156 results on '"Arnaud Pigneux"'
Search Results
2. Prise en charge des LAM chez les sujets âgés
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Pierre-Yves Dumas and Arnaud Pigneux
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging ,Hematology ,General Medicine - Published
- 2023
3. Retrospective, real‐life study of venetoclax plus azacitidine or low‐dose cytarabine in French patients with acute myeloid leukemia ineligible for intensive chemotherapy
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Louise Laloi, Natacha Chaumard Billotey, Pierre‐Yves Dumas, Franciane Paul, Alban Villate, Célestine Simand, Luc Fornecker, Florent Puisset, Sarah Bertoli, Marion Boissard Simonet, Kamel Laribi, Dyhia Houyou, Alberto Santagostino, Claire Michel, Gabrielle Roth Guepin, Elodie Guerineau, Reza Tabrizi, Mathilde Hunault, Aurélien Giltat, Eléonore Kaphan, Claude Bulabois, Elodie Cartet, Clément Rocher, Florence Lachenal, Stéphane Morisset, Christian Récher, Arnaud Pigneux, Amine Belhabri, Mauricette Michallet, and Anne‐Sophie Michallet
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging - Abstract
Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low-dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real-life conditions.This retrospective, real-life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy.Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03-16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second-line/beyond, median progression-free survival was 4.0 months (95% confidence interval [CI] 2.7-12.8) with venetoclax-HMA and 3.4 months (1.3-8.9) with venetoclax-LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax-based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed.
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- 2022
4. First clinical description of a pedigree with complete NAF1 deletion
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Jean Galtier, Sophie Dimicoli-Salazar, Aurélien Trimouille, Elodie Lainey, Patrick Revy, Audrey Bidet, Yoann Vial, Edouard Forcade, Marie-Laure Negrier-Leibreich, Etienne Rivière, Julie Tinat, Nathalie Le Meur, Christelle Ménard, Arnaud Pigneux, Thibaut Leguay, Pierre-Yves Dumas, Ba Ibrahima, and Caroline Kannengiesser
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Cancer Research ,Oncology ,Hematology - Published
- 2022
5. UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia
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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]
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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.
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- 2023
6. Azacitidine, intensive chemotherapy or best supportive care in relapsed or refractory acute myeloid leukemia, a DATAML registry study
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Noémie Gadaud, Harmony Leroy, Emilie Bérard, Suzanne Tavitian, Thibaut Leguay, Sophie Dimicoli-Salazar, Jean-Baptiste Rieu, Isabelle Luquet, Laetitia Largeaud, Audrey Bidet, Eric Delabesse, Emilie Klein, Audrey Sarry, Anne-Charlotte de Grande, Pierre Bories, Arnaud Pigneux, Christian Récher, Pierre-Yves Dumas, and Sarah Bertoli
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Antimetabolites, Antineoplastic ,Leukemia, Myeloid, Acute ,Cancer Research ,Treatment Outcome ,Oncology ,Chronic Disease ,Azacitidine ,Humans ,Registries ,Hematology - Abstract
We analyzed 526 consecutive acute myeloid leukemia patients refractory to or relapsing after chemotherapy. 270 patients received intensive salvage chemotherapy (IC), 97 azacitidine (AZA) and 159 best supportive care (BSC). Complete response was obtained in 37/19/0% (
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- 2022
7. Early detection of WT1 measurable residual disease identifies high-risk patients, independent of transplantation in AML
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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
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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.
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- 2021
8. Gilteritinib activity in refractory or relapsed FLT3-mutated acute myeloid leukemia patients previously treated by intensive chemotherapy and midostaurin: a study from the French AML Intergroup ALFA/FILO
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Pierre-Yves Dumas, Emmanuel Raffoux, Emilie Bérard, Sarah Bertoli, Marie-Anne Hospital, Maël Heiblig, Yohann Desbrosses, Caroline Bonmati, Cécile Pautas, Juliette Lambert, Corentin Orvain, Anne Banos, Florence Pasquier, Pierre Peterlin, Tony Marchand, Madalina Uzunov, Jamilé Frayfer, Pascal Turlure, Thomas Cluzeau, Eric Jourdan, Chantal Himberlin, Emmanuelle Tavernier, Alban Villate, Stephanie Haiat, Marie-Lorraine Chretien, Martin Carre, Sylvain Chantepie, Ioana Vaida, Mathieu Wemeau, Safia Chebrek, Gaelle Guillerm, Romain Guièze, Houria Debarri, Eve Gehlkopf, Kamel Laribi, Ambroise Marcais, Alberto Santagostino, Marie-Christine Béné, Ariane Mineur, Arnaud Pigneux, Hervé Dombret, and Christian Récher
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Cancer Research ,Oncology ,Hematology - Abstract
The real-world efficacy and safety of gilteritinib was assessed in an ambispective study that included 167 R/R FLT3-mutated AML patients. Among them, 140 received gilteritinib as single agent (cohort B), including 67 previously treated by intensive chemotherapy and midostaurin (cohort C). The main differences in patient characteristics in this study compared to the ADMIRAL trial were ECOG ≥ 2 (83.6% vs. 16.6%), FLT3-TKD mutation (21.0% vs. 8.5%), primary induction failure (15.0% vs. 40.0%) and line of treatment (beyond 2nd in 37.1% vs. 0.0%). The rates of composite complete remission, excluding those that occurred after hematopoietic stem cell transplantation (HSCT), were similar at respectively 25.4% and 27.5% in cohorts B and C. Median overall survival (OS) for these two groups was also similar at respectively 6.4 and 7.8 months. Multivariate analyses for prognostic factors associated with OS identified female gender (HR 1.61), adverse cytogenetic risk (HR 2.52), and allogenic HSCT after gilteritinib (HR 0.13). Although these patients were more heavily pretreated, these real-world data reproduce the results of ADMIRAL and provide new insights into the course of patients previously treated by intensive chemotherapy and midostaurin and beyond the 2nd line of treatment who can benefit from treatment in an outpatient setting.
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- 2022
9. A scoring system for AML patients aged 70 years or older, eligible for intensive chemotherapy: a study based on a large European data set using the DATAML, SAL, and PETHEMA registries
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Emilie Bérard, Christoph Röllig, Sarah Bertoli, Arnaud Pigneux, Suzanne Tavitian, Michael Kramer, Hubert Serve, Martin Bornhäuser, Uwe Platzbecker, Carsten Müller-Tidow, Claudia D. Baldus, David Martínez-Cuadrón, Josefina Serrano, Pilar Martínez-Sánchez, Eduardo Rodríguez Arbolí, Cristina Gil, Juan Bergua, Teresa Bernal, Adolfo de la Fuente Burguera, Eric Delabesse, Audrey Bidet, Pierre-Yves Dumas, Pau Montesinos, and Christian Récher
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Leukemia, Myeloid, Acute ,Oncology ,Mutation ,Humans ,Nuclear Proteins ,Hematology ,Registries ,Neoplasm Recurrence, Local ,Prognosis ,Nucleophosmin ,Aged - Abstract
In a context of therapeutic revolution in older adults with AML, it is becoming increasingly important to select patients for the various treatment options by taking account of short-term efficacy and toxicity as well as long-term survival. Here, the data from three European registries for 1,199 AML patients aged 70 years or older treated with intensive chemotherapy were used to develop a prognostic scoring system. The median follow-up was 50.8 months. In the training set of 636 patients, age, performance status, secondary AML, leukocytosis, and cytogenetics, as well as NPM1 mutations (without FLT3-ITD), were all significantly associated with overall survival, albeit not to the same degree. These factors were used to develop a score that predicts long-term overall survival. Three risk-groups were identified: a lower, intermediate and higher-risk score with predicted 5-year overall survival (OS) probabilities of ≥12% (n = 283, 51%; median OS = 18 months), 3–12% (n = 226, 41%; median OS = 9 months) and n = 47, 8%; median OS = 3 months), respectively. This scoring system was also significantly associated with complete remission, early death and relapse-free survival; performed similarly in the external validation cohort (n = 563) and showed a lower false-positive rate than previously published scores. The European Scoring System ≥70, easy for routine calculation, predicts long-term survival in older AML patients considered for intensive chemotherapy.
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- 2022
10. Outcomes of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia receiving ivosidenib who proceeded to hematopoietic stem cell transplant
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Stephanie M. Kapsalis, Arnaud Pigneux, Harry P. Erba, Sung Choe, Courtney D. DiNardo, Gail J. Roboz, Hua Liu, Eytan M. Stein, Justin M. Watts, Robert H. Collins, Stéphane de Botton, Bin Wu, Hongfang Wang, Geoffrey L. Uy, Jessica K. Altman, and Thomas Winkler
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Adult ,Male ,Cancer Research ,IDH1 ,Pyridines ,Mutant ,Glycine ,Antineoplastic Agents ,Article ,Text mining ,Refractory ,Humans ,Medicine ,Aged ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,Combined Modality Therapy ,Isocitrate Dehydrogenase ,Survival Rate ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Oncology ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,Female ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Published
- 2021
11. Abstract CT026: A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies
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Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, and Eytan M. Stein
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Cancer Research ,Oncology - Abstract
Background: LY3410738 is a potent, selective, covalent, dual inhibitor of IDH1/2 mutations (IDH1/2m). LY3410738 binds covalently at a novel binding site, enabling continued potency in preclinical models in the setting of second site IDH resistance mutations. We present initial results from the first-in-human phase 1 dose escalation study of oral LY3410738 in patients (pts) with R/R IDH1/2m hematologic cancers. Methods: Dose escalation (3+3 design) evaluated LY3410738 monotherapy in IDH1/2m R/R AML (NCT04603001). Key objectives included determining the RP2D, safety, PK, PD (inhibition of plasma D-2-HG), and preliminary antitumor activity. Results: As of 28 July 2022, 114 pts including 108 R/R AML pts received LY3410738 dosed at 5-600 mg QD or 40-300 mg BID. Pts were median 73 years of age (range, 22-92) with a median of 2 prior therapies (range, 1-10); 29% received a prior IDH inhibitor and 58% a prior BCL2 inhibitor. Median time on treatment was 2.3 months (range, 0.1-15). No DLTs or treatment related deaths were observed. Treatment emergent adverse events ≥20% were diarrhea (22%), fatigue (21%), and anemia (20%). Differentiation syndrome was reported in 11 pts (10%); 4 grade 1/2 (4%), 7 grade 3 (6%). LY3410738 exposure was dose proportional. In pts with IDH1m cancers, LY3410738 achieved sustained D-2-HG inhibition at all dose levels including in pts who received prior IDH1 inhibitor. In pts with IDH2m cancers, a higher dose (≥150 mg daily dose) was required for D-2-HG inhibition. Responses were observed in both IDH1m and IDH2m AML (Table). Higher doses were required for IDH2m AML, especially IDH2 R140m pts. Efficacy appears higher in venetoclax naïve pts and limited in IDH inhibitor pre-treated pts. Conclusions: LY3410738 demonstrated a favorable safety profile with potent and sustained D-2-HG inhibition in pts with IDH1m R132, IDH2m R172, and IDH2m R140 mutations. Preliminary efficacy was also seen in all genotypes, in a dose dependent manner. RP2D evaluation is ongoing. Table: Response in R/R AML IDH Inhibitor Naive (N=68) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=13) Prior Venetoclax (n=19) Total (N=32) Low Dosesa (n=5) (High Dosesb) Total (N=13) Low Dosesa (n=9) (High Dosesb) Total (N=23) No prior Venetoclax (n=3) Prior Venetoclax (n=5) No prior Venetoclax (n=6) Prior Venetoclax (n=8) CR+CRh, n (%) 5 (38%) 2 (11%) 7 (22%) - 3 (100%) 2 (40%) 5 (38%) - 2 (33%) - 2 (9%) CR, n (%) 3 (23%) 2 (11%) 5 (16%) - 2 (67%) 2 (40%) 4 (31%) - 2 (33%) - 2 (9%) CRh, n (%) 2 (15%) - 2 (6%) - 1 (33%) - 1 (8%) - - - - CRc (CR+CRh+CRi/CRp), n (%) 6 (46%) 6 (32%) 12 (38%) - 3 (100%) 3 (60%) 6 (46%) - 2 (33%) - 2 (9%) MFLS, n (%) 1 (8%) 3 (16%) 4 (13%) 2 (40%) - - 2 (15%) 1 (11%) - - 1 (4%) IDH Inhibitor Pre-Treated (N=33) IDH1 R132 IDH2 R172 IDH2 R140 No prior Venetoclax (n=2) Prior Venetoclax (n=8) Total (N=10) Low Dosesa (n=6) (High Dosesb) Total (N=8) Low Dosesa (n=4) (High Dosesb) Total (N=15) No prior Venetoclax (n=1) Prior Venetoclax (n=1) No prior Venetoclax (n=3) Prior Venetoclax (n=8) CR+CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CR, n (%) - - - - - - - - - - - CRh, n (%) - - - - - - - - - 1 (13%) 1 (7%) CRc (CR+CRh+CRi/CRp), n (%) - - - - - - - 1 (25%) - 1 (13%) 1 (7%) MLFS, n (%) - - - - - - - - - - - Among the 108 treated R/R AML pts, 101 were efficacy evaluable (42 IDH1 R132, 21 IDH2 R172, 38 IDH2 R140); 68 pts were IDH inhibitor naïve and 33 had received a prior IDH inhibitor treatment. Efficacy evaluable pts are those who had completed the first bone marrow assessment or had discontinued treatment prior to first bone marrow assessment aTotal daily low doses: ≤75 mg Arm A, ≤30 mg Arm B bTotal daily high doses: ≥150 mg Arm A, ≥60 mg Arm B Arm A: not requiring a strong CYP3A4 inhibitor Arm B: requiring a strong CYP3A4 inhibitor Citation Format: Courtney D. DiNardo, Pau Montesinos, Lina Benajiba, Ana Triguero, Christian Recher, Andre C. Schuh, Maël Heiblig, Ashish Bajel, Arnaud Pigneux, Juan M. Alonso-Domiguez, Amir T. Fathi, Carolyn Grove, Hsin-An Hou, Michael Heuser, Sarit Assouline, Shaun Fleming, Dong-Yeop Shin, Kendra Sweet, Olatoyosi Odenike, Jessica Altman, Melissa Gaik Ming Ooi, Lao Zhentang, Nobert Vey, Joshua Zeidner, Amandeep Salhotra, Eunice Wang, Gary Schiller, Kimmo Porkka, Tsila Zuckerman, Violaine Havelange, Brian A. Jonas, Sujaatha Narayanan, Jun Ho Jang, Je-Hwan Lee, Anna M. Szpurka, Dana Heirich, Hsiao Rong Chen, Violet Hanft, Junjie Zhao, Ivelina Gueorguieva, Yin Zhang, Eytan M. Stein. A first-in-human phase 1 study of LY3410738, a covalent inhibitor of mutant IDH, in advanced myeloid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT026.
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- 2023
12. Looking for somatic mutations in UBA1 in patients with chronic myelomonocytic leukemia associated with systemic inflammation and autoimmune diseases
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Joël Decombe, Audrey Bidet, Anne-Charlotte De-Grande, Pierre-Yves Dumas, Estibaliz Lazaro, Pierre Duffau, Jean-François Viallard, Charles Dussiau, Etienne Rivière, Mathieu Sauvezie, Henry Dupuy, Arnaud Pigneux, Sophie Dimicoli-Salazar, Edouard Forcade, Fabrice Bonnet, Bordeaux population health (BPH), and Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0303 health sciences ,Cancer Research ,Somatic cell ,business.industry ,Chronic myelomonocytic leukemia ,Hematology ,UBA1 ,Systemic inflammation ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,medicine ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,In patient ,medicine.symptom ,business ,030304 developmental biology - Published
- 2021
13. Antifungal Stewardship in Hematology: Reflection of a Multidisciplinary Group of Experts
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Mauricette Michallet, Jean-Pierre Gangneux, Gilbert Deray, Jean-Paul Mira, Raoul Herbrecht, Jean-François Timsit, Arnaud Pigneux, Yasmine Nivoix, Serge Alfandari, Patricia Ribaud, Mohamad Sobh, Ibrahim Yakoub-Agha, and Dominique Larrey
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0301 basic medicine ,Antifungal ,Cancer Research ,medicine.medical_specialty ,Antifungal Agents ,Hematology ,business.industry ,medicine.drug_class ,030106 microbiology ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Multidisciplinary approach ,Internal medicine ,medicine ,Humans ,Medical physics ,Prospective Studies ,030212 general & internal medicine ,Stewardship ,business - Abstract
We have presented a practical guide developed by a working group of experts in infectious diseases and hematology to summarize the different recommendations issued by the different international groups on antifungal agents used for hematology patients. In addition, a working group of experts in the domains of nephrology, hepatology, and drug interactions have reported their different recommendations when administering antifungal agents, including dose adjustments, monitoring, and management of their side effects. This guide will enable prescribers to have a document available that will allow for better and optimal use of antifungal agents for hematology patients with consideration of the toxicity and interactions adjusted to each indication.
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- 2021
14. Phenotypically-defined stages of leukemia arrest predict main driver mutations subgroups, and outcome in acute myeloid leukemia
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François Vergez, Laetitia Largeaud, Sarah Bertoli, Marie-Laure Nicolau, Jean-Baptiste Rieu, Inès Vergnolle, Estelle Saland, Audrey Sarry, Suzanne Tavitian, Françoise Huguet, Muriel Picard, Jean-Philippe Vial, Nicolas Lechevalier, Audrey Bidet, Pierre-Yves Dumas, Arnaud Pigneux, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Martin Carroll, Gwenn Danet-Desnoyers, Jean-Emmanuel Sarry, and Christian Récher
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Leukemia, Myeloid, Acute ,Oncology ,Core Binding Factor Alpha 2 Subunit ,Mutation ,Humans ,Hematology ,HLA-DR Antigens ,Immunophenotyping - Abstract
Classifications of acute myeloid leukemia (AML) patients rely on morphologic, cytogenetic, and molecular features. Here we have established a novel flow cytometry-based immunophenotypic stratification showing that AML blasts are blocked at specific stages of differentiation where features of normal myelopoiesis are preserved. Six stages of leukemia differentiation-arrest categories based on CD34, CD117, CD13, CD33, MPO, and HLA-DR expression were identified in two independent cohorts of 2087 and 1209 AML patients. Hematopoietic stem cell/multipotent progenitor-like AMLs display low proliferation rate, inv(3) or RUNX1 mutations, and high leukemic stem cell frequency as well as poor outcome, whereas granulocyte–monocyte progenitor-like AMLs have CEBPA mutations, RUNX1-RUNX1T1 or CBFB-MYH11 translocations, lower leukemic stem cell frequency, higher chemosensitivity, and better outcome. NPM1 mutations correlate with most mature stages of leukemia arrest together with TET2 or IDH mutations in granulocyte progenitors-like AML or with DNMT3A mutations in monocyte progenitors-like AML. Overall, we demonstrate that AML is arrested at specific stages of myeloid differentiation (SLA classification) that significantly correlate with AML genetic lesions, clinical presentation, stem cell properties, chemosensitivity, response to therapy, and outcome.
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- 2022
15. Long-term survival after intensive chemotherapy or hypomethylating agents in AML patients aged 70 years and older: a large patient data set study from European registries
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Audrey Bidet, Hubert Serve, Pierre-Yves Dumas, Carsten Müller-Tidow, Josefina Serrano, Teresa Bernal, Sarah Bertoli, Juan Bergua, Eduardo Rodriguez Arbolí, Uwe Platzbecker, Pilar Martínez-Sánchez, Martin Bornhäuser, Eric Delabesse, Adolfo de la Fuente Burguera, Christian Recher, Arnaud Pigneux, Michael Kramer, Claudia D. Baldus, David Martínez-Cuadrón, Pau Montesinos, Emilie Bérard, Cristina Gil, Christoph Röllig, and Suzanne Tavitian
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Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,EARLY DEATH ,NEWLY-DIAGNOSED AML ,Intensive chemotherapy ,ACUTE MYELOID-LEUKEMIA ,REGIMENS ,Lower risk ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Long term survival ,MANAGEMENT ,Humans ,Medicine ,In patient ,VENETOCLAX ,Registries ,ELDERLY-PATIENTS ,AZACITIDINE ,Aged ,Aged, 80 and over ,Chemotherapy ,EPIGENETIC THERAPY ,business.industry ,Significant difference ,Myeloid leukemia ,Hematology ,Patient data ,CARE ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Oncology ,Azacitidine ,business - Abstract
The outcome of acute myeloid leukemia patients aged 70 years or older is poor. Defining the best treatment option remains controversial especially when choosing between intensive chemotherapy and hypomethylating agents. We set up a multicentric European database collecting data of 3 700 newly diagnosed acute myeloid leukemia patients ≥70 years. The primary objective was to compare overall survival in patients selected for intensive chemotherapy (n = 1199) or hypomethylating agents (n = 1073). With a median follow-up of 49.5 months, the median overall survival was 10.9 (95% CI: 9.7–11.6) and 9.2 months (95% CI: 8.3–10.2) with chemotherapy and hypomethylating agents, respectively. Complete remission or complete remission with incomplete hematologic recovery was 56.1% and 19.7% with chemotherapy and hypomethylating agents, respectively (P
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- 2022
16. Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations
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Daniel A. Pollyea, Courtney D. DiNardo, Martha L. Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A. Rizzieri, B. Douglas Smith, Atsushi Shinagawa, Roberto M. Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L. Miller, and Hagop M. Kantarjian
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Cancer Research ,Leukemia, Myeloid, Acute ,Sulfonamides ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Mutation ,Azacitidine ,Humans ,Dancing ,Bridged Bicyclo Compounds, Heterocyclic ,Isocitrate Dehydrogenase ,Aged - Abstract
Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719
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- 2022
17. Autologous stem cell transplantation (ASCT) for acute myeloid leukemia in patients in first complete remission after one versus two induction courses: A study from the ALWP of the EBMT
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Arnon Nagler, Jacques‐Emmanuel Galimard, Myriam Labopin, Didier Blaise, William Arcese, Silvia Maria Trisolini, Depei Wu, Arnaud Pigneux, Gwendolyn Van Gorkom, Marie‐Thérèse Rubio, Tobias Gedde‐Dahl, Anne Huynh, Francesco Lanza, Norbert‐Claude Gorin, Mohamad Mohty, Nagler, Arnon, Galimard, Jacques-Emmanuel, Labopin, Myriam, Blaise, Didier, Arcese, William, Trisolini, Silvia Maria, Wu, Depei, Pigneux, Arnaud, Van Gorkom, Gwendolyn, Rubio, Marie-Thérèse, Gedde-Dahl, Tobia, Huynh, Anne, Lanza, Francesco, Gorin, Norbert-Claude, Mohty, Mohamad, RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Interne Geneeskunde, and MUMC+: MA Hematologie (9)
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Cancer Research ,BLOOD ,complete remission ,CYCLES ,autologous ,acute myeloid leukemia ,stem cell transplantation ,DISEASE ,MARROW ,AML ,Oncology ,WORKING PARTY ,SURVIVAL ,Radiology, Nuclear Medicine and imaging ,IMMUNOTHERAPY ,induction chemotherapy ,autologou - Abstract
Background Achieving complete remission (CR) is the main goal in AML treatment and a prerequisite for successful autologous stem cell transplantation (ACT). Methods Comparing results of peripheral blood ACT in patients with AML in CR1 attained following 1 versus 2 chemotherapy courses transplanted in 2000-2019. Results Patients 1532 (84%) with one and 293 (16%) patients with two induction chemotherapies courses (a total of 1825 patients) were included in the study. Follow-up was 7.9 (95% CI: 7.4-8.4) and 7.7 (95% CI: 7.0-8.6) years (p = 0.8). Time from diagnosis to ACT was 4.7 (range, 3.9-5.8) versus 5.7 (range, 4.7-7.1) months (p < 0.001), respectively. Leukemia free survival (LFS) and overall survival (OS) at 5 years were inferior for patients achieving CR1 with 2 versus 1 course of chemotherapy: 26.6% versus 41.7% (HR = 1.42 [95% CI: 1.22-1.66], p < 0.001) and 36.2% versus 53.3%, (HR = 1.48 [95% CI: 1.25-1.75], p < 0.001), and 5-year relapse incidence (RI) was higher: 67.2% versus 52.3%, (HR = 1.46 [95% CI: 1.25-1.72], p < 0.001). Five-year non-relapse mortality (NRM) was 6.2% versus 6.0% for patients with 2 versus 1 chemotherapy courses, and did not differ significantly (HR = 1.31 [95% CI: 0.81-2.10], p = 0.27). Conclusions LFS and OS were inferior and relapse rate was higher in AML patients who received two inductions chemotherapy courses to reach CR1 before being autografted. AML patients who required 2 induction courses to achieve remission, may be offered allogeneic transplantation rather than an autologous one in an attempt to reduce their high RI and improve outcomes.
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- 2022
18. Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells
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Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, Jean-Max Pasquet, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Etablissement Français du Sang Nouvelle Aquitaine [Bordeaux] (EFS Bordeaux Nouvelle Aquitaine), and Vigon, Isabelle
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[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,Cancer Research ,autophagy ,FLT3-ITD ,leukemic initiating cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,persistence ,acute myeloid leukemia ,Article ,Oncology ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,hemic and lymphatic diseases ,tyrosine kinase inhibitors ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,RC254-282 - Abstract
Simple Summary One of the most frequent molecular anomalies in acute myeloid leukemia (AML) is the mutation of the fms-like receptor tyrosine kinase 3 through internal tandem duplications, giving rise to a constitutive proliferative signaling. Even though clinical trials have shown that targeting this mutated kinase is of interest and well tolerated, there is still a high frequency of relapse. The emergence of AML cells upon treatment is linked to their maintenance through resistance and persistence mechanisms. Because FLT3-ITD AML cells require autophagy, we explored the consequence of autophagy inhibition by blocking the PI3-kinase class III, Vps34, when AML cells were committed. Results in vitro, ex vivo and in vivo suggest that remission with low minimal residual disease in FLT3-ITD AML offers a promising therapeutic window to target persistent leukemic cells. Abstract Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.
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- 2021
19. Intermediate-dose cytarabine or standard-dose cytarabine plus single-dose anthracycline as post-remission therapy in older patients with acute myeloid leukemia: impact on health care resource consumption and outcomes
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François Vergez, Suzanne Tavitian, Audrey Bidet, Pierre-Yves Dumas, Jean-Philippe Vial, Anne-Charlotte de Grande, Sarah Bertoli, Nicolas Lechevalier, Arnaud Pigneux, Emilie Klein, Isabelle Luquet, Jean Galtier, Emilie Bérard, Thibaut Leguay, Eric Delabesse, Christian Recher, Camille Alric, Audrey Sarry, and Jean Baptiste Rieu
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Male ,Oncology ,medicine.medical_specialty ,Anthracycline ,Acute myeloid leukaemia ,Older patients ,Internal medicine ,Correspondence ,Antineoplastic Combined Chemotherapy Protocols ,Health care ,medicine ,Humans ,Anthracyclines ,Registries ,Resource consumption ,RC254-282 ,Aged ,business.industry ,Remission Induction ,Cytarabine ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Myeloid leukemia ,Hematology ,Middle Aged ,Leukemia, Myeloid, Acute ,Female ,business ,medicine.drug - Published
- 2021
20. Dual Inhibition of FLT3 and AXL by Gilteritinib Overcomes Hematopoietic Niche-Driven Resistance Mechanisms in FLT3 -ITD Acute Myeloid Leukemia
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Arnaud Villacreces, Olivier Mansier, Isabelle Vigon, Jean-Max Pasquet, Audrey Bidet, Pierre-Yves Dumas, Amelie V. Guitart, Arnaud Pigneux, Vanessa Desplat, Ali El-habhab, Solène Fernandez, Layal Massara, Delphine Martineau, Thibaut Leguay, CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France, INSERM U1034, Institut National de la Santé et de la Recherche Médicale, University of Bordeaux, Bordeaux, France, Service d'Hématologie Biologique, CHU Bordeaux, Bordeaux, France, Centre National de la Recherche Scientifique (CNRS), 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 Biologique [CHU Bordeaux], CHU Bordeaux [Bordeaux], and Vigon, Isabelle
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Cancer Research ,Stromal cell ,FLT3-ITD ,[SDV]Life Sciences [q-bio] ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,AML ,In vivo ,hemic and lymphatic diseases ,medicine ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Quizartinib ,0303 health sciences ,Chemistry ,leukemia ,Myeloid leukemia ,AXL ,Gilteritinib ,TKI ,microenvironment ,3. Good health ,[SDV] Life Sciences [q-bio] ,Haematopoiesis ,ASP2215 ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Tyrosine kinase ,Ex vivo - Abstract
Purpose: AXL has been shown to play a pivotal role in the selective response of FLT3-ITD acute myeloid leukemia (AML) cells to FLT3 tyrosine kinase inhibitors (TKI), particularly within the bone marrow microenvironment. Experimental Design: Herein, we compared the effect of dual FLT3/AXL-TKI gilteritinib with quizartinib through in vitro models mimicking hematopoietic niche conditions, ex vivo in primary AML blasts, and in vivo with dosing regimens allowing plasma concentration close to those used in clinical trials. Results: We observed that gilteritinib maintained a stronger proapoptotic effect in hypoxia and coculture with bone marrow stromal cells compared with quizartinib, linked to a dose-dependent inhibition of AXL phosphorylation. In vivo, use of the MV4–11 cell line with hematopoietic engraftment demonstrated that gilteritinib was more effective than quizartinib at targeting leukemic cells in bone marrow. Finally, FLT3-ITD AML patient-derived xenografts revealed that this effect was particularly reproducible in FLT3-ITD AML with high allelic ratio in primary and secondary xenograft. Moreover, gilteritinib and quizartinib displayed close toxicity profile on normal murine hematopoiesis, particularly at steady state. Conclusions: Overall, these findings suggest that gilteritinib as a single agent, compared with quizartinib, is more likely to reach leukemic cells in their protective microenvironment, particularly AML clones highly dependent on FLT3-ITD signaling.
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- 2021
21. AML-108 SELECT-AML-1 Trial in Progress: A Phase 2 Study of Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-Positive AML who are Ineligible for Standard Induction Therapy
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Suman Kambhampati, Alireza Eghtedar, Christine McMahon, Stephane de Botton, Arnaud Pigneux, Brian Ball, Gautam Borthakur, Angela Volkert, Joanie Aasen Gausman, Kristen Baker, Graeme Hodgson, Erica Warlick, David Roth, Michael Kelly, Daniel Pollyea, and Eytan Stein
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Cancer Research ,Oncology ,Hematology - Published
- 2022
22. Poster: AML-108 SELECT-AML-1 Trial in Progress: A Phase 2 Study of Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-Positive AML who are Ineligible for Standard Induction Therapy
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Suman Kambhampati, Alireza Eghtedar, Christine McMahon, Stephane de Botton, Arnaud Pigneux, Brian Ball, Gautam Borthakur, Angela Volkert, Joanie Aasen Gausman, Kristen Baker, Graeme Hodgson, Erica Warlick, David Roth, Michael Kelly, Daniel Pollyea, and Eytan Stein
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Cancer Research ,Oncology ,Hematology - Published
- 2022
23. Characteristics and clinical outcomes of SARS-CoV-2 infection in adult patients with acute leukemia in France
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Pierre-Yves, Dumas, Sarah, Bertoli, Caroline, Bonmati, Martin, Carre, Juliette, Lambert, Mario, Ojeda-Uribe, Sylvain, Chantepie, Franciane, Paul, Eric, Jourdan, Stéphanie, Haiat, Emmanuelle, Tavernier, Pierre, Peterlin, Jean-Pierre, Marolleau, Kamel, Laribi, Corentin, Orvain, Quentin, Cabrera, Pascal, Turlure, Stéphane, Girault, Marie, Balsat, Marc, Bernard, Marie-Christine, Bene, Arnaud, Pigneux, Hervé, Dombret, and Christian, Récher
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Adult ,Leukemia, Myeloid, Acute ,Cancer Research ,Oncology ,SARS-CoV-2 ,Acute Disease ,COVID-19 ,Humans ,France ,Hematology - Published
- 2022
24. Improved survival with enasidenib versus standard of care in relapsed/refractory acute myeloid leukemia associated with IDH2 mutations using historical data and propensity score matching analysis
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Bruno Quesnel, Roland Marion-Gallois, Andrew H. Wei, Muhaimen Siddiqui, Sylvain Chantepie, Brian Hutton, Alessandra Tosolini, Ollivier Legrand, Eytan M. Stein, Arnaud Pigneux, Xavier Thomas, Salem Abi Nehme, Christian Recher, Jixian J. Wang, Mark G. Frattini, Joseph Brandwein, Mathilde Hunault-Berger, Stéphane de Botton, Chris Cameron, Gary Milkovich, and Nicolas Boissel
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Oncology ,Male ,Cancer Research ,medicine.medical_treatment ,Aminopyridines ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Multicenter Studies as Topic ,Prospective cohort study ,RC254-282 ,Research Articles ,Relative survival ,Clinical Trials, Phase I as Topic ,Triazines ,Hazard ratio ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Myeloid leukemia ,Standard of Care ,Middle Aged ,Isocitrate Dehydrogenase ,Leukemia, Myeloid, Acute ,Observational Studies as Topic ,Treatment Outcome ,enasidenib ,Female ,France ,Research Article ,IDH2 mutations ,Adult ,medicine.medical_specialty ,Adolescent ,overall survival ,Enasidenib ,acute myeloid leukemia ,Young Adult ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Propensity Score ,Aged ,business.industry ,Clinical Cancer Research ,Confidence interval ,Drug Resistance, Neoplasm ,Propensity score matching ,Mutation ,Neoplasm Recurrence, Local ,business - Abstract
Background The present study evaluated the relative survival benefits associated with enasidenib and current standard of care (SoC) therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and an isocitrate dehydrogenase 2 (IDH2) mutation who are ineligible for hematopoietic stem cell transplantation (HSCT). Methods Propensity score matching (PSM) analysis compared survival outcomes observed with enasidenib 100 mg daily in the phase I/II AG221‐C‐001 trial and SoC outcomes obtained from a real‐world chart review of patients in France. Results Before matching, enasidenib (n = 195) was associated with numerically improved overall survival (OS) relative to SoC (n = 80; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.61–1.11). After matching and adjusting for covariates (n = 78 per group), mortality risk was significantly lower with enasidenib than with SoC (HR, 0.67; 95% CI, 0.47–0.97). The median OS was 9.26 months for enasidenib (95% CI, 7.72–13.24) and 4.76 months for SoC (95% CI, 3.81–8.21). Results remained robust across all sensitivity analyses conducted. Conclusions PSM analyses indicate that enasidenib significantly prolongs survival relative to SoC among patients with R/R AML and an IDH2 mutation who are ineligible for HSCT. Future prospective studies are needed to validate these findings using other data sources and to assess the comparative efficacy of enasidenib for other treatment outcomes., Overall survival was improved with enasidenib compared with SoC. Enasidenib may be an important advance in treatment for patients with R/R acute myeloid leukemia associated with IDH2 mutations who are ineligible for hematopoietic stem cell transplantation.
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- 2021
25. Ivosidenib in patients with IDH1-mutant relapsed/refractory myelodysplastic syndrome (R/R MDS): Updated enrollment and results of a phase 1 dose-escalation and expansion substudy
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David Andrew Sallman, James M. Foran, Justin M. Watts, Eytan Stein, Stéphane De Botton, Amir Tahmasb Fathi, Gabrielle T. Prince, Richard M. Stone, Prapti Arvind Patel, Gail J. Roboz, Martha Lucia Arellano, Harry Paul Erba, Arnaud Pigneux, Praneeth Baratam, Xavier G. Thomas, Xiaofei Bai, Stephanie M. Kapsalis, Guillermo Garcia-Manero, and Courtney Denton Dinardo
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Cancer Research ,Oncology - Abstract
7053 Background: Mutations in isocitrate dehydrogenase 1 ( IDH1) occur in ̃3% of patients (pts) with MDS and are associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO), an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, is FDA approved for m IDH1 R/R AML and m IDH1 newly diagnosed AML in pts ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human study of IVO in pts with m IDH1 advanced hematologic malignancies (NCT02074839), 12 pts with R/R MDS received IVO 500 mg once daily (QD). Based on encouraging safety and efficacy findings, including an investigator-assessed overall response rate (ORR) of 75%, with median response duration of 21.4 months, the FDA granted Breakthrough Therapy designation to IVO in m IDH1 R/R MDS and the study was amended to enroll additional pts. We report updated results. Methods: This substudy of the single-arm, open-label study of IVO evaluated pts with R/R MDS after documented failure or relapse following prior standard therapy including intensive chemotherapy and hypomethylating agents. Other key eligibility criteria included: high disease burden based on IPSS or IPSS-R risk at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and no prior IDH1 inhibitor therapy. Pts received IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: As of 08May2021, 16 pts with R/R MDS were enrolled: 5 (31%) pts remained on treatment and free from leukemic transformation; 11 (69%) had discontinued including 6 for disease progression, 1 for allogeneic stem cell transplantation, and 1 owing to an adverse event (AE) of sepsis (the only fatal AE; reported by investigator as not related to IVO). AEs are summarized in the Table. 2 pts each experienced differentiation syndrome (grade 2) and QTcF prolongation (grade 1 and 2). 7/16 pts achieved complete response (CR, 44%; 95% CI, 20%, 70%), 1 achieved partial response (6%), and 5 achieved marrow CR (31%), resulting in an ORR of 81% (95% CI, 54%, 96%). Hematologic improvement in ≥1 lineages was achieved by 11/16 (69%) pts. The Kaplan-Meier estimate of duration of CR+PR at 12 months was 60%. 3 pts experienced CRs lasting 24.0, 63.7, and 65.4 months, which remain ongoing. 5/7 pts (71%) who were transfusion dependent at baseline became independent of red blood cell or platelet transfusions for 56 or more consecutive days on treatment. Additional translational data are being analyzed. Conclusions: In pts with m IDH1 R/R MDS, IVO monotherapy was tolerable and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for pts with m IDH1 R/R MDS. Clinical trial information: NCT02074839. [Table: see text]
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- 2022
26. Tamibarotene in combination with venetoclax and azacitidine in previously untreated adult patients selected for RARA-positive AML who are ineligible for standard induction therapy (SELECT AML-1)
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Eytan Stein, Stéphane De Botton, Arnaud Pigneux, Christine McMahon, Brian Ball, Gautam Borthakur, Alireza Eghtedar, Suman Kambhampati, Jason Tache, Eunice S. Wang, Heather Kelley, Angela Volkert, Kristen Baker, Qing Kang-Fortner, Catherine Madigan, Erica D. Warlick, David A. Roth, Michael Kelly, and Daniel Aaron Pollyea
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Cancer Research ,Oncology - Abstract
TPS7065 Background: RARA-positive (RARA+) AML is a novel genomically defined patient subset with an actionable biological target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown 2017). RARA+ patients can be selected by a blood-based biomarker test, with approximately 30% of newly diagnosed (ND) AML patients being RARA+ (Vigil 2017). As a biologically targeted agent for patients with RARA overexpression, tamibarotene has the potential to provide benefit irrespective of mutation or cytogenetic risk classification. In RARA+ ND AML patients ineligible for standard induction therapy, tamibarotene plus azacitidine (aza) led to a CR/CRi rate of 61% and a rapid onset of response (de Botton 2020). Approximately one-third of patients with ND unfit AML do not respond to front-line standard of care venetoclax (ven)/aza (DiNardo 2020). Translational data suggest RARA positivity enriches for monocytic features reported to be associated with ven resistance (Fiore 2020, Pei 2020). This data suggests the RARA biomarker selects for patients who may respond to tamibarotene and may be less likely to respond to ven/aza. Given that tamibarotene plus aza has been generally well tolerated, with no increase in myelosuppression compared to single agent aza (de Botton 2020), it is anticipated that tamibarotene can be administered safely in combination with ven/aza. Methods: This is a Phase 2, open-label, multi-center study in the U.S. and France comparing the clinical activity of tamibarotene/ven/aza to ven/aza in treatment-naive RARA+ AML patients ineligible for standard induction chemotherapy. The primary objectives are to characterize the safety of the combination and to compare the CR/CRi rate of tamibarotene/ven/aza vs. ven/aza, with secondary objectives to compare CR rate, CR/CRh rate, duration of response, and time to response. The overall response rate using tamibarotene/ven/aza following ven/aza treatment failure will be explored. Clinical activity will be characterized by ELN criteria (Dohner 2017). This 3-part trial includes a safety lead-in, randomized efficacy study, and salvage arm. Following the safety lead-in, approximately 80 patients will be randomized 1:1 to receive tamibarotene/ven/aza or ven/aza. Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. In the salvage arm, tamibarotene will be added for study patients randomized to ven/aza who experience progressive disease, relapse, or treatment failure. Patients will be treated with aza at 75 mg/m2 IV/SC daily on days 1-7, ven on days 1-28 per VENCLEXA USPI, followed by tamibarotene at 6 mg twice per day by mouth on days 8-28 of each 28-day cycle. The SELECT AML-1 trial opened in July 2021 with ongoing enrollment. Clinical trial information: NCT04905407.
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- 2022
27. Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)
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Phong-Dinh Nguyen, Lucile Couronné, Arnaud Jaccard, Olivier Hermine, Société Française de Greffe de Moelle et de Thérapie Cellulaire, Mohamad Mohty, Patrice Chevallier, Laure Philippe Walter, Ibrahim Yakoub-Agha, Régis Peffault de Latour, Nathalie Fegueux, Catherine Thieblemont, Emmanuel Bachy, Arnaud Pigneux, Jean-Philippe Jais, Didier Blaise, Gérard Socié, 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, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Oncology ,Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Nose Neoplasms ,Graft vs Host Disease ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,ComputingMilieux_MISCELLANEOUS ,Aged ,Chemotherapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Hematology ,Middle Aged ,medicine.disease ,Natural killer T cell ,Prognosis ,Progression-Free Survival ,Lymphoma ,Transplantation ,Radiation therapy ,Lymphoma, Extranodal NK-T-Cell ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cohort ,Female ,France ,Stem cell ,business ,030215 immunology - Abstract
We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing haematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs 26%, p=0.12 and OS: 52% vs 53%, p=0.74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p=0.031 and PFS: HR: 5.231 [1.625; 16.838], p=0.006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design. This article is protected by copyright. All rights reserved.
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- 2021
28. Molecular classification and prognosis in younger adults with acute myeloid leukemia and intermediate-risk cytogenetics treated or not by gemtuzumab ozogamycin: Final results of the GOELAMS/FILO acute myeloid leukemia 2006-intermediate-risk trial
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Norbert Ifrah, Hacene Zerazhi, Pierre-Yves Dumas, Norbert Vey, Isabelle Luquet, Denis Caillot, Marie-Christine Béné, Célestine Simand, Marie-Pierre Ledoux, Véronique Dorvaux, Yosr Hicheri, Anne Banos, Maria Pilar Gallego Hernanz, Chantal Himberlin, Odile Blanchet, Eric Delabesse, Catherine Humbrecht, Pascal Turlure, Arnaud Pigneux, Eric Jourdan, Jacques Delaunay, Didier Bouscary, Emmanuelle Tavernier, Christian Recher, Gaelle Guillerm, Mathilde Hunault-Berger, Romain Guieze, Martin Carre, Anne Bouvier, Jean-Pierre Marolleau, Claude Eric Bulabois, Pascale Cornillet-Lefebvre, Mario Ojeda-Uribe, Marc Bernard, Magda Alexis, Jean-François Hamel, Etienne Daguindau, Pierre Peterlin, Gabrielle Roth Guepin, Emmanuel Gyan, Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital privé du Confluent [Nantes], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de Strasbourg Europe (ICANS), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire [Grenoble] (CHU), Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne (UCA), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire de Reims (CHU Reims), Fédérations hospitalo-universitaires Grand Ouest Acute Leukemia [Angers] (FHU GOAL), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service des maladies du sang [Angers], CHU Pontchaillou [Rennes], Département d'Hématologie [CHU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier de la Côte Basque (CHCB), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT)-Université de Tours (UT), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Régional d'Orléans (CHRO), 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), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Henri Duffaut (Avignon), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Ressources Biologiques [CHU Angers], 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), 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], Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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Oncology ,Adult ,Male ,Risk ,medicine.medical_specialty ,NPM1 ,Adolescent ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Phases of clinical research ,Gene mutation ,Disease-Free Survival ,Cytogenetics ,Young Adult ,Internal medicine ,hemic and lymphatic diseases ,CEBPA ,Medicine ,Cluster Analysis ,Humans ,Chemotherapy ,business.industry ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,General Medicine ,Middle Aged ,Prognosis ,Gemtuzumab ,Transplantation ,Leukemia, Myeloid, Acute ,Karyotyping ,Cytogenetic Analysis ,Mutation ,Female ,business - Abstract
International audience; In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m(2) of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (
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- 2021
29. Data from French named patient program of quizartinib in relapsed/refractory acute myeloid leukemia
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Anne Banos, Stefan Wickenhauser, Fabrice Larosa, Filo, R. Redjoul, Pierre-Yves Dumas, Nolwenn Lucas, Jamile Frayfer, Martin Carre, M. Alexis, M. Elassy, Arnaud Pigneux, Emmanuel Raffoux, Pierre Peterlin, Marie-Virginie Larcher, N. Maillard, Christian Recher, J. Michel, J. B. Mear, M. Detrait, V. Morel, Sylvain Chantepie, Mario Ojeda-Uribe, Y. Desbrosses, S. Fodil, Celia Salanoubat, Hervé Dombret, Thomas Cluzeau, C. Mediavilla, Sarah Bertoli, Driss Chaoui, Mathilde Hunault-Berger, and V. Vidal
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Oncology ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Text mining ,Internal medicine ,medicine ,Overall survival ,Humans ,Benzothiazoles ,Quizartinib ,Chemotherapy ,business.industry ,Phenylurea Compounds ,Hazard ratio ,Myeloid leukemia ,Hematology ,Leukemia, Myeloid, Acute ,chemistry ,fms-Like Tyrosine Kinase 3 ,030220 oncology & carcinogenesis ,Relapsed refractory ,business ,030215 immunology ,Chemotherapy group - Abstract
Quizartinib improved outcome compared to chemotherapy in the QuANTUM-R study (median overall survival (OS): 6.2 months for quizartinib vs. 4.7 in the chemotherapy group; hazard ratio 0.76, p = 0.02...
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- 2021
30. In-depth time-dependent analysis of the benefit of allo-HSCT for elderly patients with CR1 AML: a FILO study
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Alice Garnier, Gaelle Guillerm, Anne Bouvier, Patrice Ceballos, Marie C. Béné, Yosr Hicheri, Arnaud Pigneux, Christian Recher, Mathilde Hunault-Berger, Sarah Guenounou, Raynier Devillier, Patrice Chevallier, Anne Huynh, Edouard Forcade, Pierre-Yves Dumas, Sylvain Thepot, Didier Blaise, Pierre Peterlin, Norbert Vey, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Association internationale pour le développement de l’agroenvironnement (AIDA), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Lapeyronie [Montpellier] (CHU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique et Thérapie Cellulaire [CHU Bordeaux], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux], Laboratoire d'Hematologie [CHU Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département d’Oncologie Médicale [IPC, Marseille], and Institut National de la Santé et de la Recherche Médicale (INSERM)
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Oncology ,medicine.medical_specialty ,Multivariate analysis ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Allo hsct ,Hematopoietic stem cell transplantation ,European LeukemiaNet ,Recurrence ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Aged ,Proportional Hazards Models ,business.industry ,Hazard ratio ,Remission Induction ,Complete remission ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Leukemia ,Leukemia, Myeloid, Acute ,Receptors, Complement 3b ,business - Abstract
The benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with acute myeloid leukemia (AML) aged >60 years remains a matter of debate, notably when performed in first complete remission (CR1). To clarify this issue, the French Innovative Leukemia Organization (FILO) performed a 10-year real-world time-dependent analysis. The study enrolled patients between 60 and 70 years of age with AML in CR1 after intensive chemotherapy with intermediate (IR) or unfavorable (UR) risk according to the European LeukemiaNet (ELN) 2010 classification. The impact of allo-HSCT was analyzed through three models: (1) time-dependent Cox; (2) multistate for dynamic prediction; and (3) super landmark. The study enrolled 369 (73%) IR and 138 (27%) UR patients with AML, 203 of whom received an allo-HSCT. Classical multivariate analysis showed that allo-HSCT significantly improved relapse-free survival (RFS; hazard ratio [HR] [95% confidence interval (CI)], 0.47 [0.35-0.62]; P < .001) and overall survival (OS; HR [95% CI], 0.56 [0.42-0.76]; P < .001), independently of the ELN risk group. With the multistate model, the predicted 5-year probability for IR and UR patients to remain in CR1 without allo-HSCT was 8% and 1%, respectively. Dynamic predictions confirmed that patients without allo-HSCT continue to relapse over time. Finally, the super landmark model showed that allo-HSCT significantly improved RFS (HR [95% CI], 0.47 [0.36-0.62]; P < .001) and OS (HR [95% CI], 0.54 [0.40-0.72]; P < .001). allo-HSCT in CR1 is reported here as significantly improving the outcome of fit older patients with AML. Long-term RFS without allo-HSCT is very low (
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- 2021
31. Unsupervised Flow Cytometry Analysis Allows for an Accurate Identification of Minimal Residual Disease Assessment in Acute Myeloid Leukemia
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Audrey Bidet, Pierre-Yves Dumas, Jean-Philippe Vial, Marie C. Béné, François Vergez, Nicolas Lechevalier, Arnaud Pigneux, Thibaut Leguay, and Francis Lacombe
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,multiparameter flow cytometry ,Acute myeloblastic leukemia ,molecular markers ,Concordance ,acute myeloid leukemia ,lcsh:RC254-282 ,Article ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immunophenotyping ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Multiparameter flow cytometry ,FlowSOM ,medicine.diagnostic_test ,business.industry ,unsupervised analysis ,Myeloid leukemia ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Minimal residual disease ,030104 developmental biology ,medicine.anatomical_structure ,minimal/measurable residual disease ,030220 oncology & carcinogenesis ,Bone marrow ,business - Abstract
Simple Summary In acute myeloid leukemia (AML), minimal/measurable residual disease (MRD) can be assessed based on molecular markers or immunophenotypic features evaluated at diagnosis, through multiparameter flow cytometry (MFC) for the latter. New artificial intelligence tools allow to perform unsupervised analysis of MFC data. The Flow-Self-Organizing-Maps (FlowSOM) tool was used here to concomitantly compare MFC features of normal bone marrow together with diagnosis and follow-up bone marrow samples from 40 AML patients for the evaluation of MRD. MFC results were compared to molecular MRD, showing high concordance. This opens the road for a new easy and objective way of assessing MRD even in AML patients without molecular markers. Abstract The assessment of minimal residual disease (MRD) is increasingly considered to monitor response to therapy in hematological malignancies. In acute myeloblastic leukemia (AML), molecular MRD (mMRD) is possible for about half the patients while multiparameter flow cytometry (MFC) is more broadly available. However, MFC analysis strategies are highly operator-dependent. Recently, new tools have been designed for unsupervised MFC analysis, segregating cell-clusters with the same immunophenotypic characteristics. Here, the Flow-Self-Organizing-Maps (FlowSOM) tool was applied to assess MFC-MRD in 96 bone marrow (BM) follow-up (FU) time-points from 40 AML patients with available mMRD. A reference FlowSOM display was built from 19 healthy/normal BM samples (NBM), then simultaneously compared to the patient’s diagnosis and FU samples at each time-point. MRD clusters were characterized individually in terms of cell numbers and immunophenotype. This strategy disclosed subclones with varying immunophenotype within single diagnosis and FU samples including populations absent from NBM. Detectable MRD was as low as 0.09% in MFC and 0.051% for mMRD. The concordance between mMRD and MFC-MRD was 80.2%. MFC yielded 85% specificity and 69% sensitivity compared to mMRD. Unsupervised MFC is shown here to allow for an easy and robust assessment of MRD, applicable also to AML patients without molecular markers.
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- 2021
32. MDS-335: Ivosidenib (IVO) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome (R/R MDS): Updated Enrollment for the MDS Sub-Study
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Vickie Zhang, Xavier Thomas, James M. Foran, Stéphane de Botton, Martha Arellano, Amir T. Fathi, Justin M. Watts, Richard Stone, Courtney D. DiNardo, Harry P. Erba, Guillermo Garcia-Manero, Ian R Lemieux, Geoffrey L. Uy, Gail J. Roboz, Eytan M. Stein, Robert K. Stuart, Anthony S. Stein, Arnaud Pigneux, Gabrielle T. Prince, David A. Sallman, Stephanie M. Kapsalis, and Prapti A. Patel
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Cancer Research ,Cytopenia ,medicine.medical_specialty ,business.industry ,Induction chemotherapy ,Context (language use) ,Hematology ,medicine.disease ,Discontinuation ,Clinical trial ,Oncology ,Tolerability ,hemic and lymphatic diseases ,Pharmacodynamics ,Internal medicine ,medicine ,Adverse effect ,business - Abstract
Context: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of patients with MDS and are associated with increased transformation to acute myeloid leukemia (AML). IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme and is FDA-approved for mIDH1 R/R AML and mIDH1 newly diagnosed AML in patients ≥75 years old or with comorbidities precluding the use of intensive induction chemotherapy. In the first-in-human, phase 1 study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839), 12 patients with R/R MDS, with median age 72.5 years (range 52–78), received IVO 500 mg once daily (QD). All patients received prior MDS treatment. Investigator-assessed ORR (CR + PR + marrow CR, per IWG 2006) was 75% (95% CI 43–95), with median duration of response of 21.4 months (95% CI 2.3–NE). Nine (75%) patients were transfusion-independent for ≥56 days during treatment. No dose-limiting toxicities or adverse events leading to treatment discontinuation were reported among patients with MDS. Based on these encouraging data, the FDA granted Breakthrough Therapy Designation to IVO in mIDH1 MDS; the study was amended to enroll additional patients with mIDH1 R/R MDS. Objective: To evaluate safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: A sub-study of the single-arm, open-label, phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies, evaluating patients with R/R MDS. Patients must have R/R disease after prior standard therapy; high disease burden based on cytopenia and/or transfusion dependence at baseline; an Eastern Cooperative Oncology Group performance status score of 0–2; and be amenable to bone marrow aspirate and/or core biopsy at specified study timepoints. Patients with documented AML are not eligible. IVO 500 mg QD orally on days 1–28 of 28-day cycles. Results: Study is open; enrollment of ~23 patients from the US and France planned. Results not yet available. Conclusions: This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios; Servier.
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- 2021
33. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort
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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
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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
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- 2021
34. Prognostic significance of concurrent gene mutations i n intensively treated patients with IDH-mutated AML: an ALFA study
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Céline Berthon, Lionel Ades, Nicolas Boissel, Emilie Lemasle, Christian Recher, Xavier Thomas, Nicolas Duployez, Norbert Vey, Raphael Itzykson, Sylvain Chantepie, Karine Celli-Lebras, Arnaud Pigneux, Pascal Turlure, Stéphane de Botton, Claude Preudhomme, Claude Gardin, Denis Caillot, Jean-Pierre Marolleau, Christine Terré, Jean-Baptiste Micol, Hervé Dombret, Thorsten Braun, Juliette Lambert, Emmanuel Raffoux, Jean-Valère Malfuson, Matthieu Duchmann, Cécile Pautas, Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Gustave Roussy (IGR), Université Paris-Saclay, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHU Amiens-Picardie, Hôpital Avicenne [AP-HP], Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital Henri Mondor, Centre Hospitalier de Versailles André Mignot (CHV), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Centre de Transfusion Sanguine des Armées (CTSA), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Universitaire d'Hématologie (IUH), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], and DESSAIVRE, Louise
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Male ,Oncology ,medicine.medical_specialty ,NPM1 ,IDH1 ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Immunology ,Abnormal Karyotype ,Hematopoietic stem cell transplantation ,Gene mutation ,medicine.disease_cause ,Biochemistry ,Disease-Free Survival ,DNA Methyltransferase 3A ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Point Mutation ,Medicine ,Prospective Studies ,In Situ Hybridization, Fluorescence ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Chromosome Aberrations ,Clinical Trials as Topic ,Mutation ,Acute leukemia ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,Middle Aged ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,[SDV] Life Sciences [q-bio] ,Leukemia, Myeloid, Acute ,Isocitrate dehydrogenase ,Female ,France ,business ,Nucleophosmin - Abstract
International audience; In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P< .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy.
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- 2021
35. A personalized approach to guide allogeneic stem cell transplantation in younger adults with acute myeloid leukemia
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Norbert Vey, Mauricette Michallet, Sylvain Chantepie, Xavier Thomas, Paul-Arthur Meslin, Delphine Lebon, Christine Terré, Sylvie Chevret, Claude Preudhomme, Pascal Turlure, Emilie Lemasle, Sébastien Maury, Emmanuel Raffoux, Karine Celli-Lebras, Nicolas Duployez, Pierre-Yves Dumas, Raphael Itzykson, Céline Berthon, Jean-Valère Malfuson, Denis Caillot, Arnaud Pigneux, Ibrahim Yakoub-Agha, Juliette Lambert, Auriane Lesieur, Christian Recher, Claude Gardin, Pierre Sujobert, Cécile Pautas, Benoît Ducourneau, Gérard Socié, Gael Fortin, Stéphanie Nguyen, Laurène Fenwarth, Stéphane de Botton, Hervé Dombret, Nicolas Boissel, Jean-Henri Bourhis, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Gustave Roussy (IGR), Département d'hématologie [Gustave Roussy], Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Hôpital Avicenne [AP-HP], Centre Hospitalier de Versailles André Mignot (CHV), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre de Transfusion Sanguine des Armées (CTSA), Service de Santé des Armées, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Henri Mondor [Créteil], Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), DESSAIVRE, Louise, Centre International des greffes [CHU Saint-Antoine] (EBMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Henri Mondor, Service d'Hématologie [CHU Toulouse], and CHU Toulouse [Toulouse]
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Oncology ,Male ,Myeloid ,Neoplasm, Residual ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Datasets as Topic ,Hematopoietic stem cell transplantation ,Biochemistry ,European LeukemiaNet ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Multicenter Studies as Topic ,Precision Medicine ,Randomized Controlled Trials as Topic ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Nuclear Proteins ,Hematology ,Middle Aged ,Prognosis ,Combined Modality Therapy ,[SDV] Life Sciences [q-bio] ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,surgical procedures, operative ,Female ,Nucleophosmin ,Algorithms ,Adult ,medicine.medical_specialty ,NPM1 ,Adolescent ,Immunology ,Clinical Decision-Making ,Risk Assessment ,Young Adult ,Clinical Trials, Phase II as Topic ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,business.industry ,Cell Biology ,Models, Theoretical ,medicine.disease ,Minimal residual disease ,Transplantation ,business - Abstract
A multistage model instructed by a large dataset (knowledge bank [KB] algorithm) has recently been developed to improve outcome predictions and tailor therapeutic decisions, including hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML). We assessed the performance of the KB in guiding HSCT decisions in first complete remission (CR1) in 656 AML patients younger than 60 years from the ALFA-0702 trial (NCT00932412). KB predictions of overall survival (OS) were superior to those of European LeukemiaNet (ELN) 2017 risk stratification (C-index, 68.9 vs 63.0). Among patients reaching CR1, HSCT in CR1, as a time-dependent covariate, was detrimental in those with favorable ELN 2017 risk and those with negative NPM1 minimal residual disease (MRD; interaction tests, P = .01 and P = .02, respectively). Using KB simulations of survival at 5 years in a scenario without HSCT in CR1 (KB score), we identified, in a similar time-dependent analysis, a significant interaction between KB score and HSCT, with HSCT in CR1 being detrimental only in patients with a good prognosis based on KB simulations (KB score ≥40; interaction test, P = .01). We could finally integrate ELN 2017, NPM1 MRD, and KB scores to sort 545 CR1 patients into 278 (51.0%) HSCT candidates and 267 (49.0%) chemotherapy-only candidates. In both time-dependent and 6-month landmark analyses, HSCT significantly improved OS in HSCT candidates, whereas it significantly shortened OS in chemotherapy-only candidates. Integrating KB predictions with ELN 2017 and MRD may thus represent a promising approach to optimize HSCT timing in younger AML patients.
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- 2021
36. Publisher Correction: Outcome of older (=70 years) APL patients frontline treated with or without arsenic trioxide-an International Collaborative Study
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Sabine Kayser, Marta Sobas, Olga Salamero, Cristina Gil, Uwe Platzbecker, Richard F. Schlenk, Gabriel Ghiaur, Javier de la Serna, Mar Tormo, David Martínez-Cuadrón, Mark J. Levis, Miguel A. Sanz, Emmanuel Raffoux, Eva Lengfelder, Norbert Vey, Pierre Fenaux, Arnaud Pigneux, Agnès Guerci-Bresler, Ana Garrido, Xavier Thomas, Pau Montesinos, Lionel Adès, and Ramy Rahmé
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Cancer Research ,medicine.medical_specialty ,business.industry ,Hematology ,Outcome (game theory) ,Acute myeloid leukaemia ,chemistry.chemical_compound ,Text mining ,Oncology ,chemistry ,Internal medicine ,medicine ,Clinical genetics ,Arsenic trioxide ,business - Published
- 2021
37. Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study
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Eric Delabesse, Emilie Bérard, Noémie Gadaud, Isabelle Luquet, Nicolas Lechevalier, Anne-Charlotte de Grande, Audrey Sarry, François Vergez, Laetitia Largeaud, Jean Baptiste Rieu, Harmony Leroy, Arnaud Pigneux, Christian Recher, Emilie Klein, Jean-Philippe Vial, Thibaut Leguay, Audrey Bidet, Pierre-Yves Dumas, and Sarah Bertoli
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Primary Induction Failure ,medicine.drug_class ,primary induction failure ,acute myeloid leukemia ,lcsh:RC254-282 ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,tyrosine kinase inhibitors ,medicine ,Quizartinib ,relapse ,business.industry ,Myeloid leukemia ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,FLT3-ITD mutation ,Transplantation ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Cohort ,Cytarabine ,business ,medicine.drug - Abstract
Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen, none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations <, 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.
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- 2020
38. Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT
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Gérard Socié, Jordi Esteve, Christoph Schmid, Jan J. Cornelissen, Tomasz Czerw, Arnaud Pigneux, Ibrahim Yakoub-Agha, Sebastian Giebel, Vladimir Koza, Hélène Labussière-Wallet, Nigel H. Russell, Depei Wu, Avichai Shimoni, Mohamad Mohty, Patrice Chevallier, Arnon Nagler, Myriam Labopin, Zinaida Peric, Liisa Volin, Anton Schattenberg, Rainer Schwerdtfeger, Robin Foà, Johan Maertens, and Hematology
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0301 basic medicine ,Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Transplantation Conditioning ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Translocation, Genetic ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,hemic and lymphatic diseases ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Medicine ,Humans ,Transplantation, Homologous ,Survival rate ,B cell ,Retrospective Studies ,Acute leukemia ,biology ,business.industry ,Chromosomes, Human, Pair 11 ,Hazard ratio ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Histone-Lysine N-Methyltransferase ,Prognosis ,Transplantation ,DNA-Binding Proteins ,Survival Rate ,030104 developmental biology ,KMT2A ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Female ,Chromosomes, Human, Pair 4 ,Transcriptional Elongation Factors ,business ,Myeloid-Lymphoid Leukemia Protein ,Follow-Up Studies - Abstract
Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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- 2020
39. Outcome of Relapsed or Refractory FLT3-Mutated Acute Myeloid Leukemia Before Second-Generation FLT3 Tyrosine Kinase Inhibitors: A Toulouse–Bordeaux DATAML Registry Study
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Arnaud Pigneux, Audrey Sarry, Eric Delabesse, Emilie Bérard, Harmony Leroy, Jean-Baptiste Rieu, Suzanne Tavitian, Christian Recher, Noémie Gadaud, Jean-Philippe Vial, Isabelle Luquet, François Vergez, Emilie Klein, Nicolas Lechevalier, Anne-Charlotte de Grande, Sarah Bertoli, Thibaut Leguay, Audrey Bidet, Pierre-Yves Dumas, and Laetitia Largeaud
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,medicine.drug_class ,Azacitidine ,Salvage therapy ,FLT3-TKD mutation ,primary induction failure ,acute myeloid leukemia ,FLT3-ITD mutation ,lcsh:RC254-282 ,Gastroenterology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Interquartile range ,Internal medicine ,hemic and lymphatic diseases ,tyrosine kinase inhibitors ,medicine ,relapse ,business.industry ,Myeloid leukemia ,hemic and immune systems ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Transplantation ,refractory ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,embryonic structures ,Cytarabine ,business ,gilteritinib ,medicine.drug - Abstract
A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse&ndash, Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%, relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0&ndash, 32), 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27&ndash, 45), 24.7% (95%CI: 1&ndash, 33) and 19.7% (95%CI: 1&ndash, 28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.
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- 2020
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40. Very Long Term Follow up a Phase II Study of Post-Remission Subcutaneous (SC) Azacitidine (AZA) in Patients with AML Post-MDS or Higher-Risk (HR) MDS
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Lionel Ades, Krimo Bouabdallah, Xavier Thomas, Chantal Himberlin, Denis Caillot, Emmanuel Raffoux, Amina Cherait, Agnès Guerci, Hervé Dombret, Fatiha Chermat, Arnaud Pigneux, Sylvie Chevret, Pierre Fenaux, Anne Banos, Claude Gardin, Thorsten Braun, Jean Pierre Marolleau, Norbert Vey, Cécile Pautas, Anne Laure Taksin, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], 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), CHU Bordeaux [Bordeaux], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nancy (CHU Nancy), CHU Amiens-Picardie, CHU Henri Mondor, Le CHCB, Centre Hospitalier de la Côte Basque, Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier de Versailles André Mignot (CHV), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), and DESSAIVRE, Louise
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Oncology ,medicine.medical_specialty ,Long term follow up ,business.industry ,[SDV]Life Sciences [q-bio] ,Immunology ,Azacitidine ,Phases of clinical research ,Cell Biology ,Hematology ,Biochemistry ,[SDV] Life Sciences [q-bio] ,Internal medicine ,medicine ,In patient ,business ,ComputingMilieux_MISCELLANEOUS ,medicine.drug - Abstract
Background: Results of the phase III QUAZAR trial suggest that post-remission treatment with an oral form (CC-486) of azacitidine (AZA) can prolong CR duration and overall survival(OS) in AML patients reaching at least PR with intensive chemotherapy (IC) (Wei et al, ASH 2019). Maintenance treatment with subcutaneous (SC) AZA was recently shown to improve DFS in elderly AML (Huls et al, Blood 2019, a study that also included 10% MDS). We report very long term results of a study evaluating SC AZA as post-remission treatment in patients with AML post-MDS or high-risk MDS (HR-MDS) who achieved at least PR after IC, a population known to have short responses with IC. Methods: Inclusion criteria were (1) HR-MDS according to IPSS, or AML after a documented phase of MDS(2) who entered CR, CRi or PR after IC with anthracycline and AraC within 28 days of inclusion (3) ECOG Results: From July 2006 to June 2009, 51 pts (M:31/F:20) were included. The 46 evaluable pts had achieved CR (n=28), CRi (n=11), and PR (n=7) before study entry. Median age was 66y (range 55-78). Diagnosis at IC onset was MDS (n=13) and AML (n=33), IPSS cytogenetics was normal (n= 28), intermediate (n=10), high (n= 6), and failed (n=2). Median time from diagnosis of MDS to IC was 8 months (range 0.5-101). Median number of AZA maintenance cycles was 7.5 (1-76) in CR pts (>23 cycles in 5 of them) and 4.5 (1-24) in CRi or PR pts (> 23 cycles in 1). Two patients were allografted and censored at allo SCT. Median follow-up was 16.5 months As of May 2020 (cut off date of analysis) median DFS and OS from response were 6.9 m and 16.9 m, respectively (figure). In CR patients, median and 18 months OS were 18.9 months and 58%, versus 12.8 months and 50% in CRi-PR patients (p=0.33) All non allografted patients eventually relapsed. 7 had a response duration >18 months (6 CR patients: 22, 23, 25, 36, 40, and 84 months; 1 CRi patient: 24 months) OS from inclusion was >3 years in 7 patients (CR pts: 150, 126,74, 51, 50,40 months; CRi pt:58 months), in addition to the 2 allografted pts who remained alive in CR at 156+ and 159+ months No baseline factor including cytogenetics, diagnosis at IC onset (MDS vs AML), % bone marrow blasts, age or time from MDS diagnosis to treatment, significantly predicted DFS or OS. AZA dosing in CR patients was escalated in 9 pts to 75mg/m2/d due to good tolerance but had to be reduced in 6 pts, due to GI toxicity (n=1) and cytopenias (n=5). During SC AZA maintenance, 2/28 CR pts developed febrile neutropenia, compared to 4/18 pts in CRi or PR (including 1 fatal case). In the 22 AML post MDS pts who reached CR, DFS and OS were similar to those observed in 46 AML post AML pts included in a previous ALFA study where pts in CR after IC received DNR/IDA-AraC post-remission therapy (Gardin, Blood 2007). Conclusion: In the very long term analysis of this trial in AML post MDS and HR-MDS treated with induction intensive chemotherapy, post-remission therapy with SC AZA alone was associated with a median DFS and OS of 6.9 and 16.9 months, respectively, with some prolonged response. Results appeared similar to those we had reported with intensive consolidation chemotherapy, but using an ambulatory treatment with limited myelosuppression. Figure Disclosures Braun: Daiichy-Sankyo: Honoraria; Servier: Research Funding. Bouabdallah:Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Fenaux:Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.
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- 2020
41. Outcome of older (≥70 years) APL patients frontline treated with or without arsenic trioxide-an International Collaborative Study
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Pierre Fenaux, Ana Garrido, David Martínez-Cuadrón, Uwe Platzbecker, Gabriel Ghiaur, Olga Salamero, Javier de la Serna, Lionel Adès, Sabine Kayser, Norbert Vey, Richard F. Schlenk, Xavier Thomas, Eva Lengfelder, Pau Montesinos, Arnaud Pigneux, Ramy Rahmé, Agnès Guerci-Bresler, Miguel A. Sanz, Marta Sobas, Cristina Gil, Mar Tormo, Mark J. Levis, Emmanuel Raffoux, Institut Català de la Salut, [Kayser S] Medical Clinic and Policlinic I, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany. German Cancer Research Center (DKFZ), Heidelberg, Germany. Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. [Rahmé R] Hôpital Saint Louis, Université Paris Diderot, Paris, France. [Martínez-Cuadrón D] Hematology Department, Hospital Universitari i Politècnic, La Fe, Avinguda Fernando Abril Martorell, 106, 46026 València, Spain. CIBERONC, Instituto Carlos III, Madrid, Spain. [Ghiaur G] Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. [Thomas X] Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre Bénite, Lyon, France. [Sobas M] Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland. [Salamero O] Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Male ,Cancer Research ,ANTHRACYCLINE MONOCHEMOTHERAPY ,Myeloid ,medicine.medical_treatment ,International Cooperation ,ACUTE PROMYELOCYTIC LEUKEMIA ,Leucèmia mieloide aguda - Quimioteràpia ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Gastroenterology ,chemistry.chemical_compound ,Remission induction ,Arsenic Trioxide ,Antineoplastic Combined Chemotherapy Protocols ,Cumulative incidence ,Arsenic trioxide ,ELDERLY-PATIENTS ,Aged, 80 and over ,ADDITIONAL CHROMOSOME-ABNORMALITIES ,Remission Induction ,Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute [DISEASES] ,Hematology ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,Female ,FLT3 GENE ,Acute promyelocytic leukemia ,medicine.medical_specialty ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,ACUTE MYELOID-LEUKEMIA ,Article ,Acute myeloid leukaemia ,neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda [ENFERMEDADES] ,Internal medicine ,White blood cell ,medicine ,Humans ,Clinical genetics ,neoplasms ,CONSOLIDATION THERAPY ,Aged ,Chemotherapy ,business.industry ,organic chemicals ,diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Correction ,biochemical phenomena, metabolism, and nutrition ,Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,TANDEM DUPLICATION ,bacterial infections and mycoses ,biological factors ,RISK-ADAPTED TREATMENT ,TRANS-RETINOIC ACID ,chemistry ,Avaluació de resultats (Assistència sanitària) ,business - Abstract
Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P P = 0.20). High (>10 × 109/l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis.
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- 2019
42. Phase 3 results for vosaroxin/cytarabine in the subset of patients ≥60 years old with refractory/early relapsed acute myeloid leukemia
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Hamid Sayar, Heinz A. Horst, Stephen A. Strickland, Arnaud Pigneux, Gary J. Schiller, Michael Craig, Robert K. Stuart, Miklos Egyed, Renee Ward, Elias Jabbour, Jennifer A. Smith, Hagop M. Kantarjian, Jorge E. Cortes, Gary Acton, Utz Krug, Angelo Michele Carella, Farhad Ravandi, Ellen K. Ritchie, Judith A. Fox, Adam R. Craig, Norbert Vey, Jeffrey E. Lancet, Virginia M. Klimek, and Christian Recher
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Oncology ,medicine.medical_specialty ,Standard of care ,business.industry ,Myeloid leukemia ,Hematology ,Vosaroxin ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,Refractory ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cytarabine ,In patient ,Online Only Articles ,business ,030215 immunology ,medicine.drug - Abstract
Refractory/early relapsed (Ref/eRel) acute myeloid leukemia (AML) in patients ≥60 years old is the most important unmet medical need in the salvage setting, where outcomes are exceptionally poor and no standard of care exists.[1][1] Vosaroxin is a first-in-class anticancer quinolone derivative
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- 2018
43. Molecular Characteristics of Response to Olutasidenib (FT-2102) in Patients with Relapsed/Refractory mIDH1 Acute Myeloid Leukemia
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Sylvie Guichard, Andrew H. Wei, Brian A. Jonas, Jennifer Sweeney, Christophe Marzac, Justin M. Watts, Jürgen Krauter, A Khwaja, Pierre Peterlin, Joseph G. Jurcic, Carolyn S. Grove, Montserrat Arnan Sangerman, Daniela Cilloni, Jorge E. Cortes, Pau Montesinos, David Taussig, Karen W.L. Yee, Alex Sedkov, Antonio Curti, Jay Yang, Zihao Xin, Xavier Thomas, Devendra K Hiwase, Christian Recher, Jordi Esteve, Pierre Fenaux, Stéphane de Botton, Thorsten Braun, Arnaud Pigneux, William Blum, and Olivier Legrand
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Relapsed refractory ,medicine ,Myeloid leukemia ,In patient ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1). Olutasidenib has previously shown clinical activity in high-risk AML patients (pts) in a Phase 1 clinical trial (Watts, Blood 2019). The planned interim analysis of an ongoing Phase 2 clinical trial (NCT02719574) in R/R mIDH1 AML pts receiving single-agent olutasidenib 150 mg twice-daily showed an overall response rate (ORR) of 46%, including 33% of pts with CR/CRh (de Botton et al., ASCO/EHA 2021). Here we present data analysis on the mutational characteristics of these pts and the relationship between mutations and clinical response. Methods: The Efficacy Evaluable (EE) set comprised mIDH1R132X pts whose first dose was ≥180 days before the data cut-off (18-JUN-20). The primary endpoint was CR/CRh (complete remission [CR] according to modified IWG 2003 criteria plus CR with partial hematologic recovery [CRh]) response rate. CRh was defined as bone marrow blasts 0.5×10 9/L, and platelet count >50×10 9/L. ORR, a secondary endpoint, comprised CR+CRh+CR with incomplete recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR). IDH1 mutation subtypes were determined by central analysis, co-mutations were reported by investigators. Baseline characteristics and mutation subtypes were tabulated for the safety population and analysis of response rate by mutation type was performed on the EE set. Results: There were 153 R/R AML pts treated with olutasidenib 150 mg BID (safety set). Of those, 123 were in the efficacy evaluable (EE) set (centrally confirmed IDH1R132 mutation and received first dose at least 180 days prior to the data cut off). For the safety population, cytogenetic risk classification was favorable in 6 (4%) pts, intermediate in 109 (71%) pts, and poor in 25 (16%) pts (unknown, 13 [8%] pts). Eighty-five (56%) pts had IDH1R132C mutation subtype, followed by IDH1R132H (n=35 [23%]), IDH1R132G (n=12 [8%]), IDH1R132S (n=11 [7%]), and IDH1R132L (n=4 [3%]). Ninety-four (61%) pts had 1-3 co-mutations reported by the investigator at baseline, with 4-7 co-mutations in 20 (13%) pts, none in 6 (4%) pts, and not done/unknown in 33 (22%) pts. The most common co-mutations at baseline were: NPM1 (n=40 [26%]), DNMT3A (n=36 [24%]), and ASXL1 (n=21 [14%]. Receptor tyrosine kinase (RTK) mutations were reported in 32 (21%) pts (FLT3, n=18 [12%]; NRAS, n=10 [7%]; KRAS, n=3 [2%]; PTPN11, n=3 [2%]; KIT, n=2 [1%]; NF1, n=2 [1%]), with multiple mutations reported in some pts. For the EE population, responses were achieved in all IDH1R132 mutation subtypes, with ORR and CR/CRh response rates ranging from 27%-54% and 17%-50%, respectively (Table 1). The CR/CRh response rate was lower for pts with IDH1R132H mutations; notably, these pts tended to have a higher percentage of co-mutations, particularly mutations in NPM1 and RTK genes, including FLT3. For EE pts with available co-mutation data (n=96), the mean (SD) number of co-mutations was lower (p Conclusions: Responses were observed across IDH1R132 mutation subtypes, with a relatively lower CR/CRh response rate for pts with a R132H mutation as compared to other subtypes. Pts with a best response of CR/CRh had fewer co-mutations than pts who did not achieve CR/CRh. While the ORR was not significantly reduced for pts with RTK mutations, these pts had a lower CR/CRh response rate compared to pts without any RTK mutations. Additional genetic analyses using ddPCR for IDH1 mutations and NGS on a targeted panel of genes at baseline, best response, and end of study will be presented to further explore primary and secondary resistance mechanisms. Figure 1 Figure 1. Disclosures De Botton: Celgene, Agios, Forma Therapeutics, Astella, Daiichi Sankyo, Syros, Abbvie, Bayer, Seattle Genetics, Janssen: Honoraria; Celgene, Agios, Astellas, Daiichi Sankyo, Syros, Abbvie, Bayer, Janssen, Pierre Fabre, Novartis, Pfizer, Servier: Consultancy; Celgene: Speakers Bureau; Agios, Forma Therapeutics: Research Funding. Yee: Forma Therapeutics: Research Funding; Onconova: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Jazz: Research Funding; Tolero: Research Funding; AbbVie: Honoraria; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Geron: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Recher: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei: Gilead: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Montesinos: Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Stemline/Menarini: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Braun: Servier: Research Funding; Daiichi-Sankyo, Celgene: Consultancy, Honoraria. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Esteve: Novartis: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; Novartis: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy. Grove: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Khwaja: Pfizer, Abbvie: Honoraria; Novartis, Jazz: Speakers Bureau. Blum: Forma Therapeutics, Xencor; Celyad: Research Funding; Amerisource Bergen; Abbvie, Syndax: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding. Xin: Forma Therapeutics, Inc.: Current Employment. Sedkov: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Guichard: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sweeney: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Cortes: Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Fenaux: Syros Pharmaceuticals: Honoraria; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.
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- 2021
44. Long-Term Outcome of Peripheral Blood Autologous Stem Cell Transplantation (AutoSCT) for De Novo Acute Myeloid Leukemia in Patients Achieving First Complete Remission after One Vs Two Induction Courses: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
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Norbert Claude Gorin, William Arcese, Silvia Maria Trisolini, Francesco Lanza, Myriam Labopin, Tobias Gedde-Dahl, Depei Wu, Anne Huynh, Gwendolyn Van Gorkom, Mohamad Mohty, Jacques-Emmanuel Galimard, Arnaud Pigneux, Didier Blaise, Arnon Nagler, and Marie-Thérèse Rubio
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Oncology ,medicine.medical_specialty ,Acute leukemia ,Marrow transplantation ,business.industry ,Immunology ,De novo acute ,Complete remission ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Peripheral blood ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,In patient ,business - Abstract
Background: Achieving a first complete remission (CR1) is the primary goal in the treatment of AML and is an important prognostic factor for transplantation outcome in general and even more so for autologous transplantation (AutoSCT). However, there are no data for AutoSCT indicating whether the number of chemotherapy courses (1 vs 2) needed to achieve CR1 is of prognostic significance for transplantation outcome. Methods: Using the EBMT/ALWP registry, we compared transplantation outcomes of adult patients (pts) aged ≥18 years with de novo AML that underwent a peripheral blood AutoSCT in 2000-2019 in CR1 achieved following one vs two chemotherapy courses. The primary outcome was the Leukemia Free Survival (LFS). Multivariate analysis (MVA) adjusting for differences between the groups and knowns factors were performed using Cox's proportional- hazards regression model for outcomes. Results: 1825 pts were included: 1532 (84%) with one and 293 (16%) with two induction chemotherapies courses. Time from diagnosis to AutoSCT was 4.7 (3.9-5.8) vs 5.7 (4.7-7.1) months, respectively (p 90 was higher in pts receiving 1 vs 2 inductions, 71% and 58% of pts, respectively (p Day 30 neutrophil engraftment incidence was 96% and 96.5%. Five -year non-relapse mortality (NRM) was 6.2% vs 6.0% for pts achieving CR1 with 2 vs 1 chemotherapy courses, respectively, and did not differ significantly (HR=1.31 (95% CI: 0.81-2.10), p=0.27). Five -year relapse incidence (RI) was higher :67.2% vs 52.3%, (HR=1.46 (95% CI: 1.25-1.72), p Conclusions: The five -year RI was higher and transplantation outcomes significantly inferior in pts with AML undergoing AutoSCT but who received two lines of chemotherapy to achieve CR1. Such pts may benefit from additional novel therapies in the conditioning or post-AutoSCT or be considered for allogeneic transplantation in an attempt to reduce their high RI and improve outcomes. Figure 1 Figure 1. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Blaise: Jazz Pharmaceuticals: Honoraria. Huynh: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Gilead: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.
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- 2021
45. Real Life Study on Allogeneic Hematopoietic Cell Transplantation Practice According to International Guidelines and Its Impact on Survival in Acute Myeloid Leukemia French Population
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Nathalie Contentin, Alain Monnereau, Nicole Raus, Jean-Baptiste Mear, Gaelle Guillerm, Charlotte Jubert, Xavier Troussard, Arnaud Pigneux, Mohamad Sobh, Jacques-Olivier Bay, Sylvie François, Stephanie Nguyen Quoc, Edouard Forcade, Edouard Cornet, Sébastien Orazio, Marc Maynadié, Sylvain Chantepie, Denis Caillot, Remy Dulery, Mohamad Mohty, Marie Robin, Anna Berceanu, Loic Abed, Mauricette Michallet, and Morgane Mounier
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Oncology ,medicine.medical_specialty ,education.field_of_study ,Hematopoietic cell ,business.industry ,Immunology ,Population ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,Internal medicine ,Medicine ,business ,Life study ,education - Abstract
Introduction Allogeneic Hematopoietic Cell Transplantation (allo-HCT) has proved its efficiency in reducing Acute Myeloid Leukemia (AML) recurrence, although it was associated with high rates of complications especially in older patients. The worldwide number of allo-HCT has increased within 35 years, from 10.000 transplantations before 1985 to over a million in 2012. The decision to perform transplantation depends on the estimated risk-benefit ratio. High-risk prognostic factors include cytogenetics, age at diagnosis, presence of comorbidities and the response to treatment. By using combination of risk factors, international recommendations have been published to harmonize AML care and maximize the benefit of using allo-HCT. The principal aim of this study is to describe real life AML care management in all consecutive patients diagnosed and registered on 3 regional cancer registries in France, to analyze their outcome after different therapeutic strategies, following or not the international recommendations. Method This retrospective study included all AML patients diagnosed between January 2012 and December 2016 reported to the French population data-based of regional cancer registries specialized in hematological malignancies. Allo-HCT data were extracted from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry. Two groups of patients were defined according to the treatment received: i) group 1, patients who have received the best recommended care including allo-HCT considering HLA compatibility and best donor choice or best conventional treatment according to therapeutic guidelines based on individuals and clinical characteristics from The American Society for Blood and Marrow Transplantation guidance; ii) group 2, patients who received a treatment outside the recommendations. To study the impact of therapeutic decision on overall survival, a case-control study was performed using a one for one matching between group 1 and group 2. An exact matching on individual and disease characteristics (cytogenetic risk, Charlson score class, age group at diagnosis, subtype AML and response to treatment) allowed to pair-match patients following or not the international recommendations for therapeutic strategy. Net survival was estimated until five-year using non-parametric Pohar-Perme estimator (survival distribution compared using Grafféo test). Results A total of 1039 AML patients diagnosed from 2012 to 2016 were identified, 449 (43 %) received a curative treatment and 540 patients a non-curative treatment (hypomethylating agents, low dose of cytarabine or other palliative treatment, best supportive care combined to no effective treatment). Based on available clinical data, 430 patients were included in the study. Group 1 included 296 patients (68%), 167 males and 129 females with 54 receiving allo-HCT (32 geno-identical and 22 unrelated). Group 2 included 134 patients (31%), 72 males and 62 females with 94 receiving allo-HCT (14 geno-identical, 50 unrelated and 30 mismatched). In patients for whom allo-HCT represented the best option according to the recommendations (Figure B, n = 44), a very significant lower survival was observed in patients who did not receive allo-HCT when they were compared to patients who received allo-HCT, with a 5 year-overall survival probability of 7 % and 50 % respectively (p= 0.019). In patients for whom allo-HCT was not recommended (Figure A, n = 42), we did not observe any significant difference of survival between patients transplanted or not. Conclusion This analysis shows the importance of allo-HCT decision in AML patients, especially when following international guidelines. Although individual risks factors have been previously studied, our analysis sums up theses factors and allow to understand the importance of integrating allo-HCT in the therapeutic strategy of AML and to re-evaluate current practices and its impact on patient outcome. Figure 1 Figure 1. Disclosures Pigneux: Roche: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Amgen: Consultancy; Novartis: Consultancy, Research Funding. Forcade: Novartis: Other: travel grant. Mohty: Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria. Dulery: Novartis: Honoraria; Takeda: Consultancy; Gilead: Other: Travel support and registration fees for scientific meetings .
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- 2021
46. Retrospective Analysis of the Outcomes of Patients with Relapsed/Refractory Acute Myeloid Leukemia Included in a Patient Named Program of Gemtuzumab Ozogamicin
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Philippe Rousselot, Arnaud Pigneux, Juliette Lambert, Denis Caillot, Emmanuel Raffoux, Omar Benbrahim, Sylvain Chantepie, Jean Valère Malfuson, Ollivier Legrand, Caroline Bonmati, Hunault-Berger Mathilde, Anna Berceanu, Lauris Gastaud, Magalie Joris, Sylvie Castaigne, Cécile Pautas, Hervé Dombret, Pierre Peterlin, Marc Bernard, and Sylvie Chevret
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Oncology ,medicine.medical_specialty ,business.industry ,Gemtuzumab ozogamicin ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,Relapsed refractory ,Retrospective analysis ,Medicine ,business ,medicine.drug - Abstract
Introduction: In 2010 the French Health Agency opened a compassionate patient named program of gemtuzumab ozogamicin (GO, Mylotarg®) in relapsed/refractory (R/R) patients with acute myeloid leukemia (AML). Of note, since 2012, it was recommended to use GO at the dose of 3 or 6 mg/m 2 in addition to chemotherapy. We conducted a retrospective trial (NCT03287128) to evaluate the efficacy and the safety of GO-based regimen in R/R adult AML patients. Patients and methods: We retrospectively collected data of patients older than 18 years treated with GO-based regimen for AML in first relapse or for refractory AML, defined by failure after a prior standard intensive chemotherapy, in 18 French centers between December 15, 2011 and November 10, 2016. The primary objective was to assess the response to GO-based regimen. Patients were considered in response if reaching complete remission (CR), CR without platelet recovery (CRp) or CR with incomplete hematological recovery (CRi). Secondary objectives were the cumulative incidence of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the safety of the use of GO-based regimen. Results: Three hundred and thirty-five adult patients with R/R AML were included. Median age was 58 years (20 to 80 years). At diagnosis, cytogenetics was favorable in 50 (17%) patients, intermediate in 173 (59%) and adverse in 60 (20%). ELN distribution was favorable: 35%, intermediate: 42% and unfavorable: 23%. NPM1 mutation was present in 29% of patients and FLT3 mutation in 23%. Most patients had de novo AML (84%). Two hundred and thirty-eight patients (79%) were in first relapse and 65 (21%) had a refractory AML. The time between first diagnosis of AML and treatment with GO-based regimen was 4 to 16 months (median 9.4 months). Most patients (88%) received GO in combination with various intensive chemotherapy scheme including "7+3" with anthracycline/cytarabine (n=39 patients), intermediate and high-dose cytarabine (n=68), cytarabine in continuous intravenous infusion (n=78), mitoxantrone/cytarabine (n=49) and fludarabine/cytarabine and/or amsacrine and/or etoposide chemotherapy (n=35). Median follow-up time was 11 months. Among the 305 patients, 191 responded to GO-based regimen: 110 (36%) were in CR, 62 (20%) were in CRp and 19 (6%) in CRi for an overall response rate (CR+CRp+CRi, ORR) of 63%. In multivariate analysis, response was associated with age Regarding safety of GO-based regimen, early deaths occurred within Conclusion. Our study is the first to report efficacy data in the real-world setting of R/R AML adult patients treated with GO-based regimen. In our cohort of 305 patients, response rate was 63% and GO-based regimen appears as a valuable bridge-to-transplant option. Safety analysis showed toxicities consistent with the known safety profile of GO and chemotherapy. Figure 1 Figure 1. Disclosures Lambert: ASTELLAS: Consultancy; CELGENE/BMS: Consultancy. Pautas: PFIZER: Consultancy; ABBVIE: Consultancy. Raffoux: ASTELLAS: Consultancy; PFIZER: Consultancy; ABBVIE: Consultancy; CELGENE/BMS: Consultancy. Legrand: Servier: Consultancy. Gastaud: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; GSK: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Mathilde: SERVIER: Consultancy; ABBVIE: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Castaigne: PFIZER: Consultancy.
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- 2021
47. Artificial Intelligence-Based Predictive Models for Acute Myeloid Leukemia
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Eric Delabesse, François Vergez, Isabelle Luquet, Jean-Marc Alliot, Suzanne Tavitian, Emilie Bérard, Anne-Charlotte de Grande, Christian Recher, David Simoncini, Audrey Bidet, Pierre-Yves Dumas, Nicolas Lechevalier, Sarah Bertoli, Ibrahim Didi, Jean-Baptiste Rieu, Laetitia Largeaud, Arnaud Pigneux, and Audrey Sarry
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Myeloid leukemia ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Introduction In the acute myeloid leukemia (AML) setting, artificial intelligence has mainly been used to facilitate diagnosis or to identify biological subcategories. In this work, we trained and compared machine learning and deep learning predictive models of outcome on the data of 3687 consecutive adult AML patients included in the DATAML registry between 2000 and 2019. We also trained a model to predict the best treatment for newly diagnosed AML over 70 years. Methods Feature engineering and selection were done to keep the most relevant variables among clinical and biological characteristics at diagnosis. We worked with 54 features per patient, as well as information about the treatment received (intensive chemotherapy (IC) or azacitidine (AZA)), response and survival. We compared the performance of a gradient boosting algorithm (XGBoost) and three neural networks architectures: a multilayer perceptron (MLP), a neural oblivious decision ensemble model (NODE) and a recurrent relational network (RRN). We calibrated XGBoost with a grid search algorithm, and used 5-fold cross-validation on the dataset to evaluate all the models. The Shapley Additive Explanations method (SHAP) was used to showcase the importance and influence of variables on the predictions. The Boruta algorithm was then used to extract the most important features for prediction. Results In our cohort, 3030 patients (82.2%) received IC and 657 (17.8%) AZA as first line treatment. Median overall survival (OS) was 18 and 9 months, respectively. We first designed models for OS prediction. In the IC cohort, we achieved an accuracy of 68.5% on predicting OS at the 18-month mark, an improvement of 17.5% over a naïve predictor. The Boruta algorithm selected 13 variables as the most important, with decreasing order of importance: age, cytogenetic risk, WBC, LDH, platelets count, albumin, MPO, mean corpuscular volume, CD117, NPM1 mutation, AML status, multilineage dysmyelopoiesis, ASXL1 mutation (Figure 1). When training with only these 13 variables, we achieved an accuracy of 67.8%. In the AZA cohort, we achieved an accuracy of 62.1% on predicting OS at the 9-month mark, an improvement of 11.1% over a naïve predictor. Here the Boruta algorithm selected only 7 variables: blood blasts, serum ferritin, CD56, LDH, hemoglobin, CD13 and the presence of a disseminated intravascular coagulation. When training with only these 7 variables, we achieved a 61.9% accuracy. We then designed models to predict the best treatment between IC and AZA for the 1032 patients older than 70 years. We achieved a 88.5% accuracy, which is 37.5% more than a naïve predictor given the distribution of the cohort: 51% having received IC and 49% having received AZA. For this model, 12 features out of 54 were selected by the Boruta algorithm as the most important: age, TP53 mutation, bone marrow blasts, AML status, disseminated intravascular coagulation, blood blasts, cytogenetic risk, IDH2 mutation, IDH1 mutation, presence of an infection at diagnosis, ASXL1 mutation and presence of leukostasis. Conclusion We show that predictive models can be trained on our database to predict with characteristics at diagnosis the treatment that would be chosen by an expert hematologist between IC and AZA in newly diagnosed AML, give an indication of OS with each treatment, and outperform classical statistical analysis or naïve predictors. For the task of predicting OS, the improvement over naïve predictors is maximal at the median time of OS. We show with the Boruta algorithm that a small number of variables can recapitulate the accuracy of neural networks, which renders this type of model of high interest for routine practice, especially with the advent of targeted therapies. Figure 1 Figure 1. Disclosures Vergez: Pierre Fabre Laboratory: Research Funding; Roche: Research Funding. Dumas: BMS Celgene: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Tavitian: Novartis: Consultancy. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Pigneux: Amgen: Consultancy; Sunesis: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Recher: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; MaatPharma: Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bertoli: Astellas: Consultancy; BMS Celgene: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy.
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- 2021
48. Poster: MDS-335: Ivosidenib (IVO) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome (R/R MDS): Updated Enrollment for the MDS Sub-Study
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Courtney D DiNardo, James M Foran, Justin M Watts, Eytan M Stein, Stéphane De Botton, Amir T Fathi, Gabrielle T Prince, Anthony S Stein, Richard M Stone, Prapti A Patel, Gail J Roboz, Martha L Arellano, Harry P Erba, Arnaud Pigneux, Robert K Stuart, Xavier Thomas, Geoffrey L Uy, Ian R Lemieux, Vickie Zhang, Stephanie M Kapsalis, Guillermo Garcia-Manero, and David A Sallman
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Cancer Research ,Oncology ,Hematology - Published
- 2021
49. Comparison of a Combination of Vosaroxin (VOS) and Intermediate-Dose Cytarabine (IDAC) with Idac for the Consolidation Therapy of Younger Patients with Favorable- and Intermediate-Risk Acute Myeloid Leukemia (AML) in First Complete Remission (CR): Preliminary Results of a Randomized Phase 2 R4-VOS Study of the French ALFA-Filo AML Intergroup
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Xavier Thomas, Chantal Himberlin, Anne Banos, Clémence Loiseau, Emmanuel Raffoux, Corentin Orvain, Amine Belhabri, Isabelle Luquet, Christian Recher, Mathilde Hunault, Norbert Vey, Pierre Peterlin, Sylvain Chantepie, Christine Terré, Claude Gardin, Ariane C Mineur, Eric Delabesse, Cécile Pautas, Claude Preudhomme, Romain Guieze, Jean Francois Hamel, Emilie Lemasle, Martin Carre, Karine Celli-Lebras, Arnaud Pigneux, Hervé Dombret, Jean-Francois Brasme, and Marc Bernard
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Complete remission ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Vosaroxin ,Consolidation therapy ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,Cytarabine ,Intermediate risk ,business ,medicine.drug - Abstract
In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.
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- 2020
50. Ivosidenib Improves Overall Survival Relative to Standard Therapies in Relapsed or Refractory Mutant IDH1 AML: Results from Matched Comparisons to Historical Controls
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Hervé Dombret, John Reitan, Karl-Anton Kreuzer, Evelyn Acuña-Cruz, Mathilde Hunault-Berger, Eyal C. Attar, Thomas Winkler, Pau Montesinos Fernandez, Sylvain Chantepie, Stephanie M. Kapsalis, Christian Recher, Michael Heuser, Sarah C MacDonald, Gary Milkovich, Peter Paschka, Paresh Vyas, Klaus H. Metzeler, Mohamad Mohty, Daniela Weber, Konstanze Döhner, Bruno Quesnel, Michael Dennis, Hua Liu, Stéphane de Botton, Xavier Thomas, Deborah Casso, Hartmut Döhner, Michael Storm, and Arnaud Pigneux
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Oncology ,medicine.medical_specialty ,IDH1 ,business.industry ,Immunology ,Mutant ,Cell Biology ,Hematology ,Biochemistry ,Refractory ,Internal medicine ,Overall survival ,Medicine ,business - Abstract
Background: A European Marketing Authorization Application for ivosidenib (IVO) is currently under review for the indication of mutant isocitrate dehydrogenase 1 (mIDH1) R132 relapsed/refractory (R/R) acute myeloid leukemia (AML) in adult patients (pts) who have received ≥ 2 prior regimens, including ≥ 1 standard intensive chemotherapy (IC) regimen, or are not candidates for IC and have received ≥ 1 prior non-intensive regimen. IVO is an oral, potent, targeted inhibitor of mIDH1 and was approved by the FDA for the treatment of mIDH1 R/R AML in 2018, and in newly diagnosed AML in adults ≥ 75 years of age or pts ineligible for IC in 2019, based on the results of the open-label AG120-C-001 (NCT02074839) study. Aims: To evaluate the comparative benefit of IVO within the proposed EU indication, matched pt analyses were conducted using data on mIDH1 R/R AML pts from the AML Study Group (AMLSG) registry (NCT01252485) and a real-world chart review study (RWD) from France, Germany, UK, and Spain. Methods: Individual pt data from Arm 1+ of the AG120-C-001 study (n = 159) was compared to a historical control (HC), combining individual pt data from the AMLSG registry (n = 127) and the RWD (n = 148). A medical review was conducted to identify Arm 1+ IVO pts in the AG120-C-001 study and HC pts who fell within the proposed EU indication. Treatment with IVO was compared with the most recent therapy received by HC pts. HC pts treated with IC as their most recent therapy were excluded, as IVO pts, based on the AG120-C-001 study's eligibility criteria, were not considered candidates for IC. Propensity score-based matching/weighting methods were used to adjust for imbalances in baseline prognostic factors between the 2 cohorts (optimal full matching and inverse probability of treatment weighting [IPTW]). A literature review and data availability led to the inclusion of 6 baseline prognostic factors for estimation of propensity scores (age, history of hematopoietic stem cell transplantation, number of prior regimens for AML, nature of AML, cytogenetic risk, and primary refractory status). Balance between populations was assessed pre- and post-match via comparison of (weighted) standardized differences (SDs) for each covariate. Time-to-event data were summarized via Kaplan-Meier (KM) estimators with 2-sided 95% confidence intervals (CI). Cox regression analysis, using the key prognostic factors as covariates, was applied to estimate hazard ratios (HR) of overall survival (OS), and the corresponding 95% CI was estimated using the sandwich estimator. Complete remission (CR) rates were also compared between IVO pts and RWD non-IC HC pts (AMLSG pts were excluded as the response data did not allow for identification of CRs distinct from other response types). Results: One hundred and nine IVO pts and 60 HC pts fell within the proposed EU indication. The IPTW-matched dataset was selected for analysis, as it more strongly minimized the absolute weighted SDs between cohorts as compared with optimal full matching, with all SDs < 0.05. Median OS was 8.1 months (mo) (95% CI: 5.7, 9.8) with IVO compared with 2.9 mo (95% CI: 1.9, 4.5) in the HC pts. The HR for OS was 0.396 (95% CI: 0.279, 0.562), strongly in favor of IVO (p < 0.0001). There was clear and early separation of the IVO and HC KM curves, reflecting the early and sustained benefit of IVO treatment in this setting (Fig). Six- and 12-mo survival rates in the IVO cohort were 57.7% (95% CI: 48.2, 67.2) and 35.0% (95% CI: 25.7, 44.3), respectively, representing improvements versus 6- and 12-mo survival rates in the HC cohort of 29.1% (95% CI: 17.4, 40.8) and 10.8% (95% CI: 2.7, 18.9), respectively. The IVO cohort also demonstrated higher rates of CR than the HC cohort, with an observed CR rate of 18.3% (95% CI: 11.6, 26.9), compared with 7.0% (95% CI: 1.5, 19.1). Conclusion: IVO monotherapy demonstrated prolonged OS and the potential to increase CR rates vs standard of care therapies in a HC population. Disclosures Paschka: Amgen: Other; AbbVie: Other: Travel, accommodation or expenses, Speakers Bureau; Astellas Pharma: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, accommodations or expenses; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Otsuka: Consultancy; Janssen Oncology: Other; Astex Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Consultancy, Speakers Bureau; BerGenBio ASA: Research Funding. Dombret:Novartis: Consultancy; Cellectis: Consultancy; Sunesis: Consultancy; Abbvie: Consultancy; Immunogen: Consultancy; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Shire: Honoraria; Otsuka: Consultancy, Honoraria; Menarini: Honoraria; Daiichi Sankyo: Consultancy, Other: travel, accommodation expenses; Incyte: Consultancy, Other: travel, accommodation expenses; Celyad: Consultancy. Montesinos Fernandez:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vyas:Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven: Research Funding; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Kreuzer:Daiichi Sankyo: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Grifols: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Hexal: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Otsuka: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau; Biotest: Consultancy, Honoraria, Other: Personal fees, Research Funding, Speakers Bureau. Heuser:Karyopharm: Research Funding; Janssen: Consultancy; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Abbvie: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BerGenBio ASA: Research Funding; Bayer: Consultancy, Research Funding; PriME Oncology: Honoraria. Metzeler:Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Astellas: Honoraria. Quesnel:Abbvie: Other: travel expenses; Daichii Sankyo: Other: travel expenses, Research Funding. Mohty:Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. De Botton:Pierre Fabre: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Celgene: Consultancy, Honoraria, Speakers Bureau; Agios: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Seattle Genetics: Honoraria; Janssen: Consultancy, Honoraria. Döhner:Pfizer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Roche: Consultancy; Astellas Pharma: Consultancy; Astex Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Honoraria; Sunesis Pharmaceuticals: Research Funding; Janssen: Consultancy, Honoraria; Agios: Consultancy; Novartis: Honoraria, Research Funding; Abbvie: Consultancy. Milkovich:RJM Group LLC: Current Employment. Reitan:RJM Group LLC: Current Employment. MacDonald:IQVIA: Current Employment. Casso:IQVIA: Current Employment. Storm:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Liu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Kapsalis:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Attar:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Döhner:Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Sunesis: Other, Research Funding.
- Published
- 2020
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