by comparing the risk of relapse, the relapse-free survival (RFS), and the overall survival (OS). Interaction between MRD response and the allo-SCT effect was evaluated in patients by comparing the influence of allo-SCT on the outcomes of patients with MRDhigh with those with MRDlow. The results showed that patients with MRDhigh after induction had a higher risk of relapse and a shorter RFS and OS. The MRD response remained of strong prognostic value in the subset of 225 patients with intermediate-/unfavorable-risk AML who were eligible for allo-SCT, because patients with MRDhigh had a significantly higher risk of relapse resulting in worse RFS and OS. The effect of allo-SCT was higher in patients with MRDlow than in those with MRDhigh, but not significantly different. The early WT1 MRD response highlights a population of high-risk patients in need of additional therapy.

Published
2021

36. Functional classification of RUNX1 variants in familial platelet disorder with associated myeloid malignancies

Author

Brigitte Schlegelberger, Martijn P. T. Ernst, Charlotte M. Niemeyer, Andreas Flaum, Ayami Yoshimi, Miriam Erlacher, Melanie Decker, Thomas Illig, Tim Lammens, Nicolas Duployez, Alina Ferster, Doris Steinemann, Tim Ripperger, Marc H.G.P. Raaijmakers, and Hematology

Subjects
Transcriptional Activation, Cancer Research, medicine.medical_specialty, Cancer genetics, Genetic testing, Translational research, Genetics research, Letter, Myeloid, Platelet disorder, MEDLINE, HEMATOPOIESIS, Bioinformatics, Anesthésiologie, Core Binding Factor beta Subunit, chemistry.chemical_compound, Text mining, Internal medicine, Medicine and Health Sciences, Medicine, Humans, Genetic Predisposition to Disease, Phosphorylation, Hematology, Myeloproliferative Disorders, business.industry, PREDISPOSITION, Cancérologie, Leukemia, Myeloid, Acute, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Oncology, RUNX1, chemistry, Core Binding Factor Alpha 2 Subunit, Mutation, Biological Assay, Blood Platelet Disorders, Leukemia, Erythroblastic, Acute, business, LEUKEMIA, Hématologie
Abstract

SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2021

37. 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

38. Clonal haematopoiesis of indeterminate potential and cardiovascular events in systemic lupus erythematosus (HEMATOPLUS study)

Author

Clémence David, Nicolas Duployez, Philippine Eloy, Drifa Belhadi, Julie Chezel, Véronique Le Guern, Cédric Laouénan, Laurène Fenwarth, Diane Rouzaud, Alexis Mathian, Sébastien de Almeida Chaves, Pierre Duhaut, Olivier Fain, Lionel Galicier, Pascale Ghillani-Dalbin, Jean Emmanuel Kahn, Nathalie Morel, Laurent Perard, Micheline Pha, Francoise Sarrot-Reynauld, Olivier Aumaitre, François Chasset, Nicolas Limal, Helene Desmurs-Clavel, Felix Ackermann, Zahir Amoura, Thomas Papo, Claude Preudhomme, Nathalie Costedoat-Chalumeau, Karim Sacre, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Université Paris Cité (UPCité), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], 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), CHU Lille, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Amiens-Picardie, Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Saint-Antoine [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Ambroise Paré [AP-HP], 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 Saint Joseph - Saint Luc [Lyon], Hôpital Michallon, CHU Clermont-Ferrand, CHU Tenon [AP-HP], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), and Hôpital Foch [Suresnes]

Subjects
Male, Cardiovascular Diseases/complications, Lupus Erythematosus, Systemic/complications, Hematopoiesis, Hematopoiesis/genetics, cardiovascular events, Rheumatology, Cardiovascular Diseases, Lupus Erythematosus, Systemic, Humans, Pharmacology (medical), Female, Clonal Hematopoiesis, clonal haematopoiesis of indeterminate potential, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Retrospective Studies
Abstract

Objective The detection of somatic mutations among the genes of myeloid cells in asymptomatic patients—defining clonal haematopoiesis of indeterminate potential (CHIP)—is associated with a predisposition to cardiovascular events (CVEs) in the general population. We aimed to determine whether CHIP was associated with CVEs in SLE patients. Methods The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicentre PLUS trial conducted from June 2007 through August 2010 at 37 centres in France, involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal haematopoiesis was performed on genomic DNA collected at PLUS inclusion. CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of haematological malignancy. The primary outcome was an incident CVE in SLE. Results Screening for CHIP was performed in 438 SLE patients [38 (29–47) years, 91.8% female]. Overall, 63 somatic mutations were identified in 47 patients, defining a CHIP prevalence of 10.7% in SLE. Most SLE patients (78.7%) carried a single mutation. Most variants (62.5%) were located in the DNMT3A gene. CHIP frequency was related to age and to age at SLE diagnosis, and was associated with a lower frequency of aPLs. CHIP occurred >20 years earlier (P Conclusion The prevalence of CHIP is relatively high in SLE for a given age, but was not found to be associated with incident CVEs. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.

Published
2022

39. [Management of genetic predisposition to hematologic malignancies in patients undergoing allogeneic hematopoietic cell transplantation (HCT): Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]

Author

Valérie, Coiteux, Laurène, Fenwarth, Nicolas, Duployez, Malika, Ainaoui, Cécile, Borel, Alice, Polomeni, Ibrahim, Yakoub-Agha, and Yves, Chalandon

Abstract

The advent of new technologies has made it possible to identify genetic predispositions to myelodysplastic syndromes (MDS) and acute leukemias (AL) more frequently. The most frequent and best characterized at present are mutations in CEBPA, RUNX1, GATA2, ETV6 and DDX41 and, either in the presence of one of these mutations with a high allelic frequency, or in the case of a personal or family history suggestive of blood abnormalities such as non-immune thrombocytopenia, it is recommended to look for the possibility of a hereditary hematological malignancy (HHM). Indeed, early recognition of these HHMs allows better adaptation of the management of patients and their relatives, as allogeneic hematopoietic stem cell transplantation (HSCT) is very often proposed for these pathologies. According to current data, with the exception of the GATA2 mutation, the constitutional or somatic nature of the mutations does not seem to influence the prognosis of hematological diseases. Therefore, the indication for an allograft will be determined according to the usual criteria. However, when searching for a family donor, it is important to ensure that there is no hereditary disease in the donor. In order to guarantee the possibility of performing the HSC allograft within a short period of time, it may be necessary to initiate a parallel procedure to find an unrelated donor. Given the limited information on the modalities of HSC transplantation in this setting, it is important to assess the benefit/risk of the disease and the procedure to decide on the type of conditioning (myeloablative or reduced intensity). In view of the limited experience with the risk of secondary cancers in the medium and long-term, it may be appropriate to recommend reduced intensity conditioning, as in the case of better characterized syndromic hematological diseases such as Fanconi anemia or telomere diseases. In summary, it seems important to evoke HHM more frequently, particularly in the presence of a family history, certain mutations or persistent blood abnormalities, in order to discuss the specific modalities of HSC allografting, particularly with regard to the search for a donor and the evaluation of certain modalities of the procedure, such as conditioning. It should be noted that the discovery of HHM, especially if the indication of an allogeneic HSC transplant is retained, will raise ethical and psychological considerations not only for the patient, but also for his family. A multidisciplinary approach involving molecular biologists, geneticists, hematologists and psychologists is essential.

Published
2022

40. Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy

Author

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]

Subjects
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.

Published
2021

41. Optical genome mapping, a promising alternative to gold standard cytogenetic approaches in a series of acute lymphoblastic leukemias

Author

Jean-Pierre Marolleau, Guillaume Jedraszak, Catherine Devoldere, Nicolas Duployez, Isabelle Luquet, Michaela West, Dominique Penther, Claude Preudhomme, Hakim Ouled-Haddou, Valentin Lestringant, Coralie Derrieux, Anne Lutun, Yann Ferret, Loïc Garçon, 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Laboratoire d'Hématologie [CHU Amiens], Service Hydrographique et Océanographique de la Marine (SHOM), Ministère de la Défense, and Université de Picardie Jules Verne (UPJV)

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Adolescent, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Computational biology, Biology, Polymorphism, Single Nucleotide, Translocation, Genetic, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Gene mapping, Biomarkers, Tumor, Genetics, medicine, Humans, Multiplex, Child, Cytogenetics, Chromosome Mapping, Karyotype, Variant allele, Gold standard (test), Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Gene Expression Regulation, Neoplastic, Child, Preschool, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Acute lymphoblastic leukemias, Female, Cytogenetic Techniques
Abstract

International audience; Acute lymphoblastic leukemias (ALL) are characterized by a large number of cytogenetic abnormalities of clinical interest that require the use of several complementary techniques. Optical genome mapping (OGM) is based on analysis of ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. We compared OGM to standard techniques (karyotyping, fluorescent in situ hybridization, single nucleotide polymorphism-array and reverse transcription multiplex ligation-dependent probe amplification) in 10 selected B or T-ALL. Eighty abnormalities were found using standard techniques of which 72 (90%) were correctly detected using OGM. Eight discrepancies were identified, while 12 additional anomalies were found by OGM. Among the discrepancies, four were detected in raw data but not retained because of filtering issues. However, four were truly missed, either because of a low variant allele frequency or because of a low coverage of some regions. Of the additional anomalies revealed by OGM, seven were confirmed by another technique, some of which are recurrent in ALL such as LMO2-TRA and MYC-TRB fusions. Despite false positive anomalies due to background noise and a case of inter-sample contamination secondarily identified, the OGM technology was relatively simple to use with little practice. Thus, OGM represents a promising alternative to cytogenetic techniques currently performed for ALL characterization. It enables a time and cost effective analysis allowing identification of complex cytogenetic events, including those currently inaccessible to standard techniques.

Published
2021

42. Targeting RUNX1 in acute myeloid leukemia: preclinical innovations and therapeutic implications

Author

Adeline Barthelemy, Meyling Cheok, Nicolas Duployez, Pauline Peyrouze, Claude Preudhomme, Laurène Fenwarth, and Fanny Gonzales

Subjects
0301 basic medicine, BRD4, Clinical Biochemistry, Antineoplastic Agents, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Germline mutation, Genome editing, hemic and lymphatic diseases, Drug Discovery, Animals, Humans, Medicine, Molecular Targeted Therapy, Transcription factor, Germ-Line Mutation, Pharmacology, business.industry, Myeloid leukemia, Prognosis, Pre-clinical development, Survival Rate, Leukemia, Myeloid, Acute, Haematopoiesis, 030104 developmental biology, RUNX1, chemistry, 030220 oncology & carcinogenesis, Core Binding Factor Alpha 2 Subunit, Mutation, embryonic structures, Disease Progression, Cancer research, Molecular Medicine, business
Abstract

Introduction: RUNX1 is an essential transcription factor for normal and malignant hematopoiesis. RUNX1 forms a heterodimeric complex with CBFB. Germline mutations and somatic alterations (i.e. translocations, mutations and abnormal expression) are frequently associated with acute myeloid leukemia (AML) with RUNX1 mutations conferring unfavorable prognosis. Therefore, RUNX1 constitutes a potential innovative and interesting therapeutic target. In this review, we discuss recent therapeutic advances of RUNX1 targeting in AML.Areas covered: Firstly, we cover the clinical basis for RUNX1 targeting. We have subdivided recent therapeutic approaches either by common biochemical pathways or by similar pharmacological targets. Genome editing of RUNX1 induces anti-leukemic effects; however, off-target events prohibit clinical use. Several molecules inhibit the interaction between RUNX1/CBFB and control AML development and progression. BET protein antagonists target RUNX1 (i.e. specific BET inhibitors, BRD4 shRNRA, proteolysis targeting chimeras (PROTAC) or expression-mimickers). All these molecules improve survival in mutant RUNX1 AML preclinical models.Expert opinion: Some of these novel molecules have shown encouraging anti-leukemic potency at the preclinical stage. A better understanding of RUNX1 function in AML development and progression and its key downstream pathways, may result in more precise and more efficient RUNX1 targeting therapies.

Published
2021

46. Prognostic Impact of Monoallelic Versus Biallelic TP53 Alterations in Intensively-Treated Adults AML Patients: A Retrospective Study from the ALFA Group

Author

Laurène Fenwarth, Loïc Vasseur, Nicolas Duployez, Claude Gardin, Christine Terré, Juliette Lambert, Stéphane de Botton, Karine Celli-Lebras, Pascal Turlure, Thomas Cluzeau, Thorsten Braun, Xavier Thomas, Christian Recher, Sylvain Chantepie, Cécile Pautas, Hervé Dombret, Claude Preudhomme, and Raphael Itzykson

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

47. Disease escape with the selective loss of the Philadelphia chromosome after tyrosine kinase inhibitor exposure in Ph-positive acute lymphoblastic leukemia

Author

Nicolas Gazeau, Catherine Roche-Lestienne, Valérie Coiteux, Nicolas Duployez, Coralie Derrieux, Bruno Quesnel, Céline Berthon, Claude Preudhomme, Laure Goursaud, Thomas Boyer, Florent Dumezy, Nathalie Grardel, and Olivier Nibourel

Subjects
Cancer Research, medicine.medical_specialty, business.industry, medicine.drug_class, Cytogenetics, Hematology, Disease, Philadelphia chromosome, medicine.disease, Tyrosine-kinase inhibitor, Oncology, Ph-positive acute lymphoblastic leukemia, medicine, Cancer research, Acute lymphocytic leukaemia, business
Published
2020

48. Subclonal acquisition of a BCR::ABL1 fusion in a chronic myelomonocytic leukemia

Author

Benjamin Podvin, Hélène Guermouche, Pauline Roynard, Laure Goursaud, Céline Berthon, Mahdi Ouafi, Elise Fourner, Nicolas Duployez, Olivier Nibourel, and Catherine Roche-Lestienne

Subjects
Leukemia, Myelomonocytic, Juvenile, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, Humans, Leukemia, Myelomonocytic, Chronic, Hematology, General Medicine
Published
2022

49. Somatic mutational landscape of hereditary hematopoietic malignancies associated with germline variants in RUNX1, GATA2 and DDX41

Author

Anna L. Brown, Claire Homan, Michael W. Drazer, Kai Yu, David Lawrence, Jinghua Feng, Luis Arriola-Martinez, Matthew Pozsgai, Kelsey McNeely, Thuong Ha, Parvathy Venugopal, Peer Arts, Sarah King-Smith, Jesse JC Cheah, Mark Armstrong, Csaba Bödör, Paul Wang, Alan B. Cantor, Mario Cazzola, Erin Degelman, Courtney D. DiNardo, Nicolas Duployez, Remi Favier, Stefan Fröhling, Ana Rio-Machin, Jeffery M. Klco, Alwin Krämer, Mineo Kurokawa, Joanne Lee, Luca Malcovati, Neil V Morgan, Georges Natsoulis, Carolyn Owen, Keyur P. Patel, Claude Preudhomme, Hana Raslova, Hugh Young Rienhoff, Tim Ripperger, Rachael Schulte, Kiran Tawana, Elvira Deolinda Rodrigues Pereira Velloso, Benedict Yan, Raman Sood, Amy Hsu, Steven M. Holland, Kerry Phillips, Nicola Poplawski, Milena Babic, Erika M Kwon Kim, Andrew H. Wei, Cecily Forsyth, Helen Mar Fan, Ian D Lewis, Julian Cooney, Rachel Susman, Lucy C Fox, Piers Blombery, Deepak Singhal, Devendra Hiwase, Andreas W Schreiber, Christopher N Hahn, Hamish S Scott, Paul P. Liu, Lucy A. Godley, Brown, Anna L, Homan, Claire, Drazer, Michael W, Yu, Kai, Ha, Thuong, Arts, Peer, King Smith, Sarah, Cheah, Jesse JC, Armstrong, Mark, Wang, Paul, Babic, Milena, Hahn, Christopher N, Scott, Hamish S, Godley, Lucy, and 64th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) New Orleans, US 10-13 December 2022

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Germline variants in RUNX1, GATA2 and DDX41 may confer a predisposition to hereditary haematopoietic malignancies (HHMs) such as MDS and AML yet have distinct age ranges of malignancy diagnosis and a highly variable overall risk for leukemogenesis. The increased awareness and identification of carriers of these germline variants, particularly before development of malignancy, has changed the way in which individuals and families need to be managed in the clinic. Individuals need lifelong monitoring and may also need modification to treatments when malignancy does develop, compared to sporadic counterparts. Gaps in understanding pre-malignant states in HHM syndromes have hampered efforts to design effective clinical surveillance regimes, provide personalized pre-emptive treatments, and appropriate counselling to patients.

Published
2022

50. A Randomised Phase II Study of Azacitidine (AZA) Alone or with Lenalidomide (LEN), Valproic Acid (VPA) or Idarubicin (IDA) in Higher-Risk MDS or Low Blast AML: GFM's 'Pick a Winner' Trial, with the Impact of Somatic Mutations

Author

Lionel, Adès, Nicolas, Duployez, Agnes, Guerci-Bresler, Kamel, Laribi, Pierre, Peterlin, Norbert, Vey, Sylvain, Thepot, Stefan, Wickenhauser, Hacene, Zerazhi, Aspassia, Stamatoullas, Eric, Wattel, Christian, Recher, Andrea, Toma, Sophie, Dimicoli-Salazar, Thorsten, Braun, Odile, Beyne-Rauzy, Jean-Pierre, Marolleau, Stéphane, Cheze, Sophie, Park, Thomas, Cluzeau, Stanislas, Nimubona, Dominique, Bordessoule, Riad, Benramdane, Bruno, Quesnel, Shanti, Amé, Stéphane, de Botton, Fathia, Chermat, Claude, Preudhomme, Sylvie, Chevret, Pierre, Fenaux, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), 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 Universitaire de Nancy (CHU Nancy), Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier universitaire de Nantes (CHU Nantes), Nantes Université (Nantes Univ), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Aix Marseille Université (AMU), 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), Stress Adaptation and Tumor Escape - SATE (CRCI2NA / Eq 7), 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)-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 (Nantes Univ)-Nantes Université (Nantes Univ), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Henri Duffaut (Avignon), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), 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 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), Hôpital Henri Mondor, Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Grenoble, XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Centre Hospitalier René Dubos [Pontoise], Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Equipe 2 : ECSTRA - Epidémiologie Clinique, STatistique, pour la Recherche en Santé (CRESS - U1153), 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)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), and 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)

Subjects
Leukemia, Myeloid, Acute, Treatment Outcome, Valproic Acid, Antineoplastic Combined Chemotherapy Protocols, Mutation, Azacitidine, Humans, Idarubicin, Lenalidomide, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; In order to improve the outcome observed with azacitidine (AZA) in higher-risk Myelodysplastic syndrome (MDS), its combination with other drugs in MDS must be evaluated. So far, no combination has not been shown to be more effective than AZA alone. AZA-PLUS was a phase II trial that, in a "pick a winner" approach, randomly assigned patients with higher-risk MDS, CMML and low blast count AML to: AZA; AZA plus lenalidomide; AZA plus Valproic Acid or AZA plus Idarubicin. 322 patients were included. After six\,cycles, 69 (21.4%) CR\,+\,PR were observed with no benefit from any combination. Median EFS and OS were 17.2 and 19.7\,months in the whole cohort, respectively, with no difference across randomised arms. Infection and rates of hospitalisation during the first six\,cycles were higher in the AZA-LEN And AZA-IDA arm, related to increased myelosuppression. Factors associated with better response were IPSS, favourable or intermediate karyotype, haemoglobin, lower circulating blast count, fibrinogen level and lower LDH, while poorer survival was seen in therapy-related MDS and, in the case of TP53, PTPN11 or CSF3R mutation. The combinations used did not improve the outcome obtained with AZA alone. However, our "pick a winner" randomised strategy may remain useful with potentially more active drugs to be tested in combination with AZA.

Published
2022

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