617 results on '"Gardin, Claude"'
Search Results
202. Is Arsenic Trioxide (ATO) Required in the Treatment of High Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL2006) By the French Belgian Swiss APL Group
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Ades, Lionel, Raffoux, Emmanuel, Spertini, Olivier, Guerci, Agnès, Recher, Christian, Guyotat, Denis, Deconinck, Eric, Lamy De La Chapelle, Thierry, Thomas, Xavier, Bordessoule, Dominique, Vey, Norbert, de Botton, Stephane, Pigneux, Arnaud, Caillot, Denis, Cahn, Jean-Yves, Chevallier, Patrice, Lambert, Jean-Francois, Gardin, Claude, Dombret, Herve, Lejeune, Julie, Chevret, Sylvie, and Fenaux, Pierre
- Abstract
Ades: Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Fenaux:Celgene, Novartis, Teva: Honoraria; Celgene, Janssen, Novartis, Astex, Teva: Research Funding.
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- 2016
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203. The role of cytogenetic abnormalities in acute myeloid leukemia with NPM1mutations and no FLT3internal tandem duplication
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Micol, Jean Baptiste, Boissel, Nicolas, Renneville, Aline, Castaigne, Sylvie, Gardin, Claude, Preudhomme, Claude, and Dombret, Hervé
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- 2009
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204. Azacitidine in Older Patients with Acute Myeloid Leukemia (AML). Results from the Expanded International E-Alma Series (E-ALMA+) According to the MRC Risk Index Score
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Falantes, Jose, Thepot, Sylvain, Pleyer, Lisa, Maurillo, Luca, Martínez-Robles, Violeta, Itzykson, Raphaël, Bargay, Joan, Stauder, Reinhard, Venditti, Adriano, Martinez, Maria Pilar, Seegers, Valerie, Foncillas, Maria Angeles, Burgstaller, Sonja, Gardin, Claude, Montesinos, Pau, Musto, Pellegrino, Greil, Richard, Sanz, Miguel, Fenaux, Pierre, and Ramos, Fernando
- Abstract
Falantes: Celgene: Honoraria. Off Label Use: Azacitidine in AML patients with >30% blasts. Pleyer:Celgene: Consultancy, Honoraria; AOP Orphan Pharmaceuticals: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Itzykson:Oncoethix: Research Funding. Venditti:Celgene: Honoraria. Burgstaller:AOP Orphan Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria. Musto:Celgene: Honoraria. Greil:AOP Orphan: Research Funding; GSK: Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Eisai: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Honoraria; Janssen-Cilag: Honoraria; Genentech: Honoraria, Research Funding; Celgene: Consultancy; Ratiopharm: Research Funding; Sanofi Aventis: Honoraria; Pfizer: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Astra-Zeneca: Honoraria; Novartis: Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria; Roche, Celgene: Honoraria, Research Funding. Fenaux:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria.
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- 2015
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205. Correlation Between Bone Marrow Dysplasia and Genomic Profile in De Novo Acute Myeloid Leukemia (AML): A Study By the ALFA Group
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Cluzeau, Thomas, Wagner-Ballon, Orianne, Boyer, Thomas, Guerin, Estelle, Benayoun, Emmanuel, Lusina, Daniel, Garcia, Isabelle, Gardin, Claude, Fenaux, Pierre, Pautas, Cecile, Quesnel, Bruno, Bordessoule, Dominique, Terré, Christine, Thomas, Xavier, Castaigne, Sylvie, Renneville, Aline, Preudhomme, Claude, and Dombret, Herve
- Abstract
Fenaux: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
- Published
- 2015
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206. Activity of OTX015 (MK-8628), a BET-Bromodomain Inhibitor, in Acute Myeloid Leukemia (AML) Progenitor Cells
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Roulin, Louise, Ali, Ashfaq, Masse, Aline, Coudé, Marie-Magdelaine, Bluteau, Dominique, Braun, Thorsten, Berrou, Jeannig, Bluteau, Olivier, Delord, Marc, Riveiro, Maria Eugenia, Herait, Patrice EDOUARD, Soulier, Jean, Baruchel, André, Gardin, Claude, Dombret, Hervé, and Itzykson, Raphaël
- Abstract
CONTEXT: Eradication of leukemic progenitor cells, defined by functional assays such as long-term culture (leukemic long-term culture initiating cells [L-LTC-IC]) is the goal of therapy in AML. Bromodomain and ExtraTerminal (BET) proteins are epigenetic readers that regulate the expression of genes with super-enhancers, including CMYC. BET inhibitors (BETi) such as JQ1 induce proliferation arrest and apoptosis in murine models of AML, in human AML cell lines and primary blasts. Their activity in human leukemic progenitors has not yet been reported. OTX015 (MK-8626) is an orally available BETi that can be safely administered to patients with a continuous low-dose regimen (Dombret et al. Blood. 2014). Single-dose exposure to OTX015 induces gene expression modulation characteristic of bromodomain inhibition, including downregulation of CMYCand upregulation of HEXIM1, inhibiting the viability of AML cell lines, and inducing apoptosis in primary AML blasts (Coudé et al. Oncotarget. 2015). To address the activity of OTX015 on leukemic progenitors, we analyzed (A) the clonogenicity of AML cell lines and (B) the frequency of primary L-LTC-IC after repeated low-dose exposure to OTX015.
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- 2015
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207. Correlation Between Bone Marrow Dysplasia and Genomic Profile in De NovoAcute Myeloid Leukemia (AML): A Study By the ALFA Group
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Cluzeau, Thomas, Wagner-Ballon, Orianne, Boyer, Thomas, Guerin, Estelle, Benayoun, Emmanuel, Lusina, Daniel, Garcia, Isabelle, Gardin, Claude, Fenaux, Pierre, Pautas, Cecile, Quesnel, Bruno, Bordessoule, Dominique, Terré, Christine, Thomas, Xavier, Castaigne, Sylvie, Renneville, Aline, Preudhomme, Claude, and Dombret, Herve
- Abstract
Introduction: AML with multilineage dysplasia (MLD) are included in the WHO subset of "AML with myelodysplasia-related changes" (AML-MRC), together with AML arising from previous MDS or AML with MDS-related cytogenetic abnormalities. In the WHO classification, MLD is defined by dysplasia in at least 50% of the cells in at least two bone marrow (BM) myeloid cell lines. On the other hand, some genetically defined AML subgroups are specifically associated with morphologic changes, but close correlations do not exist for most of these entities. We searched for correlations between BM dysplasia and molecular aberrations in de novoAML patients included in 2 ALFA clinical trials
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- 2015
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208. Efficacy of Azacitidine (AZA) in Autoimmune and Inflammatory Disorders (AID) Associated with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)
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Fraison, Jean-Baptiste, Mekinian, Arsène, Grignano, Eric, Kahn, Jean-Emmanuel, Arlet, Jean-Benoît, Decaux, Olivier, Guillaume, Denis, Buchdahl, Anne-Laure, Omouri, Mohamed, Maigne, Gwenola, Aouba, Achille, Leon, Nathalie, Berthier, Sabine, Liozon, Eric, Park, Sophie, Gardin, Claude, Lortholary, Olivier, Rossignol, Julien, Fenaux, Pierre, Fain, Olivier, and Braun, Thorsten
- Abstract
Background:AID are seen in 10-30% of MDS and CMML. After initial response to steroids, AID are often poorly controlled and steroid-sparing drugs are difficult to use due to the underlying MDS/CMML. Some case reports suggest a beneficial role of AZA treatment in AID associated to MDS/CMML.
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- 2015
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209. Bendamustine Treatment in Refractory or Relapsed T Cell Lymphomas: A Retrospective Multicenter Study
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Reboursiere, Emilie, Le Bras, Fabien, Morschhauser, Franck, Gyan, Emmanuel, Clavert, Aline, Malak, Sandra, Sibon, David, Damge, Marion, Gardin, Claude, Fornecker, Luc-Matthieu, Garidi, Reda, Tricot, Sabine, Houot, Roch, Joly, Bertrand, Abarah, Wajed, Choufi, Bachra, Pham, Anne-dominique, Chantepie, Sylvain P, Fruchart, Christophe, Gac, Anne-Claire, Ollivier, Catherine, Marin, Emilie, Safar, Violaine, Parcelier, Anne, Maisonneuve, Herve, Bachy, Emmanuel, Cartron, Guillaume, Jaccard, Arnaud, Tournilhac, Olivier, Rossi, Cedric, Perrot, Aurore, Martignoles, Jean-Alain, Tilly, Herve, and Damaj, Gandhi
- Abstract
Peripheral T-cell lymphoma (PTCL) is an aggressive disease with poor outcome. First line therapies are usually unsatisfactory with frequent need for second-line therapies. Median progression free survival (PFS) and overall survival (OS) for relapse PTCL patients are very short with few available therapeutic options. Bendamustine has been shown to be effective in this setting.
- Published
- 2015
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210. Is Arsenic Trioxide (ATO) Required in the Treatment of Standard Risk Newly Diagnosed APL? Analysis of a Randomized Trial (APL 2006) By the French Belgian Swiss APL Group
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Ades, Lionel, Thomas, Xavier, Guerci-Bresler, Agnes, Emmanuel, Raffoux, Spertini, Olivier, Vey, Norbert, Lamy, Thierry, Récher, Christian, Pigneux, Arnaud, Bordessoule, Dominique, Deconinck, Eric, Gardin, Claude, Tournilhac, Olivier, Lambert, Jean-Francois, Chevallier, Patrice, de Botton, Stephane, Lejeune, Julie, Dombret, Hervé, Chevret, Sylvie, and Fenaux, Pierre
- Abstract
Guerci-Bresler: ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Vey:Roche: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Deconinck:NOVARTIS: Other: Travel for international congress; PFIZER: Research Funding; CHUGAI: Other: Travel for international congress; ALEXION: Other: Travel for international congress; JANSSEN: Other: Travel for international congress; ROCHE: Research Funding; LFB loboratory: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.
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- 2015
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211. Value of EVI1Gene Expression Level in Adult Acute Lymphoblastic Leukemia (ALL): A Study from the Group for Research on Adult ALL (GRAALL)
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Abbal, Claire, Ben Abdelali, Raouf, Lafage, Marina, Huguet, Françoise, Leguay, Thibaut, Spertini, Olivier, Boissel, Nicolas, Gardin, Claude, Graux, Carlos, Cayuela, Jean-Michel, Boulland, Marie-Laure, Grardel, Nathalie, Bouvier, Anne, Duchosal, Michel, Lhéritier, Véronique, Chalandon, Yves, Asnafi, Vahid, Ifrah, Norbert, and Dombret, Hervé
- Abstract
Background:EVI1gene overexpression is found in approximately 10% of acute myeloid leukemia (AML) patients, with a higher frequency seen in AML carrying chromosome 3q26 abnormality or MLLgene rearrangement, and associated with a dismal prognosis. Deregulation of EVI1expression has also been reported in ALL, but its prognostic impact is unclear. Here, we retrospectively analyzed EVI1expression in a large cohort of adult ALL patients, its correlation with ALL subsets, and its impact on patient outcome.
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- 2014
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212. Incidence of AtrxMutations in Myelodysplastic Syndromes (MDS)
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Herbaux, Charles, Duployez, Nicolas, Badens, Catherine, Poret, Nicolas, Gardin, Claude, Eclache, Virginie, Daliphard, Sylvie, Murati, Anne, Cony-Makhoul, Pascale, Cheze, Stephane, Beve, Blandine, Prebet, Thomas, Hunault-Berger, Mathilde, Renneville, Aline, Figeac, Martin, Stamatoullas, Aspasia, Bastard, Christian, Fenaux, Pierre, Preudhomme, Claude, and Rose, Christian
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INTRODUCTION
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- 2014
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213. Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL).
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Berrou, Jeannig, Dupont, Mélanie, Djamai, Hanane, Adicéam, Emilie, Parietti, Véronique, Kaci, Anna, Clappier, Emmanuelle, Cayuela, Jean-Michel, Baruchel, André, Paublant, Fabrice, Prudent, Renaud, Ghysdael, Jacques, Gardin, Claude, Dombret, Hervé, and Braun, Thorsten
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NILOTINIB , *LYMPHOBLASTIC leukemia , *SMALL molecules , *ACUTE leukemia , *KINASES , *CELL cycle - Abstract
Ph+ (BCR::ABL+) B-ALL was considered to be high risk, but recent advances in BCR::ABL-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1/2, ROCK is constitutively activated by BCR::ABL, and upon activation, ROCK leads to the phosphorylation of LIMK1/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for BCR::ABL-driven B-ALL. The IC50 value of CEL_Amide was ≤1000 nM in BCR::ABL+ TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1/2 were expressed in BCR::ABL+ cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and BCR::ABL TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2Ako/BCR::ABL1+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with BCR::ABL-targeting TKIs, showing promising synergy that warrants further investigation. [ABSTRACT FROM AUTHOR]
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- 2022
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214. Effector CD4+CD45RA−CD25brightFoxp3brightRegulatory T Cell (eTreg) Distribution Is Significantly Impaired in Chronic Myelomonocytic Leukemia (CMML) and Correlates with TET 2 Mutational Status.
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Braun, Thorsten, Miyara, Makoto, Itzykson, Raphael, Renneville, Aline, Kosmider, Olivier, Gardin, Claude, Solary, Eric, Gorochov, Guy, Fenaux, Pierre, and Ades, Lionel
- Abstract
Abstract 2808
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- 2012
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215. Effectiveness and Pharmacokinetics of Low-Dose All-trans Retinoic Acid (25 mg/m2) in Acute Promyelocytic Leukemia
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Castaigne, Sylvie, Lefebvre, Philippe, Chomienne, Christine, Suc, Etienne, Rigal-Huguet, Francoise, Gardin, Claude, Delmer, Alain, Archimbaud, Eric, Tilly, Hervé, Janvier, Maud, Isnard, Françoise, Travade, Philippe, Montfort, Luc, Delannoy, A., Rapp, Marie Josée, Christian, Bernard, Montastruc, Marion, Weh, Hans, Fenaux, Pierre, Dombret, Hervé, Gourmel, Bernard, and Degos, Laurent
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- 1993
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216. Fractionated Doses of Gemtuzumab Ozogamicin (GO) Combined to Standard Chemotherapy (CT) Improve Event-Free and Overall Survival in Newly-Diagnosed De NovoAML Patients Aged 50–70 Years Old: A Prospective Randomized Phase 3 Trial From the Acute Leukemia French Association (ALFA)
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Castaigne, Sylvie, Pautas, Cécile, Terre, Christine, Raffoux, Emmanuel, Bordessoule, Dominique, Bastie, Jean-Noel, Legrand, Ollivier, Thomas, Xavier, Turlure, Pascal, Reman, Oumedaly, De Revel, Thierry, Gastaud, Lauris, Gardin, Claude, Sutton, Laurent, Marolleau, Jean Pierre, De Botton, Stephane, Hermine, Olivier, Plantier, Isabelle, Janvier, Maud, Dupriez, Brigitte, Simon, Marc, De Gunzburg, Noemie, Foucault-Haiat, Stephanie, Contentin, Nathalie, Berthon, Celine, Fenaux, Pierre, Henry, Estelle, Rousselot, Philippe, Preudhomme, Claude, Chevret, Sylvie, and Dombret, Hervé
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Abstract 6
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- 2011
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217. Prognostic Significance of DNA Methyltransferase 3AMutations in Cytogenetically Normal Acute Myeloid Leukemia: A Study by the Acute Leukemia French Association
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Renneville, Aline, Boissel, Nicolas, Nibourel, Olivier, Berthon, Céline, Helevaut, Nathalie, Gardin, Claude, Cayuela, Jean-Michel, Hayette, Sandrine, Reman, Oumedaly, Contentin, Nathalie, Bordessoule, Dominique, Pautas, Cécile, de Botton, Stephane, De Revel, Thierry, Terre, Christine, Fenaux, Pierre, Thomas, Xavier, Castaigne, Sylvie, Dombret, Herve, and Preudhomme, Claude
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Abstract 2506
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- 2011
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218. Long-Term Outcome Associated with Current Allogeneic Stem Cell Transplantation Procedures In Younger Adults with Adverse-Risk AML In First CR – A Real-Life Transplant VersusNo-Transplant Analysis of the Acute Leukemia French Association (ALFA)
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Hospital, Marie-Anne, Thomas, Xavier, Castaigne, Sylvie, Raffoux, Emmanuel, Maury, Sébastien, Gardin, Claude, Bourhis, Jean-Henri, Reman, Oumedaly, Botton, Stéphane de, Revel, Thierry de, Terré, Christine, Preudhomme, Claude, Pautas, Cécile, Fenaux, Pierre, Michallet, Mauricette, Socié, Gérard, and Dombret, Hervé
- Abstract
Abstract 3513
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- 2010
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219. Insights into the cellular pharmacological properties of the BET-inhibitor OTX015/MK-8628 (birabresib), alone and in combination, in leukemia models.
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Astorgues-Xerri, Lucile, Vázquez, Ramiro, Odore, Elodie, Rezai, Keyvan, Kahatt, Carmen, Mackenzie, Sarah, Bekradda, Mohamed, Coudé, Marie-Magdelaine, Dombret, Herve, Gardin, Claude, Lokiec, Francois, Raymond, Eric, Noel, Kay, Cvitkovic, Esteban, Herait, Patrice, Bertoni, Francesco, and Riveiro, María E.
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AZACITIDINE , *LEUKEMIA - Abstract
The bromodomain and extra-C-terminal domain (BET) protein family is a class of epigenetic readers that recognize acetyl-lysine residues of histones, and their targeting with small molecules is a novel therapeutic approach [[1]]. Cell cycle and apoptosis induction were evaluated in a subset of cell lines, including two resistant models (NALM1, K562) after 48-h treatments with 500 nM OTX015 (Figure 1(A)). Similarly, OTX015 significantly down-regulated I MTHFD1L i and I BCL2 i in all leukemic cell lines after 4 or 24 h of treatment, in a similar manner as I MYC i , although the effect on I BCL2 i appeared reversible in three nonresistant cell lines (Figure S2). We then evaluated the downstream effects of OTX015 (500 nM) combined with azacitidine (3 µM) or panobinostat (20 nM) in sensitive and resistant OTX015 cell lines. [Extracted from the article]
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- 2019
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220. Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+).
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for the European ALMA + Investigators, Falantes, José, Itzykson, Raphael, Fenaux, Pierre, Pinto, Ricardo, Bargay, Joan, Burgstaller, Sonja, Martínez, María Pilar, Seegers, Valerie, Gardin, Claude, Cortesão, Emilia, Foncillas, María Ángeles, Montesinos, Pau, Sanz, Miguel Angel, Musto, Pellegrino, Pleyer, Lisa, Greil, Richard, Thépot, Sylvain, Almeida, António M., and Maurillo, Luca
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HEALTH of older people , *MYELOID leukemia , *AZACITIDINE , *CANCER chemotherapy , *HEMATOLOGIC malignancies - Abstract
Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (
N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA. [ABSTRACT FROM AUTHOR]- Published
- 2018
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221. Autoimmune and inflammatory diseases associated with chronic myelomonocytic leukemia: A series of 26 cases and literature review.
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Grignano, Eric, Mekinian, Arsene, Braun, Thorsten, Liozon, Eric, Hamidou, Mohamed, Decaux, Olivier, Puéchal, Xavier, Kahn, Jean Emmanuel, Schoindre, Yoland, Rossignol, Julien, Lortholary, Olivier, Lioger, Bertrand, Hermine, Olivier, Park, Sophie, Ades, Lionel, Montestruc, François, Ricard, Laure, Gardin, Claude, Fenaux, Pierre, and Fain, Olivier
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AUTOIMMUNE diseases , *RETROSPECTIVE studies , *INFLAMMATION treatment , *CHRONIC myeloid leukemia , *STEROID drugs , *DIAGNOSIS , *THERAPEUTICS ,MEDICAL literature reviews - Abstract
We wanted to describe the characteristics, treatment and outcome of autoimmune and inflammatory diseases (SAIDs) associated with chronic myelomonocytic leukemia (CMML), and conducted a French multicenter retrospective study and a literature review. We included 26 cases of CMML (median age 75 years, 54% female), 80% with CMML-1. CPSS score was low (0 or 1) in 75% of cases. SAIDS was systemic vasculitis in 54%. Diagnosis of the 2 diseases was concomitant in 31% cases, and CMML was diagnosed before SAIDs in 12 cases (46%). First line treatment for SAIDs consisted mostly of steroid, with 85% of response. Second-line treatment was needed in 40% cases. Six patients received hypomethylating agents, with 66% response on SAIDs. A literature review found 49 cases of CMML-associated SAIDs, in whom SAIDs was systemic vasculitis in 29% cases. Hence, vasculitis is the most frequent SAIDs associated with CMML. After initial response to steroids, recurrence and steroid-dependence were frequent. Hypomethylating agents may be interesting in this context. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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222. Efficacy of Azacitidine in autoimmune and inflammatory disorders associated with myelodysplastic syndromes and chronic myelomonocytic leukemia.
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Fraison, Jean-Baptiste, Mekinian, Arsène, Grignano, Eric, Kahn, Jean-Emmanuel, Arlet, Jean-Benoit, Decaux, Olivier, Denis, Guillaume, Buchdahl, Anne-Laure, Omouri, Mohamed, Maigne, Gwenola, Aouba, Achille, Leon, Nathalie, Berthier, Sabine, Liozon, Eric, Park, Sophie, Gardin, Claude, Lortholary, Olivier, Rossignol, Julien, Fenaux, Pierre, and Fain, Olivier
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AZACITIDINE , *AUTOIMMUNE disease treatment , *DRUG efficacy , *MYELODYSPLASTIC syndromes , *CHRONIC leukemia , *IMMUNOSUPPRESSIVE agents - Abstract
This retrospective study describes efficacy of Azacitidine on autoimmune disorders (AID) associated with MDS/CMML in 22 patients. Response of AID to Azacitidine was observed in 19 patients (86%). Reduction or discontinuation of steroids and/or immunosuppressive therapy (IST) was possible in 16 cases (73%). Hematologic response was seen in 55% of the patients. MDS/CMML and AID evolution was concordant in 13 cases (59%): both favorable (n = 11), both unfavorable (n = 2), but AID improved while MDS/CMML worsened (n = 8) and vice versa (n = 1). Azacitidine frequently seems effective in controlling steroid-dependent AID associated with MDS/CMML, but prospective studies are necessary to confirm those findings. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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223. Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure.
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Harel, Stéphanie, Cherait, Amina, Berthon, Céline, Willekens, Christophe, Park, Sophie, Rigal, Marthe, Brechignac, Sabine, Thépot, Sylvain, Quesnel, Bruno, Gardin, Claude, Adès, Lionel, Fenaux, Pierre, and Braun, Thorsten
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MYELODYSPLASTIC syndromes , *HEALTH outcome assessment , *DECITABINE , *AZACITIDINE , *HEMATOPOIETIC stem cell transplantation , *PATIENTS , *DISEASE risk factors , *THERAPEUTICS - Abstract
Outcome of patients with high risk MDS and CMML who failed treatment with azacitidine remains poor with a median survival of 6 months, without established therapy available except allogeneic hematopoietic stem cell transplantation. The objective of our study was to evaluate efficacy of decitabine after azacitidine failure in a relatively large patient cohort based on conflicting results with 0–28% response rates (RR) in this setting in small patient series. Thirty-six consecutive high risk MDS and CMML patients who received decitabine after azacitidine failure were retrospectively reviewed. Response was based on IWG 2006 criteria for MDS and CMML with WBC <13 G/l and also included for proliferative CMML the evolution of WBC, splenomegaly (SMG) and extramedullary disease (EMD). Patients received a median number of 3 (range 1–27) cycles of decitabine and 12 patients received at least 6 cycles. Seven (19.4%) patients were responders including 3 marrow CR (mCR), 2 stable disease (SD) with HI-E, 1 SD with HI-N and HI-P and 1 SD with HI-N. In a CMML patient with SD, specific skin lesions resolved with decitabine. Responses were generally short lived (2–5 months) except 1 responder currently ongoing with +11 months follow up. Two non-responders had prolonged SD (without HI) of 21 and 27 months duration respectively. Median OS from onset of decitabine was 7.3 months, without significant difference between responders and non-responders. Treatment with decitabine after azacitidine failure yielded modest ORR (19.4%) with short response duration and poor OS. Thus, use of decitabine in such patients who failed or progressed after azacitidine cannot be recommended, underscoring the need for novel strategies in this setting. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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224. Outcome of treatment after first relapse in younger adults with acute myeloid leukemia initially treated by the ALFA-9802 trial
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Thomas, Xavier, Raffoux, Emmanuel, Renneville, Aline, Pautas, Cécile, de Botton, Stéphane, de Revel, Thierry, Reman, Oumedaly, Terré, Christine, Gardin, Claude, Chelghoum, Youcef, Boissel, Nicolas, Quesnel, Bruno, Cordonnier, Catherine, Bourhis, Jean-Henri, Elhamri, Mohamed, Fenaux, Pierre, Preudhomme, Claude, Socié, Gérard, Michallet, Mauricette, and Castaigne, Sylvie
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ACUTE myeloid leukemia treatment , *HEALTH outcome assessment , *STEM cell transplantation , *CLINICAL trials , *MEDICAL statistics , *ADOLESCENT medicine , *CANCER relapse - Abstract
Abstract: Forty-seven percent of adults with acute myeloid leukemia (AML) who entered the ALFA-9802 trial and achieved a first complete remission (CR) experienced a first relapse. We examined the outcome of these 190 adult patients. Eighty-four patients (44%) achieved a second CR. The median overall survival (OS) after relapse was 8.9months with a 2-year OS at 25%. Factors predicting a better outcome after relapse were stem cell transplant (SCT) performed in second CR and a first CR duration >1year. Risk groups defined at the time of diagnosis and treatment received in first CR also influenced the outcome after relapse. The best results were obtained in patients with core binding factor (CBF)-AML, while patients initially defined as favorable intermediate risk showed a similar outcome after relapse than those initially entering the poor risk group. We conclude that most adult patients with recurring AML could not be rescued using current available therapies, although allogeneic SCT remains the best therapeutic option at this stage of the disease. [Copyright &y& Elsevier]
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- 2012
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225. Minimal residual disease monitoring based on FLT3 internal tandem duplication in adult acute myeloid leukemia
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Abdelhamid, Emna, Preudhomme, Claude, Helevaut, Nathalie, Nibourel, Olivier, Gardin, Claude, Rousselot, Philippe, Castaigne, Sylvie, Gruson, Bérengère, Berthon, Céline, Soua, Zohra, and Renneville, Aline
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MYELOID leukemia , *BIOMARKERS , *POLYMERASE chain reaction , *GENETIC mutation , *GENE expression , *POLYMERIZATION - Abstract
Abstract: FLT3 internal tandem duplication (FLT3-ITD) is usually considered as a bad marker for minimal residual disease (MRD) follow-up in acute myeloid leukemia (AML). Our objective was to evaluate the suitability of FLT3-ITD as a target for MRD detection by real-time quantitative PCR, in comparison with two other molecular MRD markers, NPM1 mutation and WT1 overexpression, in 20 adult AML patients treated in Acute Leukemia French Association (ALFA) trials. Overall, these 3 MRD markers showed comparable kinetics in 17/20 (85%) cases. Furthermore, we found that FLT3-ITD MRD levels after induction chemotherapy are predictive of complete remission duration. [Copyright &y& Elsevier]
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- 2012
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226. Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: Delineation of anti-leukemic mechanisms of action
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Lainey, Elodie, Thépot, Sylvain, Bouteloup, Cyrielle, Sébert, Marie, Adès, Lionel, Tailler, Maximilien, Gardin, Claude, de Botton, Stéphane, Baruchel, André, Fenaux, Pierre, Kroemer, Guido, and Boehrer, Simone
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PROTEIN-tyrosine kinases , *ENZYME inhibitors , *ACUTE myeloid leukemia treatment , *DRUG development , *ENZYME kinetics , *CANCER cells , *EPIDERMAL growth factor , *APOPTOSIS - Abstract
Abstract: Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit “off-target” effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti-leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects. [Copyright &y& Elsevier]
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- 2011
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227. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial.
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Braun, Thorsten, Itzykson, Raphael, Renneville, Aline, Renzis, Benoit de, Dreyfus, François, Laribi, Kamel, Bouabdallah, Krimo, Vey, Norbert, Toma, Andrea, Recher, Christian, Royer, Bruno, Joly, Bertrand, Vekhoff, Anne, Lafon, Ingrid, Sanhes, Laurence, Meurice, Guillaume, Oréar, Cédric, Preudhomme, Claude, Gardin, Claude, and Ades, Lionel
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HYDROXYUREA , *LEUKEMIA treatment , *SURVIVAL analysis (Biometry) , *HEALTH outcome assessment , *BIOMARKERS , *CLINICAL trials , *GENE expression - Abstract
Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1γ, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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228. Which AML Subsets Benefit From Leukemic Cell Priming During Chemotherapy? Long-Term Analysis of the ALFA-9802 GM-CSF Study.
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Thomas, Xavier, Raffoux, Emmanuel, Renneville, Aline, Pautas, Cecile, de Botton, Stephane, Terre, Christine, Gardin, Claude, Hayette, Sandrine, Preudhomme, Claude, and Dombret, Herve
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GRANULOCYTE-macrophage colony-stimulating factor , *ACUTE myeloid leukemia , *CELL cycle , *CYTOGENETICS , *GENETIC mutation , *SPONTANEOUS cancer regression , *PATIENTS , *THERAPEUTICS - Abstract
The article presents a study on leukemic cell priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) which may modulate cell cycle kinetics and susceptible to phase-specific chemotherapeutic agents. In this study, cytogenetics, mutation detection and statistical analysis were used to 259 patients with acute myeloid leukemia (AML). The results show that priming of leukemia cells with GM-CSF may enhance complete remission (CR) rate and event-free survival (EFS).
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- 2010
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229. Erlotinib and gefitinib for the treatment of myelodysplastic syndrome and acute myeloid leukemia: A preclinical comparison
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Boehrer, Simone, Adès, Lionel, Galluzzi, Lorenzo, Tajeddine, Nicolas, Tailler, Maximilien, Gardin, Claude, de Botton, Stéphane, Fenaux, Pierre, and Kroemer, Guido
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CHEMICAL inhibitors , *EPIDERMAL growth factor , *MYELODYSPLASTIC syndromes treatment , *MYELOID leukemia , *LEUKEMIA treatment , *APOPTOSIS , *PROTEIN-tyrosine kinases , *CELL differentiation , *THERAPEUTICS - Abstract
Abstract: Erlotinib and gefitinib, two inhibitors of the epidermal growth factor receptor (EGFR), can stimulate apoptosis and differentiation of myeloid cell lines that lack EGFR, unveiling a novel, therapeutically exploitable off-target effect of tyrosine kinase inhibitors. Here, we performed a side-by-side comparison of erlotinib and gefitinib effects on a broad spectrum of malignant myeloid cell lines, as well as on primary myeloblasts freshly purified from the bone marrow of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Both erlotinib and gefitinib induce apoptosis of a cell line (KG-1) that represents AML, and differentiation in another cell line (P39) derived from a patient with high-risk MDS. In this setting, erlotinib was more efficient than gefitinib. Erlotinib and gefitinib were equipotent in inducing apoptosis of primary CD34+ myeloblasts from MDS and AML patients, yet had no toxic effect on CD34+ progenitor cells from healthy donors. Although the response of individual MDS and AML patients in vitro was highly heterogeneous, the pro-apoptotic effects of erlotinib and gefitinib correlated significantly. These results suggest that erlotinib and gefitinib share a mechanistically related off-target effect that may be taken advantage of for the therapy of MDS and AML. [Copyright &y& Elsevier]
- Published
- 2008
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230. Synchronous FIP1L1–PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy.
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Capovilla, Mathieu, Cayuela, Jean-Michel, Bilhou-Nabera, Chrystèle, Gardin, Claude, Letestu, Remi, Baran-Marzak, Fanny, Fenaux, Pierre, and Martin, Antoine
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LEUKEMIA , *ANEMIA , *EOSINOPHILIA , *LEUCOCYTOSIS , *T cells , *B cells , *CANCER - Abstract
Several reports of successful empirical treatment of idiopathic hypereosinophilic syndrome with imatinib led to the recent identification of the FIP1L1–PDGFRA fusion gene rearrangement, which characterizes a distinctive group of chronic eosinophilic leukemias. This fusion gene can be detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes in FIP1L1–PDGFRA-positive hypereosinophilic patients suggesting a multilineage involvement. Furthermore, the same FIP1L1–PDGFRA rearrangement was identified in patients with hypereosinophilia and atypical mast cell proliferations, raising the question of a disease with two concomitant lines of differentiation. In addition, a recent report noted two cases with the association of FIP1L1–PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma (T-LBL). We report here the only third case of synchronous chronic eosinophilic leukemia and T-LBL, both associated with a FIP1L1–PDGFRA fusion transcript, confirming the occurrence of such disease and suggesting a clonal proliferation with two lines of differentiation probably arising from a primitive multipotent medullary stem cell. [ABSTRACT FROM AUTHOR]
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- 2008
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231. Efficacy of granulocyte and granulocyte-macrophage colony-stimulating factors in the induction treatment of adult acute lymphoblastic leukemia: a multicenter randomized study.
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Thomas, Xavier, Boiron, Jean-Michel, Huguet, Francoise, Reman, Oumedaly, Sutton, Laurent, Turlure, Pascal, Garban, Fré déric, Gardin, Claude, Espinouse, Daniel, Boulat, Olivier, Lhéritier, Véronique, and Fiere, Denis
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- *
LYMPHOBLASTIC leukemia , *DRUG therapy , *NEUTROPENIA , *PROGNOSIS , *GRANULOCYTE-macrophage colony-stimulating factor , *HEMATOLOGY , *MEDICAL research - Abstract
In all, 236 adults with newly diagnosed acute lymphoblastic leukemia (ALL) were randomly assigned to receive either granulocyte colony-stimulating factor (G-CSF), or granulocyte- macrophage CSF (GM-CSF), or no CSF during a 4-week 4-drugs induction chemotherapy. Two successive trials were performed. CSFs were given from the last infusion of anthracycline in Trial 1 or from day 4 of induction therapy in Trial 2 until neutrophil recovery. A total of 95 patients were included in the G-CSF group, 67 in the GM-CSF group, and 74 in the control group. Overall, CSFs showed a trend for a reduced incidence of severe infections and of days with antibiotics. Median time for neutrophil recovery was 17 days with G-CSF, 18 days with GM-CSF, and 21 days without CSF. In Trial 2, duration of hospitalization was significantly lower in the G-CSF group than in the other groups (P<0.05). Time to neutrophil recovery was also significantly shorter (P<0.05) and severe infections were lower in the G-CSF group (P= 0.01). CR rate was higher in the GM-CSF group as compared to the control group. This tended to be confirmed for the most aggressive ALL and was statistically significant for Philadelphia-positive ALL after salvage therapy (P = 0.04). There were no significant differences between the three groups in terms of disease-free survival. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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232. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial.
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de Botton, Stéphane, Chevret, Sylvie, Sanz, Miguel, Dombret, Hervé, Thomas, Xavier, Guerci, Agnès, Fey, Martin, Rayon, Consuelo, Huguet, Françoise, Sotto, Jean-Jacques, Gardin, Claude, Cony Makhoul, Pascale, Travade, Philippe, Solary, Eric, Fegueux, Nathalie, Bordessoule, Dominique, San Miguel, Jesus, Link, Harmut, Desablens, Bernard, and Stamatoullas, Aspasia
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CHROMOSOME abnormalities , *LEUKEMIA , *DRUG therapy , *LEUCOCYTES , *MYELOID leukemia - Abstract
In spite of the recent improvement in the outcome of acute promyelocytic leukaemia (APL) with treatment combining all trans retinoic acid (ATRA) and chemotherapy (CT), some patients with this disease still have a poor outcome. The prognostic significance of chromosomal abnormalities in addition to t(15;17) in APL is uncertain. We examined the prognostic significance of secondary chromosomal changes in 292 patients included in a European trial who were treated with ATRA and CT. The incidence of chromosomal abnormalities in addition to t(15;17) was 26% and trisomy 8 was the most frequent secondary change (46% of the cases with secondary changes). No significant differences were seen with regard to age, sex, initial white blood cell count, % of circulating blasts, platelet count, fibrinogen level and incidence of microgranular variants between patients with or without additional rearrangements. Outcome was also similar between patients with t(15;17) alone and patients with t(15;17) and other clonal abnormalities for complete remission (92% vs. 93% respectively), event-free survival at 2 years (76·1% vs. 78·1% respectively), relapse at 2 years (16·7% vs. 11·6% respectively) and overall survival at 2 years (79·9% vs. 79·5% respectively). Analysis according to the type of induction treatment (ATRA followed by CT or ATRA plus CT) or the type of maintenance treatment (with ATRA, low-dose CT or both) also failed to show any difference between the two groups. Thus, in a large cohort of APL patients treated with ATRA and CT, additional chromosomal abnormalities had no impact on prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2000
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233. Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells.
- Author
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Djamai, Hanane, Berrou, Jeannig, Dupont, Mélanie, Kaci, Anna, Ehlert, Jan Erik, Weber, Holger, Baruchel, André, Paublant, Fabrice, Prudent, Renaud, Gardin, Claude, Dombret, Hervé, and Braun, Thorsten
- Subjects
- *
ACUTE myeloid leukemia , *SMALL molecules , *DECITABINE , *AZACITIDINE , *CELLS , *CELL growth - Abstract
• LIM kinase 1 and 2 are expressed in FLT3-ITD mutated AML cell lines. • The LIMK1/2 inhibitor CEL_Amide has antiproliferative effects in those cells. • CEL_Amide synergizes with FLT3-ITD inhibitors in vitro and in vivo. • Dephosphorylation of cofilin constitutes a potential biomarker for LIMK1/2 action. Patients with FLT3-ITD mutated (FLT3-ITD+) Acute Myeloid Leukemia (AML), have frequently relapsed or refractory disease and FLT3-ITD+ inhibitors have limited efficacy. Rho kinases (ROCK) are constitutively activated by FLT3-ITD+ in AML via PI3 kinase and Rho GTPase. Upon activation by ROCK, LIM kinases (LIMK) inactivate cofilin by phosphorylation which affects cytoskeleton dynamics, cell growth and apoptosis. LIMK inhibition leads to cofilin activation via dephosphorylation and activated cofilin localizes to mitochondria inducing apoptosis. Thus, we investigated the therapeutic potential of the LIMK1/2 inhibitor CEL_Amide (LIMKi) in FLT3-ITD+ AML. Expression of LIMK1/2 in FLT3-ITD+ cell lines MOLM-13 and MV-4-11 cells could be detected by RT-qPCR and at the protein level. IC50 after LIMKi monotherapy was 440 nM in MOLM-13 cells and 420 nM in MV4-11 cells. Treatment with LIMKi decreased LIMK1 protein levels and repression of inactivating phosphorylation of cofilin in FLT3-ITD+ cells. Combination experiments with LIMKi and FLT3 inhibitors including midostaurin, crenolanib and gilteritinib were synergistic for treatment of MOLM-13 cells while combinations with quizartinib were additive. Combinations of LIMKi and the hypomethylating agent azacitidine or the ROCK inhibitor fasudil were additive. In NOD-SCID mice engrafted with MOLM13-LUC cells, the FLT3 inhibitor midostaurin and LIMKi delayed MOLM13-LUC engraftment as detected by in vivo bioluminescence imaging and the LIMKi and midostaurin combination prolonged significantly survival of leukemic mice. LIMK1/2 inhibition by the small molecule CEL_Amide seems to have promising activity in combination with FLT3 inhibitors in vitro as well as in vivo and may constitute a novel treatment strategy for FLT3-ITD+ AML. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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234. Outcome of acute myeloid leukaemia following myelodysplastic syndrome after azacitidine treatment failure.
- Author
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Prébet, Thomas, Gore, Steven D., Thépot, Sylvain, Esterni, Benjamin, Quesnel, Bruno, Beyne Rauzy, Odile, Dreyfus, François, Gardin, Claude, Fenaux, Pierre, and Vey, Norbert
- Subjects
- *
LEUKEMIA , *DISEASE complications , *DYSPLASIA , *CELL transformation , *CELLULAR pathology - Abstract
The article presents information on a study which showed that the outcome of high risk myelodysplastic syndrome (MDS) after azacitidine (AZA) failure. The study the outcome of 74 patients with secondary acute myeloid leukaemia (AML) after AZA treatment failure, collected from two Johns Hopkins University trials and the French AZA compassionate programme.
- Published
- 2012
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235. BET inhibitors impair leukemic stem cell function only in defined oncogenic subgroups of acute myeloid leukaemias.
- Author
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Massé, Aline, Roulin, Louise, Pasanisi, Justine, Penneroux, Justine, Gachet, Stéphanie, Delord, Marc, Ali, Ashfaq, Alberdi, Antonio, Berrou, Jeannig, Passet, Marie, Hernandez, Lucie, Quentin, Samuel, Gardin, Claude, Raffoux, Emmanuel, Adès, Lionel, Braun, Thorsten, Soulier, Jean, Clappier, Emmanuelle, Dombret, Hervé, and Puissant, Alexandre
- Subjects
- *
CELL physiology , *STEM cells , *LEUKEMIA , *GENE fusion , *GAMBLING - Abstract
Bromodomain and Extra-Terminal inhibitors (BETi) such as OTX015 are active in Acute Myeloid Leukaemias (AML). Their activity on Leukemic Stem Cells (LSCs) is less documented. We interrogated the anti-LSC activity of OTX015 in a niche-like long-term culture in 26 primary AML samples and validated our findings in vivo. OTX015 impaired LSCs in AMLs harbouring Core Binding Factor or KMT2A gene fusions, NPM1 or chromatin/spliceosome genes mutations, but not in those with aneuploidy/TP53 mutations. In four patients, we dissected the transcriptomic footprint of Bet inhibition on LSCs versus blasts. Our results can instruct future clinical trials of BETi in AML. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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236. To the editor: Long-term outcome of higher-risk MDS patients treated with azacitidine: an update of the GFM compassionate program cohort.
- Author
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Itzykson, Raphael, Thépot, Sylvain, Quesnel, Bruno, Dreyfus, Francois, Recher, Christian, Wattel, Eric, Gardin, Claude, Adès, Lionel, and Fenaux, Pierre
- Subjects
- *
LETTERS to the editor , *MYELODYSPLASTIC syndromes , *AZACITIDINE , *PATIENTS - Abstract
A letter to the editor is presented which talks about the risks associated with azacitidine treatment of myelodysplastic syndromes (MDS) patients is presented.
- Published
- 2012
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237. UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.
- Author
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Duployez N, Vasseur L, Kim R, Largeaud L, Passet M, L'Haridon A, Lemaire P, Fenwarth L, Geffroy S, Helevaut N, Celli-Lebras K, Adès L, Lebon D, Berthon C, Marceau-Renaut A, Cheok M, Lambert J, Récher C, Raffoux E, Micol JB, Pigneux A, Gardin C, Delabesse E, Soulier J, Hunault M, Dombret H, Itzykson R, Clappier E, and Preudhomme C
- Subjects
- Adult, Child, Humans, Disease-Free Survival, fms-Like Tyrosine Kinase 3 genetics, Mutation, Prognosis, Remission Induction, Leukemia, Myeloid, Acute genetics
- 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., (© 2023. The Author(s).)
- Published
- 2023
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238. Relative Mitochondrial Priming Predicts Survival in Older AML Patients Treated Intensively.
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Dal Bello R, Pacchiardi K, Chauvel C, Adès L, Braun T, Pasanisi J, Fournier E, Berthon C, Clappier E, Raffoux E, Lebon D, Cluzeau T, Roumier C, Plesa A, Celli-Lebras K, Dombret H, Preudhomme C, Mathis S, Puissant A, Gardin C, and Itzykson R
- Published
- 2022
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239. Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study.
- Author
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Duployez N, Largeaud L, Duchmann M, Kim R, Rieunier J, Lambert J, Bidet A, Larcher L, Lemoine J, Delhommeau F, Hirsch P, Fenwarth L, Kosmider O, Decroocq J, Bouvier A, Le Bris Y, Ochmann M, Santagostino A, Adès L, Fenaux P, Thomas X, Micol JB, Gardin C, Itzykson R, Soulier J, Clappier E, Recher C, Preudhomme C, Pigneux A, Dombret H, Delabesse E, and Sébert M
- Subjects
- DEAD-box RNA Helicases genetics, Female, Germ-Line Mutation, Humans, Male, Prognosis, Prospective Studies, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy
- 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)., (© 2022 by The American Society of Hematology.)
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- 2022
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240. Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia.
- Author
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Pardieu B, Pasanisi J, Ling F, Dal Bello R, Penneroux J, Su A, Joudinaud R, Chat L, Wu HC, Duchmann M, Sodaro G, Chauvel C, Castelli FA, Vasseur L, Pacchiardi K, Belloucif Y, Laiguillon MC, Meduri E, Vaganay C, Alexe G, Berrou J, Benaksas C, Forget A, Braun T, Gardin C, Raffoux E, Clappier E, Adès L, de Thé H, Fenaille F, Huntly BJ, Stegmaier K, Dombret H, Fenouille N, Lobry C, Puissant A, and Itzykson R
- Subjects
- Cell Line, Tumor, Cysteine, Daunorubicin pharmacology, Daunorubicin therapeutic use, Humans, Nuclear Proteins, Sulfasalazine pharmacology, Sulfasalazine therapeutic use, Cystine metabolism, Cystine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
By querying metabolic pathways associated with leukemic stemness and survival in multiple AML datasets, we nominated SLC7A11 encoding the xCT cystine importer as a putative AML dependency. Genetic and chemical inhibition of SLC7A11 impaired the viability and clonogenic capacity of AML cell lines in a cysteine-dependent manner. Sulfasalazine, a broadly available drug with xCT inhibitory activity, had anti-leukemic activity against primary AML samples in ex vivo cultures. Multiple metabolic pathways were impacted upon xCT inhibition, resulting in depletion of glutathione pools in leukemic cells and oxidative stress-dependent cell death, only in part through ferroptosis. Higher expression of cysteine metabolism genes and greater cystine dependency was noted in NPM1-mutated AMLs. Among eight anti-leukemic drugs, the anthracycline daunorubicin was identified as the top synergistic agent in combination with sulfasalazine in vitro. Addition of sulfasalazine at a clinically relevant concentration significantly augmented the anti-leukemic activity of a daunorubicin-cytarabine combination in a panel of 45 primary samples enriched in NPM1-mutated AML. These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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241. Machine learning identifies the independent role of dysplasia in the prediction of response to chemotherapy in AML.
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Duchmann M, Wagner-Ballon O, Boyer T, Cheok M, Fournier E, Guerin E, Fenwarth L, Badaoui B, Freynet N, Benayoun E, Lusina D, Garcia I, Gardin C, Fenaux P, Pautas C, Quesnel B, Turlure P, Terré C, Thomas X, Lambert J, Renneville A, Preudhomme C, Dombret H, Itzykson R, and Cluzeau T
- Subjects
- Adult, Aged, Cytogenetic Analysis, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Machine Learning, Male, Megakaryocytes pathology, Middle Aged, Prognosis, Treatment Outcome, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
The independent prognostic impact of specific dysplastic features in acute myeloid leukemia (AML) remains controversial and may vary between genomic subtypes. We apply a machine learning framework to dissect the relative contribution of centrally reviewed dysplastic features and oncogenetics in 190 patients with de novo AML treated in ALFA clinical trials. One hundred and thirty-five (71%) patients achieved complete response after the first induction course (CR). Dysgranulopoiesis, dyserythropoiesis and dysmegakaryopoiesis were assessable in 84%, 83% and 63% patients, respectively. Multi-lineage dysplasia was present in 27% of assessable patients. Micromegakaryocytes (q = 0.01), hypolobulated megakaryocytes (q = 0.08) and hyposegmented granulocytes (q = 0.08) were associated with higher ELN-2017 risk. Using a supervised learning algorithm, the relative importance of morphological variables (34%) for the prediction of CR was higher than demographic (5%), clinical (2%), cytogenetic (25%), molecular (29%), and treatment (5%) variables. Though dysplasias had limited predictive impact on survival, a multivariate logistic regression identified the presence of hypolobulated megakaryocytes (p = 0.014) and micromegakaryocytes (p = 0.035) as predicting lower CR rates, independently of monosomy 7 (p = 0.013), TP53 (p = 0.004), and NPM1 mutations (p = 0.025). Assessment of these specific dysmegakarypoiesis traits, for which we identify a transcriptomic signature, may thus guide treatment allocation in AML., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2022
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242. Biological Effects of BET Inhibition by OTX015 (MK-8628) and JQ1 in NPM1-Mutated (NPM1c) Acute Myeloid Leukemia (AML).
- Author
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Djamai H, Berrou J, Dupont M, Coudé MM, Delord M, Clappier E, Marceau-Renaut A, Kaci A, Raffoux E, Itzykson R, Berthier C, Wu HC, Hleihel R, Bazarbachi A, de Thé H, Baruchel A, Gardin C, Dombret H, and Braun T
- Abstract
BET inhibitors (BETi) including OTX015 (MK-8628) and JQ1 demonstrated antileukemic activity including NPM1c AML cells. Nevertheless, the biological consequences of BETi in NPM1c AML were not fully investigated. Even if of better prognosis AML patients with NPM1c may relapse and treatment remains difficult. Differentiation-based therapy by all trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) demonstrated activity in NPM1c AML. We found that BETi, similar to ATO + ATRA, induced differentiation and apoptosis which was TP53 independent in the NPM1c cell line OCI-AML3 and primary cells. Furthermore, BETi induced proteasome-dependent degradation of NPM1c. BETi degraded NPM1c in the cytosol while BRD4 is degraded in the nucleus which suggests that restoration of the NPM1/BRD4 equilibrium in the nucleus of NPM1c cells is essential for the efficacy of BETi. While ATO + ATRA had significant biological activity in NPM1c IMS-M2 cell line, those cells were resistant to BETi. Gene profiling revealed that IMS-M2 cells probably resist to BETi by upregulation of LSC pathways independently of the downregulation of a core BET-responsive transcriptional program. ATO + ATRA downregulated a NPM1c specific HOX gene signature while anti-leukemic effects of BETi appear HOX gene independent. Our preclinical results encourage clinical testing of BETi in NPM1c AML patients.
- Published
- 2021
- Full Text
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243. Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy.
- Author
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Itzykson R, Fournier E, Berthon C, Röllig C, Braun T, Marceau-Renaut A, Pautas C, Nibourel O, Lemasle E, Micol JB, Adès L, Lebon D, Malfuson JV, Gastaud L, Goursaud L, Raffoux E, Wattebled KJ, Rousselot P, Thomas X, Chantepie S, Cluzeau T, Serve H, Boissel N, Terré C, Celli-Lebras K, Preudhomme C, Thiede C, Dombret H, Gardin C, and Duployez N
- Subjects
- Aged, Aged, 80 and over, Cytogenetics, Disease-Free Survival, Female, Follow-Up Studies, Humans, Male, Middle Aged, Survival Rate, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Mutation, Neoplasm Proteins genetics
- 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., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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244. Prognostic significance of concurrent gene mutations in intensively treated patients with IDH-mutated AML: an ALFA study.
- Author
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Duchmann M, Micol JB, Duployez N, Raffoux E, Thomas X, Marolleau JP, Braun T, Adès L, Chantepie S, Lemasle E, Berthon C, Malfuson JV, Pautas C, Lambert J, Boissel N, Celli-Lebras K, Caillot D, Turlure P, Vey N, Pigneux A, Recher C, Terré C, Gardin C, Itzykson R, Preudhomme C, Dombret H, and de Botton S
- Subjects
- Abnormal Karyotype, Aged, Chromosome Aberrations, Clinical Trials as Topic statistics & numerical data, DNA Methyltransferase 3A genetics, Disease-Free Survival, Female, France epidemiology, Humans, In Situ Hybridization, Fluorescence, Isocitrate Dehydrogenase deficiency, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Neoplasm Proteins deficiency, Nucleophosmin genetics, Proportional Hazards Models, Prospective Studies, Retrospective Studies, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Neoplasm Proteins genetics, Point Mutation
- Abstract
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., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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245. A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia.
- Author
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Fenwarth L, Thomas X, de Botton S, Duployez N, Bourhis JH, Lesieur A, Fortin G, Meslin PA, Yakoub-Agha I, Sujobert P, Dumas PY, Récher C, Lebon D, Berthon C, Michallet M, Pigneux A, Nguyen S, Chantepie S, Vey N, Raffoux E, Celli-Lebras K, Gardin C, Lambert J, Malfuson JV, Caillot D, Maury S, Ducourneau B, Turlure P, Lemasle E, Pautas C, Chevret S, Terré C, Boissel N, Socié G, Dombret H, Preudhomme C, and Itzykson R
- Subjects
- Adolescent, Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Decision-Making, Clinical Trials, Phase II as Topic statistics & numerical data, Combined Modality Therapy, Datasets as Topic, Female, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Models, Theoretical, Multicenter Studies as Topic statistics & numerical data, Neoplasm, Residual, Nuclear Proteins genetics, Nucleophosmin, Prognosis, Randomized Controlled Trials as Topic statistics & numerical data, Remission Induction, Risk Assessment, Transplantation, Homologous, Young Adult, Algorithms, Hematopoietic Stem Cell Transplantation standards, Leukemia, Myeloid, Acute therapy, Precision Medicine
- Abstract
A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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246. Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results.
- Author
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Gardin C, Pautas C, Fournier E, Itzykson R, Lemasle E, Bourhis JH, Adès L, Marolleau JP, Malfuson JV, Gastaud L, Raffoux E, Lambert J, Braun T, Thomas X, Chantepie S, Cluzeau T, de Botton S, Berthon C, Boissel N, Duployez N, Terré C, Peffault de Latour R, Michallet M, Celli-Lebras K, Preudhomme C, and Dombret H
- Subjects
- Aged, Humans, Middle Aged, Mutation, Prognosis, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes, Neoplasms, Second Primary
- Abstract
In this study, we aimed to refine prognostication of older with acute myeloid leukemia (AML) after intensive chemotherapy. Five hundred and nine patients aged 60 years or older (median age, 68 years) were prospectively enrolled in the intensive Acute Leukemia French Association (ALFA)-1200 trial between 2012 and 2016, and 471 patient samples were submitted to multigene analysis. Mutations in any of 8 genes frequently altered in myelodysplastic syndromes (MDS), including ASXL1, SRSF2, STAG2, BCOR, U2AF1, EZH2, SF3B1, and ZRSR2, defined a secondary AML (sAML)-like disease, as reported. Of the samples analyzed, 48% included sAML-like gene mutations. These mutations were associated with a shorter event-free survival, both overall (hazard ratio, 1.46; 95% confidence interval, 1.19-1.79; P < .001) and within the European LeukemiaNet (ELN)-2017 intermediate-risk subgroup (hazard ratio, 1.52; 95% confidence interval, 1.01-2.28; P = .044), which excludes ASXL1-mutated cases by definition. We therefore included patients with intermediate-risk AML carrying sAML-like mutations in a single high-risk patients group together with adverse-risk patients with AML, whereas other intermediate-risk patients were included in a standard-risk group together with favorable-risk patients (high-risk/standard-risk patient ratio, 1.00). Using this 2-class risk assessment, we observed that transplantation prolonged overall survival from remission in patients with high-risk AML only, not in patients with standard-risk AML. Routine analysis of sAML-like gene mutations may thus improve the definition of high-risk older patients with AML, and better identify the half of older patients who clearly derive survival benefit from allogeneic transplantation in first remission. This trial was registered at www.clinicaltrials.gov as #NCT01966497., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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247. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial.
- Author
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Lambert J, Pautas C, Terré C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, and Castaigne S
- Subjects
- Adult, Aged, Cytarabine administration & dosage, Daunorubicin administration & dosage, Disease-Free Survival, Female, Gemtuzumab administration & dosage, Humans, Male, Middle Aged, Survival Rate, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology
- Abstract
The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival (EFS) in adults with de novo acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with de novo AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m
2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m2 /day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results [August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided P =0.006], corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at clinicaltrials.gov; identifier: 00927498 )., (Copyright© 2019 Ferrata Storti Foundation.)- Published
- 2019
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248. Arsenic trioxide is required in the treatment of newly diagnosed acute promyelocytic leukemia. Analysis of a randomized trial (APL 2006) by the French Belgian Swiss APL group.
- Author
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Adès L, Thomas X, Bresler AG, Raffoux E, Spertini O, Vey N, Marchand T, Récher C, Pigneux A, Girault S, Deconinck E, Gardin C, Tournilhac O, Lambert JF, Chevallier P, de Botton S, Lejeune J, Dombret H, Chevret S, and Fenaux P
- Subjects
- Adult, Anthracyclines administration & dosage, Arsenic Trioxide administration & dosage, Belgium, Disease-Free Survival, Female, France, Humans, Leukemia, Promyelocytic, Acute diagnosis, Male, Middle Aged, Switzerland, Treatment Outcome, Tretinoin administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy
- Abstract
In standard-risk acute promyelocytic leukemia, recent results have shown that all- trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all- trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all- trans retinoic acid and the "classical" cytarabine for consolidation treatment (after all- trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x10
9 /L, after an induction treatment consisting of all- trans retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all- trans retinoic acid. Patients with a white blood cell count >10x109 /L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all- trans retinoic acid consolidation groups, respectively ( P =0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. ( P =0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% ( P =0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% ( P =0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. ( ClinicalTrials.gov Identifier: NCT00378365 )., (Copyright© 2018 Ferrata Storti Foundation.)- Published
- 2018
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249. Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+).
- Author
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Falantes J, Pleyer L, Thépot S, Almeida AM, Maurillo L, Martínez-Robles V, Stauder R, Itzykson R, Pinto R, Venditti A, Bargay J, Burgstaller S, Martínez MP, Seegers V, Cortesão E, Foncillas MÁ, Gardin C, Montesinos P, Musto P, Fenaux P, Greil R, Sanz MA, and Ramos F
- Subjects
- Adult, Aged, Aged, 80 and over, Biomedical Research, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Predictive Value of Tests, Remission Induction, Retrospective Studies, Risk Assessment, Survival Rate, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute mortality, Severity of Illness Index
- Abstract
Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.
- Published
- 2018
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250. Investigational BET bromodomain protein inhibitors in early stage clinical trials for acute myelogenous leukemia (AML).
- Author
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Braun T and Gardin C
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Cell Cycle Proteins, Drug Design, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Leukemia, Myeloid, Acute pathology, Nuclear Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, RNA-Binding Proteins antagonists & inhibitors, Transcription Factors antagonists & inhibitors, Antineoplastic Agents pharmacology, Drugs, Investigational pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Introduction: Acute myelogenous leukemia (AML) is a heterogeneous group of malignancies driven by genetic mutations and deregulated epigenetic control. Relapse/refractory disease remains frequent in younger patients and even more so in older patients, including treatment with epigenetic drugs in this age group, mainly with hypomethylating agents. New treatment strategies are urgently needed. The recent discovery that epigenetic readers of the bromodomain (BRD) and extraterminal (BET) protein family, are crucial for AML maintenance by transcription of oncogenic c-MYC lead to rapid development of BET inhibitors entering clinical trials. Areas covered: We provide a critical overview using main sources for the use of BET inhibitors in AML treatment. Limits of this treatment approach including resistance mechanisms and future directions including development of new generation BET inhibitors and combination strategies with other drugs are detailed. Expert opinion: BET inhibitors were expected to overcome limits of conventional treatment in patients as impressive in vitro data emerged recently in well-characterized AML subsets, including those associated with poor risk characteristics in the clinic. Nevertheless single activity of BET inhibitors appears to be modest and resistance mechanisms were already identified. BET inhibitors with alternative mechanisms of action and/or combination strategies with epigenetic drugs should be tested.
- Published
- 2017
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