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1. Early Cardiac Toxicity Associated With Post-Transplant Cyclophosphamide in Allogeneic Stem Cell Transplantation

Author

Anne Banet, Ollivier Legrand, Tounes Ledraa, Simona Lapusan, Annalisa Paviglianiti, Giorgia Battipaglia, Florent Malard, Rosa Adaeva, Clemence Mediavilla, Simona Sestili, Anne Vekhoff, Eolia Brissot, Agnès Bonnin, Razan Mohty, Françoise Isnard, Ramdane Belhocine, Stéphane Ederhy, M. Labopin, Mohamad Mohty, Ariel Cohen, Zoé Van de Wyngaert, Remy Dulery, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-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), CEREST-TC [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Service de Cardiologie [CHU Saint-Antoine], Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Oncology, CVRF, cardiovascular risk factor, medicine.medical_specialty, Standard of care, Cyclophosphamide, Post transplant cyclophosphamide, post-transplant cyclophosphamide, medicine.medical_treatment, [SDV]Life Sciences [q-bio], cardiotoxicity, Hematopoietic stem cell transplantation, CVD, cardiovascular disease, GVHD, graft-versus-host disease, 03 medical and health sciences, HSCT, hematopoietic stem cell transplantation, PT-Cy, post-transplant cyclophosphamide, 0302 clinical medicine, allogeneic stem cell transplantation, Cardiac toxicity, Internal medicine, LVEF, left ventricular ejection fraction, medicine, haploidentical transplantation, Original Research, Cardiotoxicity, LVSD, left ventricular systolic dysfunction, business.industry, HR, hazard ratio, 3. Good health, [SDV] Life Sciences [q-bio], Transplantation, CI, confidence interval, ECE, early cardiac events, surgical procedures, operative, 030220 oncology & carcinogenesis, Stem cell, Cardiology and Cardiovascular Medicine, business, Cy, cyclophosphamide, GRFS, graft-versus-host disease-free, relapse-free survival, left ventricular systolic dysfunction, 030215 immunology, medicine.drug
Abstract

Background Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce. Objectives This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy. Methods The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring. Results The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no–PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival. Conclusions PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy., Central Illustration

Published
2021
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2. Real-life experience with CPX-351 and impact on the outcome of high-risk AML patients: a multicentric French cohort

Author

Patrice Chevallier, Alexis Caulier, Gabrielle Roth-Guepin, Xavier Thomas, Pierre-Yves Dumas, Yosr Hicheri, Florence Pasquier, Sarah Bertoli, Jean-Baptiste Micol, Edmond Chiche, Thomas Cluzeau, Ramy Rahmé, Arnaud Pigneux, Magalie Joris, Patrick Auberger, Pierre Peterlin, Caroline Lejeune, Ollivier Legrand, Mohamad Mohty, Norbert Vey, Caroline Bonmati, Lionel Ades, Michael Loschi, Christian Recher, Emmanuel Raffoux, Alexis Genthon, Université Côte d'Azur - Faculté de Médecine (UCA Faculté Médecine), Université Côte d'Azur (UCA), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Bordeaux, Service d'Hématologie Clinique et Thérapie Cellulaire, F-33000 Bordeaux, France., BMGIC, U1035 INSERM, University of Bordeaux, Bordeaux, France, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CHU Saint-Eloi, CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hématologie, CHU Nice, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Hopital Saint-Louis [AP-HP] (AP-HP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Picardie Jules Verne (UPJV), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), University of Lausanne (UNIL), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Université Paris-Saclay, Département d'hématologie [Gustave Roussy], Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Cancérologie Lucien Neuwirth, CHU Saint-Etienne, Université Paris Cité (UPCité), and DESSAIVRE, Louise

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

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

Published
2021
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3. Gemtuzumab Ozogamicin Combined With Intensive Chemotherapy in Patients With Acute Myeloid Leukemia Relapsing After Allogenic Stem Cell Transplantation

Author

Rosa Adaeva, Souhila Ikhlef, Simona Lapusan, Annalisa Paviglianiti, Simona Sestili, Mohamad Mohty, Remy Dulery, Alexis Genthon, Fella M. ’Hammedi-Bouzina, Eolia Brissot, Ollivier Legrand, Myriam Labopin, Agnès Bonnin, Florent Malard, Elise Corre, Zoé Van de Wyngaert, Zora Marjanovic, Anne Banet, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CCSD, Accord Elsevier, Centre de Recherche Saint-Antoine (CRSA), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Adolescent, Gemtuzumab ozogamicin, [SDV]Life Sciences [q-bio], CD33, Salvage therapy, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Antineoplastic Agents, Immunological, 0302 clinical medicine, Recurrence, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Calicheamicin, Humans, Transplantation, Homologous, Medicine, Aged, business.industry, Myeloid leukemia, Hematology, Middle Aged, Gemtuzumab, 3. Good health, [SDV] Life Sciences [q-bio], Transplantation, Leukemia, Myeloid, Acute, chemistry, 030220 oncology & carcinogenesis, Monoclonal, Toxicity, business, 030215 immunology, medicine.drug
Abstract

Background More than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor. Patients and Methods We included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65). Results The overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively. Conclusions Our study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.

Published
2020
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4. Thiotepa and antithymocyte globulin-based conditioning prior to haploidentical transplantation with posttransplant cyclophosphamide in high-risk hematological malignancies

Author

Giorgia Battipaglia, Marie-Thérèse Rubio, Eolia Brissot, Myriam Labopin, Tounes Ledraa, Remy Dulery, Françoise Isnard, Anne Vekhoff, Juliana Bastos, Ollivier Legrand, Mohamad Mohty, Simona Sestili, Federica Giannotti, Zinaida Peric, Ramdane Belhocine, Razan Mohty, Annalisa Ruggeri, Simona Lapusan, Clemence Mediavilla, Agnès Bonnin, Florent Malard, Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie [CHU Saint-Antoine], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Peric, Z., Mohty, R., Bastos, J., Brissot, E., Battipaglia, G., Belhocine, R., Sestili, S., Giannotti, F., Vekhoff, A., Ledraa, T., Legrand, O., Lapusan, S., Isnard, F., Labopin, M., Bonnin, A., Mediavilla, C., Rubio, M. -T., Ruggeri, A., Dulery, R., Malard, F., and Mohty, M.

Subjects
medicine.medical_specialty, Transplantation Conditioning, Cyclophosphamide, Graft vs Host Disease, [SDV.CAN]Life Sciences [q-bio]/Cancer, ThioTEPA, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Refractory, Internal medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Antilymphocyte Serum, Transplantation, Neutrophil Engraftment, Hematologic Neoplasms / therapy, business.industry, Incidence (epidemiology), Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, 3. Good health, Regimen, surgical procedures, operative, 030220 oncology & carcinogenesis, Hematologic Neoplasms, Transplantation, Haploidentical, [SDV.IMM]Life Sciences [q-bio]/Immunology, Stem cell, Neoplasm Recurrence, Local, business, Graft vs Host Disease / prevention & control, Thiotepa, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030215 immunology, medicine.drug
Abstract

We report results of a thiotepa-based conditioning in haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-CY) and antithymocyte globulin (ATG), for unmanipulated peripheral blood stem cell (PBSC) transplants, in 80 patients with hematological malignancies. Patients in complete remission (CR) received a thiotepa-busulfan-fludarabine (TBF) regimen, while patients with relapsed/refractory (R/R) malignancies received a sequential regimen consisting of thiotepa-etoposide-cyclophosphamide (TEC) and reduced-intensity conditioning (RIC). The median age was 52 (range, 17-72) years, 44% patients had R/R disease at transplant, and the median follow-up was 417 (range, 180-1595) days. The median days to neutrophil engraftment was 17 (range, 12-34). The cumulative incidences (CI) of acute graft-versus-host disease (GVHD) grade III to IV, severe chronic GVHD, nonrelapse mortality (NRM), and relapse were 16%, 16%, 26, and 26%, respectively. The 2-year overall survival (OS) and disease-free survival (DFS) were 53% and 47%, respectively. There were no significant differences between the patients in CR and R/R patients in terms of engraftment, GVHD, NRM, relapse, OS, or DFS. We conclude that thiotepa-based regimen with PT-CY can be modified with PBSC and ATG, still providing low toxicity, protection against GVHD, and low relapse incidence. Particularly encouraging are the results with the modification to sequential regimen in R/R patients.

Published
2020
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5. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial

Author

Claude Preudhomme, Stephen D. Rubin, Emmanuel Raffoux, Sylvie Castaigne, Sylvie Chevret, Cécile Pautas, Xavier Thomas, Pascal Turlure, Pierre Bousset, Ollivier Legrand, Claude Gardin, Juliette Lambert, Rebecca J. Benner, Christine Terré, Hervé Dombret, Denis Caillot, Karïn Gogat-Marchant, Unité d'hématologie et d'oncologie [Centre Hospitalier de Versailles], Centre Hospitalier de Versailles André Mignot (CHV), Service d'Hématologie Biologique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Département de Génétique [CH Versailles], Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'hématologie clinique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Service d'Hématologie Cellulaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Service de biostatistiques et information médicale [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Service d'hématologie-oncologie adultes, Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier de Versailles (CHV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille

Subjects
Oncology, medicine.medical_specialty, Chemotherapy, Randomization, business.industry, Gemtuzumab ozogamicin, medicine.medical_treatment, Hazard ratio, Induction chemotherapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, 3. Good health, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, Cytarabine, Medicine, business, Survival rate, 030215 immunology, medicine.drug
Abstract

The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival (EFS) in adults with de novo acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with de novo AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m2/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results [August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49–0.89; 2-sided P=0.006], corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at clinicaltrials.gov; identifier: 00927498.)

Published
2019
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6. The odyssee study: prevention of dysbiosis complications with autologous fecal microbiota transfer (fmt) in acute myeloid leukemia (aml) patients undergoing intensive treatment: results of a prospective multicenter trial

Author

Joël Doré, Mauricette Michallet, Simona Lapusan, Florent Malard, Patrice Chevallier, Sophie Ducastelle-Lepretre, Suzanne Tavitian, Colombe Saillard, Stephanie Nguyen-Quoc, Xavier Thomas, Emilie Plantamura, Pierre Peterlin, Clément Rocher, Lilia Boucinha, Anne Vekhoff, Françoise Huguet, Ollivier Legrand, Evelyne D'Incan, Anne-Sophie Michallet, Christian Recher, Etienne Paubelle, Cyrielle Gasc, Jerome Rey, Lila Gilis, Mohamad Mohty, Françoise Isnard, Marie Virginie Larcher, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Service d'hématologie, Centre Léon Bérard [Lyon], Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MaaT Pharma [Lyon], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, MaaT Pharma, and American Society of Hematology (ASH). USA.

Subjects
0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, Population, Biochemistry, law.invention, 03 medical and health sciences, Randomized controlled trial, law, Internal medicine, Multicenter trial, medicine, Clinical endpoint, education, Adverse effect, ComputingMilieux_MISCELLANEOUS, education.field_of_study, business.industry, Induction chemotherapy, Cell Biology, Hematology, medicine.disease, Chemotherapy regimen, 3. Good health, 030104 developmental biology, business, Dysbiosis
Abstract

Introduction. AML standard intensive induction chemotherapy ("3+7" or equivalent) combined with wide spectrum antibiotics can dramatically alter the composition of the gut microbiota, leading to dysbiosis which is characterized by loss of microbial diversity. Such dysbiosis status can promote a pathological condition involving uncontrolled local immune responses, systemic inflammation and increased incidence of adverse events. The development of FMT-based drugs to restore microbial communities could offer novel therapeutic possibilities to reduce such adverse events and potentially improve outcomes in AML. We therefore conducted this single arm prospective phase I/II multicenter trial (NCT02928523) to evaluate the use of a FMT-based drug in association with AML induction treatment to restore the gut microbiota diversity. Patients and methods. A total of 62 consecutive patients aged between 24 and 69 years old with a diagnosis of de novo AML were screened in 7 French sites. At time of admission and AML diagnosis (Step 1=S1), patients' faeces were collected, rigorously screened, prepared following a standardized process, and stored at -80°C until later administration. The drug was administered as an enema after hematopoietic recovery (S2) and before consolidation chemotherapy (Conso). The primary endpoint was the recovery of at least 70% of microbiota diversity (based on the Simpson index) after drug administration and the reduction of multidrug resistant bacteria carriage. Blood and feces samples were collected at S1, S2, and around 10 days post-FMT before Conso (S3). Microbiome diversity restoration was assessed by metagenomics analysis through Illumina HiSeq shotgun sequencing. Antibiotic resistance gene carriage (ARGC, also known as resistome) was evaluated through mapping of readouts on the MEGARES database. Secondary objectives included safety and analysis of host response with assessment of blood and fecal markers by ELISA and Luminex. Results. Overall, 25 patients were actually treated with FMT, and 20 were included in the per-protocol population. Induction Chemotherapy (IC) induced a dramatic shift in microbial communities, with a significant 42.3% decrease of mean α-diversity Simpson index between S1 and S2 at species level (0.85 to 0.50; p No serious adverse events (SAE) were observed within 30 days after FMT and all post FMT SAEs were not related to the FMT procedure. Moreover, FMT did not induce any local or systemic inflammatory reaction as measured by fecal and blood markers (fecal neopterin and IgA; plasmatic CRP, IL-6 and sCD14). Interestingly, restoration of the microbiome diversity was associated with a significant reduction of CRP and fecal neopterin levels, suggesting a potential anti-inflammatory impact of FMT. Overall, FMT was well tolerated and had an excellent safety profile. The one-year overall survival estimate in the whole cohort was 84% (4 deaths among 25, none of which were related to FMT: 2 multiple organ failures, 1 heart attack and 1 grade IV resistant GVHD). The median time to death from the second FMT was 182.5 days (113-225 days). Conclusions. This is the first prospective trial testing the safety and efficacy of FMT in AML patients receiving intensive induction chemotherapy. The trial achieved its primary endpoint and established the capacity of FMT to restore a diverse microbiome with high levels of similarity to baseline, as well as reducing ARGC and intestinal inflammation. A controlled randomized trial with repeated FMT administrations is currently planned to further evaluate the impact of FMT on clinical outcomes and long-term survival. (This trial was funded by MaaT Pharma whose product was tested in this protocol). Disclosures Mohty: MaaT Pharma: Consultancy, Honoraria. Doré:MaaT Pharma: Consultancy, Honoraria.

Published
2018
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7. Targeting primary acute myeloid leukemia with a new CXCR4 antagonist IgG1 antibody (PF-06747143)

Author

Yanyan Zhang, Yin Gu, Patrick Lappin, Ollivier Legrand, Flavia Pernasetti, Fawzia Louache, Tod Smeal, Valeria Fantin, François Delhommeau, Stéphane de Botton, Shu-Hui Liu, Dusko Trajkovic, Ruoping Tang, Erika Saavedra, HAL UPMC, Gestionnaire, CNRS GDR 3697 MicroNiT, Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Gustave Roussy (IGR), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), MYPAC, Université Pierre et Marie Curie - Paris 6 (UPMC), Pfizer Oncology, Pfizer, Département d'hématologie [Gustave Roussy], Faculte de Medecine, Université Paris-Sud - Paris 11 (UP11), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Receptors, CXCR4, Myeloid, Science, Primary Cell Culture, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, CXCR4, Article, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Movement, Cell Line, Tumor, hemic and lymphatic diseases, Animals, Humans, Medicine, Molecular Targeted Therapy, Progenitor cell, Multidisciplinary, CXCR4 antagonist, business.industry, Chemotaxis, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, Xenograft Model Antitumor Assays, 3. Good health, Transplantation, Disease Models, Animal, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Immunology, Cancer research, Bone marrow, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract

The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25–30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

Published
2017
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8. The level of blast CD33 expression positively impacts the effect of gemtuzumab ozogamicin in patients with acute myeloid leukemia

Author

Adrienne de Labarthe, Florent Dumezy, Edouard Cornet, Sylvie Castaigne, Hervé Dombret, Cécile Pautas, Orianne Wagner-Ballon, Estelle Guérin, Jean-Noël Bastie, Xavier Thomas, Emmanuel Raffoux, Guillaume Olombel, Jean Feuillard, Sylvain Chantepie, Julien Guy, Ollivier Legrand, Claude Preudhomme, Adriana Plesa, Jean-Yves Perrot, Véronique Salaun, Pascal Turlure, Cheval, Christelle, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie biologique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie Biologique (HEGP - Hématologie Biologique), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Lille (CHU de Lille), Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Laboratoire d'hématologie [AP-HP Hôpital Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Hématologie Biologique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Service d'Hématologie clinique et thérapie cellulaire [CHU Limoges], CHU Limoges, Centre Hospitalier de Versailles André Mignot (CHV), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Contrôle de la Réponse Immune B et des Lymphoproliférations ( CRIBL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Service d'Hématologie Biologique ( HEGP - Hématologie Biologique ), Assistance publique - Hôpitaux de Paris (AP-HP), Centre Hospitalier Universitaire de Lille ( CHU de Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Centre Hospitalier de Versailles (CHV), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Myeloid, Patients, Gemtuzumab ozogamicin, Immunology, CD33, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, hemic and lymphatic diseases, Calicheamicin, medicine, ComputingMilieux_MISCELLANEOUS, Leukemia, business.industry, Myeloid leukemia, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Cell Biology, Hematology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, 3. Good health, Immunoconjugate, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Monoclonal, Cancer research, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, France, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology, medicine.drug
Abstract

International audience; Gemtuzumab ozogamicin (GO) is an immunoconjugate, combining an anti-CD33 monoclonal antibody to calicheamicin, a highly cytotoxic antibiotic. First developed as single agent in adults with relapsed acute myeloid leukemia (AML), it was then evaluated in combination with chemotherapy in newly diagnosed patients. In the randomized Acute Leukemia French Association (ALFA)–0701 study, we reported that sequential administration of a lower dose of GO allowed the safe delivery of a high cumulative dose associated with a substantial improvement in patient outcome. A recent meta-analysis has confirmed that adding GO to chemotherapy may provide a survival advantage in patients without adverse cytogenetic characteristics. However, these results were obtained regardless of the level of blast CD33 expression. In vitro, a clear relationship between CD33 expression and GO efficacy has nevertheless been shown. In vivo, contradictory results have been reported so far. No impact was found when CD33 expression was evaluated as a continuous covariable or using a 20% cutoff. Higher response rates were nevertheless reported for patients with CD33+ expression ≥98% in 1 phase 2 study or when showing CD33 expression as mean fluorescence intensity (MFI) using an isotype antibody as control. To further evaluate the impact of CD33 expression on GO treatment effect, we retrospectively analyzed the results of the ALFA-0701 study.

Published
2016
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9. ATP Binding Cassette transporters associated with chemoresistance: transcriptional profiling in extreme cohorts and their prognostic impact in a cohort of 281 acute myeloid leukemia patients

Author

Edith Garrido, Christophe Marzac, Jean-Yves Lallemand, Fanny Fava, Elise Corre, Eric Jacquet, Ruoping Tang, Simona Lapusan, Jean-Pierre Marie, Ollivier Legrand, Cinzia De Benedictis, Pierre Hirsch, Institut de Chimie des Substances Naturelles (ICSN), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), hotel-dieu, and service d'hématologie

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Myeloid, Adolescent, ATP-binding cassette transporter, Drug resistance, Biology, Bioinformatics, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, Outcome Assessment, Health Care, medicine, Cluster Analysis, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Myeloid leukemia, Hematology, Original Articles, Middle Aged, medicine.disease, Prognosis, 3. Good health, Gene expression profiling, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cohort, ATP-Binding Cassette Transporters, Female, Cohort study
Abstract

International audience; BACKGROUND: A major issue in the treatment of acute myeloid leukemia is resistance to chemotherapeutic drugs. An increasing number of ATP-Binding-Cassette transporters have been demonstrated to cause resistance to cancer drugs. The aim of this study was to highlight the putative role of other ATP-Binding-Cassette transporters in primary chemoresistant acute myeloid leukemia. DESIGN AND METHODS: In the first part of this study, using taqman custom arrays, we analyzed the relative expression levels of 49 ATP-Binding-Cassette genes in 51 patients divided into two extreme cohorts, one very sensitive and one very resistant to chemotherapy. In the second part of this study, we evaluated the prognostic impact, in a cohort of 281 patients, of ATP-Binding-Cassette genes selected in the first part of the study. RESULTS: In the first part of the study, six genes (ATP-Binding-CassetteA2, ATP-Binding-CassetteB1, ATP-Binding-CassetteB6, ATP-Binding-CassettC13, ATP-Binding-CassetteG1, and ATP-Binding-CassetteG2) were significantly over-expressed in the resistant group compared with the sensitive group. In the second cohort, overexpression of 5 of these 6 ATP-Binding-Cassette genes was correlated with outcome in univariate analysis, and only the well-known ATP-Binding-CassetteB1 and G2, and the new ATP-Binding-CassetteG1 in multivariate analysis. Prognosis decreased remarkably with the number of these over-expressed ABC genes. Complete remission was achieved in 71%, 59%, 54%, and 0%, (P=0.0011) and resistance disease in 21%, 37%, 43%, and 100% (P

Published
2011
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10. P-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells from acute myeloid leukaemia patients

Author

Hamid Morjani, Jean-Pierre Marie, Claudia Zuany-Amorim, Elise Corre, Ollivier Legrand, Anne-Marie Faussat, Fanny Fava, Simy Cohen, Ruoping Tang, Jean-Yves Perrot, Zora Marjanovic, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Myeloid, Immunoconjugates, medicine.drug_class, Sialic Acid Binding Ig-like Lectin 3, Antigens, Differentiation, Myelomonocytic, HL-60 Cells, Dibenzocycloheptenes, Monoclonal antibody, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, Antigen, Antigens, CD, Genetics, Medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Humans, Maytansine, ATP Binding Cassette Transporter, Subfamily B, Member 1, Cytotoxicity, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, biology, business.industry, Antibodies, Monoclonal, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 3. Good health, Immunoconjugate, Neoplasm Proteins, Leukemia, Leukemia, Myeloid, Acute, medicine.anatomical_structure, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Immunology, biology.protein, Cancer research, Quinolines, ATP-Binding Cassette Transporters, Antibody, Multidrug Resistance-Associated Proteins, business, K562 Cells, K562 cells, Research Article
Abstract

Background AVE9633 is a new immunoconjugate comprising a humanized monoclonal antibody, anti-CD33 antigen, linked through a disulfide bond to the maytansine derivative DM4, a cytotoxic agent and potent tubulin inhibitor. It is undergoing a phase I clinical trial. Chemoresistance to anti-mitotic agents has been shown to be related, in part, to overexpression of ABC proteins. The aim of the present study was to investigate the potential roles of P-gp, MRP1 and BCRP in cytotoxicity in AVE9633-induced acute myeloid leukaemia (AML). Methods This study used AML cell lines expressing different levels of P-gp, MRP1 or BCRP proteins and twenty-five samples from AML patients. Expression and functionality of the transporter protein were analyzed by flow cytometry. The cytotoxicity of the drug was evaluated by MTT and apoptosis assays. Results P-gp activity, but not MRP1 and BCRP, attenuated AVE9633 and DM4 cytotoxicity in myeloid cell lines. Zosuquidar, a potent specific P-gp inhibitor, restored the sensitivity of cells expressing P-gp to both AVE9633 and DM4. However, the data from AML patients show that 10/25 samples of AML cells (40%) were resistant to AVE9633 or DM4 (IC50 > 500 nM), and this was not related to P-gp activity (p-Value: 0.7). Zosuquidar also failed to re-establish drug sensitivity. Furthermore, this resistance was not correlated with CD33 expression (p-Value: 0.6) in those cells. Conclusion P-gp activity is not a crucial mechanism of chemoresistance to AVE9633. For patients whose resistance to conventional anthracycline AML regimens is related to ABC protein expression, a combination with AVE9633 could be beneficial. Other mechanisms such as microtubule alteration could play an important role in chemoresistance to AVE9633.

Published
2009

11. Zosuquidar restores drug sensitivity in P-glycoprotein expressing acute myeloid leukemia (AML)

Author

Zora Marjanovic, Jean-Pierre Marie, Ollivier Legrand, Ruoping Tang, Thomas Storme, Simy Cohen, Jean-Yves Perrot, Anne-Marie Faussat, Hamid Morjani, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Gemtuzumab ozogamicin, Daunorubicin, HL-60 Cells, Drug resistance, Dibenzocycloheptenes, Pharmacology, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Genetics, Idarubicin, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, P-glycoprotein, Zosuquidar, 0303 health sciences, Mitoxantrone, biology, business.industry, Myeloid leukemia, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Drug Resistance, Multiple, 3. Good health, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid, Acute, Oncology, 030220 oncology & carcinogenesis, biology.protein, Quinolines, business, medicine.drug, Research Article
Abstract

Background Chemotherapeutic drug efflux via the P-glycoprotein (P-gp) transporter encoded by the MDR1/ABCB1 gene is a significant cause of drug resistance in numerous malignancies, including acute leukemias, especially in older patients with acute myeloid leukemia (AML). Therefore, the P-gp modulators that block P-gp-mediated drug efflux have been developed, and used in combination with standard chemotherapy. In this paper, the capacity of zosuquidar, a specific P-gp modulator, to reverse chemoresistance was examined in both leukemia cell lines and primary AML blasts. Methods The transporter protein expressions were analyzed by flow cytometry using their specific antibodies. The protein functionalities were assessed by the uptake of their fluorescence substrates in presence or absence their specific modulators. The drug cytotoxicity was evaluated by MTT test. Results Zosuquidar completely or partially restored drug sensitivity in all P-gp-expressing leukemia cell lines tested and enhanced the cytotoxicity of anthracyclines (daunorubicin, idarubicin, mitoxantrone) and gemtuzumab ozogamicin (Mylotarg) in primary AML blasts with active P-gp. In addition, P-gp inhibition by zosuquidar was found to be more potent than cyclosporine A in cells with highly active P-gp. Conclusion These in vitro studies suggest that zosuquidar may be an effective adjunct to cytotoxic chemotherapy for AML patients whose blasts express P-gp, especially for older patients.

Published
2008

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