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1. Genomic landscape of liquid biopsy mutations in TP53 and DNA damage genes in cancer patients

Author

Damien Vasseur, Ahmadreza Arbab, Fabiola Giudici, Christophe Marzac, Stefan Michiels, Marco Tagliamento, Arnaud Bayle, Cristina Smolenschi, Madona Sakkal, Mihaela Aldea, Hela Sassi, Filippo Gustavo Dall’Olio, Noémie Pata-Merci, Sophie Cotteret, Alice Fiévet, Nathalie Auger, Luc Friboulet, Francesco Facchinetti, Arthur Géraud, Santiago Ponce, Antoine Hollebecque, Benjamin Besse, Jean Baptiste Micol, Antoine Italiano, Ludovic Lacroix, and Etienne Rouleau

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

Abstract Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations. In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation. These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53, and in DDR genes (ATM, CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM, TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

Published
2024
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2. An atypical promyelocytic sarcoma and pleural effusion in a patient with Gorham's disease: Efficiency of ATRA/ATO‐based treatment

Author

Romain Loyaux, Solène Lecolant, Leila Cysique Foilan, Caroline Pradon, Sophie Cotteret, Jean‐Baptiste Micol, Annabelle Stoclin, Véronique Saada, Christophe Marzac, and Ahmadreza Arbab

Subjects
all‐trans retinoic acid, myeloid sarcoma, promyelocytes, Medicine, Medicine (General), R5-920
Abstract

Key Clinical Message This is the first case of a promyelocytic sarcoma diagnosed on pleural effusion and exposed the difficulty of demonstrating a leukemic phase in patients with bone diseases, such as Gorham's disease. It also showed that promyelocytic sarcoma can be treated by ATRA/ATO‐based therapy with an efficient and tolerated response. Abstract Myeloid sarcoma (MS) is a rare extramedullary tumoral infiltration of immature myeloid cells and can occur in different sites of the body, without leukemic infiltration. A 38‐year‐old woman patient presented at emergency with a pleural effusion, bicytopenias, and Gorham's disease, a very rare bone disorder. In the following days, she worsened with a chylothorax and pancytopenias. Pleural puncture cytologically revealed promyelocytes with Auer rods. Cytogenetic and molecular analyses subsequently confirmed the presence of the t(15:17) translocation. However, no circulating phase of these atypical promyelocytes was found. Similarly, no other origin was identified. We conclude that the patient had a MS of unknown etiology in the form of a pleural effusion with pathological promyelocytes. The patient was treated with a combination of oral all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) with a cytological and molecular remission persisting 3 months after diagnosis. We report here the first case of a promyelocytic MS of pleural origin without concomitant evidence of acute promyelocytic leukemia. We also show the efficacy of ATRA/ATO treatment in this etiology.

Published
2023
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3. Impact and consequences of intensive chemotherapy on intestinal barrier and microbiota in acute myeloid leukemia: the role of mucosal strengthening

Author

Thomas Hueso, Kenneth Ekpe, Camille Mayeur, Anna Gatse, Marie Joncquel-Chevallier Curt, Guillaume Gricourt, Christophe Rodriguez, Charles Burdet, Guillaume Ulmann, Christel Neut, Salah-Eddine Amini, Patricia Lepage, Bruno Raynard, Christophe Willekens, Jean-Baptiste Micol, Stéphane De Botton, Ibrahim Yakoub-Agha, Frédéric Gottrand, Jean-Luc Desseyn, Muriel Thomas, Paul-Louis Woerther, and David Seguy

Subjects
intestinal barrier, microbiota, chemotherapy, acute leukemia, mucus, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Induction chemotherapy (7 + 3 regimen) remains the gold standard for patients with acute myeloid leukemia (AML) but is responsible for gut damage leading to several complications such as bloodstream infection (BSI). We aimed to investigate the impact of induction chemotherapy on the intestinal barrier of patients with AML and in wild-type mice. Next, we assessed the potential benefit of strengthening the mucosal barrier in transgenic mice releasing a recombinant protein able to reinforce the mucus layer (Tg222). In patients, we observed a decrease of plasma citrulline, which is a marker of the functional enterocyte mass, of short-chain fatty acids and of fecal bacterial load, except for Escherichia coli and Enterococcus spp., which became dominant. Both the α and β-diversities of fecal microbiota decreased. In wild-type mice, citrulline levels decreased under chemotherapy along with an increase of E. coli and Enterococcus spp load associated with concomitant histologic impairment. By comparison with wild-type mice, Tg222 mice, 3 days after completing chemotherapy, had higher citrulline levels, a faster healing epithelium, and preserved α-diversity of their intestinal microbiota. This was associated with reduced bacterial translocations. Our results highlight the intestinal damage and the dysbiosis induced by the 7 + 3 regimen. As a proof of concept, our transgenic model suggests that strengthening the intestinal barrier is a promising approach to limit BSI and improve AML patients’ outcome.

Published
2020
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4. 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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5. 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
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6. An atypical promyelocytic sarcoma in a pleural effusion: efficacy of ATRA/ATO treatment

Author

Romain Loyaux, Solene Lecolant, Leila CYSIQUE FOINLAN, Caroline Pradon, Sophie Cotteret, Jean-Baptiste Micol, Annabelle Stoclin, Veronique SAADA, CHRISTOPHE MARZAC, and Ahmadreza Arbab

Abstract

Myeloid sarcoma is a rare extramedullary tumoral infiltration of immature myeloid cells and can occur in different sites of the body, without leukemic infiltration A 38-year-old woman patient presented at emergency with a pleural effusion and bicytopenias. In the following days, she worsened with a chylothorax and pancytopenias. Pleural puncture cytologically

Published
2023
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7. Figure S10 from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

Metabolic perturbations induced by folate starvation in AML cells.

Published
2023
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8. Supplementary Methods, Figures 1 - 5, Tables 1 - 5 from Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Author

Omar Abdel-Wahab, Tanja A. Gruber, Neal Rosen, Jean-Francois Emile, Ahmet Dogan, Zahir Amoura, Christopher Y. Park, Barry S. Taylor, Filip Janku, José Baselga, David M. Hyman, David B. Solit, Jean Donadieu, Sebastien Héritier, Jared Block, Omotayo Fasan, Samuel R. Briggs, Siraj M. Ali, Jeffrey S. Ross, Vincent A. Miller, Philip J. Stephens, William A. Gahl, Mario Lacouture, Juvianee Estrada-Veras, David W. Ellison, James D. Dalton, Chezi Ganzel, Joy Nakitandwe, Paul Zappile, Adriana Heguy, Olga Aminova, Igor Dolgalev, Brooke Sylvester, Michael P. Walsh, Patrick Campbell, Jean-Baptiste Micol, Yijun Gao, Stanley Chun-Wei Lee, Fleur Cohen-Aubart, Eunhee Kim, John Choi, Zhaoming Wang, Sameer A. Parikh, Jing Ma, Zhan Yao, Julien Haroche, Benjamin H. Durham, and Eli L. Diamond

Abstract

Supplementary Figure 1. Somatic mutations detected in histiocytic neoplasms. Supplementary Figure 2. Frequencies of known activating kinase mutations in histiocytic neoplasms. Supplementary Figure 3. ARAF mutations and variants of unknown significance detected in BRAFV600E-wildtype, non-Langerhans Cell Histiocytic neoplasms. Supplementary Figure 4. Clinical and histological images of the non-Langerhans cell histiocytosis (non-LCH) lesions from index patients with kinase fusions identified by RNA-seq. Supplementary Figure 5. Gene expression analysis of histiocytic neoplasms by RNA-seq. Supplementary Table 1. Characteristics of patient samples with histiocytic neoplasms used in this study and genomic analysis utilized for each sample. Supplementary Table 2. Whole exome sequencing metrics. Supplementary Table 3. Somatic variants identified by whole exome and whole transcriptome sequencing and validated by droplet-digital PCR and/or custom-capture targeted next-generation sequencing with variant allele frequencies (VAFs). Supplementary Table 4. List of the top 1% of differentially expressed genes across histiocytic samples from mRNA sequencing. Supplementary Table 5. PCR primers with M13F2 and M13R2 tails (blue) for Sanger sequencing used in the targeted sequencing recurrence testing for MAP2K1 exons 2 and 3 and all coding regions of ARAF.

Published
2023
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9. Table S6 from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

List of sgRNA Guides Used in the CRISPR Screen.

Published
2023
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10. Data from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid–related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.Significance:Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.See related commentary by Marando and Huntly, p. 1791.This article is highlighted in the In This Issue feature, p. 1775

Published
2023
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11. Supplementary Data from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies

Author

Alexandre Puissant, Raphael Itzykson, Kris C. Wood, Camille Lobry, Kimberly Stegmaier, Hava M. Golan, Lina Benajiba, Nina Fenouille, Claude Preudhomme, Hervé Dombret, Thomas Cluzeau, Giovanni Roti, Jean-Baptiste Micol, Marie-Hélène Schlageter, Jun Qi, Yana Pikman, Alain Pruvost, Jean-François Benoist, Gabriela Alexe, Iléana Antony-Debré, Justine Pasanisi, Gael Fortin, Christopher F. Bassil, Justine C. Rutter, Kevin H. Lin, Bryann Pardieu, Antoine Forget, Reinaldo Dal Bello, Chaïma Benaksas, Gaetano Sodaro, Camille Vaganay, Frank Ling, and Angela Su

Abstract

Supplementary Material and Methods

Published
2023
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12. Supplementary Figure 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Flow chart of the study displaying the three cohorts.

Published
2023
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13. Supplementary Figure 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Waffle chart (%) of patients addressed for cytopenia exploration after OC exposed to a PARPi treatment from cytopenia diagnosis (A) and cytopenia diagnosis based on NGS results (B). Dot plots (C) showing the median WBC, hemoglobin, and platelet counts from patients referred for cytopenia exploration after OC exposed to a PARPi treatment according to t-MN diagnosis (“t-MN”) or not (“Cytopenia”).

Published
2023
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14. 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
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15. Supplementary Figure 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Blood smear and bone marrow aspiration of patient referred for cytopenia post PARPi.

Published
2023
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16. Supplementary Figure 4 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Commutation plot visualizing the mutated genes in t-MN after OC according to PARPi treatment.

Published
2023
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17. Supplementary Table 3 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Univariate analysis for overall survival from t-MN diagnosis of patients from the national cohort.

Published
2023
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18. Supplementary Table 2 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

TP53 mutations characteristics among t-MN PARPi national cohort.

Published
2023
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19. Data from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

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
2023
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20. Supplementary Table 1 from Therapy-related Myeloid Neoplasms Following PARP Inhibitors: Real-life Experience

Author

Jean-Baptiste Micol, Alexandra Leary, Christophe Marzac, Arnaud Pagès, Hervé Dombret, Christian Récher, Pierre Fenaux, Lionel Adès, Mauricette Michallet, Pierre-Marie Morice, Matthieu Duchmann, Pascal Bourquard, Marie-Pierre Gourin, Sylvain Thepot, Thomas Boyer, Marion Lepelley, Laetitia Stefani, Myrtille Thomas, Nathalie Auger, Véronique Vergé, Patricia Pautier, Félix Blanc-Durand, Nadine Morineau, Marion Loirat, Jérémy Delage, Emmanuelle Tavernier, Emilie Lemasle, Géraldine Salmeron, Jacques Vargaftig, Pierre-Yves Dumas, Edmond Chiche, Céline Berthon, Alexis Genthon, Madalina Uzunov, Sylvain Chantepie, Célestine Simand, Lauris Gastaud, Sarah Bertoli, Amine Belhabri, Gabriel Etienne, Sylvain Garciaz, Justine Decroocq, and Vincent Marmouset

Abstract

Univariate analysis for overall survival from t-MN diagnosis of patients diagnosed with t-MN after OC according to PARPi exposure.

Published
2023
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21. Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Therapy-Related Acute Myeloid Leukemia: a Retrospective Multicentre Study on behalf of the SFGM-TC

Author

Emmanuelle Tavernier, Gaëlle Rey, Elisabeth Daguenet, Paul Bonjean, Raynier Devillier, Nathalie Fegueux, Edouard Forcade, micha sr, patrice chevalier, marie robin, Felipe Suarez, Jean-Baptiste Micol, helene labussiere, Karin Bilger, Etienne Daguindau, Jacques Olivier Bay, Amandine Fayard, Claude-Eric BULABOIS, Stéphanie Nguyen-Quoc, Alexis Genthon, Corentin Orvain, Pascal TURLURE, Michael Loschi, Xavier Poire, Gaella Guillerm, Yves Beguin, Natacha Maillard, jean-baptiste Mear, Emilie Chalayer, and Jerome Cornillon

Abstract

We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or gynaecological neoplasia (37%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9–52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6–67.5), 52.8% (95% CI 46.5–68.4), and 44.1% (95% CI 37.6–51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4–52.1), 40.4% (95% CI 33.9–48.1), and 35.3% (95% CI 28.8–43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 39% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.

Published
2023
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22. Liquid Biopsies for Circulating Tumor DNA Detection May Reveal Occult Hematologic Malignancies in Patients With Solid Tumors

Author

Mihaela Aldea, Marco Tagliamento, Arnaud Bayle, Damien Vasseur, Véronique Vergé, Arianna Marinello, François-Xavier Danlos, Felix Blanc-Durand, Elsa Bernard, Luigi Cerbone, Maria Fernanda Mosele, Aline Renneville, Julien Hadoux, Yohann Loriot, Madona Sakkal, Aurore Vozy, Clementine Sarkozy, Cristina Smolenschi, Claudio Nicotra, Patricia Martin-Romano, Clementine Boccon-Gibod, Wafikaamira Habza, Julien Lazarovici, Santiago Ponce, Antoine Hollebecque, Christophe Marzac, Ludovic Lacroix, Fabrice Barlesi, Fabrice André, Benjamin Besse, Etienne Rouleau, Antoine Italiano, and Jean-Baptiste Micol

Subjects
Cancer Research, Oncology
Abstract

PURPOSE High-risk clonal hematopoiesis (CH) is frequently incidentally found in patients with solid tumors undergoing plasma cell–free DNA sequencing. Here, we aimed to determine if the incidental detection of high-risk CH by liquid biopsy may reveal occult hematologic malignancies in patients with solid tumors. MATERIALS AND METHODS Adult patients with advanced solid cancers enrolled in the Gustave Roussy Cancer Profiling study (ClinicalTrials.gov identifier: NCT04932525 ) underwent at least one liquid biopsy (FoundationOne Liquid CDx). Molecular reports were discussed within the Gustave Roussy Molecular Tumor Board (MTB). Potential CH alterations were observed, and patients referred to hematology consultation in the case of pathogenic mutations in JAK2, MPL, or MYD88, irrespective of the variant allele frequency (VAF), or in DNMT3A, TET2, ASXL1, IDH1, IDH2, SF3B1, or U2AF1 with VAF ≥ 10%, while also considering patient cancer-related prognosis. TP53 mutations were discussed case-by-case. RESULTS Between March and October 2021, 1,416 patients were included. One hundred ten patients (7.7%) carried at least one high-risk CH mutation: DNMT3A (n = 32), JAK2 (n = 28), TET2 (n = 19), ASXL1 (n = 18), SF3B1 (n = 5), IDH1 (n = 4), IDH2 (n = 3), MPL (n = 3), and U2AF1 (n = 2). The MTB advised for hematologic consultation in 45 patients. Overall, 9 patients of 18 actually addressed had confirmed hematologic malignancies that were occult in six patients: two patients had myelodysplastic syndrome, two essential thrombocythemia, one a marginal lymphoma, and one a Waldenström macroglobulinemia. The other three patients were already followed up in hematology. CONCLUSION The incidental findings of high-risk CH through liquid biopsy may trigger diagnostic hematologic tests and reveal an occult hematologic malignancy. Patients should have a multidisciplinary case-by-case evaluation.

Published
2023
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23. 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
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24. Reduced Venetoclax Exposition to Seven Days of Azacitidine Is Efficient in Treatment-Naïve Patients with Acute Myeloid Leukemia

Author

Christophe Willekens, Samy Chraibi, Justine Decroocq, Benjamin Carpentier, Delphine Lebon, Sarah Bonnet, Nicolas Gauthier, Arnaud Pagès, Matteo Dragani, Sabine Khalife-Hachem, Jean-Baptiste Micol, Florence Pasquier, Stefan Wickenhauser, Véronique Saada, Véronique Vergé, Ahmadreza Arbab, Christophe Marzac, Laurent Pascal, Damien Roos-Weil, Eric Jourdan, Didier Bouscary, Stéphane de Botton, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Cochin [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), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Commissariat à l'énergie atomique et aux énergies alternatives - Laboratoire d'Electronique et de Technologie de l'Information (CEA-LETI), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), 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), INSERM UMR 1287 Département d'hématologie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Département de biologie et pathologie médicales [Gustave Roussy], Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes (UGA), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), and Université de Montpellier (UM)

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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25. Myeloid malignancies with translocation t(4;12)(q11‐13;p13): molecular landscape, clonal hierarchy and clinical outcomes

Author

François Lifermann, Jean-Alain Martignoles, Anne Quinquenel, Vincent Parinet, Christine Lefebvre, Pierre Hirsch, Mélanie Martin, Sabine Defasque, Florence Nguyen-Khac, Matthieu Decamp, Laurence Simon, Dominique Penther, Nadia Ali-Ammar, Elise Chapiro, Odile Maarek, Chrystele Bilhou-Nabera, Baptiste Gaillard, Agathe Maillon, Jean-Baptiste Micol, Marine Baron, Nathalie Auger, Stéphanie Struski, Damien Roos-Weil, Sylvie Tondeur, Marie-Joelle Mozziconacci, Audrey Bidet, Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital Robert Debré, 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), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire CERBA [Saint Ouen l'Aumône], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de Génétique [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre Hospitalier de Dax, Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service d'immunologie et hématologies biologiques [CHU Saint-Antoine], Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), 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), 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), HAL-SU, Gestionnaire, École Pratique des Hautes Études (EPHE), and 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)

Subjects
Male, Oncology, Myeloid, [SDV]Life Sciences [q-bio], Chromosomal translocation, Translocation, Genetic, chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, 12), In Situ Hybridization, Fluorescence, Aged, 80 and over, CHIC2, Middle Aged, Immunohistochemistry, 3. Good health, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, medicine.anatomical_structure, RUNX1, 030220 oncology & carcinogenesis, Cytogenetic Analysis, Cohort, Molecular Medicine, Female, Original Article, Chromosomes, Human, Pair 4, medicine.medical_specialty, IDH1, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, Genetic Predisposition to Disease, acute myeloid leukaemia, Genetic Association Studies, Aged, Chromosome Aberrations, Chromosomes, Human, Pair 12, Myeloproliferative Disorders, business.industry, Myelodysplastic syndromes, Original Articles, ETV6, Cell Biology, medicine.disease, myelodysplastic syndrome, t(4, chemistry, Fusion transcript, Myelodysplastic Syndromes, prognosis, business, 030215 immunology
Abstract

International audience; Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56–88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.

Published
2021
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26. Impact of COVID-19 on healthcare organisation and cancer outcomes

Author

Caroline Robert, Christophe Massard, Samia Bouhir, Julien Hadoux, Fabrice Barlesi, Emeline Colomba, Isabelle Borget, Stefan Michiels, Julia Bonastre, Charles Honoré, A. Bardet, Matthieu Faron, Anne Auperin, Suzette Delaloge, David Planchard, Lucile Ter-Minassian, Laurence Albiges, Jean-Baptiste Micol, Michel Ducreux, Alderic M. Fraslin, and Jamila Marghadi

Subjects
0301 basic medicine, Cancer Research, medicine.medical_specialty, Survival, Health administration, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Hospital Administration, Neoplasms, Pandemic, Health care, medicine, Humans, Computer Simulation, Pandemics, Diagnostics, Proportional Hazards Models, Original Research, Delay, Hospital resources, SARS-CoV-2, business.industry, Proportional hazards model, Mortality rate, Hazard ratio, COVID-19, Cancer, medicine.disease, Hospitals, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Emergency medicine, business, Delivery of Health Care
Abstract

BACKGROUND: Changes in the management of patients with cancer and delays in treatment delivery during the COVID-19 pandemic may impact the use of hospital resources and cancer mortality. PATIENTS AND METHODS: Patient flows, patient pathways and use of hospital resources during the pandemic were simulated using a discrete event simulation model and patient-level data from a large French comprehensive cancer centre's discharge database, considering two scenarios of delays: massive return of patients from November 2020 (early-return) or March 2021 (late-return). Expected additional cancer deaths at 5 years and mortality rate were estimated using individual hazard ratios based on literature. RESULTS: The number of patients requiring hospital care during the simulation period was 13,000. In both scenarios, 6-8% of patients were estimated to present a delay of >2 months. The overall additional cancer deaths at 5 years were estimated at 88 in early-return and 145 in late-return scenario, with increased additional deaths estimated for sarcomas, gynaecological, liver, head and neck, breast cancer and acute leukaemia. This represents a relative additional cancer mortality rate at 5 years of 4.4 and 6.8% for patients expected in year 2020, 0.5 and 1.3% in 2021 and 0.5 and 0.5% in 2022 for each scenario, respectively. CONCLUSIONS: Pandemic-related diagnostic and treatment delays in patients with cancer are expected to impact patient survival. In the perspective of recurrent pandemics or alternative events requiring an intensive use of limited hospital resources, patients should be informed not to postpone care, and medical resources for patients with cancer should be sanctuarised.

Published
2021
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28. Phase I First-in-Human Dose Escalation Study of the oral SF3B1 modulator H3B-8800 in myeloid neoplasms

Author

David P. Steensma, Lionel Ades, Ian W. Flinn, Rami S. Komrokji, Jaime Pérez de Oteyza, Peter L. Greenberg, Keisuke Kuida, Hetty E. Carraway, Huilan Yao, Antonio Gualberto, James M. Foran, Catherine C. Coombs, Benoit Destenaves, Ana Alfonso-Piérola, Xiaobin Yuan, Patricia Font, Jianjun Xiao, Andrew M. Brunner, Kun Yu, Eunice S. Wang, Catherine Scholz, Uwe Platzbecker, Michael B. Maris, Jay Yang, Malgorzata McMasters, Alyssa J. Marino, Guillermo Garcia-Manero, Jean Baptiste Micol, Juan M. Alonso-Dominguez, Martin Wermke, Sara Dar, H. Joachim Deeg, Felicitas Thol, Virginia M. Klimek, Richard Stone, Justin M. Watts, Vikram Gourineni, Justin Taylor, Lernik Ohanjanian, and Aref Al-Kali

Subjects
Male, Cancer Research, medicine.medical_specialty, Myeloid, Pyridines, Nausea, Mutation, Missense, Administration, Oral, Phases of clinical research, Drug development, Gastroenterology, Piperazines, Article, Medical research, hemic and lymphatic diseases, Internal medicine, Biomarkers, Tumor, medicine, Humans, Dosing, Adverse effect, Aged, Aged, 80 and over, Hematology, Dose-Response Relationship, Drug, business.industry, Health sciences, Middle Aged, Phosphoproteins, Leukemia, Myeloid, Acute, Red blood cell, Treatment Outcome, medicine.anatomical_structure, Oncology, Myelodysplastic Syndromes, Vomiting, Female, Patient Safety, RNA Splicing Factors, medicine.symptom, business
Abstract

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1–40 mg, n = 65) and schedule II (21 days on/7 days off, 7–20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS.

Published
2021
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29. 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
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30. ATG2B/GSKIP in de novo acute myeloid leukemia (AML): high prevalence of germline predisposition in French West Indies

Author

Jean-Edouard Martin, Christine Bellanné-Chantelot, Olivier Caron, Pascal Fuseau, Nathalie Auger, Barbara Schmaltz-Panneau, Sophie Cotteret, Stéphane de Botton, Christophe Willekens, Florence Pasquier, Christophe Marzac, Jean-Baptiste Micol, Jean Pegliasco, Maureen Lopez, William Vainchenker, Adel Ben-Ali, Véronique Saada, Carole Bourdin, Flore Salviat, Odile Bera, Sabine Khalife-Hachem, Isabelle Plo, Cristina Castilla-Llorent, Philippe Helias, Jean-Côme Meniane, Samy Chraibi, and Raouf Ben-Abdelali

Subjects
Cancer Research, High prevalence, Adult patients, business.industry, De novo acute, Myeloid leukemia, Hematology, Germline, Oncology, hemic and lymphatic diseases, Immunology, Genetic predisposition, Medicine, business, West indies
Abstract

Genetic predisposition to acute myeloid leukemia (AML) concerns a minority of adult patients. Development of high-throughput sequencing technologies over the last ten years allowed identification o...

Published
2021
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31. 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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32. Enasidenib for the treatment of relapsed or refractory acute myeloid leukemia with an isocitrate dehydrogenase 2 mutation

Author

Virginie Penard-Lacronique, Jean-Baptiste Micol, Angelo Paci, Stéphane de Botton, Christophe Willekens, Sabine Hachem-Khalife, and Mael Heiblig

Subjects
Pharmacology, Mutation, Oncogene, Somatic cell, Chemistry, Point mutation, Myeloid leukemia, Enasidenib, medicine.disease_cause, IDH2, Precursor cell, Drug Discovery, Genetics, Cancer research, medicine, Molecular Medicine
Abstract

Isocitrate dehydrogenase 2 (IDH2) is a key metabolic enzyme that converts isocitrate to α-ketoglutarate (αKG). Somatic point mutations in IDH2 confer a gain-of-function in blast cells resulting in ...

Published
2020
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33. Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study

Author

Claude Preudhomme, Cyril Quivoron, Sophie Broutin, Emmanuelle Clappier, Aline Renneville, S. de Botton, Christophe Willekens, Angelo Paci, Ramy Rahmé, Julien Rossignol, Pierre Fenaux, Laurence Simon, Raphael Itzykson, Alice Marceau, Eyal C. Attar, Véronique Saada, Mark G. Frattini, Jean-Baptiste Micol, Madalina Uzunov, Florence Pasquier, Laurent Pascal, Thorsten Braun, Emmanuel Raffoux, Matthieu Duchmann, Julia Delahousse, V. Vidal, Virginie Penard-Lacronique, and Lionel Adès

Subjects
Cancer Research, Myeloid, IDH1, business.industry, Myelodysplastic syndromes, Azacitidine, Myeloid leukemia, Hematology, medicine.disease, IDH2, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Isocitrate dehydrogenase, Oncology, Multicenter study, 030220 oncology & carcinogenesis, medicine, Cancer research, business, 030215 immunology, medicine.drug
Abstract

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) re...

Published
2020
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34. Determinants of the outcomes of patients with cancer infected with SARS-CoV-2: results from the Gustave Roussy cohort

Author

Antoine Hollebecque, Fabrice Barlesi, Florence Netzer, Giulia Baciarello, Jean Baptiste Micol, Ludovic Lacroix, Fanny Pommeret, Emeline Colomba, Laurence Albiges, Bertrand Gachot, Véronique Saada, Julien Hadoux, Corinne Balleyguier, Annabelle Stoclin, Mathilde Hauchecorne, Frank Griscelli, Stéphanie Foulon, Thomas Hueso, Jean-Charles Soria, Benjamin Besse, Roger Sun, Florian Scotté, Jean-Marie Michot, Christophe Willekens, Dominique Valteau-Couanet, Mansouria Merad, A. Perret, Samy Ammari, Nathalie Chaput, Arnaud Bayle, and Fabrice Andre

Subjects
Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Cancer, Immunosuppression, Disease, Malignancy, medicine.disease, Targeted therapy, Oncology, Internal medicine, Cohort, medicine, Biomarker (medicine), Hormone therapy, business
Abstract

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients. Barlesi and colleagues describe the determinants of severe COVID-19 outcomes in patients with cancer managed at the Gustave Roussy Cancer Centre.

Published
2020
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35. Therapy-related Myeloid Neoplasms in Patients With Chronic Lymphocytic Leukemia Who Received FCR/FC as Frontline Therapy

Author

Kamel Laribi, Alix Baugier de Materre, David Ghez, Caroline Dartigeas, Cécile Tomowiak, Béatrice Mahé, Jean-Baptiste Micol, Fatiha Merabet, Stéphane Leprêtre, Charles Herbaux, Loïc Ysebaert, Ronan Le Calloch, Lise Willems, Maud Voldoire, Damien Roos-Weil, Clotilde Bravetti, Yamina Touileb, Frédéric Davi, Florence Nguyen-Khac, Karim Maloum, and Marie C. Béné

Subjects
Hematology
Published
2021

36. Abstract A027: Clonal hematopoiesis of indeterminate potential (CHIP) in patients with advanced NSCLC treated with immune checkpoint blockers (ICB) as monotherapy: Analysis of the PREMIS study. [R]

Author

Julieta Elena Rodriguez, Capucine Baldini, Francois Xavier Danlos, Aurelien Marabelle, Maxime Frelaut, Marco Tagliamento, Mihaela Aldea, Benjamin Besse, Jean Baptiste Micol, Christophe Marzac, Nathalie Chaput, and Christophe Massard

Subjects
Cancer Research, Oncology
Abstract

Introduction: Immunotherapy is one of the mainstays of lung cancer treatment. The results presented in pivotal trials do not always reflect real life, since patients (pts) are more selected for prognostic factors. Cancer is associated with advanced age and aging is the main risk factor for developing CHIP, which refers to the finding of one or more mutations affecting genes involved in hematologic malignancies in pts without hematologic disease per se. Objective: To evaluate CHIP prevalence in a prospective cohort of 104 pts treated with ICB for NSCLC and to correlate CHIP and clinical outcomes. Materials and methods: We performed a Next-Generation Sequencing (NGS) with a panel of 74-genes dedicated to hematological alteration on DNA extracted from whole blood collected before the first administration of an ICB, within the PREMIS trial (NCT03984318). To estimate the prevalence of CHIP, we selected the following 4 CHIP genes; DNMT3A, TET2, ASXL1 and JAK2. CHIP prevalence was assessed according to two variant allele frequency (VAF) thresholds (1% and 2%). The results were analyzed for the entire population and for the subgroup of pts older than 70 years. Results: We included 104 pts; 68 pts (65%) male, median age of 68 years [range 31-87] and adenocarcinoma represented the 68%. PD-L1 50%: 43%. ICB setting was 1°L 41%; 2°L 47%; > 3°L 11%, and the most used ICB was Pembrolizumab in 63% of pts. Among the 88% of the pts who discontinued treatment, 63% did it due to disease progression and 13% due to toxicity (pneumonitis was the most frequent adverse event in pts with CHIP). Overall, at least 1 CHIP mutation was found in 35 pts (34%). Incidence at VAF 1% and 2% for each mutation were DNMT3A 80% and 69%, TET2 11% respectively, ASXL1 11% respectively and JAK2 6% and 3%; for older pts subgroup VAF at 1% and 2% were: DNMT3A 71% and 59% and for TET2 and ASXL1 24% respectively for each mutation. Only 4% of pts had more than 1 CHIP mutation. No pts developed hematological disease during the follow up. There was no difference in CHIP prevalence according to line of treatment. CHIP pts achieved disease control in 51%. PFS and OS results will be presented at the conference. Conclusion: CHIP is commonly found in pts with solid tumors, including NSCLC, with a prevalence in our cohort of 34%, which is lower than that reported in literature. No pts developed a characterized hematological disease during follow up. Survival outcomes will be presented at the conference. Citation Format: Julieta Elena Rodriguez, Capucine Baldini, Francois Xavier Danlos, Aurelien Marabelle, Maxime Frelaut, Marco Tagliamento, Mihaela Aldea, Benjamin Besse, Jean Baptiste Micol, Christophe Marzac, Nathalie Chaput, Christophe Massard. Clonal hematopoiesis of indeterminate potential (CHIP) in patients with advanced NSCLC treated with immune checkpoint blockers (ICB) as monotherapy: Analysis of the PREMIS study. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A027.

Published
2023
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37. Therapy-related myeloid neoplasms following treatment with PARP inhibitors: new molecular insights

Author

Sylvain Garciaz, Olivier Caron, Amine Belhabri, Norbert Vey, Jacques Vargaftig, Veronique Verge, Sophie Cotteret, S. de Botton, Flore Salviat, Suzette Delaloge, Iléana Antony-Debré, Patricia Pautier, Christophe Marzac, Sarah Bertoli, Florence Pasquier, Jean-Baptiste Micol, Sabine Khalife-Hachem, Alexandra Leary, Etienne Rouleau, A Renneville, M Kfoury, Filippo Rosselli, Thomas Grinda, Christian Recher, Madalina Uzunov, Jean-Edouard Martin, Gabriel Etienne, Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Curie [Paris], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Intégrité du génome et cancers (IGC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Service de biostatistique et d'épidémiologie (SBE), Direction de la recherche clinique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Département de médecine oncologique [Gustave Roussy], Oncologie gynécologique, Institut Bergonié [Bordeaux], UNICANCER, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Génétique (Biologie pathologie), Département de biologie et pathologie médicales [Gustave Roussy], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), and NUNES, Jacques A

Subjects
Myeloid, DNA Repair, Poly ADP ribose polymerase, [SDV]Life Sciences [q-bio], MEDLINE, [SDV.CAN]Life Sciences [q-bio]/Cancer, Poly(ADP-ribose) Polymerase Inhibitors, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Text mining, [SDV.CAN] Life Sciences [q-bio]/Cancer, Neoplasms, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Ovarian Neoplasms, 0303 health sciences, Therapy related, business.industry, Hematology, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Poly(ADP-ribose) Polymerases, business
Abstract

International audience; No abstract available

Published
2021
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38. Coordinated alterations in RNA splicing and epigenetic regulation drive leukaemogenesis

Author

Rachel E. Miles, Catherine Cargo, Mohammad Alinoor Rahman, Omar Abdel-Wahab, Adrian R. Krainer, Heidi Dvinge, Hana Cho, Robert K. Bradley, Todd R. Albrecht, Fabio M. R. Amaral, Ross L. Levine, Kiran Batta, Daichi Inoue, Fabrizio Simeoni, Deepti P. Wilks, Alessandro Pastore, Bo Wang, Xiao Jing Zhang, Daniel H. Wiseman, Eric J. Wagner, Stéphane de Botton, Eytan M. Stein, Tim C. P. Somervaille, Jean Baptiste Micol, Virginie Penard-Lacronique, Andrew M. Intlekofer, Stanley Chun-Wei Lee, Akihide Yoshimi, and Kuan-Ting Lin

Subjects
Male, 0301 basic medicine, RNA Splicing Factors, Carcinogenesis, RNA polymerase II, Article, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Cell Line, Tumor, Gene expression, Animals, Humans, Gene, Cell Proliferation, Multidisciplinary, Serine-Arginine Splicing Factors, biology, Alternative splicing, Epigenome, DNA Methylation, Isocitrate Dehydrogenase, Cell biology, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Alternative Splicing, Leukemia, Myeloid, Acute, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, RNA splicing, biology.protein, Female, RNA Polymerase II, Transcriptome
Abstract

Transcription and pre-mRNA splicing are key steps in the control of gene expression and mutations in genes regulating each of these processes are common in leukaemia1,2. Despite the frequent overlap of mutations affecting epigenetic regulation and splicing in leukaemia, how these processes influence one another to promote leukaemogenesis is not understood and, to our knowledge, there is no functional evidence that mutations in RNA splicing factors initiate leukaemia. Here, through analyses of transcriptomes from 982 patients with acute myeloid leukaemia, we identified frequent overlap of mutations in IDH2 and SRSF2 that together promote leukaemogenesis through coordinated effects on the epigenome and RNA splicing. Whereas mutations in either IDH2 or SRSF2 imparted distinct splicing changes, co-expression of mutant IDH2 altered the splicing effects of mutant SRSF2 and resulted in more profound splicing changes than either mutation alone. Consistent with this, co-expression of mutant IDH2 and SRSF2 resulted in lethal myelodysplasia with proliferative features in vivo and enhanced self-renewal in a manner not observed with either mutation alone. IDH2 and SRSF2 double-mutant cells exhibited aberrant splicing and reduced expression of INTS3, a member of the integrator complex3, concordant with increased stalling of RNA polymerase II (RNAPII). Aberrant INTS3 splicing contributed to leukaemogenesis in concert with mutant IDH2 and was dependent on mutant SRSF2 binding to cis elements in INTS3 mRNA and increased DNA methylation of INTS3. These data identify a pathogenic crosstalk between altered epigenetic state and splicing in a subset of leukaemias, provide functional evidence that mutations in splicing factors drive myeloid malignancy development, and identify spliceosomal changes as a mediator of IDH2-mutant leukaemogenesis. Analyses of transcriptomes from patients with acute myeloid leukaemia identified frequently co-occurring mutations of IDH2 and SRSF2, which functional analyses showed to have distinct and coordinated leukaemogenic effects on the epigenome and RNA splicing.

Published
2019
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39. Disappearance of slan-positive non-classical monocytes for diagnosis of chronic myelomonocytic leukemia with an associated inflammatory state

Author

Ivan Sloma, Eric Solary, Andrea Toma, Gabriel Etienne, Nicolas Freynet, Dorothée Selimoglu-Buet, Sihem Tarfi, Margot Morabito, Jeffie Lafosse, Orianne Wagner-Ballon, Pierre Fenaux, Bouchra Badaoui, and Jean-Baptiste Micol

Subjects
medicine.diagnostic_test, business.industry, Myelodysplastic syndromes, Immunology, Medicine, Chronic myelomonocytic leukemia, Hematology, business, medicine.disease, Flow cytometry
Published
2019
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40. Germline ATG2B/GSKIP-containing 14q32 duplication predisposes to early clonal hematopoiesis leading to myeloid neoplasms

Author

Pierre Hirsch, Barbara Schmaltz-Panneau, Jean-Henri Bourhis, Caroline Deswarte, Christophe Marzac, Christine Bellanné-Chantelot, Jean-Baptiste Micol, Christine Delaunay-Darivon, Flore Sicre de Fontbrune, Hélène Guermouche, Albert Najman, William Vainchenker, Céline Lemaitre, Jean-Côme Meniane, Eolia Brissot, Florence Pasquier, Philippe Pellet, Gwendoline Leroy, François Delhommeau, Patrick R. Benusiglio, Samy Chraibi, Isabelle Plo, Olivier Caron, Pascal Fuseau, Simona Lapusan, Pascale Cony-Makhoul, Odile Bera, Chrystelle Colas, Jean Pegliasco, Graciela Rabadan Moraes, and Françoise Isnard

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Myeloid, Adolescent, DNA Copy Number Variations, Vesicular Transport Proteins, Autophagy-Related Proteins, Biology, Germline, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Gene Duplication, Gene duplication, medicine, Biomarkers, Tumor, Humans, Gene, Dominance (genetics), Aged, Retrospective Studies, Chromosomes, Human, Pair 14, Myeloproliferative Disorders, Essential thrombocythemia, Myeloid leukemia, Hematology, Middle Aged, medicine.disease, Prognosis, Repressor Proteins, Survival Rate, Haematopoiesis, Leukemia, Myeloid, Acute, 030104 developmental biology, medicine.anatomical_structure, Germ Cells, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Myelodysplastic Syndromes, Mutation, Cancer research, Female, Disease Susceptibility, Clonal Hematopoiesis, Follow-Up Studies
Abstract

The germline predisposition associated with the autosomal dominant inheritance of the 14q32 duplication implicating ATG2B/GSKIP genes is characterized by a wide clinical spectrum of myeloid neoplasms. We analyzed 12 asymptomatic carriers and 52 patients aged 18-74 years from six families, by targeted sequencing of 41 genes commonly mutated in myeloid malignancies. We found that 75% of healthy carriers displayed early clonal hematopoiesis mainly driven by TET2 mutations. Molecular landscapes of patients revealed two distinct routes of clonal expansion and leukemogenesis. The first route is characterized by the clonal dominance of myeloproliferative neoplasms (MPN)-driver events associated with TET2 mutations in half of cases and mutations affecting splicing and/or the RAS pathway in one-third of cases, leading to the early development of MPN, mostly essential thrombocythemia, with a high risk of transformation (50% after 10 years). The second route is distinguished by the absence of MPN-driver mutations and leads to AML without prior MPN. These patients mostly harbored a genomic landscape specific to acute myeloid leukemia secondary to myelodysplastic syndrome. An unexpected result was the total absence of DNMT3A mutations in this cohort. Our results suggest that the germline duplication constitutively mimics hematopoiesis aging by favoring TET2 clonal hematopoiesis.

Published
2021

41. Next-Generation Sequencing on Circulating Tumor DNA in Advanced Solid Cancer: Swiss Army Knife for the Molecular Tumor Board? A Review of the Literature Focused on FDA Approved Test

Author

Damien Vasseur, Hela Sassi, Arnaud Bayle, Marco Tagliamento, Benjamin Besse, Christophe Marzac, Ahmadreza Arbab, Nathalie Auger, Sophie Cotteret, Mihaela Aldea, Félix Blanc-Durand, Arthur Géraud, Anas Gazzah, Yohann Loriot, Antoine Hollebecque, Patricia Martín-Romano, Maud Ngo-Camus, Claudio Nicotra, Santiago Ponce, Madona Sakkal, Olivier Caron, Cristina Smolenschi, Jean-Baptiste Micol, Antoine Italiano, Etienne Rouleau, and Ludovic Lacroix

Subjects
United States Food and Drug Administration, Neoplasms, Liquid Biopsy, High-Throughput Nucleotide Sequencing, Humans, General Medicine, Cell-Free Nucleic Acids, United States, Circulating Tumor DNA
Abstract

FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels’ size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

Published
2022
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42. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort

Author

Patrice Chevallier, Alexis Caulier, Gabrielle Roth-Guepin, Xavier Thomas, Pierre-Yves Dumas, Yosr Hicheri, Florence Pasquier, Sarah Bertoli, Jean-Baptiste Micol, Edmond Chiche, Thomas Cluzeau, Ramy Rahmé, Arnaud Pigneux, Magalie Joris, Patrick Auberger, Pierre Peterlin, Caroline Lejeune, Ollivier Legrand, Mohamad Mohty, Norbert Vey, Caroline Bonmati, Lionel Ades, Michael Loschi, Christian Recher, Emmanuel Raffoux, Alexis Genthon, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Saint-Eloi, CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hématologie, CHU Nice, 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), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Hopital Saint-Louis [AP-HP] (AP-HP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Lausanne (UNIL), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), 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), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Université Paris Cité (UPCité), and DESSAIVRE, Louise

Subjects
Adult, Oncology, medicine.medical_specialty, Multivariate analysis, Daunorubicin, [SDV]Life Sciences [q-bio], Internal medicine, hemic and lymphatic diseases, medicine, Humans, Aged, Retrospective Studies, Response rate (survey), Myeloid Neoplasia, business.industry, Cytarabine, Myeloid leukemia, Hematology, Minimal residual disease, Transplantation, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Cohort, business, medicine.drug
Abstract

CPX-351 is a liposomal formulation of cytarabine and daunorubicin approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML). We retrospectively analyzed the efficacy and safety of CPX-351 in a real-world setting in 103 patients from 12 French centers, including the evaluation of molecular abnormalities at baseline and minimal residual disease (MRD) in responding patients, compared with a historical data set from Bordeaux-Toulouse DATAML registry. A favorable safety profile was observed, with a low frequency of alopecia (11%) and gastrointestinal toxicity (50%). The overall response rate after induction was 59%, and MRD

Published
2021
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43. Prognostic significance of concurrent gene mutations i n intensively treated patients with IDH-mutated AML: an ALFA study

Author

Céline Berthon, Lionel Ades, Nicolas Boissel, Emilie Lemasle, Christian Recher, Xavier Thomas, Nicolas Duployez, Norbert Vey, Raphael Itzykson, Sylvain Chantepie, Karine Celli-Lebras, Arnaud Pigneux, Pascal Turlure, Stéphane de Botton, Claude Preudhomme, Claude Gardin, Denis Caillot, Jean-Pierre Marolleau, Christine Terré, Jean-Baptiste Micol, Hervé Dombret, Thorsten Braun, Juliette Lambert, Emmanuel Raffoux, Jean-Valère Malfuson, Matthieu Duchmann, Cécile Pautas, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Université Paris-Saclay, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Hôpital Avicenne [AP-HP], Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital Henri Mondor, Centre Hospitalier de Versailles André Mignot (CHV), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Centre de Transfusion Sanguine des Armées (CTSA), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Universitaire d'Hématologie (IUH), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], and DESSAIVRE, Louise

Subjects
Male, Oncology, medicine.medical_specialty, NPM1, IDH1, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Immunology, Abnormal Karyotype, Hematopoietic stem cell transplantation, Gene mutation, medicine.disease_cause, Biochemistry, Disease-Free Survival, DNA Methyltransferase 3A, Internal medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Humans, Point Mutation, Medicine, Prospective Studies, In Situ Hybridization, Fluorescence, Aged, Proportional Hazards Models, Retrospective Studies, Chromosome Aberrations, Clinical Trials as Topic, Mutation, Acute leukemia, business.industry, Myeloid leukemia, Cell Biology, Hematology, Middle Aged, Isocitrate Dehydrogenase, Neoplasm Proteins, [SDV] Life Sciences [q-bio], Leukemia, Myeloid, Acute, Isocitrate dehydrogenase, Female, France, business, Nucleophosmin
Abstract

International audience; In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P< .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.

Published
2021
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44. Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers

Author

Silvia Salmoiraghi, Daniel Birnbaum, Loïc Garçon, Frederik Otzen Bagger, Zakia Aid, Alexandre Fagnan, Benjamin Uzan, Stephane de Botton, Maria Riera Piqué-Borràs, Cécile K. Lopez, Christine Dierks, Connor Sweeney, Eric Delabesse, Juerg Schwaller, Elie Robert, Kazuya Shimoda, Zahra Kadri, Thomas Pabst, Jaroslaw P. Maciejewski, Betty Leite, Alexis Caulier, Sébastien Malinge, Samantha Tauchmann, Catherine Carmichael, Amina Kurtovic-Kozaric, Olivier A. Bernard, Virginie Deleuze, Ute M. Moll, Paresh Vyas, Martin Carroll, Veronique De Mas, Orietta Spinelli, Thomas Mercher, Hélène Lapillonne, Cathy Ignacimouttou, Charles G. Mullighan, Eric Soler, V. Gelsi-Boyer, Peter Valent, Cécile Thirant, Jean Baptiste Micol, Eduardo Anguita, Ilaria Iacobucci, Benjamin T. Kile, and Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Myeloid, Erythroblasts, [SDV]Life Sciences [q-bio], Biochemistry, Transcriptome, Mice, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, Erythropoiesis, GATA1 Transcription Factor, Gene Knock-In Techniques, RNA-Seq, 0303 health sciences, education.field_of_study, Myeloid leukemia, GATA1, Hematology, Middle Aged, Neoplasm Proteins, 3. Good health, DNA-Binding Proteins, Leukemia, Haematopoiesis, Cell Transformation, Neoplastic, medicine.anatomical_structure, Radiation Chimera, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Female, Adult, Immunology, Population, Mice, Transgenic, Biology, Dioxygenases, Genetic Heterogeneity, Young Adult, 03 medical and health sciences, Transcriptional Regulator ERG, Proto-Oncogene Proteins, Exome Sequencing, medicine, Animals, Humans, Epigenetics, education, 030304 developmental biology, Cell Biology, Hematopoietic Stem Cells, medicine.disease, Mice, Inbred C57BL, Repressor Proteins, Mutation, Cancer research, Leukemia, Erythroblastic, Acute, Transcription Factors
Abstract

Acute erythroleukemia (AEL or acute myeloid leukemia [AML]-M6) is a rare but aggressive hematologic malignancy. Previous studies showed that AEL leukemic cells often carry complex karyotypes and mutations in known AML-associated oncogenes. To better define the underlying molecular mechanisms driving the erythroid phenotype, we studied a series of 33 AEL samples representing 3 genetic AEL subgroups including TP53-mutated, epigenetic regulator-mutated (eg, DNMT3A, TET2, or IDH2), and undefined cases with low mutational burden. We established an erythroid vs myeloid transcriptome-based space in which, independently of the molecular subgroup, the majority of the AEL samples exhibited a unique mapping different from both non-M6 AML and myelodysplastic syndrome samples. Notably, >25% of AEL patients, including in the genetically undefined subgroup, showed aberrant expression of key transcriptional regulators, including SKI, ERG, and ETO2. Ectopic expression of these factors in murine erythroid progenitors blocked in vitro erythroid differentiation and led to immortalization associated with decreased chromatin accessibility at GATA1-binding sites and functional interference with GATA1 activity. In vivo models showed development of lethal erythroid, mixed erythroid/myeloid, or other malignancies depending on the cell population in which AEL-associated alterations were expressed. Collectively, our data indicate that AEL is a molecularly heterogeneous disease with an erythroid identity that results in part from the aberrant activity of key erythroid transcription factors in hematopoietic stem or progenitor cells.

Published
2020
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45. Determinants of the outcomes of patients with cancer infected with SARS-CoV-2: results from the Gustave Roussy cohort

Author

Laurence, Albiges, Stéphanie, Foulon, Arnaud, Bayle, Bertrand, Gachot, Fanny, Pommeret, Christophe, Willekens, Annabelle, Stoclin, Mansouria, Merad, Frank, Griscelli, Ludovic, Lacroix, Florence, Netzer, Thomas, Hueso, Corinne, Balleyguier, Samy, Ammari, Emeline, Colomba, Giulia, Baciarello, Audrey, Perret, Antoine, Hollebecque, Julien, Hadoux, Jean-Marie, Michot, Nathalie, Chaput, Veronique, Saada, Mathilde, Hauchecorne, Jean-Baptiste, Micol, Roger, Sun, Dominique, Valteau-Couanet, Fabrice, André, Florian, Scotte, Benjamin, Besse, Jean-Charles, Soria, and Fabrice, Barlesi

Subjects
Cohort Studies, Male, SARS-CoV-2, COVID-19, Humans, Female, Middle Aged, Aged
Abstract

Patients with cancer are presumed to be at increased risk of severe COVID-19 outcomes due to underlying malignancy and treatment-induced immunosuppression. Of the first 178 patients managed for COVID-19 at the Gustave Roussy Cancer Centre, 125 (70.2%) were hospitalized, 47 (26.4%) developed clinical worsening and 31 (17.4%) died. An age of over 70 years, smoking status, metastatic disease, cytotoxic chemotherapy and an Eastern Cooperative Oncology Group score of ≥2 at the last visit were the strongest determinants of increased risk of death. In multivariable analysis, the Eastern Cooperative Oncology Group score remained the only predictor of death. In contrast, immunotherapy, hormone therapy and targeted therapy did not increase clinical worsening or death risk. Biomarker studies found that C-reactive protein and lactate dehydrogenase levels were significantly associated with an increased risk of clinical worsening, while C-reactive protein and D-dimer levels were associated with an increased risk of death. COVID-19 management impacted the oncological treatment strategy, inducing a median 20 d delay in 41% of patients and adaptation of the therapeutic strategy in 30% of patients.

Published
2020

46. Mutational profiling of isolated myeloid sarcomas and utility of serum 2HG as biomarker of IDH1/2 mutations

Author

Virginie Penard-Lacronique, Claire Bories, Aline Renneville, Jean-Baptiste Micol, Stéphane de Botton, Claude Preudhomme, Cyril Quivoron, Angelo Paci, Nicolas Boissel, Raphael Itzykson, Sophie Broutin, Marie Terroir-Cassou-Mounat, Véronique Saada, Vianney Poinsignon, Céline Berthon, Julia Delahousse, Jacques Bosq, and Christophe Willekens

Subjects
Adult, Male, Cancer Research, Myeloid, IDH1, Adolescent, Biopsy, DNA Mutational Analysis, Glutarates, Young Adult, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Profiling (information science), Sarcoma, Myeloid, Aged, business.industry, Hematology, Middle Aged, Isocitrate Dehydrogenase, medicine.anatomical_structure, Oncology, Positron-Emission Tomography, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, business, Biomarkers, 030215 immunology
Published
2018
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47. Frequency and Outcome of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with BCR-ABL1 Clonal Hematopoiesis after Blast Clearance: Results from the Graaph-2014 Trial

Author

Patrice Chevallier, Véronique Lhéritier, Nicole Straetmans, Céline Berthon, Nicolas Boissel, Jean-Baptiste Micol, Emmanuelle Clappier, Yves Chalandon, Xavier Thomas, Marie Passet, Rathana Kim, Sylvie Chevret, Jean-Michel Cayuela, Hervé Dombret, Philippe Rousselot, Norbert Ifrah, Isabelle Plantier, Jean Soulier, Sylvain Chantepie, Françoise Huguet, Sébastien Maury, and Georg Stussi

Subjects
Bcr abl1, Philadelphia Chromosome Positive, business.industry, hemic and lymphatic diseases, Lymphoblastic Leukemia, Immunology, Clonal hematopoiesis, Cancer research, Medicine, Cell Biology, Hematology, business, Biochemistry
Abstract

Background IG/TR-based minimal residual disease (MRD) is a faithful marker of response to therapy and the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). In adults with Philadelphia chromosome-positive (Ph+) ALL, MRD is commonly monitored by BCR-ABL1 transcript quantification, although its prognostic significance has not been compared to IG/TR MRD to date. Recently, it has been shown that BCR-ABL1 rearrangement may be found and persist in non-lymphoblastic cells in some patients. In the prospective GRAAPH-2014 trial, using a dual IG/TR and BCR-ABL1 MRD monitoring, we aimed to study the biological and clinical significance of persistent BCR-ABL1 clonal hematopoiesis (CH) in adults with de novo Ph+ ALL. Patients and Methods The study comprised 156 adults with de novo Ph+ ALL randomized in the GRAAPH-2014 trial. Bone marrow (BM) and peripheral blood (PB) follow-up (FU) samples were collected after each treatment cycle and before hematopoietic stem cell transplantation (HSCT). MRD monitoring was performed by quantification of both BCR-ABL1 transcripts and IG/TCR clonal rearrangements on all available samples and MRD quantification of genomic BCR-ABL1 breakpoint fusion was also performed for 37 patients. MRD results were considered discordant if more than one log10 difference or positivity/negativity discordance on the same FU sample was evidenced. Cell fractions from 14 peripheral blood mononuclear cells (PBMC) samples (T-cells, B-cells and monocytes) were FACS-sorted and evaluated for BCR-ABL1 expression. Achievement of major molecular response (MMR) defined as Results Quantification of BCR-ABL1 transcripts and IG/TR MRD levels on 876 samples from 156 patients (456 BM and 542 PB) identified 54 out of 142 (38%) evaluable patients with consistently discordant MRD results in at least 3 different timepoints, suggesting the persistence of non-lymphoblastic BCR-ABL1-positive cells in these patients and BCR-ABL1 CH. Possible bias related to variable BCR-ABL1 expression was ruled out by genomic BCR-ABL1 quantification on 263 FU samples (r s=0.89, p We then evaluated the clinical significance of BCR-ABL1 CH. Unexpectedly, CH+ patients had a significant lower cumulative incidence of relapse (CIR) (panel A, hazard ratio (HR) 0.37, 95% CI [0.15-0.90], p=0.03). However, this lower CIR did not translate into longer disease-free survival (DFS) (panel B, HR=0.85, 95% CI [0.44-1.63], p=0.63). Since an imbalance in alloSCT was observed between CH+ and CH- patients, we tested if the observed difference in CIR may be related to different alloSCT outcomes. When censoring patients at alloSCT, the difference in CIR was indeed no longer significant (subhazard ratio (SHR) 0.48, 95% CI [0.16-1.43], p=0.19). More interestingly, the benefit of alloSCT was restricted to CH- patients. Using alloSCT as a time-dependent variable, DFS was indeed improved by alloSCT in CH- (SHR 0.40, 95% CI [0.17-0.91], p=0.03, panel C) but not in CH+ patients (SHR 1.12, 95%CI [0.32-3.87], p=0.86, panel D) despite a non-significant interaction between CH status and alloSCT. Conclusion More than one third of adults with de novo Ph+ ALL displays persistent measurable BCR-ABL1 signal during therapy, likely related to BCR-ABL1 CH. Strikingly, this condition is not associated with a higher risk of relapse nor with poorer overall outcomes in the GRAAPH-2014 trial. Moreover, our results suggest that patients with BCR-ABL1 CH may not be good candidates for alloSCT. By contrast, IG/TR MRD may allow to identify patients with the higher risk of relapse. These results highlight the need for implementation of IG/TR MRD in adult Ph+ ALL to guide therapeutic decisions. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Straetmans: Alexion: Membership on an entity's Board of Directors or advisory committees. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: SANOFI: Honoraria; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; PFIZER: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding.

Published
2021
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48. Therapy Related Myeloid Neoplasm Post PARP Inhibitors: Potential Clonal Selection

Author

Madalina Uzunov, Sarah Bertoli, Amine Belhabri, Iléana Antony-Debré, Véronique Saada, Nathalie Auger, Thomas Grinda, Sabine Khalife-Hachem, Olivier Caron, Alexandra Leary, Maria Kfoury, Christel Guillouf, Florence Pasquier, Filippo Rosselli, Stéphane de Botton, Sylvain Garciaz, Gabriel Etienne, Etienne Rouleau, Jacques Vargaftig, Patricia Pautier, Christophe Marzac, Jean-Baptiste Micol, Norbert Vey, Jean-Edouard Martin, and Flore Salviat

Subjects
Oncology, medicine.medical_specialty, Chemotherapy, Myeloid, business.industry, medicine.medical_treatment, Immunology, Cell Biology, Hematology, Gene mutation, Biochemistry, Olaparib, Targeted therapy, Radiation therapy, chemistry.chemical_compound, medicine.anatomical_structure, Germline mutation, chemistry, Internal medicine, medicine, Rucaparib, business
Abstract

Introduction Clonal selection is one of the mechanisms leading to therapy-related myeloid neoplasms (TRMN). A preexisting somatic mutation in hematopoietic stem cell (defined as clonal hematopoiesis [CH]) emerges under pressure of chemotherapy or radiotherapy, leading to TRMN development. Most of these mutations belong to the DNA damage response (DDR) pathway as TP53 or PPM1D mutations and are known to confer a dismal prognosis. Recently authorized for the treatment of ovarian cancers (OC), the poly (ADP-ribose) polymerase inhibitors (PARPi) represent a promising targeted therapy. However, by inducing DNA damage and altering DNA repair process, PARP inhibition could represent a challenge for the genetic stability of the healthy tissues. Thus, we assessed the effect of PARP inhibition on the development of CH and TRMN after PARPi treatment for OC (TRMN-PARPi) in combination with chemotherapies. Methods Firstly, we performed a targeted 77 genes mutational analysis using Next Generation Sequencing (NGS) in 13 patients exposed to PARPi without TRMN. Secondly, we retrospectively identified, with the help of the UNIHEM group of Unicancer, 17 patients who experienced TRMN-PARPi. Clinical, biological and survival data were collected and compared to 23 OC patients with TRMN not treated with PARPi (Gustave Roussy institutional database). Lastly, NGS was performed for 3 patients with TRMN-PARPi with sequential sampling. Patient's samples were obtained with informed consent. Results Thirteen OC patients during maintenance treatment with PARPi without TRMN were explored by NGS. Median age at NGS was 64.5 years old (yo) (40.5-75.3). 4/13 (31%) patients harbored BRCA1/2 germline mutation. Time between OC diagnosis and NGS was 4.3 y (1-11.6). The median number of chemotherapy line at PARPi initiation was 2 (1-3). 7 received Olaparib, 5 Niraparib and 1 Rucaparib. The median duration of PARPi treatment before NGS was 4.7 months (1.1-25.1). 12/13 patients experienced hematological toxicities during the PARPi treatment. CH was found in 10/13 (77%) patients (Figure 1a), including mutations of DDR genes in 8/10 (80%). 6/8 (75%) patients had 2 or more gene mutations. Next we identified 17 cases of TRMN occurring during or after PARPi administration for OC (6/17 [35%] t-AML and 11/17 [65%] t-MDS). 12/17 (71%) patients had BRCA germline mutations (7 BRCA1 and 5 BRCA2). All received Olaparib with a median dose of 600mg/d (400-1200). Median duration of Olaparib treatment was 1.7 years (0.2-4.6). TRMN-PARPi were described 1.4 months (0-10.9) after the end of PARPi administration. We compared these patients to a cohort of TRMN post OC not treated by PARPi. Number of therapy lines for OC, time between TRMN and OC diagnosis, median age at TRMN, were, for TRMN-PARPi, 2 (1-8), 5.9 y (0.9-20.8), 64.4 yo (46-74); respectively, compared to 3 (1-8), 4.9 y (1.7-36.9), 59.3 yo (35.7-85.7); (p=ns). TRMN-PARPi cytogenetic was unfavorable for 16/17 (94%) (including 11/17 [65%] complex karyotype) compared to 16/23 (70%) (11/23 [48%] complex karyotype). C Median survival was significantly lower in the TRMN-PARPi group 3.9 months 95%CI [2.0-9.7] and 6.1 months 95%CI [4.1-15.8] respectively, p=0.046, Fig 1b). However, median survival from OC diagnosis was not different between the two groups 6.2 y 95%CI [5.6-NA] for TRMN-PARPi vs 5.6 y 95%CI [5.0-11.6]. NGS was available for 8/17 TRMN-PARPi and revealed mutations in DDR genes in 7/8 patients (6 patients with TP53 mutation, 2 with PPM1D mutation). For 3 patients, we had samples from OC stage, before PARPi administration. We found that mutations from TRMN stage were present at lower frequency, confirming clonal selection by PARPi treatment (Figure 1c). Conclusions Here we described, for the first time, a cohort of TRMN patients previously treated with PARPi for an OC. Intriguingly, most of these TRMN occurred with a short latency at the end of PARPi treatment, with unfavorable cytogenetic and very short OS. Moreover, we found a very high percentage of CH involved in the DDR pathway (62%) in patients under PARPi treatment without TRMN suggesting a potential clonal selection which could lead ultimately to TRMN. PARPi are now indicated in 1rst line high grade OC regardless of BRCA status, which should expand indications. Benefit for OC patients is not questionable; however, caution will be warranted for patients with CH before PARPi treatment, especially implicating DDR mutations. Disclosures Etienne: Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau.

Published
2020
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49. Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts

Author

Hubert Serve, Pierre-Yves Dumas, Meaghan Wall, Wolfgang E. Berdel, Claude Preudhomme, Vladimir Lazarevic, Rita Exeler, Christian Recher, Gunnar Juliusson, Gerhard Ehninger, Christian Thiede, Raimundo García, Friedrich Stölzel, Sören Lehmann, Sarah Bertoli, Arnaud Pigneux, Carole Shaw, Jean Baptiste Micol, Ing Soo Tiong, Christoph Schliemann, Eva Barragán, Christoph Röllig, Zdeněk Ráčil, Linus Angenendt, Pilar Rodríguez Martínez, Jan Henrik Mikesch, Jan Novák, Elihu H. Estey, Hagop M. Kantarjian, Lisa Wagenführ, Pavel Žák, Tapan M. Kadia, Michael Kramer, Farhad Ravandi, Georg Lenz, Pau Montesinos, Jorge E. Cortes, Andrew H. Wei, Christine Terré, Hervé Dombret, Matthias Stelljes, Martin Höglund, David Martínez-Cuadrón, Utz Krug, and Carmen Botella

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, NPM1, Myeloid, Childhood leukemia, Adolescent, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, medicine, Humans, Cumulative incidence, 030304 developmental biology, Aged, Aged, 80 and over, Chromosome Aberrations, 0303 health sciences, business.industry, Cytogenetics, Myeloid leukemia, Nuclear Proteins, hemic and immune systems, ORIGINAL REPORTS, Middle Aged, medicine.disease, Prognosis, Pediatric cancer, 3. Good health, body regions, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, fms-Like Tyrosine Kinase 3, 030220 oncology & carcinogenesis, embryonic structures, Fms-Like Tyrosine Kinase 3, Mutation, Female, business, Nucleophosmin, psychological phenomena and processes
Abstract

PURPOSE Nucleophosmin 1 ( NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene ( FLT3) is absent ( FLT3-ITDneg) or present with a low allelic ratio ( FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. METHODS We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/ FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. RESULTS Among 2,426 patients with NPM1mut/ FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/ FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors ( P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. CONCLUSION Karyotype abnormalities are significantly associated with outcome in NPM1mut/ FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/ FLT3-ITDneg/low AML.

Published
2019

50. Bortezomib, Lenalidomide, and Dexamethasone in Elderly Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm

Author

Christophe Marzac, Jean-Baptiste Micol, Claude Chahine, Damien Roos-Weil, David Ghez, Véronique Saada, Stéphane de Botton, and Stéphane Barete

Subjects
0301 basic medicine, Male, Cancer Research, Plasmacytoid dendritic cell, Dexamethasone, Bortezomib, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lenalidomide, Aged, business.industry, Hematology, Dendritic Cells, medicine.disease, Transplantation, Leukemia, 030104 developmental biology, Oncology, Hematologic Neoplasms, Proteasome inhibitor, Cancer research, Stem cell, business, 030215 immunology, medicine.drug
Abstract

Blastic plasmacytoid dendritic cell neoplasms are very rare aggressive haematologic malignancies associated with a poor prognosis, especially in older patients who cannot benefit from acute leukaemia-based induction chemotherapies before allogeneic stem cell transplantation. Here we report the results of a combination of bortezomib, lenalidomide and dexamethasone in two elderly patients considered unfit for intensive treatment.

Published
2019

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