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1. Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100 mg/m2 seems sufficient

Author

Justine Solignac, Laure Farnault, Thomas Robert, Raphaelle Fanciullino, Sylvain Choquet, Philippe Brunet, Geoffroy Venton, and Mickaël Bobot

Subjects
Metotrexato, Sistema nervioso central, Linfoma, Hemodiálisis, Toxicidad farmacológica, Diseases of the genitourinary system. Urology, RC870-923
Abstract

High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX.We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100 mg/m2, instead of the usual dose of 3500 mg/m2, and daily hemodialysis started 24 h later. The patient had no significant toxicity and was in complete remission at 1 year after the end of the treatment.We argue that ESRD is not an absolute pitfall to the use of HD-MTX for hematological malignancies. Experts should consider the use of adjusted dose at 100 mg/m2 as a viable therapeutic modality in ESRD patients. Resumen: La quimioinmunoterapia basada en una dosis elevada de metotrexato (HD-MTX) es una parte central del enfoque terapéutico estándar del linfoma primario del sistema nervioso central (PCNSL). La insuficiencia renal causa la demora de la eliminación completa de MTX, así como la concentración crítica del mismo. A pesar de las recomendaciones, el estatus de hemodiálisis no debería excluir la HD-MTX.Reportamos el caso de una mujer de 64 años con PCNSL y tratamiento de hemodiálisis crónica que fue exitosamente tratada con quimioinmunoterapia basada en HD-MTX con una dosis ajustada de 100 mg/m2, en lugar de la dosis habitual de 3.500 mg/m2, iniciándose la hemodiálisis diaria al cabo de 24 h. La paciente no reflejó toxicidad significativa y experimentó remisión completa al cabo de un año desde la finalización del tratamiento.Nosotros argumentamos que la enfermedad renal en etapa terminal (ESRD) no constituye un escollo en absoluto para utilizar la HD-MTX para neoplasias hematológicas. Los expertos deberían considerar el uso de una dosis ajustada a 100 mg/m2 como modalidad terapéutica viable en los pacientes de ESRD.

Published
2022
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2. The contribution of single-cell analysis of acute leukemia in the therapeutic strategy

Author

Lamia Madaci, Julien Colle, Geoffroy Venton, Laure Farnault, Béatrice Loriod, and Régis Costello

Subjects
Acute myeloid leukemia, Single cell, Tumor heterogeneity, Clonal evolution, Drug resistance, Targeted therapy, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.

Published
2021
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3. Impact of Molecular Biology in Diagnosis, Prognosis, and Therapeutic Management of BCR::ABL1-Negative Myeloproliferative Neoplasm

Author

Norman Abbou, Pauline Piazzola, Jean Gabert, Vincent Ernest, Robin Arcani, Anne-Laure Couderc, Antoine Tichadou, Pauline Roche, Laure Farnault, Julien Colle, L’houcine Ouafik, Pierre Morange, Régis Costello, and Geoffroy Venton

Subjects
myeloproliferative neoplasms, next-generation sequencing, driver mutations, additional somatic mutations, Cytology, QH573-671
Abstract

BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include three major subgroups—polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)—which are characterized by aberrant hematopoietic proliferation with an increased risk of leukemic transformation. Besides the driver mutations, which are JAK2, CALR, and MPL, more than twenty additional mutations have been identified through the use of next-generation sequencing (NGS), which can be involved with pathways that regulate epigenetic modifications, RNA splicing, or DNA repair. The aim of this short review is to highlight the impact of molecular biology on the diagnosis, prognosis, and therapeutic management of patients with PV, ET, and PMF.

Published
2022
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4. Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio‐Oncology Guidelines

Author

Joachim Alexandre, Jennifer Cautela, Stéphane Ederhy, Ghandi Laurent Damaj, Joe‐Elie Salem, Fabrice Barlesi, Laure Farnault, Aude Charbonnier, Mariana Mirabel, Stéphane Champiat, Alain Cohen‐Solal, Ariel Cohen, Charles Dolladille, and Franck Thuny

Subjects
cancer, cardio‐oncology, cardiotoxicity, guidelines, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short‐ and long‐term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio‐oncology expert panel from the French Working Group of Cardio‐Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

Published
2020
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5. CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

Author

Raphaelle Fanciullino, Laure Farnault, Mélanie Donnette, Diane-Charlotte Imbs, Catherine Roche, Geoffroy Venton, Yael Berda-Haddad, Vadim Ivanov, Joseph Ciccolini, L'Houcine Ouafik, Bruno Lacarelle, and Regis Costello

Subjects
Specialties of internal medicine, RC581-951
Abstract

Abstract: Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 7+3 (Ara-C + anthracyclines) protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 ± 0.7 U/mg vs 3.95 ± 3.1 U/mg; Student t test P < .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 ± 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

Published
2018
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6. High incidence of atrial fibrillation in patients treated with ibrutinib

Author

Florian Baptiste, Jennifer Cautela, Yan Ancedy, Noémie Resseguier, Thérèse Aurran, Laure Farnault, Marion Escudier, Chloé Ammar, Mélanie Gaubert, Charles Dolladille, Jeremie Barraud, Michael Peyrol, Ariel Cohen, Franck Paganelli, Joachim Alexandre, Stephane Ederhy, and Franck Thuny

Subjects
Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Objective Atrial fibrillation (AF) is one of the most common side effects of ibrutinib, a drug that has dramatically improved the prognosis of chronic B-cell malignancies such as chronic lymphocytic leukaemia (CLL). The true incidence of ibrutinib-related AF (IRAF) is not well known and its therapeutic management poses unique challenges especially due to the inherent risk of bleeding. We aimed to determine the incidence and predictors of IRAF, and to analyse its management and outcome.Methods A standardised monitoring was applied at two cardio-oncology clinics in consecutive patients referred before and during ibrutinib therapy. The primary endpoint was the incidence of IRAF. The excess of AF incidence with ibrutinib was studied by comparing the incidence of IRAF with the expected incidence of AF in general population and in patients with CLL not exposed to ibrutinib.Results 53 patients were included. The incidence of IRAF was 38% at 2 years and the risk was 15-fold higher than the AF risk in both the general population and patients with CLL not exposed to ibrutinib (p

Published
2019
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7. Hematological Malignancies Escape from NK Cell Innate Immune Surveillance: Mechanisms and Therapeutic Implications

Author

Laure Farnault, Carole Sanchez, Céline Baier, Thérèse Le Treut, and Régis T. Costello

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Hematological malignancies treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed. Therefore, sustainment of long-term remission is crucial. Immune system has a key role in tumor surveillance. Natural killer (NK) cells, at the frontier of innate and adaptive immune system, have a central role in tumor cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumor cells develop various mechanisms to escape from NK cells innate immune pressure. Abnormal NK cytolytic functions have been described in nearly all hematological malignancies. We present here various mechanisms involved in the escape of hematological malignancies from NK cells surveillance: NK cells quantitative deficiency and NK cell qualitative deficiency by increased inhibition signaling or decreased activating stimuli. A challenge of immunotherapy is to restore an efficient antitumor response. A combination of classical therapy plus immune modulation strategies will soon become a standard of care for hematological malignancies.

Published
2012
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10. Blinatumomab during Consolidation in High-Risk Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL) Adult Patients: A Two-Cohort Comparison within the Graall-2014/B Study

Author

Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Mathilde Hunault, Rathana KIM, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Sébastien Maury, Anne Thiebaut-Bertrand, Florence Van Obbergh, Thomas Cluzeau, Martine Escoffre-Barbe, Nicole Straetmans, Johanna Konopacki, Amine Belhabri, Alban Villate, Florence Pasquier, Ioana Vaida, Laurence Sanhes, Magda Alexis, Cedric Pastoret, Mathlide Lamarque, Laure Farnault, Nathalie Grardel, Celine Berthon, Eric Delabesse, Veronique Lheritier, Norbert Ifrah, Carlos Graux, Yves Chalandon, Emmanuelle Clappier, and Herve Dombret

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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11. Impact of Molecular Biology in Diagnosis, Prognosis, and Therapeutic Management of BCR::ABL1-Negative Myeloproliferative Neoplasm

Author

Norman Abbou, Pauline Piazzola, Jean Gabert, Vincent Ernest, Robin Arcani, Anne-Laure Couderc, Antoine Tichadou, Pauline Roche, Laure Farnault, Julien Colle, L’houcine Ouafik, Pierre Morange, Régis Costello, Geoffroy Venton, Laboratoire de Biologie Moléculaire (MARSEILLE - Biolo Moléculaire), Assistance Publique - Hôpitaux de Marseille (APHM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Département de médecine interne, Hôpital de la Timone, APHM, Marseille France, Département de Gériatrie, Hôpital Sainte-Marguerite, Piici, UMR 7298, Aix-Marseille Université-CNRS, Marseille, France, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service d'OncoBiologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Laboratoire d’Hématologie [AP-HM Hôpital de la Timone], Hôpital de la Timone [CHU - APHM] (TIMONE), Theories and Approaches of Genomic Complexity (TAGC), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
driver mutations, additional somatic mutations, next-generation sequencing, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, myeloproliferative neoplasms
Abstract

International audience; BCR::ABL1-negative myeloproliferative neoplasms (MPNs) include three major subgroups—polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)—which are characterized by aberrant hematopoietic proliferation with an increased risk of leukemic transformation. Besides the driver mutations, which are JAK2, CALR, and MPL, more than twenty additional mutations have been identified through the use of next-generation sequencing (NGS), which can be involved with pathways that regulate epigenetic modifications, RNA splicing, or DNA repair. The aim of this short review is to highlight the impact of molecular biology on the diagnosis, prognosis, and therapeutic management of patients with PV, ET, and PMF.

Published
2023
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12. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

Author

Yael Berda-Haddad, Laure Farnault, Mourad Hamimed, Joseph Ciccolini, Geoffroy Venton, Régis Costello, L'Houcine Ouafik, Mélanie Donnette, Raphaelle Fanciullino, Elise Kaspi, Bruno Lacarelle, Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire de Biologie Cellulaire [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital Nord [CHU - APHM], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Adult, Daunorubicin, [SDV]Life Sciences [q-bio], Pharmaceutical Science, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Humans, Medicine, ComputingMilieux_MISCELLANEOUS, business.industry, Cytarabine, Myeloid leukemia, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, medicine.disease, 3. Good health, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Pharmacogenetics, [SDV.TOX]Life Sciences [q-bio]/Toxicology, 030220 oncology & carcinogenesis, Toxicity, Bone marrow, business, Febrile neutropenia, medicine.drug
Abstract

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown. We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)). Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome.

Published
2021
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13. Cytidine deaminase activity predicts clinical outcome of azacitidine in real-world MDS patients

Author

Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Guillaume Sicard, Florian Correard, Laure Farnault, L'Houcine Ouafik, Geoffroy Venton, and Raphaelle Fanciullino

Abstract

Azacitidine (Vidaza®, Aza) is a mainstay for treating acute myeloid leukemia (AML) in patients unfit for induction chemotherapy and other high risk myelodysplastic syndromes (MDS). Only half of patients usually respond and almost all patients will relapse eventually. There are no predictive factors for response to Aza. Aza is detoxified in the liver by a single enzyme, cytidine deaminase (CDA). CDA is a ubiquitous enzyme coded by a highly polymorphic gene, with subsequent great variability in resulting liver activity. Here we investigated on the link between CDA phenotypic status, toxicity and efficacy of Aza in adult patients treated for AML and MDS. A total of 104 patients were screened in this retrospective, real-world study. Of the 104 patients treated, 67.3% received more than 3 cycles. Treatment was postponed due to Aza-related toxicity in 66% (before Course-2) and 53% (before Course-3) of the patients. Median overall survival (OS) were 15 months (95% CI: 10–22) and 13 months (95% CI: 9–21) in AML and high MDS cohorts, respectively. Responding patients at 3-months showed prolonged survivals, with landmark OS of 17 and 14 months for AML and MDS, respectively. Half of the patients had deficient CDA activity (i.e., < 2 UA/mg), with a lower proportion of deficient patients in MDS patients (34%) as compared with AML patients (67%). In MDS patients, CDA deficiency was correlated with longer landmark OS (14 VS. 8 months; p = 0.03 multivariate analysis), but not in AML patients. In addition, our data suggest that delay in Aza treatment is not associated with lack of efficacy, and thus should not be considered as a signal to shift to other drugs. Overall, our data suggest that CDA is an independent covariate could thus be a marker for predicting clinical outcome in MDS patients treated with Aza.

Published
2022
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14. Clinical characteristics and outcomes of patients with haematologic malignancies and COVID-19 suggest that prolonged SARS-CoV-2 carriage is an important issue

Author

Régis Costello, J Colle, Raphael Cauchois, Gilles Kaplanski, Pierre-André Jarrot, Anne-Laure Couderc, Julie Lachamp, Rodolphe Jean, Antoine Tichadou, Geoffroy Venton, Arthur Boyer, Robin Arcani, Laure Farnault, Marie Koubi, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), and RANCHON, GUILLAUME

Subjects
Adult, Male, medicine.medical_specialty, Lymphoma, [SDV]Life Sciences [q-bio], Haematologic malignancies, Comorbidity, Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, Hospital Mortality, Mortality, Multiple myeloma, Aged, Aged, 80 and over, Leukemia, Hematology, SARS-CoV-2, business.industry, Malnutrition, Smoking, COVID-19, Super-spreader, General Medicine, Middle Aged, Viral Load, medicine.disease, [SDV] Life Sciences [q-bio], Treatment Outcome, Carriage, Cardiovascular Diseases, Hematologic Neoplasms, Original Article, Female, Multiple Myeloma, business, Viral load
Abstract

Specificities of COVID-19 disease course in patients with haematologic malignancies are still poorly studied. So, we aimed to compare patients with haematologic malignancies to patients without malignancies, matched by sex and age and hospitalised for COVID-19 at the same time and in the same centre. Among 25 patients with haematologic malignancies, we found that mortality (40% versus 4%, p

Published
2021
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15. Acceptance, efficacy, and safety of COVID-19 vaccination in older patients with cancer

Author

Anne-Laure Couderc, Laetitia Ninove, Emilie Nouguerède, Dominique Rey, Marina Rebroin, Aurélie Daumas, Pascale Tomasini, Laurent Greillier, Sebastien Salas, Florence Duffaud, Laetitia Dahan, Muriel Duluc, Marie-Eve Garcia, Johan Pluvy, Solène Chaléat, Laure Farnault, Geoffroy Venton, Toscane Fourié, Elif Nurtop, Xavier de Lamballerie, Patrick Villani, Remi Charrel, Florian Correard, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Unité de coordination en oncogériatrie (UCOG Paca ouest), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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), Aix Marseille Université (AMU), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Marseille, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Male, COVID-19 Vaccines, Medical oncology, Second-line, Drug-related side effects and adverse reactions, MESH: Aged, 80 and over, Neoplasms, Humans, Lenvatinib, MESH: COVID-19, Thymic epithelial tumors, MESH: Neoplasms, MESH: BNT162 Vaccine, BNT162 Vaccine, Aged, Aged, 80 and over, MESH: Aged, Vaccines, MESH: Humans, Vaccination, COVID-19, MESH: Vaccination, Geriatric assessment, MESH: Male, MESH: Vaccines, Oncology, MESH: COVID-19 Vaccines, Female, Immunotherapy, Geriatrics and Gerontology, Pembrolizumab, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The COVID-19 vaccination campaign began in December 2020, in France, and primarily targeted the oldest people. Our study aimed to determine the level of acceptance of vaccination in a population of older patients with cancer.From January 2021, we offered vaccination with the BNT162b2 COVID-19 vaccine to all patients 70 years and older referred to our geriatric oncology center in Marseille University Hospital (AP-HM) for geriatric assessment before initiation of an oncological treatment. Objectives were to evaluate acceptance rate of COVID-19 vaccination and to assess vaccine safety, reactogenicity, and efficacy two months after the first dose.Between January 18, 2021 and May 7, 2021, 150 older patients with cancer were offered vaccination after a geriatric assessment. The majority were men (61.3%), with a mean age of 81 years. The two most frequent primary tumors were digestive (29.4%) and thoracic (18%). The vaccine acceptance rate was 82.6% and the complete vaccination rate (2 doses) reached 75.3%. Among the vaccinated patients, 15.9% reported mild side effects after the first dose and 23.4% after the second dose, mostly arm pain and fatigue. COVID-19 cases were observed in 5.1% of vaccinated patients compared with 16.7% in unvaccinated patients. Of the 22 vaccinated patients who agreed to have their serum tested, 15 had antibodies against the spike protein at day 21 after the first dose.Our study showed a high acceptance rate of COVID-19 vaccination, with good tolerance in this frail population. These results highlight the benefits of organizing vaccination campaigns at the very beginning of oncological management in older patients.This study was registered May 23, 2019 in ClinicalTrials.gov (NCT03960593).

Published
2022
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16. High Serum Vitamin B12 Levels Associated with C-Reactive Protein in Older Patients with Cancer

Author

Patrick Villani, Gaëtan Gentile, Florence Duffaud, Aurélie Daumas, Sébastien Salas, Vincent Pradel, Laure Farnault, Geoffroy Venton, Fabrice Barlesi, Anais Courcier, Anne-Laure Couderc, Robin Arcani, Laurent Greillier, Pierre Suchon, Régis Costello, Eddy Puchades, Assistance Publique - Hôpitaux de Marseille (APHM), Aix-Marseille Université - École de médecine (AMU SMPM MED), Aix-Marseille Université - Faculté des sciences médicales et paramédicales (AMU SMPM), Aix Marseille Université (AMU)-Aix Marseille Université (AMU), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Unité de coordination en oncogériatrie (UCOG Paca ouest), and Lucas, Nelly

Subjects
Cancer Research, medicine.medical_specialty, Activities of daily living, Palliative care, Multivariate analysis, [SDV]Life Sciences [q-bio], High serum vitamin B12 levels, [SDV.CAN]Life Sciences [q-bio]/Cancer, Logistic regression, [SHS]Humanities and Social Sciences, C-reactive protein, 03 medical and health sciences, 0302 clinical medicine, Ambulatory care, Neoplasms, Internal medicine, Activities of Daily Living, Humans, Medicine, 030212 general & internal medicine, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Geriatric Assessment, Aged, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Cancer, Early death, medicine.disease, 3. Good health, Hospitalization, Unplanned hospitalization, Vitamin B 12, Geriatric Oncology, Oncology, Geriatric oncology, 030220 oncology & carcinogenesis, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Older patients with cancer, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background A Comprehensive Geriatric Assessment (CGA) has been proposed to assess prognosis and to adapt oncological care in older patients with cancer. However, few biological markers are incorporated in the CGA. Methods This comparative study on older patients with cancer was realized before final therapeutic decision and during a CGA that included biological markers. Our objective study was to know if the serum vitamin B12–C-reactive protein index (BCI) can help to estimate early death and unplanned hospitalization. Associations between BCI and unplanned hospitalization or mortality were analyzed using ordered multivariate logistic regression. Findings We included 621 older cancer adults in outpatient care with a median age of 81 years (range, 70–98 years) from September 2015 to May 2018. In this study, 5.6% of patients died within 3 months, 8.8% had unplanned hospitalization within 1 month, and 11.4% had unplanned hospitalization within 3 months. Hypercobalaminemia was present in 83 patients (13.4%), and 34 patients (5.5%) had BCI >40,000. According to the multivariate analysis, BCI was a prognostic factor of mortality within 3 months and unplanned hospitalizations at 1 and 3 months. Impaired activities of daily living (ADL) and palliative care were also risk factors for mortality within 3 months. Impaired instrumental ADL, low albumin level, and palliative care were risk factors for unplanned hospitalization at 1 month. Interpretation BCI could be routinely added to the CGA process, as part of a pretreatment workup, in order to assess more precisely the frailties and to adapt oncological care in older patients treated for cancer. Implications for Practice Aging comes with an increase of frailties and comorbidities. To identify frailties in older patients with cancer, this study used a Comprehensive Geriatric Assessment, which allowed for the adaptation of each treatment plan in accordance with the individual needs of the patients. However, biological characteristics were not included in this assessment. This study showed that hypercobalaminemia and vitamin B12 -C-reactive protein index may be potential markers for cancer with poor prognosis, particularly in the older population. These biological markers can be used in geriatric oncology and general medicine.

Published
2020
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17. ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Author

Oussama Abla, Stephen Peeke, Irem Eldem, Marianne D. van de Wetering, Jennifer Picarsic, Kseniya Petrova-Drus, Robert B. Lorsbach, Jan A M van Laar, Paul Geraeds Kemps, Sylvie Fraitag, Sébastien Héritier, Kristian T. Schafernak, Amy A. Swanson, Eli L. Diamond, Raf Sciot, Karen Ernestus, Mariko Suchi, Nabeel R. Yaseen, Sanda Alexandrescu, Laura Sophia Hiemcke-Jiwa, Matthew Collin, Ingrid S Tam, Sabrina Rossi, Benjamin H. Durham, F J Sherida H Woei-A-Jin, James A. Whitlock, Brianna Empringham, Laura Munoz-Arcos, Falko Fend, Olga Gryniewicz-Kwiatkowska, Majid Madni, Verena Wiegering, Kerry Turner, Dina El Demellawy, Gianpiero Tamburrini, Aditya Raghunathan, Lucas R. Massoth, Carel J. M. van Noesel, Robert Möhle, Cor van den Bos, Jacinthe Bonneau-Lagacherie, Somak Roy, Pasquale M Barbaro, Andreas Beilken, Stefania Gaspari, Jean-François Emile, David D. Grier, Claire Lamaison, Kee Kiat Yeo, Jean Donadieu, Jon M Brandt, Laure Farnault, Friedrich Feuerhake, Marie-Laure Jullie, Uta Flucke, Pancras C.W. Hogendoorn, Astrid G. S. van Halteren, Antje Bornemann, Bryan A. Sisk, Tina Méry, Joanna Weinstein, Ashish R Kumar, Robert M. Verdijk, V. Baykov, Alysa A Poulin, Mandy M Atkinson, VG Potapenko, Vaish Sridhar, Julien Haroche, Zofia Hélias-Rodzewicz, Shipra Garg, Susan Picton, Michael M. Henry, Jackie Allotey, Daniel Leino, Nishant Tiwari, Martin Ebinger, Jason L Hornick, Bożenna Dembowska-Bagińska, Marco Gessi, Dmitry A Evseev, Paediatric Oncology, CCA - Cancer biology and immunology, Pathology, CCA - Cancer Treatment and Quality of Life, Leiden University Medical Center (LUMC), Universiteit Leiden, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pontchaillou [Rennes], CHU Marseille, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], CHU Pitié-Salpêtrière [AP-HP], National Institutes of Health, NIH, National Cancer Institute, NCI: P30 CA008748, R37 CA259260-01, Cincinnati Children's Hospital Medical Center, University of Saskatchewan, Leids Universitair Medisch Centrum, LUMC, Institut National Du Cancer, INCa: PRT-K19-143, P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143)., and The authors acknowledge the International Rare Histiocytic Disorders Registry (IRHDR, ClinicalTrial.gov number NCT02285582), which included some patients described in this study. The authors thank Chris Woods (Lead Analyst, Imaging Informatics) and the Research Pathology Laboratory at Cincinnati Children's Hospital Medical Center, John DeCoteau (molecular pathologist) at University of Saskatchewan, Sven van Kempen (senior laboratory technician) and Lennart Kester (clinical molecular biologist in pathology in training) at Princess M?xima Center for Pediatric Oncology, and Demi van Egmond (laboratory technician), Tom van Wezel (clinical molecular biologist in pathology), and Arjen Cleven (pathologist) at Leiden University Medical Center for technical assistance. The authors thank Els Wauters (pulmonologist and respiratory oncologist) at University Hospitals Leuven, Andreas Rosenwald (pathologist) at the Institute of Pathology of the University of W?rzburg, and Bipin Mathew (pathologist) at Leeds Teaching Hospitals for clinical care and/or diagnostics of patients described in this study. The authors thank Les Laboratoires Servier for allowing the use of their medical illustrations (Servier Medical Art, https://smart.servier.com) in the visual abstract. Figure 6 was created with BioRender.com. P.G.K. received a grant from Leiden University Medical Center. A.G.S.v.H. is supported by Stichting 1000 kaarsjes voor Juultje. E.L.D. is supported by the National Institutes of Health/National Cancer Institute Core Grant (P30 CA008748), National Cancer Institute (R37 CA259260-01), the Frame Fund, Applebaum Foundation, and Joy Family West Foundation. J.-F.E. is supported by the Programme de Recherche Translationnelle sur le Cancer from the French National Cancer Institute (PRT-K19-143).

Subjects
Adult, Histiocytic Disorders, Malignant, Male, Pathology, medicine.medical_specialty, Adolescent, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], BLOOD COMMENTARY, Immunology, Disease, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Biochemistry, Young Adult, hemic and lymphatic diseases, medicine, Humans, Anaplastic Lymphoma Kinase, Child, Protein Kinase Inhibitors, Histiocyte, Retrospective Studies, business.industry, Infant, Histology, Cell Biology, Hematology, medicine.disease, Phenotype, Histiocytosis, Histiocytic neoplasm, Child, Preschool, Female, Nervous System Diseases, business
Abstract

Contains fulltext : 249882.pdf (Publisher’s version ) (Closed access) ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Published
2022
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18. Functional status in older patients with cancer

Author

Dominique Rey, Bérengère Saliba-Serre, Laure Farnault, Anais Courcier, Anne-Laure Couderc, Geoffroy Venton, Fabrice Barlesi, Laurent Greillier, Patrick Villani, Florence Duffaud, Emilie Nouguerède, Robin Arcani, Aurélie Daumas, Pierre Suchon, Régis Costello, Sébastien Salas, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Unité de coordination en oncogériatrie (UCOG Paca ouest), Assistance Publique - Hôpitaux de Marseille (APHM), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone [CHU - APHM] (TIMONE), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Coordination en Oncogériatrie [CHU de Dijon] (UCOGB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Aix Marseille Université (AMU), Service d’Oncologie Médicale [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Nord [CHU - APHM], Institut Gustave Roussy (IGR), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-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), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Male, medicine.medical_specialty, Activities of daily living, [SDV]Life Sciences [q-bio], Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer management, Logistic regression, [SHS]Humanities and Social Sciences, Cohort Studies, Older patients, Neoplasms, Internal medicine, Activities of Daily Living, medicine, Humans, Stage (cooking), Mortality, Prospective cohort study, education, Geriatric Assessment, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, education.field_of_study, business.industry, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, Hazard ratio, Cancer, Functional status, medicine.disease, Unplanned hospitalization, Oncology, Geriatrics and Gerontology, business, human activities
Abstract

Background Functional Status (FS) is an important domain in Comprehensive Geriatric Assessment (CGA) and is most often evaluated using the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales separately. Method and objectives This secondary analysis of a previous prospective cohort study was conducted between September 2015 and May 2018 at Marseille University Hospital, France, on 613 cancer outpatients aged ≥70 years. The first objective of this study was to determine the prevalence of FS impairment in older outpatients with cancer using a combination of the information collected with the ADL and short IADL scales. Our second objective was to describe the potential impact of this combined FS on three-month unplanned hospitalizations and three-month mortality in this population. Results The median age was 81 years and 61.2% were men. The most common types of tumours were lung and thoracic (22.3%). Concerning FS, 255 patients (41.6%) had unimpaired ADL-IADL, 131 patients (21.4%) had IADL impairment, 38 patients (6.2%) had ADL impairment, and 189 patients (30.8%) had impaired ADL-IADL. In the multivariate Cox analysis, metastatic stage (adjusted Hazard Ratio (aHR) = 1.79; 95% CI [1.14–2.80]) and impaired ADL-IADL (aHR = 3.46; 95% CI [1.89–6.33]) were independently associated with three-month mortality. In the logistic regression model, impaired ADL-IADL (adjusted Odd ratio (aOR) = 3.64; 95% CI [1.84–7.20]) was the only factor independently associated with three-month unplanned hospitalizations. Interpretation The combined use of the ADL and IADL scales to evaluate functional status in older patients with cancer is of significant prognostic value regarding the risks of three-month unplanned hospitalizations and mortality.

Published
2022
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19. The contribution of single-cell analysis of acute leukemia in the therapeutic strategy

Author

Laure Farnault, Béatrice Loriod, Geoffroy Venton, Julien Colle, Régis T. Costello, Lamia Madaci, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Transscriptomics and Genomics of Marseille-Luminy (TGML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Spinelli, Lionel

Subjects
0301 basic medicine, Tumor heterogeneity, Acute myeloblastic leukemia, medicine.medical_treatment, Clinical Biochemistry, Leukemia stem cell, Review, RM1-950, Biology, Somatic evolution in cancer, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Single-cell analysis, Next generation sequencing, medicine, Single cell, Acute leukemia, Clonal evolution, Acute myeloid leukemia, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biochemistry (medical), Immunotherapy, medicine.disease, 3. Good health, Leukemia, 030104 developmental biology, Tumor Escape, 030220 oncology & carcinogenesis, Drug resistance, Cancer research, Molecular Medicine, Therapeutics. Pharmacology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.

Published
2021
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20. Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2

Author

Rathana Kim, Nicolas Boissel, Hervé Dombret, Florence Van Obbergh, Sébastien Maury, Carlos Graux, Yosr Hicheri, Laure Farnault, Yves Chalandon, Thibaut Leguay, Thomas Cluzeau, Cedric Pastoret, Alban Villate, Emmanuelle Clappier, Françoise Huguet, Philippe Rousselot, Martine Escoffre-Barbe, Florence Pasquier, Marie Balsat, Anne Thiebaut-Bertrand, Mathilde Hunault, Eric Delabesse, Patrice Chevallier, Véronique Lhéritier, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Catholique de Louvain = Catholic University of Louvain (UCL), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Henri Mondor [Créteil], CHU Pontchaillou [Rennes], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Institut Gustave Roussy (IGR), Centre Hospitalier de Versailles André Mignot (CHV), Hôpitaux Universitaires de Genève (HUG), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), and Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Oncology, Philadelphia negative, medicine.medical_specialty, Adult patients, Consolidation (soil), business.industry, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Biology, Hematology, Biochemistry, Early results, Internal medicine, Medicine, Blinatumomab, business, medicine.drug
Abstract

Introduction: Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) with high-risk genetics and/or measurable residual disease (MRD) are at high-risk of disease recurrence. In the previous GRAALL-2005 study, we identified KMT2A rearrangements (KMT2A-r), IKZF1 intragenic deletion (IKZF1del) and post-induction (TP1, week 6) MRD ≥ 0.01% as independent factors to predict relapse in Ph-negative B-cell precursor (BCP) ALL (Beldjord K, Blood 2014). In the GRAALL-2014 trial, high-risk (HR) patients were thus defined by the presence of at least one of these three factors. Among them, only those with higher MRD levels defined as TP1-MRD ≥ 0.1% and/or week 12 (TP2) MRD ≥ 0.01% were considered at very high risk (VHR) and proposed allogeneic hematopoietic stem cell transplant (alloSCT) in first remission (Dhedin et al., Blood 2015). Since October 2018, all these patients were eligible to be included in the GRAALL-2014-QUEST phase 2 study to receive blinatumomab as part of consolidation and maintenance phases or as a bridge to transplant. Methods: From October 2018 to December 2020, 95 patients with high-risk Ph-negative BCP-ALL without central nervous system involvement at diagnosis and in continuous complete remission after induction and consolidation 1, were prospectively included to start blinatumomab at week 12. One patient was excluded because of T-ALL phenotype (with CD19 aberrant expression). Patients with alloSCT indication and a stem cell source received blinatumomab 28 microg/d administered by continuous intravenous infusion (cIV) until transplant. A minimum of 4 weeks blinatumomab was recommended before proceeding to transplantation. All other patients received 5 cycles of blinatumomab 28 microg/day cIV (for 28 days), during consolidation 2 and 3 and at months 1/3/5 of the maintenance phase respectively. The primary objective was disease-free survival (DFS). Secondary objectives included post-blinatumomab MRD response at TP3 (after consolidation 2 or before alloSCT), overall survival (OS), and safety. Early results are reported here. Results: Median age was 35 years old (range, 18-60). Median white blood cell count (WBC) at diagnosis was 12 G/L (range, 1-449). Oncogenetic analyses allowed classifying ALL as Ph-like (18%), KMT2A-r (17%), DUX4/ERGdel (13%), ZNF384-r (11%), low hypodiploidy/near triploidy (7%), B-other (26%) or unknown (9%). An IKZF1del was found in 37/93 (40%). A TP1-MRD ≥ 0.01% was found in 46/94 patients (49%). Final risk group was HR for 45 patients and VHR for 49 patients. Last pre-blinatumomab MRD was Conclusion. In patients wih high-risk BCP-ALL, blinatumomab added to consolidation is safe and gives promising results. A comparison to similar patients treated in the same GRAALL-2014 study before October 2018 is planned with a longer follow-up. Figure 1 Figure 1. Disclosures Boissel: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; SANOFI: Honoraria; Servier: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; CELGENE: Honoraria; JAZZ Pharma: Honoraria, Research Funding; PFIZER: Consultancy, Honoraria. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Delabesse: Astellas: Consultancy; Novartis: Consultancy. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Blinatumomab in frontline high-risk acute lymphoblastic leukemia

Published
2021
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21. Successful treatment with adapted high dose methotrexate in a hemodialysis patient with primary central nervous system lymphoma: 100mg/m

Author

Justine, Solignac, Laure, Farnault, Thomas, Robert, Raphaelle, Fanciullino, Sylvain, Choquet, Philippe, Brunet, Geoffroy, Venton, and Mickaël, Bobot

Subjects
Central Nervous System, Central Nervous System Neoplasms, Methotrexate, Lymphoma, Renal Dialysis, Humans, Kidney Failure, Chronic, Female, Middle Aged
Abstract

High dose methotrexate (HD-MTX) based chemoimmunotherapy is a central part of the standard approach to treatment of primary central nervous system lymphoma (PCNSL). Renal dysfunction leads to delayed MTX complete elimination and critical MTX concentration. Despite the recommendations, hemodialysis status should not exclude HD-MTX. We report the case of a 64 years old woman on chronic hemodialysis with PCNSL successfully treated with HD-MTX-based chemoimmunotherapy with an adjusted dose of 100mg/m

Published
2021

22. Could daratumumab induce the maturation of plasmablasts in Plasmablastic lymphoma?-Potential therapeutic applications

Author

Régis Costello, Raphaelle Fanciullino, Hubert Lepidi, Geoffroy Venton, Pauline Roche, Cédric Mercier, J Colle, Laure Farnault, Shirley Fritz, Yael Berda-Haddad, Vadim Ivanov, Antoine Tichadou, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-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)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
business.industry, [SDV]Life Sciences [q-bio], Plasma Cells, Daratumumab, Antibodies, Monoclonal, Cell Differentiation, Hematology, General Medicine, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, 030220 oncology & carcinogenesis, medicine, Cancer research, Plasmablastic Lymphoma, Humans, Molecular Targeted Therapy, business, Plasmablastic lymphoma, ComputingMilieux_MISCELLANEOUS, 030215 immunology
Abstract

International audience

Published
2020
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23. Cardiovascular Toxicity Related to Cancer Treatment: A Pragmatic Approach to the American and European Cardio-Oncology Guidelines

Author

Charles Dolladille, Aude Charbonnier, Franck Thuny, Mariana Mirabel, Stéphane Champiat, Alain Cohen-Solal, Joe-Elie Salem, Joachim Alexandre, Laure Farnault, Ariel Cohen, Stéphane Ederhy, Fabrice Barlesi, Ghandi Damaj, Jennifer Cautela, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Aix Marseille Université (AMU), Sorbonne Université (SU), Université Paris-Saclay, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Fédération Française de Cardiologie, Service de cardiologie et de pathologie vasculaire [CHU Caen], 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), Département de Pharmacologie [CHU Caen], Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance Publique - Hôpitaux de Marseille (APHM), Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Thrombose, atherothrombose et pharmacologie appliquée, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie Biologique [CHU Caen], Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIC Paris Est, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Normandie Université (NU), Hôpital Nord [CHU - APHM], Groupe Méditerranéen de Cardio-Oncologie, Partenaires INRAE, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Tenon [AP-HP], Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Aix Marseille Université (AMU), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Service de Pharmacologie médicale [CHU Pitié-Salpêtrière], Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Gestionnaire, Hal Sorbonne Université

Subjects
Cardiovascular toxicity, medicine.medical_specialty, cardio-oncology, INDUCED CARDIOTOXICITY, TROPONIN-I, [SDV]Life Sciences [q-bio], cardiotoxicity, ADULT SURVIVORS, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, 030204 cardiovascular system & hematology, THERAPY, 03 medical and health sciences, 0302 clinical medicine, LEFT-VENTRICULAR DYSFUNCTION, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Neoplasms, medicine, MANAGEMENT, BREAST-CANCER, Humans, cancer, guidelines, Cardio oncology, Intensive care medicine, OCCLUSIVE DISEASE, Special Report, cardio‐oncology, RISK, Cardiotoxicity, business.industry, Cancer, medicine.disease, PREVENTION, United States, 3. Good health, Cancer treatment, [SDV] Life Sciences [q-bio], Europe, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Practice Guidelines as Topic, Immunotherapy, Cardiology and Cardiovascular Medicine, business
Abstract

The considerable progress made in the field of cancer treatment has led to a dramatic improvement in the prognosis of patients with cancer. However, toxicities resulting from these treatments represent a cost that can be harmful to short‐ and long‐term outcomes. Adverse events affecting the cardiovascular system are one of the greatest challenges in the overall management of patients with cancer, as they can compromise the success of the optimal treatment against the tumor. Such adverse events are associated not only with older chemotherapy drugs such as anthracyclines but also with many targeted therapies and immunotherapies. Recognizing this concern, several American and European governing societies in oncology and cardiology have published guidelines on the cardiovascular monitoring of patients receiving potentially cardiotoxic cancer therapies, as well as on the management of cardiovascular toxicities. However, the low level of evidence supporting these guidelines has led to numerous discrepancies, leaving clinicians without a consensus strategy to apply. A cardio‐oncology expert panel from the French Working Group of Cardio‐Oncology has undertaken an ambitious effort to analyze and harmonize the most recent American and European guidelines to propose roadmaps and decision algorithms that would be easy for clinicians to use in their daily practice. In this statement, the experts addressed the cardiovascular monitoring strategies for the cancer drugs associated with the highest risk of cardiovascular toxicities, as well as the management of such toxicities.

Published
2020
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24. Different sensitivity of CD19-positive bone marrow and lymph node lymphoblasts may cause resistance to blinatumomab in relapsed B-cell acute lymphoblastic leukemia/lymphoma

Author

Geoffroy Venton, Raphaelle Fanciullino, Cédric Mercier, J Colle, Régis T. Costello, Vadim Ivanov, Cécile Colavolpe, Corinne Nicolino-Brunet, Isabelle Arnoux, Yael Berda-Haddad, Hubert Lepidi, Gleb E. Ivanov, Laure Farnault, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-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), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Assistance Publique - Hôpitaux de Marseille (APHM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'Anatomie Pathologique et de Neuropathologie, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), and Laboratoire de Biologie médicale, AP-HM

Subjects
Cancer Research, Lymphoma, [SDV]Life Sciences [q-bio], Antigens, CD19, Antineoplastic Agents, CD19, 03 medical and health sciences, 0302 clinical medicine, Antigen, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Bone Marrow, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, hemic and lymphatic diseases, Antibodies, Bispecific, medicine, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Lymph node, ComputingMilieux_MISCELLANEOUS, B-Lymphocytes, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, business.industry, Lymphoblast, hemic and immune systems, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Cancer research, Blinatumomab, Lymph Nodes, Bone marrow, Antibody, business, 030215 immunology, medicine.drug
Abstract

Blinatumomab, a new bispecific CD19/CD3 T-cell engager antibody, has been shown to improve the outcome in patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (R/R ALL) comp...

Published
2020
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25. Response to trametinib of histiocytosis with an activating PTPN11 mutation

Author

Julien Haroche, Zofia Hélias-Rodzewicz, Jean-François Emile, Laure Farnault, Raphaelle Fanciullino, J. Donadieu, Lénaïg Mescam, Geoffroy Venton, Sophie Gabriel, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), 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)-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), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Imagerie MOléculaire pour applications THéranostiques personnalisées (IMOTHEP), Institut FRESNEL (FRESNEL), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Trametinib, Cancer Research, [SDV]Life Sciences [q-bio], Hematology, Biology, medicine.disease, Phenotype, 3. Good health, PTPN11, 03 medical and health sciences, Histiocytosis, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Histiocytoses, Mutation (genetic algorithm), medicine, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, ComputingMilieux_MISCELLANEOUS, 030215 immunology
Abstract

Histiocytoses are disorders characterized by the accumulation of cells with the morphology and phenotype of dendritic cells or macrophages. These diseases may involve any organ and the clinical beh...

Published
2020
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27. Simultaneous determination of cytosine arabinoside and its metabolite uracil arabinoside in human plasma by LC-MS/MS: Application to pharmacokinetics-pharmacogenetics pilot study in AML patients

Author

Bruno Lacarelle, Régis Costello, Le Thi Thu Hau, Mélanie Donnette, Caroline Solas, Madeleine Giocanti, Raphaelle Fanciullino, Geoffroy Venton, L'Houcine Ouafik, Laure Farnault, Joseph Ciccolini, Yael Berda-Haddad, Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Laboratoire de pharmacocinétique et toxicologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d’hématologie et de thérapie cellulaire, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire de Biologie médicale, AP-HM, Assistance Publique - Hôpitaux de Marseille (APHM), Service de Transfert d’Oncologie Biologique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), 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)-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), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), and Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM)

Subjects
Metabolite, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Pilot Projects, MESH: Arabinofuranosyluracil, Pharmacology, 030226 pharmacology & pharmacy, 01 natural sciences, Biochemistry, Analytical Chemistry, MESH: Linear Models, chemistry.chemical_compound, 0302 clinical medicine, Tandem Mass Spectrometry, MESH: Drug Monitoring, MESH: Cytarabine, ComputingMilieux_MISCELLANEOUS, Chromatography, High Pressure Liquid, media_common, MESH: Antimetabolites, Antineoplastic, Chemistry, Cytarabine, Myeloid leukemia, General Medicine, Cytidine deaminase, 3. Good health, MESH: Reproducibility of Results, Leukemia, Myeloid, Acute, Drug Monitoring, MESH: Leukemia, Myeloid, Acute, medicine.drug, Drug, Antimetabolites, Antineoplastic, media_common.quotation_subject, Purine analogue, Acute myeloid leukemia patients, [SDV.CAN]Life Sciences [q-bio]/Cancer, Sensitivity and Specificity, 03 medical and health sciences, Pharmacokinetics, medicine, Humans, LC-MS/MS, MESH: Chromatography, High Pressure Liquid, Chromatography, MESH: Humans, 010401 analytical chemistry, Arabinofuranosyluracil, Reproducibility of Results, MESH: Tandem Mass Spectrometry, Cell Biology, MESH: Pilot Projects, MESH: Sensitivity and Specificity, 0104 chemical sciences, Linear Models, Pharmacogenetics
Abstract

International audience; Purine analogs like aracytine (AraC) are a mainstay for treating acute myeloid leukemia (AML). There are marked differences in drug dosing and scheduling depending on the protocols when treating AML patients with AraC. Large inter-patient pharmacokinetics variability has been reported, and genetic polymorphisms affecting cytidine deaminase (CDA), the liver enzyme responsible for the conversion of Ara-C to inactive uracil arabinoside (AraU) could be a culprit for either life-threatening toxicities or poor efficacy related to substantial changes in plasma exposure levels among patients. The quantitative determination of Ara-C in plasma is challenging due the required sensitivity because of the short half-life of this drug (i.e.

Published
2019
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28. Response to trametinib of histiocytosis with an activating

Author

Laure, Farnault, Zofia, Hélias-Rodzewicz, Geoffroy, Venton, Raphaelle, Fanciullino, Sophie, Gabriel, Lénaïg, Mescam, Julien, Haroche, Jean, Donadieu, and Jean-François, Emile

Subjects
Pyridones, Mutation, Humans, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Pyrimidinones, Histiocytosis
Published
2019

29. Efficacy and safety of autologous stem cell transplantation after induction therapy with lenalidomide, bortezomib, and dexamethasone

Author

Raphaelle Fanciullino, Bertrand Pourroy, Pierre Suchon, Laure Farnault, Vadim Ivanov, Pauline Roche, Geoffroy Venton, Régis Costello, Corinne Brunet, Marina Lafage, J Colle, Wakil Azouza, Cédric Mercier, Robin Arcani, Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Service d’hématologie et de thérapie cellulaire, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Cergy Pontoise (UCP), Université Paris-Seine, Laboratoire de Génie Génétique [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service Pharmacie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Simulation and Modeling of Adaptive Response for Therapeutics in Cancer (SMARTc), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Spinelli, Lionel

Subjects
Male, Oncology, Melphalan, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Dexamethasone, 0302 clinical medicine, Autologous stem-cell transplantation, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Multiple myeloma, Bortezomib, bortezomib, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Induction Chemotherapy, Hematology, General Medicine, Middle Aged, Prognosis, Combined Modality Therapy, 3. Good health, [SDV] Life Sciences [q-bio], multiple myeloma, Treatment Outcome, 030220 oncology & carcinogenesis, Female, immunomodulatory therapy, medicine.drug, Adult, medicine.medical_specialty, lenalidomide, [SDV.CAN]Life Sciences [q-bio]/Cancer, Transplantation, Autologous, 03 medical and health sciences, Internal medicine, medicine, Humans, Aged, Neoplasm Staging, Retrospective Studies, Lenalidomide, Chemotherapy, business.industry, medicine.disease, Survival Analysis, Minimal residual disease, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology
Abstract

OBJECTIVES Recently, phase III trials assessed a new combination of lenalidomide, bortezomib, and dexamethasone (RVD) in induction therapy in transplantation-eligible multiple myeloma (MM) patients, before consolidation with RVD and lenalidomide maintenance. We present a retrospective study evaluating this approach with patients from the real life. METHODS We conducted a retrospective single-arm study to assess efficacy and safety of RVD combination in induction therapy before high-dose chemotherapy with melphalan followed by autologous stem cell transplantation, and RVD consolidation followed by lenalidomide maintenance, from February 2011 to May 2016. RESULTS Forty patients were enrolled. The mean age at diagnosis was 56 years. Median progression-free survival was 45 months, and median overall survival was 76 months. The only factor found associated with better PFS was a negative minimal residual disease (P

Published
2019
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30. Severe renal insufficiency is not an absolute pitfall to autologous stem cell transplantation with BeEAM (bendamustine, etoposide, cytarabine, melphalan) conditioning regimen

Author

Geoffroy Venton, Raphaelle Fanciullino, Régis Costello, B Pourroy, Laure Farnault, P Roche, J Colle, N Jourde-Chiche, V Ivanov, Cédric Mercier, Robin Arcani, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de néphrologie et transplantation rénale [Hôpital de la Conception - APHM], and Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
Bendamustine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], 030226 pharmacology & pharmacy, Conditioning regimen, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Internal medicine, Severity of illness, Medicine, Cytarabine/Melphalan, Etoposide, ComputingMilieux_MISCELLANEOUS, Transplantation, business.industry, Hematology, medicine.disease, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, Transplantation Conditioning, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

International audience

Published
2019
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31. Pulmonary hypertension in patients with myeloproliferative neoplasms: A large cohort of 183 patients

Author

Jennifer Cautela, Pauline Roche, Raphaelle Fanciullino, Safia Chebrek, Geoffroy Venton, Pierre-André Jarrot, Pierre Suchon, Cédric Mercier, Robin Arcani, Laure Farnault, J Colle, Karim Aissi, Régis Costello, Mihai Turcanu, Vadim Ivanov, Franck Thuny, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix-Marseille Université - Faculté de médecine (AMU MED), Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), and Assistance Publique - Hôpitaux de Marseille (APHM)

Subjects
Adult, Male, medicine.medical_specialty, Cardiac Catheterization, [SDV]Life Sciences [q-bio], Hypertension, Pulmonary, Population, 030204 cardiovascular system & hematology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Internal Medicine, medicine, Humans, In patient, 030212 general & internal medicine, education, Myelofibrosis, ComputingMilieux_MISCELLANEOUS, Aged, Aged, 80 and over, education.field_of_study, Chronic eosinophilic leukemia, business.industry, Myeloid leukemia, Middle Aged, medicine.disease, Pulmonary hypertension, 3. Good health, Large cohort, Echocardiography, Cohort, Female, business, Bone Marrow Neoplasms, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (pH). We ought to describe the prevalence and characteristics of PH in a cohort of MPN who were screened using transthoracic echocardiography (TTE). Methods One hundred eighty-three newly diagnosed consecutive MPN patients were prospectively evaluated using TTE to detect PH. Results Two patients were diagnosed with chronic eosinophilic leukemia, two patients had post-essential thrombocythemia (ET) myelofibrosis (MF), two patients had post-polycythemia vera (PV) MF, 11 patients had primary myelofibrosis (PMF), 28 patients had chronic myeloid leukemia (CML), 51 patients had PV, and 87 patients had ET. TTE was used to determine PH, and PH was suspected in 16 of 183 patients as follows: four with PV, seven with ET, two with PMF, and three with CML. Two patients with ET were excluded because of global cardiac failure. Three patients underwent right heart catheterization to confirm PH. The 14 (7.7%) patients with PH had no cardiac or lung disease that directly involved MPN in PH development. Conclusion: In this large cohort of 183 MPN patients, TTE was used to diagnose PH, and 14 patients (7.7%) developed PH. This prevalence was lower than expected based on previously reported data, but it remains higher than in the general population.

Published
2019
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32. High incidence of atrial fibrillation in patients treated with ibrutinib

Author

Charles Dolladille, Jennifer Cautela, Thérèse Aurran, Franck Paganelli, Marion Escudier, Franck Thuny, Florian Baptiste, Ariel Cohen, Noémie Resseguier, Michael Peyrol, Yan Ancedy, Jeremie Barraud, Mélanie Gaubert, Laure Farnault, Stéphane Ederhy, Joachim Alexandre, Chloé Ammar, Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), and Aix Marseille Université (AMU)

Subjects
medicine.medical_specialty, cardio-oncology, [SDV]Life Sciences [q-bio], Population, cardiotoxicity, 030204 cardiovascular system & hematology, Asymptomatic, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, ibrutinib, Internal medicine, Inherent risk, Clinical endpoint, Medicine, atrial fibrillation, Arrhythmias and Sudden Death, education, ComputingMilieux_MISCELLANEOUS, Cardiotoxicity, education.field_of_study, business.industry, Incidence (epidemiology), Atrial fibrillation, medicine.disease, 3. Good health, chemistry, Ibrutinib, medicine.symptom, Cardiology and Cardiovascular Medicine, business, 030215 immunology
Abstract

ObjectiveAtrial fibrillation (AF) is one of the most common side effects of ibrutinib, a drug that has dramatically improved the prognosis of chronic B-cell malignancies such as chronic lymphocytic leukaemia (CLL). The true incidence of ibrutinib-related AF (IRAF) is not well known and its therapeutic management poses unique challenges especially due to the inherent risk of bleeding. We aimed to determine the incidence and predictors of IRAF, and to analyse its management and outcome.MethodsA standardised monitoring was applied at two cardio-oncology clinics in consecutive patients referred before and during ibrutinib therapy. The primary endpoint was the incidence of IRAF. The excess of AF incidence with ibrutinib was studied by comparing the incidence of IRAF with the expected incidence of AF in general population and in patients with CLL not exposed to ibrutinib.Results53 patients were included. The incidence of IRAF was 38% at 2 years and the risk was 15-fold higher than the AF risk in both the general population and patients with CLL not exposed to ibrutinib (p2 at treatment initiation identified patients at high risk of developing IRAF. No major bleeding events occurred in patients on ibrutinib, although the majority of patients with IRAF were treated with anticoagulants.ConclusionsThis cardio-oncology study showed that the risk of IRAF was much higher than previously reported. The majority of cases occurred in asymptomatic patients justifying close monitoring.

Published
2019
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33. Pharmacokinetics/pharmacodynamics of liposomal cytarabine (VYXEOS) in AML patients: Influence of cytidine deaminase genetic polymorphisms

Author

Geoffroy Venton, Mélanie Donnette, Laure Farnault, L'Houcine Ouafik, Bruno Lacarelle, Raphaelle Fanciullino, Régis Costello, Joseph Ciccolini, and Bertrand Pourroy

Subjects
Cancer Research, Oncology, Pharmacokinetics, Daunorubicin, business.industry, Pharmacodynamics, Cytarabine, medicine, Liposomal cytarabine, Cytidine deaminase, Pharmacology, business, medicine.drug
Abstract

e19517 Background: Vyxeos is a liposomal formulation of daunorubicin and cytarabine recently approved for treating adults with newly-diagnosed sAML subtypes therapy-related (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The objective of this pilot study was to evaluate the influence of cytidine deaminase, the enzyme responsible for cytarabine detoxification step in the liver, on drug exposition and clinical outcome. Methods: In this proof-of-concept study, 9 adult patients were treated with Vyxeos. CDA status (i.e., determination of Poor Metabolizer or Extensive Metabolizer phenotypes) was evaluated before treatment by measuring residual CDA activity in serum. Pharmacokinetic sampling was performed 90min before infusion stops, then from T4H to T168H after the end of the infusion. Total cytarabine, encapsulated cytarabine and released cytarabine were discriminated and assayed using a validated LC-MS/MS method. Results: Nine Vyxeos patients (3M, 6F, 66 ±13 years) were included in this pilot study. Aplasia duration was significantly longer in AML-MRC patients than in AML-t (38 ±5.5 days VS. 28 ±3 days, respectively (p < 0.05)). All AML-t had complete response after induction phase (VS. 60% in AML-MRC, p > 0.05). Similar cytarabine exposure was measured in both population. Surprisingly, 8 out of 9 patients (i.e., 88%) were identified as CDA PM (CDA < 2UI/mg). Marked differences in pharmacokinetics were observed between PM and EM patients. Total, encapsulated and released cytarabine AUC’s were 2.77, 1.42, and1.46 mg/ml*h in PM patients. In EM patient, total, encapsulated and released cytarabine AUC’s were 0.97, 0.76 and 0.17 mg/ml*h. When available, microscopy analysis confirmed the presence of liposomes in patients bone marrow. Conclusions: Differences in clinical outcome between AML-t and AML-MRC patient are not supported by differences in exposure levels upon Vyxeos administration. Surprisingly, we found that CDA status has a strong impact on cytarabine pharmacokinetics since PM patients treated with Vyxeos present a +185% increase in cytarabine levels as compared with EM patient. This suggests that upfront CDA testing could help to predict clinical outcome.

Published
2020
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34. A transcriptomic signature predicting septic outcome in patients undergoing autologous stem cell transplantation

Author

Nicolas Fernandez-Nunez, Cédric Mercier, Laure Farnault, Céline Baier, Béatrice Loriod, Geoffroy Ventona, Vadim Ivanov, Corinne Nicolino, Yasmine Labiad, Pascal Rihet, Jean-Camille Mattei, Magali Torres, Catherine Nguyen, J Colle, Régis Costello, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pharmacocinétique Toxicocinétique - [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM), and Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)

Subjects
0301 basic medicine, Oncology, Treatment related mortality (TRM), Cancer Research, medicine.medical_specialty, Fever, medicine.medical_treatment, Transcriptomic Analysis, Gene Expression, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, Transplantation, Autologous, Peripheral blood mononuclear cell, Sepsis, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, immune system diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, hemic and lymphatic diseases, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, medicine, Humans, Genetic Testing, Prospective Studies, Molecular Biology, Systemic Inflammatory Response Syndrome (SIRS), Multiple myeloma, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, medicine.disease, 3. Good health, Lymphoma, Transplantation, Systemic inflammatory response syndrome, 030104 developmental biology, RNA, Autologous Hematopoietic Stem Cell Transplantation (Auto-HSCT), Transcriptome, business, 030215 immunology
Abstract

Autologous hematopoietic stem cell transplantation is the standard treatment for multiple myeloma and relapsed or refractory lymphomas. After autologous hematopoietic stem cell transplantation, hematologic reconstitution and infectious complications are the two most critical issues. Although many patients develop infectious complications after therapeutic intensification, it remains impossible to predict infection for each individual. The goal of this work was to determine and identify a predictive transcriptomic signature of systemic inflammatory response syndrome and/or sepsis in patients receiving autologous hematopoietic stem cell transplantation. High-throughput transcriptomic and bioinformatics analysis were performed to analyze gene expression modulation in peripheral blood mononuclear cells in 21 patients undergoing autologous hematopoietic stem cell transplantation for hematological malignancies (lymphoma or multiple myeloma). Transcriptomic analysis of peripheral blood mononuclear cells samples collected just after conditioning regimen identified an 11-gene signature (CHAT, CNN3, ANKRD42, LOC100505725, EDAR, GPAT2, ENST00000390425, MTRM8, C6orf192, LOC10289230, and XLOC-005643) that was able to early predict (at least 2-7 days before its occurrence) the development of systemic inflammatory response syndrome or sepsis. The possibility of systemic inflammatory response syndrome or sepsis occurrence early prediction (2-7 days before occurrence) opens up new therapeutic strategies based on preemptive antibiotic and/or antifungal prophylaxis adapted to the specific risk profile of each patient.

Published
2018
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36. Full but impaired activation of innate immunity effectors and virus-specific T cells during CMV and EBV disease following cord blood transplantation

Author

Laure Farnault, Françoise Gondois-Rey, Julie Gertner-Dardenne, Ivan Hirsch, Gérard Michel, Hervé Chambost, and Daniel Olive

Subjects
Transplantation, Innate immune system, business.industry, Effector, Hematology, Disease, medicine.disease, Virology, Virus, Graft-versus-host disease, Immunology, Medicine, Progenitor cell, Stem cell, business
Abstract

Full but impaired activation of innate immunity effectors and virus-specific T cells during CMV and EBV disease following cord blood transplantation

Published
2015
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37. Is R-CHOP Therapy a Lymphoma Growth Factor?

Author

Laure Farnault, Cédric Mercier, Yael Berda-Haddad, Gérard Sébahoun, Régis Costello, Service d’hématologie et de thérapie cellulaire, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie, Hôpital Nord [CHU - APHM], Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Vincristine, Pathology, medicine.medical_specialty, Lymphoma, Lymphocytosis, Cyclophosphamide, [SDV]Life Sciences [q-bio], Lymphocyte, Antibodies, Monoclonal, Murine-Derived, 03 medical and health sciences, 0302 clinical medicine, Prednisone, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Pharmacology (medical), Aged, Pharmacology, business.industry, General Medicine, medicine.disease, 3. Good health, medicine.anatomical_structure, Doxorubicin, 030220 oncology & carcinogenesis, Rituximab, Bone marrow, medicine.symptom, business, 030215 immunology, medicine.drug
Abstract

International audience; This article describes the first reported case of dramatic lymphocytosis flare after initiation of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy for an indolent lymphoma. The study patient exhibited a marginal zone lymphoma with mild nodal involvement but packed infiltration of the bone marrow. After initiation of RCHOP therapy, lymphocyte count increased from 329 to 707 x 10(9)/L at day 7. Patient exhibited grade III infusion-related side effect during rituximab therapy. Lymphocyte flare was not accompanied with other clinical manifestation such as lymph node enlargement. Because patient's bone marrow aspirate showed a packed infiltration, it was hypothesized that lymphocytosis flare was a link to lymphocyte release from bone marrow and lymphocyte demargination. This report highlights the necessity to be vigilant after initiation of RCHOP therapy for lymphoma when pathologist notified a pack infiltration of the bone marrow.

Published
2016
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38. Natural killer cells in acute myeloid leukemia patients: from phenotype to transcriptomic analysis

Author

Magali Torres, Pierre Suchon, Geoffroy Venton, Pascal Rihet, Céline Baier, Aurélie Bergon, Régis Costello, Sarwat Afridi, J. C. Mattei, S. Monteuil, Nicolas Fernandez-Nunez, A. Fino, Béatrice Loriod, J Colle, Yasmine Labiad, Laure Farnault, Cong Tu Nguyen, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 6578 : Anthropologie Bio-Culturelle (UAABC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Adult, Cytotoxicity, Immunologic, Male, [SDV]Life Sciences [q-bio], Immunology, Biology, Receptors, Natural Cytotoxicity Triggering, Immunophenotyping, Cell therapy, Proto-Oncogene Protein c-ets-1, 03 medical and health sciences, Interleukin 21, Young Adult, 0302 clinical medicine, Immune system, Humans, Cells, Cultured, Aged, Regulation of gene expression, Aged, 80 and over, Myeloid leukemia, Middle Aged, NKG2D, Killer Cells, Natural, Leukemia, Myeloid, Acute, 030104 developmental biology, Gene Expression Regulation, Tissue Array Analysis, Interleukin 12, Female, Transcriptome, 030215 immunology
Abstract

International audience; Chemotherapies allow complete remission in more than 50 % of patients with acute myeloid leukemia (AML), however, with frequent relapse. This suggests that residual leukemic cells may escape to chemotherapy and immune system. Natural killer (NK) cells from AML patients (AML-NK) have a weaker natural cytotoxicity-activating receptors (NCRs) expression than NK cells from healthy donors (HD-NK). Coding genes for NCR1/NKp46, NCR2/NKp44 and NCR3/NKp30 are located at different loci on two different chromosomes; however, their expression is tightly coordinated. Most NK cells express either high (NCRbright) or low levels (NCRdull) of all three NCRs. This suggests the existence of negative/positive regulation factor(s) common to the three receptors. In order to find transcription factor(s) or pathway(s) involved in NCRs co-regulation, this study compared the transcriptomic signature of HD-NK and AML-NK cells, before and after in vitro NK cells culture. Microarrays analysis revealed a specific NK cells transcriptomic signature in patients with AML. However, in vitro NK cells expansion erased this signature and up-regulated expression of central molecules of NK functions, such as NCR, NKG2D and also ETS-1, regardless of their origin, i.e., AML-NK vs HD-NK. ETS-1 transcription factor was shown to bind to a specific and common region in the NCRs promoters, thus appearing as a good candidate to explain the coordinated regulation of three NCRs. Such results are encouraging regarding in vitro AML-NK cytotoxicity restoration and provide a new conceptual support for innovative cellular therapy based on in vitro NK cells expansion before their reinfusion in AML patients.

Published
2016
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39. Aldehyde dehydrogenases inhibition eradicates leukemia stem cells while sparing normal progenitors

Author

Guy Fournet, I Ceylan, G. Quash, Céline Baier, P. Poullin, M Pérez-Alea, Yasmine Labiad, Pierre Suchon, C Brunet, Geoffroy Venton, Régis Costello, Laure Farnault, Cong Tu Nguyen, Guillaume Martin, F. Sanderson, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 6578 : Anthropologie Bio-Culturelle (UAABC), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Synthèse de Molécules d'Intérêt Thérapeutique (SMITh), Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'Hémaphérèse - Médecine Interne, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 6578 : Adaptabilité Biologique et Culturelle (UAABC), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Myeloid, CD34, Apoptosis, Mice, Immunophenotyping, Child, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Myeloid leukemia, Hematology, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Haematopoiesis, Leukemia, Phenotype, medicine.anatomical_structure, Oncology, Alkynes, Caspases, Neoplastic Stem Cells, Original Article, Female, Stem cell, Adult, Adolescent, Cell Survival, Biology, Young Adult, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, [CHIM]Chemical Sciences, Sulfhydryl Compounds, Progenitor cell, Aged, Aldehyde Dehydrogenase, Hematopoietic Stem Cells, medicine.disease, Xenograft Model Antitumor Assays, Disease Models, Animal, 030104 developmental biology, Immunology, Cancer research, Biomarkers
Abstract

The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38− leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38− subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.

Published
2016
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40. Micafungin as primary antifungal prophylaxis in patients presenting withacute myeloid leukemia

Author

Geoffroy Venton, Vadim Ivanov, Raphaelle Fanciullino, J Colle, Régis Costello, Yasmine Labiad, Cédric Mercier, Pierre Suchon, Laure Farnault, Hélène Adam, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’hématologie et de thérapie cellulaire, Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d’hématologie, Hôpital de la Timone [CHU - APHM] (TIMONE), Unité pharmacie hospitalière, Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Costello, Regis, and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU)

Subjects
Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, 0301 basic medicine, Antifungal Agents, Myeloid, Echinocandins, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Prospective Studies, Aged, 80 and over, education.field_of_study, Cytarabine, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Bacterial Infections, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Infectious Diseases, medicine.anatomical_structure, Aspergillus, 030220 oncology & carcinogenesis, Female, lipids (amino acids, peptides, and proteins), medicine.drug, Adult, medicine.medical_specialty, 030106 microbiology, Population, Lipopeptides, Young Adult, 03 medical and health sciences, Internal medicine, medicine, Humans, education, Aged, Febrile Neutropenia, Acute myeloid leukemia, business.industry, Daunorubicin, Micafungin, Induction chemotherapy, medicine.disease, bacterial infections and mycoses, Discontinuation, Surgery, Mycoses, Idarubicin, business, Febrile neutropenia
Abstract

International audience; Objective. – To study the efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing inductionchemotherapy for acute myeloid leukemia.Patients and methods. – A prospective observational single-center study of 41 patients from the hematology department between May 2012 andApril 2015. Micafungin was administered once daily from the first day of induction chemotherapy to the end of the neutropenic phase.Results. – Neither Candida nor Aspergillus infection was documented in our 41 patients from the first day of micafungin infusion to the end ofthe neutropenic phase. Patients were followed for three months after discontinuation of micafungin and none of them contracted an invasive fungalinfection. Only one patient presented with grade III–IV hepatic and ionic toxicities.Conclusion. – Micafungin is associated with a good safety profile and is an interesting option for preventing invasive fungal infections in thehigh-risk population of patients presenting with hematological disorders.

Published
2016
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41. Early Recovery of Immunity after Cord-Blood Transplantation in Children: Qualitative Features and Impact of Cytomegalovirus Infection

Author

Vincent Barlogis, Christine Zandotti, Daniel Olive, Claire Galambrun, Hervé Chambost, Françoise Mallet, Gérard Michel, and Laure Farnault

Subjects
CD4-Positive T-Lymphocytes, Male, Adolescent, Lymphocyte, Congenital cytomegalovirus infection, CD8-Positive T-Lymphocytes, Severity of Illness Index, Young Adult, Immunity, medicine, Humans, Lymphocyte Count, Stage (cooking), Child, Bone Marrow Transplantation, biology, business.industry, Lymphocyte differentiation, Infant, Cell Differentiation, Hematology, General Medicine, Fetal Blood, medicine.disease, Transplantation, medicine.anatomical_structure, Perforin, Child, Preschool, Immune System, Cytomegalovirus Infections, Immunology, biology.protein, Female, Cord Blood Stem Cell Transplantation, Unrelated Donors, business, CD8
Abstract

This study investigated immune recovery and the effect of cytomegalovirus (CMV) infection on the early stages of T-lymphocyte recovery after cord-blood transplantation (CBT) from unrelated donors to 24 children. In addition, 15 children who were recipients of a bone-marrow transplant (BMT) were studied concomitantly. The main objectives of the study were whether lymphocytes from CBT recipients were capable of rapid qualitative differentiation in the effector memory (EM) stage, of regenerating de novo naïve cells and of responding to CMV infection. Results showed that CB lymphocytes were mainly differentiated into the EM stage at 3 months and into the naïve stage at 6 months. CMV infection induced a dramatic increase in CD8 but not CD4 T-cell counts, and differentiation into the EM stage with high perforin contents. Our data suggest that CB lymphocytes are capable of rapid differentiation in children, but stabilization of lymphocyte counts in children is associated with effective naïve subset regeneration at 6 months. Moreover, the T-cell repertoire is capable of rapid adjustment when CMV infection occurs.

Published
2012
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42. Mycosis fungoïdes and Sézary syndrome

Author

Régis Costello, Laure Farnault, Thérèse Le Treut, Brigitte Kahn-Perlès, Nathalie Bonnet, and Pascale Poullin

Subjects
Mycosis fungoides, business.industry, Medicine, Hematology, business, medicine.disease, Molecular biology
Abstract

Le mycosis fungoide (MF) et le syndrome de Sezary (SS) sont des hemopathies T de pronostic sombre. Neanmoins, notre connaissance de ces pathologies s’est accrue de facon significative durant ces dernieres annees. Tout d’abord, la contrepartie cellulaire de ces pathologies a ete precisee : lymphocytes T centraux-memoires pour les cellules de Sezary, alors que les cellules de MF ont un phenotype de lymphocytes T effecteurs-memoires. Les etudes de genomique ont montre une hypermethylation correlee a l’agressivite de la maladie. Les etudes en microarrays ont determine des profils d’expression genique non entierement specifiques du MF ou du SS mais permettant de prevoir l’efficacite de drogues telles que l’interferon ou le vorinostat. De plus ces etudes en microarrays ont permis de mettre en evidence l’activation d’oncogenes ou de voies metaboliques orientant vers de nouvelles approches therapeutiques probablement combinees, puisque aucune drogue n’a montre a ce jour, en monotherapie, une grande efficacite dans les formes graves.

Published
2011
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43. Outcome of Patients Receiving Venetoclax for Chronic Lymphocytic Leukemia (CLL) in Real-Life Clinical Practice: Results of the French ATU Program on Behalf of the Filo Group

Author

Pierre Morel, Laure Farnault, Thérèse Aurran, Caroline Dartigeas, Sandy Amorim, Alain Delmer, Isabelle Plantier, Florian Bouclet, Loic Ysebaert, Sophie de Guibert, Olivier Tournilhac, Charles Herbaux, Bénédicte Hivert, Anaise Blouet, Marie-Sarah Dilhuydy, Romain Guieze, Emmanuelle Tchernonog, Anne Calleja, Jacques-Olivier Bay, Anne Lavaud, Florence Cymbalista, Damien Roos-Weil, Anne-Sophie Michallet, Natalia Dmytruk, Kamel Laribi, Pierre Feugier, and Jehan Dupuis

Subjects
0301 basic medicine, Cytopenia, medicine.medical_specialty, business.industry, Venetoclax, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Tumor lysis syndrome, Clinical trial, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Autologous stem-cell transplantation, chemistry, 030220 oncology & carcinogenesis, Internal medicine, Cohort, medicine, business, Adverse effect, IGHV@
Abstract

Introduction.The BCL-2 inhibitor venetoclax has demonstrated high efficiency in relapsed/refractory (R/R) CLL patients with an overall response rate (ORR) of 79%, regardless of the TP53gene status. Venetoclax has then been EMEA-approved for CLL patients with TP53disruption who are unsuitable for or have failed a BCR inhibitor (BCRi) and those without TP53 inactivation who have failed both immunochemotherapy and a BCRi. Whether this agent provides a well-balanced safety/efficacy profile and a prolonged survival in real-world practice remains to be investigated. Methods. An early access program (ATU) of venetoclax was available in France between July 22thand December 4th, 2016 for R/R CLL patients as per EMEA label. We retrospectively analyzed the outcome of patients included in this program who had received at least one day of venetoclax. Data quality was ensured using on-site data verification and computerized discrepancy errors. Results. Data concerning both clinical features andoutcome were available for 72 of the 93 patients for whom venetoclax was requested in this program. Among them, only 63 patients received at least one day of venetoclax for progressive CLL or Richter syndrome (RS) and were included in the present analysis. Median age was 69 years (range, 25-89) and sex ratioM/F was 47/16. A total of 56 patients received venetoclax for CLL and 7 for RS. Patients had previously received a median of 4 prior therapeutic lines (range, 0-7) including FCR in 43 (68%) of them, BTK inhibitor (BTKi) in 46 (73%) and PI3Kδ inhibitor (PI3Kδi) in 21 (33%); 5 had prior autologous stem cell transplantation (SCT) and 4 allogeneic SCT. At time of treatment with venetoclax, 32 (76%) patients carried TP53disruption (data available for 42 patients) and 19 (61%) had complex karyotype (CK) defined as ≥ 3 abnormalities (data available for 31 patients). IGHV mutational status was available for 26 patients. Treatment was administered as per label recommandations with a 5-week ramp up phase until the target dosage of 400 mg per day. Median follow-up was 17 months. Median time on therapy was 11.9 months (range, 0.1-24.6). Among adverse events of interest, tumor lysis syndrome (TLS) was observed in 19% of case, most of them being biological TLS and 3% were clinical TLS, and 15 (24%) patients developed infections requiring hospitalization. Autoimmune cytopenia was seen in 9.5% of patients. Four (7%) patients developed RS while on venetoclax for progressive CLL. To date, a total of 30% of patients remains on therapy. Three patients proceeded to allo-SCT after venetoclax therapy. Among the 7 patients who received venetoclax for RS, 2 had an objective response that lasted 7 and 14 months. However, median overall survival (OS) was only 1.1 months (95% CI, 0.7-1.5). Regarding the CLL cohort, ORR was 73%. It did not significantly differ according to the TP53status (90% with TP53disruption vs 69%, P= 0.189). Conversely, CK was associated with a lower ORR (92% vs 56%, P= 0.024). No impact of the type of prior BCRi (BTKi vs PI3Kδ inhibitor) was noted. 2-year progression-free survival (PFS) was 62% without significant impact of the TP53status (59% in case of TP53disruption vs 68% if wt-TP53,P= 0.587). Patients with CK had 2-year PFS of 44% compared to 78% for those without CK (P= 0.182). 2-year overall survival (OS) was 65% for the whole cohort and significantly better for responding patients than for non responders (76% vs 31%, P< 0.001). TP53disruption was associated with 2-year OS of 65% vs 90% (P= 0.176). Patients with CK had 53% of 2-year OS vs 62% for the remaining cohort (P= 0.236). There was no difference for the type of prior therapies (BTKi, PI3Kδ inhibitor or prior SCT) or IGHV mutational status. Patients who stopped venetoclax therapy had a very poor outcome with a median OS of 5 months. Conclusions.Our real-life study shows response rates and survival data that are in line with those observed in pioneer venetoclax clinical trials. CK should be evaluated as a predictive factor for response to venetoclax. Disclosures Herbaux: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria. Laribi:Roche: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Sandoz: Other: Grant; Gilead: Other: Personal fees; Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Amgen: Other: Personal fees. Feugier:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Published
2018
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44. Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies

Author

Laure Farnault, Benjamin Esterni, Reda Bouabdallah, Christian Chabannon, Mohamad Mohty, Thomas Prebet, Catherine Faucher, Jean El Cheikh, Anne-Marie Stoppa, Nicholas Marchetti, Luca Castagna, Sabine Furst, Claude Lemarie, Patrick Ladaique, Norbert Vey, Boris Calmels, and Didier Blaise

Subjects
Adult, Male, Cancer Research, medicine.medical_specialty, Transplantation Conditioning, Adolescent, Graft vs Host Disease, Autologous stem-cell transplantation, Internal medicine, Genetics, medicine, Humans, Cumulative incidence, Busulfan, Molecular Biology, Antilymphocyte Serum, Thymoglobulin, business.industry, Hazard ratio, Hematopoietic Stem Cell Transplantation, Antibodies, Monoclonal, Cell Biology, Hematology, Transplant-Related Mortality, Middle Aged, Surgery, Transplantation, Hematologic Neoplasms, Cohort, Female, business, Vidarabine, medicine.drug
Abstract

Objective The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. Materials and Methods In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantatioon from a human leukocyte antigen–matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. Results Median age was 50 years (range, 18–64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio=6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1–52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34 + cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. Conclusions These results are encouraging for populations different in term of age, diagnosis, and disease status.

Published
2010
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45. Abstract 3898: CDA predicts life-threatening toxicities in AML patients treated with cytarabine

Author

Vadim Ivanov, Régis Costello, L'Houcine Ouafik, Joseph Ciccolini, Raphaelle Fanciullino, Catherine Roche, Bruno Lacarelle, Mélanie Donnette, Geoffroy Venton, Yael Berda-Haddad, and Laure Farnault

Subjects
Oncology, Cancer Research, medicine.medical_specialty, education.field_of_study, Nucleoside analogue, business.industry, Population, Gemcitabine, Regimen, Internal medicine, Toxicity, medicine, Cytarabine, business, education, Prospective cohort study, Pharmacogenetics, medicine.drug
Abstract

Cytarabine (Ara-C) is the backbone for treating accute myeloid leukemia (AML). As most nucleoside analogs, Ara-C is metabolized in the liver by an exclusive enzymatic step driven by cytidine deaminase (CDA). CDA is a ubiquitous enzyme that proved to be highly polymorphic, with activities in patients ranging from poor metabolizer (PM) to ultra metabolizer (UM). To date, deregulated CDA has been evidenced as a culprit for life-threatening toxicities with gemcitabine. Little evidences have been collected thus far about the possible role erratic CDA could further play with Ara-C. Here, we investigated whether deregulations affecting CDA could be at the origin of unexpectedly severe, and sometimes lethal, toxicities with Ara-C in patients with AML. In this clinical observational study we determined CDA activity levels and searched for CDA genetic polymorphisms in 58 adult patients (25F, 33M, mean age 63 ±15 years) hospitalized for AML and scheduled for induction therapy. All patients were treated following current standard care by Ara-C-containing regimen (i.e., 7+3 protocol) and monitored for toxicity (CTCAEv4 grading) and response. Efficacy was evaluated one-month after starting the induction protocol. Mean CDA activity in the studied population was 3.14 ± 3 U/mg. No relationship was found between CDA phenotype and genotype (i.e., 79A>C polymorphism). A total of 20 patients (43%) displayed severe toxicities (i.e. grade-3 and above) upon administration, including 3 unrecoverable grade-5 toxicities (5%). Relationship between CDA activity and severe toxicity was investigated using ROC analysis. We observed that the incidence of CDA deficiency was much higher in AML patients (40%) than what we previously observed in patients with solid tumors. A cut-off value in CDA ≤ 2 U/mg was associated with increased risk of experiencing severe/lethal toxicities with 74% sensitivity and 65% specificity. Among the 20 patients with severe toxicities, 14 (72 %) were categorized as PM. Importantly, patients who experienced lethal toxicities were all profoundly PM patients. CR was achieved in 35 patients (60%), CRI achieved in 4 patients (7%) whereas 16 patients (27%) failed to respond (PD). No relationship was evidenced between CDA status and response, however regardless of the karyotype we observed that PM patients tended to have longer PFS (278 vs. 517 days) and OS (570 days vs. not reached) as compared with EM patients. Overall this proof-of-concept study strongly suggests that CDA status could be a relevant marker for predicting clinical outcome in patients treated with Ara-C, especially treatment-induced toxicities. A prospective study including full PK and pharmacogenetics support is currently ongoing in our institute to confirm these observations. Should the role CDA plays be confirmed, this marker could be used as a covariate to customize Ara-C dosing in AML patients. Citation Format: Raphaelle Fanciullino, Laure Farnault, Mélanie Donnette, Vadim Ivanov, Geoffroy Venton, Joseph Ciccolini, Yael Berda-Haddad, Catherine Roche, L'Houcine Ouafik, Bruno Lacarelle, Regis Costello. CDA predicts life-threatening toxicities in AML patients treated with cytarabine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3898.

Published
2018
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46. Pulmonary hypertension in patients with chronic myeloproliferative neoplasms

Author

Karim Aissi, Laure Farnault, Yves Frances, Gérard Sébahoun, Safia Chebrek, Cédric Mercier, and Régis T. Costello

Subjects
Cancer Research, medicine.medical_specialty, Myeloproliferative Disorders, business.industry, Hypertension, Pulmonary, MEDLINE, food and beverages, Hematology, medicine.disease, Pulmonary hypertension, World health, Oncology, Internal medicine, medicine, Humans, In patient, business
Abstract

Chronic myeloproliferative neoplasms (MPN) are recognized as a cause of pulmonary hypertension (PHT) in the World Health Organization (WHO) revised 2008 classification group 1 [1]. PHT is defined a...

Published
2013
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47. Characterization of the novel Sezary lymphoma cell line BKP1

Author

Yael Berda-Haddad, Jean Gabert, Thérèse Le Treut, Laure Farnault, Cornel Popovici, Régis Costello, Nathalie Beaufils, Brigitte Kahn-Perlès, Hélène Zattara, John Boudjarane, Arnaud Essaydi, Romaric Lacroix, Marina Lafage-Pochitaloff, and Corinne Nicolino-Brunet

Subjects
Biopsy, Dermatology, Human leukocyte antigen, Biology, Biochemistry, Cutaneous lymphoma, Chromosomes, Immunophenotyping, hemic and lymphatic diseases, Cell Line, Tumor, medicine, T-cell lymphoma, Humans, Sezary Syndrome, Molecular Biology, In Situ Hybridization, Fluorescence, Skin, Chromosome Aberrations, Mycosis fungoides, medicine.disease, Flow Cytometry, Lymphoma, Lymphoma, T-Cell, Cutaneous, Gene Expression Regulation, Neoplastic, Karyotyping, Immunology, Cancer research, CD5, Comparative genomic hybridization
Abstract

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphomas primarily involving the skin. The most common types are mycosis fungoides (MF) and Sezary Syndrome (SS). We report a novel long-term fast-growing SS line termed BKP1 that was characterized by flow cytometry (FC), conventional and molecular cytogenetic [FISH/multi-FISH together with array comparative genomic hybridization (aCGH)]. FC immunophenotype of the BKP1 is CD2+CD5+CD3+CD4+CD8-CD7-CD25-CD26-CD30-CD158k+. The TCRγ characterization of BKP1 by PCR identified a clonal rearrangement. The conventional cytogenetic and Multi-FISH analysis showed complex chromosomal rearrangements. aCGH analysis highlighted the loss of genes involved in cell cycle control, in immune response (HLA, complement complex) and DNA damage repair mechanisms. The BKP1 is another lymphoma cell line thoroughly characterized that can be a valuable tool for both basic and applied research such as identification of deregulated genes and/or pathways and screening for new antilymphoma drugs.

Published
2014

48. Persistence of natural killer cells with expansion of a hypofunctional CD56-CD16+KIR+NKG2C+ subset in a patient with atypical Janus kinase 3-deficient severe combined immunodeficiency

Author

Capucine Picard, Florence Orlanducci, Catherine Farnarier, Daniel Olive, Geneviève de Saint Basile, Alain Fischer, Laure Farnault, Hervé Chambost, Alessandro Moretta, Christophe Picard, Gérard Michel, Isabelle Thuret, Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Dipartimento di Medicina Sperimentale, Universita degli studi di Genova, Collège de France - Chaire Médecine expérimentale (A. Fischer), Università degli studi di Genova = University of Genoa (UniGe), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), and University of Genova

Subjects
MESH : Janus Kinase 3, Persistence (psychology), MESH: Killer Cells, Natural, MESH : Male, [SDV]Life Sciences [q-bio], Immunology, MESH : Severe Combined Immunodeficiency, MESH: Severe Combined Immunodeficiency, MESH : Child, Preschool, Biology, CD16, MESH: Receptors, IgG, MESH : B-Lymphocytes, MESH: Janus Kinase 3, 03 medical and health sciences, 0302 clinical medicine, MESH: Receptors, KIR, MESH: B-Lymphocytes, MESH : Consanguinity, medicine, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Immunology and Allergy, MESH : Receptors, IgG, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, MESH : T-Lymphocytes, MESH: Consanguinity, 0303 health sciences, Severe combined immunodeficiency, MESH: Humans, [ SDV ] Life Sciences [q-bio], Janus kinase 3, MESH : Humans, MESH: Child, Preschool, MESH : Receptors, KIR, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Antigens, CD56, medicine.disease, Virology, MESH: Male, MESH : NK Cell Lectin-Like Receptor Subfamily C, 3. Good health, MESH: NK Cell Lectin-Like Receptor Subfamily C, MESH: T-Lymphocytes, MESH : Antigens, CD56, MESH : Killer Cells, Natural, 030215 immunology
Abstract

International audience

Published
2013
Full Text
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49. Natural killer cells modulation in hematological malignancies

Author

Carole Sanchez, Laure Farnault, Céline Baier, Régis Costello, Aurore Fino, Pascal Rihet, Brigitte Kahn-Perlès, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Rihet, Pascal

Subjects
medicine.medical_treatment, Mini Review, [SDV]Life Sciences [q-bio], Immunology, Human leukocyte antigen, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, Immunology and Allergy, hematological malignancies, 030304 developmental biology, 0303 health sciences, Innate immune system, natural killer cells, business.industry, immune escape, Immunotherapy, Acquired immune system, Minimal residual disease, 3. Good health, Transplantation, [SDV] Life Sciences [q-bio], immunotherapy, Stem cell, business, natural cytotoxicity receptors, 030215 immunology
Abstract

International audience; Hematological malignancies (HM) treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed, due to remaining minimal residual disease.Therefore, sustainment of long-term remission is crucial, using either drug maintenance treatment or by boosting or prolonging an immune response. Immune system has a key role in tumor surveillance. Nonetheless, tumor-cells evade the specific T-lymphocyte mediated immune surveillance using many mechanisms but especially by the down-regulation of the expression of HLA class I antigens. In theory, these tumor-cells lacking normal expression of HLA class I molecules should be destroyed by natural killer (NK) cells, according to the missing-self hypothesis. NK cells, at the frontier of innate and adaptive immune system, have a central role in tumor-cells surveillance as demonstrated in the setting of allogenic stem cell trans-plantation. Nevertheless, tumors develop various mechanisms to escape from NK innate immune pressure. Abnormal NK cytolytic functions have been described in many HM. We present here various mechanisms involved in the escape of HM from NK-cell surveillance, i.e., NK-cells quantitative and qualitative abnormalities.

Published
2013
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50. Hematological Malignancies Escape from NK Cell Innate Immune Surveillance: Mechanisms and Therapeutic Implications

Author

Carole Sanchez, Thérèse Le Treut, Régis T. Costello, Laure Farnault, and Céline Baier

Subjects
lcsh:Immunologic diseases. Allergy, Innate immune system, medicine.medical_treatment, Immunology, Innate lymphoid cell, General Medicine, Immunotherapy, Review Article, Biology, Acquired immune system, Transplantation, Killer Cells, Natural, Immune system, Tumor Escape, Hematologic Neoplasms, medicine, Immunology and Allergy, Cytokines, Humans, Stem cell, lcsh:RC581-607, Immunologic Surveillance
Abstract

Hematological malignancies treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed. Therefore, sustainment of long-term remission is crucial. Immune system has a key role in tumor surveillance. Natural killer (NK) cells, at the frontier of innate and adaptive immune system, have a central role in tumor cells surveillance as demonstrated in the setting of allogenic stem cell transplantation. Nevertheless, tumor cells develop various mechanisms to escape from NK cells innate immune pressure. Abnormal NK cytolytic functions have been described in nearly all hematological malignancies. We present here various mechanisms involved in the escape of hematological malignancies from NK cells surveillance: NK cells quantitative deficiency and NK cell qualitative deficiency by increased inhibition signaling or decreased activating stimuli. A challenge of immunotherapy is to restore an efficient antitumor response. A combination of classical therapy plus immune modulation strategies will soon become a standard of care for hematological malignancies.

Published
2012

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