86 results on '"Martine Escoffre"'
Search Results
2. 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
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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
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
3. Bortezomib and high-dose melphalan conditioning regimen in frontline multiple myeloma: an IFM randomized phase 3 study
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Murielle Roussel, Valérie Lauwers-Cances, Margaret Macro, Xavier Leleu, Bruno Royer, Cyrille Hulin, Lionel Karlin, Aurore Perrot, Cyrille Touzeau, Marie-Lorraine Chrétien, Sophie Rigaudeau, Mamoun Dib, Emmanuelle Nicolas-Virelizier, Martine Escoffre-Barbe, Karim Belhadj, Clara Mariette, Anne-Marie Stoppa, Carla Araujo, Chantal Doyen, Jean Fontan, Brigitte Kolb, Laurent Garderet, Sabine Brechignac, Jean-Valère Malfuson, Arnaud Jaccard, Pascal Lenain, Cécile Borel, Benjamin Hebraud, Omar Benbrahim, Véronique Dorvaux, Salomon Manier, Karine Augeul-Meunier, Marie-Christiane Vekemans, Edouard Randriamalala, Driss Chaoui, Jo Caers, Carine Chaleteix, Lofti Benboubker, Laure Vincent, Sylvie Glaisner, Patricia Zunic, Borhane Slama, Jean-Richard Eveillard, Catherine Humbrecht-Kraut, Véronique Morel, Philippe Mineur, Jean-Claude Eisenmann, Hélène Demarquette, Valentine Richez, Marguerite Vignon, Denis Caillot, Thierry Facon, Philippe Moreau, Anne-Laurène Colin, Pascale Olivier, Soraya Wuilleme, Hervé Avet-Loiseau, Jill Corre, Michel Attal, UCL - (MGD) Service d'hématologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne
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Bortezomib ,Antineoplastic Combined Chemotherapy Protocols ,Immunology ,Humans ,Cell Biology ,Hematology ,Multiple Myeloma ,Melphalan ,Transplantation, Autologous ,Biochemistry - Abstract
High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days −6, –3, +1, and +4 and melphalan (200 mg/m2 IV) on day –2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM–treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.
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- 2022
4. In Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL), Age-Adapted Chemotherapy Intensity and MRD-Driven Transplant Indication Significantly Reduces Treatment-Related Mortality (TRM) and Improves Overall Survival - Results from the Graall-2014 Trial
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Nicolas Boissel, Francoise Huguet, Thibaut Leguay, Hunault-Berger Mathilde, Carlos Graux, Yves Chalandon, Eric Delabesse, Yosr Hicheri, Patrice Chevallier, Marie Balsat, Cedric Pastoret, Martine Escoffre-Barbe, Florence Pasquier, Jean-Pierre Marolleau, Anne Thiebaut-Bertrand, Anne Huynh, Nathalie Dhedin, Emilie Lemasle, Caroline Bonmati, Sébastien Maury, Gaëlle Guillerm, Anna Berceanu, Urs Schanz, Thomas Cluzeau, Pascal Turlure, Philippe Rousselot, Bernard J.M. De Prijck, Nathalie Grardel, Marie C Bene, Marine Lafage, Norbert Ifrah, Veronique Lheritier, Vahid Asnafi, Emmanuelle Clappier, Herve Dombret, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU UCL Namur, Hôpitaux Universitaires de Genève (HUG), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], 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), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique moléculaire de la transformation hématopoïétique (Dynamo), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), CHU Amiens-Picardie, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Henri Mondor, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), University hospital of Zurich [Zurich], Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CHU Limoges, Centre Hospitalier de Versailles André Mignot (CHV), CHU Sart Tilman [Liege, Belgium], CHU Lille, Hôpital de la Timone [CHU - APHM] (TIMONE), Aix Marseille Université (AMU), CHU d'Angers [Département Urgences], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Coordination du Groupe GRAALL [CH Lyon-Sud], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], 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), and DESSAIVRE, Louise
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[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Background During the 2005-2014 period, the GRAALL conducted the GRAALL-2005 trial in patients (pts) with Philadelphia chromosome (Ph)-negative ALL aged 18-59y. In this trial, all pts received a pediatric-inspired chemotherapy, whatever their age. Post-hoc analysis revealed an unacceptable TRM in pts aged 45-59y (Huguet et al. J Clin Oncol 2018; 36:2514-23). Allogeneic hematopoietic stem cell transplantation (HSCT) was offered in first complete remission (CR) to most CR pts, defined at high-risk (HR) by at least one baseline clinical or biological HR factor (CNS involvement, complex karyotype [≥5 abns.], low hypodiploidy/near triploidy, poor early blast clearance, late CR, as well as WBC ≥ 30x109/L, lack of CD10 expression, KMT2A rearrangement or TCF3::PBX1 fusion for B-cell precursor [BCP] ALL). Minimal residual disease (MRD) response was not considered for HSCT indication at that time.In the next GRAALL-2014 trial conducted in a similar population, we introduced two major changes in the treatment strategy. First, chemotherapy intensity (steroids, anthracycline and L-asparaginase) was reduced in pts aged 45-59y to decrease excessive TRM. Secondly, the indication for HSCT was modified, relying on IG/TR MRD response only (post-induction MRD ≥10-3 and/or post-consolidation MRD ≥10-4) while not on any former baseline HR criterion. Here, we compare the outcomes of the two trials, focusing on the impact of these two major evolutions.Patients & Methods A total of 743 pts treated in the GRAALL-2014 trial between 2015 and 2020 were compared to the 787 pts from the historical GRAALL-2005 trial, in terms of CR and induction death rates, rate of HSCT in CR1, cumulative incidence of TRM (CITRM) and relapse (CIR), relapse-free (RFS) and overall (OS) survival. It should be noted that two nested Phase 2 trials were introduced by amendment during the GRAALL-2014 course (in 2017 and 2018, respectively), aiming to evaluate post-remission addition of nelarabine and blinatumomab in 87 T-ALL and 94 BCP-ALL selected pts, respectively.Results Main patient characteristics, including age, gender, BCP/T-ALL, WBC, and historical baseline HR features, did not significantly differ between the two trial cohorts, even if CNS disease at diagnosis was more frequent in the 2014 cohort (12 vs 7%, p= 0.001).Outcome comparisons are shown in Table 1. Overall, the induction death rate was significantly reduced in the GRAALL-2014 (3 vs 6%, p= 0.005). As expected, this was only observed in pts aged 44-59y (3 vs 11%, p= 0.001), in whom dose-intensity reduction also translated into a higher need for second induction course (9 vs 5%, p= 0.05) eventually resulting in a higher CR rate (92 vs 86%, p= 0.05). Due to the newly introduced MRD-based stratification, the rate of pts with HSCT indication was markedly reduced (30 vs 65%, p
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- 2022
5. Up-front carfilzomib, lenalidomide, and dexamethasone with transplant for patients with multiple myeloma: the IFM KRd final results
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Michel Attal, Xavier Leleu, Salomon Manier, Lotfi Benboubker, Clara Mariette, Cécile Sonntag, Karim Belhadj, Denis Caillot, Cyrille Touzeau, Martine Escoffre-Barbe, Benjamin Hebraud, Laurent Garderet, Soraya Wuilleme, Philippe Moreau, Jill Corre, Valérie Lauwers-Cances, Thierry Facon, Jehan Dupuis, and Murielle Roussel
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Male ,medicine.medical_specialty ,Neoplasm, Residual ,Immunology ,Kaplan-Meier Estimate ,Biochemistry ,Gastroenterology ,Dexamethasone ,Disease-Free Survival ,chemistry.chemical_compound ,Internal medicine ,medicine ,Humans ,Adverse effect ,Lenalidomide ,Multiple myeloma ,business.industry ,Bortezomib ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Carfilzomib ,Minimal residual disease ,Transplantation ,Treatment Outcome ,chemistry ,Female ,Multiple Myeloma ,business ,Oligopeptides ,medicine.drug - Abstract
Bortezomib, lenalidomide, and dexamethasone plus transplant is a standard of care for eligible patients with multiple myeloma. Because responses can deepen with time, regimens with longer and more potent induction/consolidation phases are needed. In this phase 2 study, patients received eight 28-day cycles of carfilzomib (K) 20/36 mg/m2 (days 1-2, 8-9, 15-16), lenalidomide (R) 25 mg (days 1–21), and dexamethasone (d) 20 mg (days 1-2, 8-9, 15-16, 22-23). All patients proceeded to transplant after 4 cycles and received 1 year of lenalidomide maintenance (10 mg, days 1-21). The primary objective was stringent complete response at the completion of consolidation. Overall, 48 patients were screened and 46 enrolled; 21% had adverse cytogenetics. Among 42 evaluable patients after consolidation, 26 were in stringent complete response (CR; 61.9%), 27 were at least in CR (64.3%): 92.6% had undetectable minimal residual disease according to flow cytometry (≥2.5 × 10−5) and 63.0% according to next-generation sequencing (10−6). Median time to CR was 10.6 months. According to multiparametric flow cytometry and next-generation sequencing, 69.0% and 66.7% of patients, respectively, had undetectable minimal residual disease at some point. With a median follow-up of 60.5 months, 21 patients progressed, and 10 died (7 of multiple myeloma). Median progression-free survival was 56.4 months. There were no KRd-related deaths. Four patients discontinued the program due to toxicities; 56 serious adverse events were reported in 31 patients, including 8 cardiovascular events (2 heart failures, 5 pulmonary embolisms or deep vein thrombosis). Common grade 3/4 adverse events were hematologic (74%) and infectious (22%). In summary, 8 cycles of KRd produce fast and deep responses in transplant-eligible patients with newly diagnosed multiple myeloma. The safety profile is acceptable, but cardiovascular adverse events should be closely monitored. This clinical trial is registered at www.clinicaltrials.gov as #NCT02405364.
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- 2021
6. Frontline Consolidation with Blinatumomab for High-Risk Philadelphia-Negative Acute Lymphoblastic Adult Patients. Early Results from the Graall-2014-QUEST Phase 2
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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)
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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
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- 2021
7. Impact of Central Nervous System Involvement in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatrics-Inspired Protocol - a Graall Study
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Corentin Orvain, Sylvain Chantepie, Xavier Thomas, Martine Escoffre-Barbe, Francoise Huguet, Yohan Desbrosses, Gaelle Guillerm, Thibaut Leguay, Sarah Barbieux, Norbert Vey, Patrice Chevallier, Jean Valere Malfuson, Stephane Lepretre, Jean Pierre Marolleau, Hacene Zerazhi, Diana Carp, Ambroise Marçais, Maria Pilar Gallego Hernanz, Iona Vaida, Florence Pasquier, Veronique Lheritier, Norbert Ifrah, Hervé Dombret, Nicolas Boissel, and Hunault-Berger Mathilde
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Background: The prognosis of central nervous system (CNS) involvement in adult patients with acute lymphoblastic leukemia (ALL) has been historically associated with a dismal outcome. Whereas the prognosis of adult patients with ALL has greatly improved since the advent of pediatrics-inspired regimens, the prognostic impact of CNS involvement has not been formerly reevaluated. We report herein the impact of CNS involvement in patients included in the pediatric-inspired prospective GRAALL-2005 study. Methods: All patients received a 5-drug induction therapy with native E. Coli-ASP intravenous injections. Patients in complete remission (CR) received two consolidation courses with alternating cycles including high dose cytarabine (2g/m2/12h on days 1 and 2), high dose methotrexate (3 g/m2 on day 1), and cyclophosphamide. All patients in persistent CR and with no indication for allogeneic stem cell transplantation (SCT) received late intensification, followed by one last consolidation course. Patients with initial CNS involvement, clinically and/or cytologically (cerebrospinal fluid), were recommended to receive an increased number of triple intrathecal therapy, CNS irradiation, and were eligible for allogeneic SCT in first CR. They received less Asp injections during induction therapy to avoid CNS adverse events. CNS irradiation included two lateral fields encompassing the skull, facial, the base of the skull, and the first two cervical vertebrae at a dose of 24 grays for those not receiving allogeneic SCT and 15 grays for those receiving allogeneic SCT. Results: Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included with 55 (7%) having initial CNS involvement. These patients were more likely to be of T-phenotype (51 versus 32%, p=.004) and had more white blood cells at diagnosis (median 23 G/l versus 11 G/l, p=.02). Most patients (36 pts, 66%) were classified as CNS-3 (> 5 white blood cells/µl and a positive cytospin and/or clinical signs) whereas 5 patients (9%) were CNS-2 (< 5 white blood cells/µl and a positive cytospin), and 14 (25%) have data pending. Among patients with details regarding CNS involvement, 25/41 (61%) had clinical signs including trigeminal anesthesia (9 pts, 36%), facial paralysis (4 pts, 16%), extremities paresthesia (4 pts, 16%), visual signs (2 pts, 8%), meningeal syndrome (2 pts, 8%), and motor deficit (2 pts, 8%), and 4/18 (22%) had radiological signs. Induction death, CR1 rate, and negative minimal residual disease after induction were similar whether patients had CNS involvement or not (6 vs 6%, 89 vs 89%, 73 vs 62%, 26 vs 22%, respectively). Patients with CNS involvement had a worse outcome than those without with a median event-free survival (EFS) of 391 days (versus not reached for patients without CNS involvement, HR: 1.7, 95% CI: 1.2 - 2.5, p=.002) and a median overall survival (OS) of 608 days (versus not reached for patients without CNS involvement, HR: 1.8, 95% CI: 1.3 - 2.6, p=.001) (figure). Similar results were observed when patients who received allogeneic SCT in CR1 were censored at the time of graft. As recommended, patients with CNS involvement were more likely to receive allogeneic SCT than those without (53 versus 34%, p=.01), with a median time of 169 days. A 150-day landmark analysis, excluding 12 patients with an EFS event before 150 days, was performed to study the impact of allogeneic SCT on the outcome of patients with CNS involvement. Allogeneic SCT had no impact on either EFS (HR: .5, 95% CI: .2 - 1.2, p=.15) or OS (HR: .8, 95% CI: .3 - 1.8, p=.53). Conclusion: Despite improved outcome in young adult ALL patients with pediatrics-inspired protocols, CNS involvement remains a poor-risk feature. The historical use of allogeneic SCT does not improve outcome. Specific regimens should be developed for adult ALL patients with CNS involvement. Figure 1 Figure 1. Disclosures Huguet: Amgen: Other: Advisor; BMS: Other: Advisor; Celgene: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Novartis: Other: Advisor; Pfizer: Other: Advisor. Barbieux: ASTRA-ZENECCA: Consultancy. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Boissel: Bristol-Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; JAZZ Pharma: Honoraria, Research Funding; CELGENE: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria. Mathilde: ABBVIE: Consultancy; SERVIER: Consultancy.
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- 2021
8. Phase II Study of the Combination of Pomalidomide with Dexamethasone As Maintenance Therapy after First Relapse Treatment with PCD Followed or Not By Autologous Stem Cell Transplant in Multiple Myeloma Patients
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Michel Attal, Frédérique Orsini-Piocelle, Herve Avet Loiseau, Lotfi Benboubker, Carla Araujo, Mourad Tiab, Sabine Brechignac, Eric Voog, Laurent Garderet, Karim Belhadj, Margaret Macro, Jean-Richard Eveillard, Brigitte Pegourie, Gerald Marit, Carine Chaleteix, Claire Mathiot, Arnaud Jaccard, Pascal Lenain, Benoit Berge, Bruno Royer, Anne-Marie Stoppa, Aurore Perrot, Mohamad Mohty, Xavier Leleu, Frédérique Kuhnowski, Murielle Roussel, Cyrille Hulin, Sylvie Glaisner, Ingrid Lafon, Martine Escoffre-Barbe, Olivier Allangba, Lionel Karlin, Marc Wetterwald, Philippe Moreau, Thierry Facon, Jean Claude Eisenmann, and Eric Jourdan
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,Pomalidomide ,medicine.disease ,Biochemistry ,First relapse ,Maintenance therapy ,Internal medicine ,medicine ,Stem cell ,business ,Multiple myeloma ,Dexamethasone ,medicine.drug - Abstract
Background: The role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure: pomalidomide as maintenance treatment
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- 2021
9. Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial
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Aude Charbonnier, Franck E. Nicolini, Stéphane Courby, Corentin Orvain, Martine Escoffre-Barbe, Stephane Morisset, Gabriel Etienne, Delphine Rea, Pascale Cony-Makhoul, Lydia Roy, Françoise Huguet, Laurence Legros, Viviane Dubruille, Shanti Ame, Pascal Lenain, Agnès Guerci-Bresler, Denis Caillot, Eric Hermet, Hyacinthe Johnson-Ansah, Philippe Rousselot, Jean-Christophe Ianotto, Valérie Coiteux, Stéphanie Dulucq, Simona Lapusan, Pascal Turlure, Francois-Xavier Mahon, Philippe Quittet, Eric Deconinck, and Denis Guyotat
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Gastroenterology ,Nilotinib ,Pegylated interferon alpha 2a ,Internal medicine ,medicine ,Petal ,business ,medicine.drug - Abstract
Aims: Combining 2GTKI+pegylated IFN-a (Peg-IFN) represents an attractive approach for first-line treatment of CP CML, while providing somewhat light additional AEs, it induces high rates of deep molecular responses. We evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82) and analysed here the proportion of patients reaching Treatment-Free Remission (TFR) and outcome. Methods: Newly diagnosed CP CML pts ≤65 years, without vascular history were randomized 1:1 to get NIL 300 mg BID alone [M0 to M72 (unless TFR), arm A] vs Peg-IFN alone for 30 days (M-1→M0) 30 mg/wk, prior to NIL 300 mg BID + Peg-IFN 30 mg/wk 2 wks, upgraded to 45 mg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone until M72 unless TFR. The primary endpoint was the rate of MR4.5 by M12, and after amendment, the trial was extended to 72 months follow-up in order to add, as a secondary endpoint, the TFR rate in pts reaching MR4.5 ≥2 y. The trigger for treatment resumption was loss of MMR. All molecular assessments were centralised until M36, and in case of TFR, MR4.5 was centrally confirmed at M0 TFR, and further molecular follow-up was then performed locally. All molecular quantifications are expressed as BCR-ABL1/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control in the central lab and in the local labs all involved to the pluri-annual French external quality controls. Results are analysed in intention-to-treat. Results: As previously reported, 200 pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. The median follow-up (FU) since diagnosis is now 47.5 (33.77-62.39) Mo. and the median FU since discontinuation is 9.86 (5.8-23) Mo. in arm A and 15.57 (12.62-22.77) Mo. in arm B. Sokal and ELTS scores were high in 25% and 2.5%, intermediate in 33% and 16.5% and low in 42% and 81% pts respectively, equally balanced. All pts harboured a "Major" BCR transcript. We have previously shown that by M12, the rate of MR4.5 was 15.9% vs 21.5% (primary endpoint met, p=0.049) and that the overall cumulative incidence of MR4.5 was somewhat superior in arm B (54.6 [43.7-65.5] %) vs A (44 [31.5-54] %), p=0.05. Two pts died, one from myeloid blast crisis before TFR (arm A), one from a solid tumour (arm A). Overall, 40 pts (20%) reached the TFR criteria, 21 in arm A with a median FU of 9.86 (5.8-23) Mo. and 19 in arm B with a median FU since Nilo cessation of 15.57 (12.62-22.77) Mo, partly related to slightly different time for obtaining sustained MR4.5 in favour of arm B (16 vs 13 Mo.). For these 40 pts reaching TFR criteria, there was no statistical difference in terms of age at diagnosis and age at TFR, gender, Sokal, ELTS, FU since diagnosis, undetectability at cessation, BCR-ABL1 levels at 3 Mo. after cessation between the 2 arms. The survival without loss of MMR after cessation is illustrated in Figure 1. It looks superior in arm B over arm A, but did not reach statistical difference (p=0.445), but the FU is very short after cessation yet, especially in arm A. Once NIL was resumed in the pts that failed TFR, all pts recovered MMR within 6 Mo., with no difference between arms (p=1.00). In univariate analysis, we did not identify significant factor impacting on the TFR success (age at cessation, sex, undetectability at cessation, Sokal, ELTS) except the BCR-ABL1 value at M3-TFR (undetectable versus detectable, HR 7.15 [2.06-24.75], p=0.002), and the duration of MR4.5 before discontinuation (HR 1.11 [1.03-1.19], p=0.004). During this TFR phase 7 SAEs were reported in arm A (2 pregnancies, 1 obstructive sleep apnea, 1 fever episode, 1 carotid stenosis and 1 femoral stenosis in the same patient at 2 Mo. after cessation, 1 lung carcinoid tumor) and 2 in arm B (1 persistent atrial fibrillation, 1 cholecystectomy). Conclusions: The combination of NIL + Peg-IFN induces higher MR4.5 rates by M36 in newly diagnosed CP CML pts that may translate in higher successful TFR rates, however a longer follow-up is needed to see consistent significant differences. Updated data will be presented. Figure 1 Figure 1. Disclosures Nicolini: Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Etienne: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Guerci-Bresler: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Charbonnier: Incyte: Speakers Bureau; Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Deconinck: Stemline Therapetutics: Membership on an entity's Board of Directors or advisory committees; Imunogen: Membership on an entity's Board of Directors or advisory committees; Chugai: Research Funding; Novartis: Research Funding; Pfizer: Other: Travel Grants, Research Funding; Abbevie: Research Funding. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2021
10. The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study
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Carlos Graux, Xavier Thomas, Olivier Spertini, Florence Pasquier, Martine Escoffre-Barbe, Emmanuel Raffoux, Céline Berthon, Amine Belhabri, Anne Thiebaut-Bertrand, Yves Chalandon, Jean-Michel Cayuela, Emmanuelle Clappier, Gabrielle Roth Guepin, Pascal Turlure, Jean Pierre Marolleau, Norbert Vey, Sylvain Chantepie, Françoise Huguet, Sylvie Chevret, Nicolas Boissel, Isabelle Plantier, Laure Vincent, Véronique Lhéritier, Patrice Chevallier, Philippe Rousselot, and Hervé Dombret
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Oncology ,Chemotherapy ,medicine.medical_specialty ,MRD Response ,business.industry ,medicine.medical_treatment ,Immunology ,Ph Positive ,Cell Biology ,Hematology ,Biochemistry ,Intensity (physics) ,Bcr abl1 ,Increased risk ,High dose cytarabine ,Nilotinib ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia
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- 2021
11. Acceptable Toxicity and Good Hematological and Renal Responses after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective SFGM-TC Observational Study
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Anaise Blouet, Elisabeth Daguenet, Lionel Karlin, Jérôme Cornillon, Pierre Morel, Lila Gilis, Emanuelle Leray, Hafida Ouldjeriouat, Laurent Garderet, Mohamed Amine Bekadja, Marguerite Vignon, Redhouane Ahmed Nacer, Mohamad Mohty, Jean Jacques Boffa, Marie Robin, Denis Caillot, Marie-Thérèse Rubio, Martine Escoffre-Barbe, Nicole Raus, Damien roos Weil, Bruno Lioure, Pierre Ronco, Clara Mariette, Laure Vincent, and Julie Abraham
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Salvage therapy ,High dose melphalan ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Maintenance therapy ,Internal medicine ,Medicine ,Observational study ,In patient ,business ,health care economics and organizations ,Multiple myeloma ,Lenalidomide ,medicine.drug - Abstract
Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in multiple myeloma (MM) patients as upfront and salvage therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here we analyzed prospectively the outcomes of MM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively 50 newly diagnosed MM patients who had a serum CrCl of Results: The patients characteristics at enrollment are given in Table 1. We focused on 44 patients who were beyond 3 months post-ASCT. Light chain MM was frequent (12%), 10% had high risk cytogenetics, 36% increased serum LDH and 10% extramedullary disease. Induction chemotherapies included bortezomib plus IMiDs in 25/44 patients with ≥2 lines of chemotherapy in 12/44. The pre-transplant disease status was sCR in =5%, CR in =15%, VGPR in =39%, and PR in =41% of patients. The number of days of cytapheresis was 2 or less in 95% of cases and the median number of CD34+ cells collected was 3.3 x 106 (1.3-9.5). The median time from diagnosis to ASCT was 175 days (103-307). HDM was 140 mg/m2 in 42/44 patients and 200 mg/m2 in 2/44. All, except two, received consolidation post ASCT (34% missing) and 52% had maintenance therapy (all lenalidomide except two receiving bortezomib) and 7% had no maintenance (41% pending). Toxicity: We observed one death during the first 100 days post-ASCT, secondary to a septic shock on day 42. The median time to neutrophil engraftment was 12 days (9-68) and to platelet engraftment 13 days (10-70). Among patients receiving RBC transfusions (75%) and platelet transfusions (84%), the median number of RBC transfusions was 3 (1-6) and that of platelet transfusions was 3 (1-10). Response: Nine patients (70%) achieved dialysis independence from the time of diagnosis: 13 patients were on dialysis at diagnosis, 5 at the time of ASCT and 4 three months post-ASCT. Renal function improved post-ASCT in 34% of patients, 14% moving from a CrCl of Conclusions: In this preliminary analysis, HDM with ASCT proved to be safe and effective in MM patients with RI at transplant. We observed one death among 44 patients within the first 3 months post-ASCT. A more detailed report of the toxicity will be presented during the meeting along with the survival. Disclosures Vincent: takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Congress support; janssen: Membership on an entity's Board of Directors or advisory committees, Other: Congress support. Mohty:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karlin:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: Personal fees; Sanofi: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees. Morel:Janssen: Honoraria. Rubio:Medac: Consultancy; Gilead: Honoraria; MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding.
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- 2020
12. The TKI-Free Duration after a First Discontinuation Attempt That Failed in CP CML Patients Is a Predictive Factor of TKI-Free Remission after a Second Attempt
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Stephane Morisset, Stéphane Giraudier, Agnès Guerci, Franck E. Nicolini, Françoise Huguet, Laurence Legros, Valérie Coiteux, Gabriel Etienne, Jean-Christophe Ianotto, Delphine Rea, Francois-Xavier Mahon, Martine Gardembas, Philippe Rousselot, Martine Escoffre-Barbe, and Bruno Varet
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Oncology ,medicine.medical_specialty ,Univariate analysis ,Measles-Mumps-Rubella Vaccine ,business.industry ,Immunology ,Cancer ,Cell Biology ,Hematology ,medicine.disease ,Blast Phase ,Biochemistry ,Discontinuation ,Predictive factor ,Imatinib mesylate ,Internal medicine ,Medicine ,Duration (project management) ,business - Abstract
Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients in chronic phase (CP), long-term molecular response 4.5 (MR4.5) and several studies have now demonstrated that TKIs could be safely discontinued in those patients with a Treatment-Free Remission (TFR) rate reaching ~50%. The French CML group had recently demonstrated that a failure of the first TKI discontinuation attempt does not preclude a 2nd successful attempt (RE-STIM study, Legros et al. Cancer 2017). Methods: The RE-STIM study is a national observational multicentre study collecting all cases of 2nd TKI discontinuation attempt of regardless the type, the duration of TKI, the duration of MR4.5 and the reason of discontinuation. CP-CML Patients in failure of a 1st attempt, had to recover a 2nd sustained MR4.5 on TKI to be eligible for this new analysis of the enlarged database (n=106). Loss of MMR loss was the trigger for therapy re-introduction. Results: At the time of analysis (1st June 2019), 106 patients (median age: 55 years (range: 25-81 years)) were included with 41 months (2-131) of follow-up after 2nd discontinuation. Fifty males and 56 females were enrolled. The Sokal risk score was low in 45%, intermediate in 26.5%, high in 20% and unknown in 8.5% of patients. The majority of patients (95%) were treated with imatinib as first-line, and the others with a 2nd generation TKI. The median total time on TKI prior to a 2nd discontinuation was 104 months (range: 38-235) and the median duration of a 2nd MR4.5 prior to a 2nd discontinuation was 68 months (range: 20-176). After a 1st discontinuation attempt, the reason for TKI re-challenge was in majority a loss of MMR (66%), a loss of MR4.5 in 33% of patients (missing data in 1%). The TFR rates after a 2nd discontinuation attempt were 44.3% [95% CI 35.48-55.41] at 24 months, 38.5% [95% CI 29.65- 50.09] at 36 months and 33.2% [95% CI 24.31- 45.39] at 48 months. In univariate analysis, we failed to find any association between TFR and: age, gender, Sokal score, prior exposure to IFN, TKI in combination versus monotherapy, TKI type, TKI treatment duration and uMR4.5 duration before the 1st and 2nd discontinuation attempts, and type of molecular relapse after the 1st discontinuation attempt (MR4.5 versus MMR loss). However, the speed of molecular relapse after the 1st TKI discontinuation remains a factor significantly associated with outcome. In patients who remained in uMR4.5 at 3 months after the 1st discontinuation, the TFR rate at 48 months was 53% [95% CI: 35.32-79.31] and 26% [95% CI: 16.88-40.28] for others. Another factor significantly associated with outcome is the TKI-free duration after the 1st attempt (Figure). The TFR rate at 48 months was 45 % [95% CI: 28.64- 69.62] in patients who remained without treatment more than 6 months after their 1st attempt and 27% [95% CI: 17.57- 41.34] for others. All patients are alive at last follow-up except 2 who died from CML-unrelated reasons. One patient developed a sudden blast crisis at 4 years from 2nd discontinuation. The last previous molecular biology 3 months before transformation was MR4. In patients in TKI re-challenge (n=63), median TKI-free duration was 6 months (2-64), 55% of patients regained their MMR within 3 months (0-35) and 41% regained MR4.5 within 5 months (2-53). Conclusions: This larger cohort confirms that TKIs could safely and successfully be discontinued a 2nd time in CP CML patients despite a 1st failure. The speed of molecular relapse after the 1st TKI discontinuation and TKI-free duration remain major factors significantly associated with TFR outcome. Figure: TFR according TKI-free duration after the 1st attempt of discontinuation Figure Disclosures Legros: Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Etienne:BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria. Guerci:INCYTE: Consultancy, Honoraria. Huguet:Incyte Biosciences: Honoraria; Novartis: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Coiteux:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.
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- 2019
13. Sensitive Monitoring of BCR-ABL1 Kinase Domain Mutations By Next Generation Sequencing for Optimizing Clinical Decisions in Philadelphia-Positive Acute Lymphoblastic Leukemia in the Graaph-2014 Trial
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Xavier Thomas, Franciane Paul, Patrice Chevallier, Violaine Havelange, Philippe Rousselot, Anne Thiebaut-Bertrand, Yves Chalandon, Francois Lay, Céline Berthon, Nicolas Boissel, Mathilde Hunault, Véronique Lhéritier, Carlos Graux, Norbert Vey, Sylvain Chantepie, Jean-Michel Cayuela, Françoise Huguet, Hervé Dombret, Sylvie Chevret, Isabelle Plantier, and Martine Escoffre-Barbe
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0301 basic medicine ,clone (Java method) ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Immunology ,Context (language use) ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,hemic and lymphatic diseases ,Internal medicine ,Acute lymphocytic leukemia ,medicine ,Chemotherapy ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Leukemia ,030104 developmental biology ,Nilotinib ,business ,030215 immunology ,medicine.drug - Abstract
A high proportion of Ph-positive Acute Lymphoblastic Leukemia (Ph+ ALL) patients still undergo relapses despite the use of Tyrosine Kinase Inhibitors (TKIs) in addition to chemotherapy as frontline therapy. In this leukemia subtype, the role of BCR-ABL1 kinase domain (KD) mutations as a driver of resistance to TKIs has already been documented by previous studies and such mutations have been reported in up to 80% of the patients at relapse. Next-generation sequencing (NGS) has been proposed to characterize these mutations with a higher sensitivity than Sanger. We report here a prospective study aiming at detecting potentially resistant cell populations by NGS in Ph+ ALL patients enrolled in the GRAAPH 2014-trial. Between March 2016 and February 2019, 156 patients aged 18 to 59 years with newly diagnosed Ph+ and/or BCR-ABL1 positive ALL have been included in the GRAAPH 2014 trial (NCT02619630). BCR-ABL1 isoforms were E1A2 69%, B2A2/B3A2 29%, atypical 2%. After a prephase of steroid, treatment consisted of 4 blocks of chemotherapy + nilotinib. 118 patients (76%) underwent allogeneic or autologous stem cell transplantation (SCT). 22 medullary relapses were recorded within a median time of 9 months (range, 2 - 35). Blood and marrow samples harvested at diagnosis, after each treatment block, before and 3 months after SCT, and at relapse, were sequenced if BCR-ABL1/ABL1 ratio were above 0.001. Mutated BCR-ABL1 transcripts were detected by sequencing the KD of BCR-ABL1 transcripts by NGS with a limit of detection (LOD) of 0.03. T315I allele specific oligonucleotide (ASO) droplet digital RT-PCR (ddRT-PCR) with a LOD of 0.0005 was also performed at diagnosis on a subset of 63 patients, including 5 who have subsequently developed a T315I clone. NGS. At diagnosis, no KD mutation was found by NGS in pretreatment samples of 137 patients. During follow-up (FU), only 12 mutations were found by NGS in 7 out of the 88 patients tested (81, 45, 30, 20, 19, 9 after block 1, 2, 3, 4, before and 3 months after SCT, respectively). Mutations were T315I (N=6), Y253H (N=1), E255K (N=2), E255V (N=1), Q252H (N=1), Y253F (N=1). At relapse, 16 mutations were identified by NGS in 12 patients out of the 17 tested (71%). Mutations were T315I (N=7), Y253H (N=n=3), F359V (N=2), E255K (N=1), E255V (N=1), Q252H (N=1), Y253F (N=1). More than 1 mutated clone were present in 2 patients (E255V+T315I+F359V and Y253H+F359V), and a compound mutation was found in 1 patient (Q252H/Y253F). Out of the 7 patients found mutated during FU, 5 have relapsed with a rapid expansion (1 to 3 months) of the mutated clone. One patient harboring a sub-clonal (10%) E255K at MRD1 has relapsed 9 months later without any detectable mutation. One patient identified with 3 mutated clones (E255K 10%, E255V 10%, T315I 80%) underwent SCT and has not relapsed so far. We failed to anticipate expansion of any mutated clone in the 7 remaining patients found mutated at relapse. T315I ASO ddRT-PCR on diagnostic samples. Low-level T315I mutated BCR-ABL1 transcripts (0.00051 to 0.0013) were detected in 14 out of 63 patients (24%) tested. Only one has expanded a T315I clone later on. In the context of the GRAAPH 2014 trial, 71% of the 17 relapses tested so far were associated with BCR-ABL1 KD mutations. Expansion of the mutated clone could have been characterized before the onset of hematological relapses in only 5 out of 12 patients (42%). Unfortunately in these cases, lags between first detection and relapse were very short (1 to 3 months). On the contrary, occurrences of relapses associated with expansion of KD-mutated clones could not have been anticipated in 58%. All mutations identified, including T315I, F359V, E255K/V and Y253F/H, Q252H/Y253F are known for conferring resistance to nilotinib. NGS is a valuable method for KD mutation detection in Ph+ ALL. It allows a quantitative characterization of KD mutations at relapse. However in our hands and in the context of an intensive therapy combining chemotherapy, nilotinib and SCT, its enhanced sensitivity as compared to Sanger (3% vs 20%) does not translate into the capacity of anticipating expansion of KD-mutated clones. Moreover, in this study, NGS did not detect any mutation in pre-therapeutic samples while T315I mutated BCR-ABL1 transcripts were found at low-level in 24% of these samples by ddRT-PCR. However it should be emphasized that when detected, low-level T315I mutated sub-clones present at diagnosis failed to expand in most instances. Disclosures Cayuela: Incyte: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chalandon:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rousselot:Pfizer: Research Funding. Thomas:PFIZER: Honoraria; ABBVIE: Honoraria; INCYTE: Honoraria; DAICHI: Honoraria. Huguet:Amgen: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte Biosciences: Honoraria; Novartis: Honoraria. Chevallier:Incyte: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Daiichi Sankyo: Honoraria. Boissel:NOVARTIS: Consultancy. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Berthon:PFIZER: Other: DISCLOSURE BOARD; JAZZPHARMACEUTICAL: Other: DISCLOSURE BOARD; CELGEN: Other: DISCLOSURE BOARD.
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- 2019
14. The Combination of Nilotinib + Pegylated IFN Alpha 2a Provides Somewhat Higher Cumulative Incidence Rates of MR4.5 at M36 Versus Nilotinib Alone in Newly Diagnosed CP CML Patients. Updated Results of the Petals Phase III National Study
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Pascal Turlure, Denis Caillot, Martine Escoffre-Barbe, Martine Gardembas, Pascal Lenain, Madeleine Etienne, Hyacinthe Johnson-Ansah, Pascale Cony-Makhoul, Françoise Huguet, Laurence Legros, Alexandre Deloire, Simona Lapusan, Stéphanie Dulucq, Stephane Morisset, Gabriel Etienne, Valérie Coiteux, Agnès Guerci-Bresler, Jean-Christophe Ianotto, Denis Guyotat, Francois-Xavier Mahon, Philippe Quittet, Eric Deconinck, Fabrice Larosa, Franck E. Nicolini, Aude Charbonnier, Stéphane Courby, Lydia Roy, Shanti Ame, Philippe Rousselot, Eric Hermet, Delphine Rea, and Viviane Dubruille
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0301 basic medicine ,medicine.medical_specialty ,business.industry ,Immunology ,Alpha interferon ,Cell Biology ,Hematology ,Newly diagnosed ,Neutropenia ,medicine.disease ,Biochemistry ,Ifn alpha ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Nilotinib ,Internal medicine ,National study ,Medicine ,Cumulative incidence ,Recurrent pericarditis ,business ,030215 immunology ,medicine.drug - Abstract
The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5]%) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting
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- 2019
15. Prognostication of Molecular Relapses after Dasatinib or Nilotinib Discontinuation in Chronic Myeloid Leukemia (CML): A FI-LMC STOP 2G-TKI Study Update
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François Guilhot, Joelle Guilhot, Gabriel Etienne, Michel Tulliez, Delphine Rea, Bruno Villemagne, Laurence Legros, Martine Gardembas, Jean-Michel Pignon, Francois-Xavier Mahon, Franck E. Nicolini, Martine Escoffre-Barbe, Gaelle Guillerm, Philippe Rousselot, Valérie Coiteux, Marie-Pierre Noel, and Agnès Guerci
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medicine.medical_specialty ,business.industry ,Immunology ,Ponatinib ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Discontinuation ,Transplantation ,Dasatinib ,chemistry.chemical_compound ,Imatinib mesylate ,Nilotinib ,chemistry ,Internal medicine ,medicine ,Cumulative incidence ,business ,medicine.drug - Abstract
Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later. Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.
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- 2019
16. Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma
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Eric Jourdan, Carla Araujo, Eric Voog, Jean-Richard Eveillard, Murielle Roussel, Carine Chaleteix, Philippe Moreau, Claire Mathiot, Jean-Claude Eisenmann, Mohamad Mohty, Michel Attal, Karim Belhadj, Bruno Royer, Arnaud Jaccard, Gerald Marit, Aurore Perrot, Martine Escoffre-Barbe, Frédérique Kuhnowski, Lofti Benboubker, Ingrid Lafon, Marc Wetterwald, Pascal Lenain, Laurent Garderet, Anne-Marie Stoppa, Benoit Berge, Thierry Facon, Cyrille Hulin, Xavier Leleu, Brigitte Pegourie, Olivier Allangba, Mourad Tiab, Sabine Brechignac, Margaret Macro, Frédérique Orsini-Piocelle, Herve Avet Loiseau, Sylvie Glaisner, and Lionel Karlin
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Cyclophosphamide ,Immunology ,Administration, Oral ,Biochemistry ,Gastroenterology ,Dexamethasone ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,medicine ,Humans ,Multiple myeloma ,Lenalidomide ,Aged ,Bortezomib ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,Pomalidomide ,medicine.disease ,Thalidomide ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Toxicity ,Female ,business ,Multiple Myeloma ,medicine.drug ,Follow-Up Studies - Abstract
It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.
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- 2018
17. First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients
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Fabrice Larosa, Franck E. Nicolini, Marc G. Berger, Gaelle Fossard, Viviane Dubruille, Stéphane Courby, Marie Balsat, Emilie Cayssials, Lydia Roy, Martine Escoffre-Barbe, Delphine Rea, Stephane Morisset, Shanti Ame, Françoise Huguet, Hyacinthe Johnson-Ansah, Laurence Legros, Martine Gardembas, Jean-Christophe Ianotto, Gabriel Etienne, Aude Charbonnier, Francois-Xavier Mahon, Vincent Alcazer, and Alain Delmer
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0301 basic medicine ,Univariate analysis ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Dasatinib ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Imatinib mesylate ,Nilotinib ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,business ,Tyrosine kinase ,medicine.drug - Abstract
Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.
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- 2018
18. Nilotinib (Tasigna®) and Low Intensity Chemotherapy for First-Line Treatment of Elderly Patients with BCR-ABL1-Positive Acute Lymphoblastic Leukemia: Final Results of a Prospective Multicenter Trial (EWALL-PH02)
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Joachim Beck, Jean-Yves Cahn, Patrice Chevallier, Jean-Michel Cayuela, Knut Wendelin, Pascal Turlure, Stéphane Leprêtre, Laurence Sanhes, Josep-Maria Ribera, Albrecht Reichle, Hervé Dombret, Philippe Rousselot, Oliver G. Ottmann, Karsten Spiekermann, Sébastien Maury, Dieter Hoelzer, Heike Pfeifer, Françoise Huguet, Wolfram Jung, Nicola Goekbuget, Martine Escoffre-Barbe, Emmanuel Raffoux, Chantal Himberlin, Andreas Viardot, and Françoise Isnard
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medicine.medical_specialty ,business.industry ,Immunology ,Ponatinib ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Transplantation ,Dasatinib ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Imatinib mesylate ,Maintenance therapy ,chemistry ,Nilotinib ,030220 oncology & carcinogenesis ,Multicenter trial ,Internal medicine ,Medicine ,business ,030215 immunology ,medicine.drug - Abstract
Background. Tyrosine kinase inhibitors (TKI) are standard front-line therapy for patients with BCR-ABL1/Philadelphia positive ALL (Ph+ ALL), but the relative merits of available TKIs remain uncertain. Nilotinib is a potent inhibitor of BCR-ABL1 with broader activity against ABL kinase domain mutations than imatinib and greater selectivity than dasatinib or ponatinib. As there is a paucity of data on nilotinib as first-line therapy for Ph+ ALL, the EWALL (European Working Group for Adult ALL) conducted an international clinical trial to evaluate efficacy and safety of the combination of nilotinib with low intensity chemotherapy. Patients and Methods. After a prephase with dexamethasone (DEX) and cyclophosphamide, nilotinib (400 mg BID) was given concurrently with the same chemotherapy backbone employed in the EWALL-PH01 assessing the combination with dasatinib (Rousselot et al, Blood 2016;128:774-82). Induction consisted of nilotinib combined with weekly vincristine (VCR, 1mg iv) and oral dexamethasone 40mg 2 days (20 mg over 70y). Nilotinib was continued throughout six consolidation cycles, followed by 24 months maintenance therapy with nilotinib, 6-MP, MTX and DEX/VCR boosts. Stem cell transplantation (SCT) was permitted as considered appropriate. BCR-ABL1 RTQ-PCR and kinase domain resistance mutations were centrally monitored. Primary endpoint was event-free survival (EFS) at 12 months, secondary endpoints included rates of CR, major and complete molecular response, relapse free survival (RFS), EFS and overall survival (OS). Results. 72/79 enrolled pts. were evaluable for response, 3 withdrew consent, 4 did not meet eligibility criteria. Median age was 65.5 (55-85) years, male/female ratio 0.85, ECOG status 0 or 1 in 89% of pts., median CIRS comorbidity score 5(0-19). Baseline vascular risk factors including high blood pressure (grade ≥2) were present in 36% of pts.. Sixty-eight of 72 pts. (94.4%) achieved CR, one died during induction and one was refractory, 2 pts. discontinued study therapy. Non-hematologic adverse events (AE) grades 3/4 during induction (in ≥ 5% of pts. irrespective of causality) included infections (n=20), elevated transaminases or bilirubin (n=18) and gastrointestinal AEs (n=12). The spectrum of AEs was similar during consolidation, without concerns related to cardiovascular events. 24 pts. (61y; 55-69y) underwent allogeneic (9 MUD, 12 SIB, 3 Haplo) and 3 autologous SCT. 21 pts. received reduced intensity conditioning (including 8Gy TBI, n=11) regimens. Among all pts., relapse was the main cause of treatment failure (n=23; 17 BM, 2 CNS, 3 other sites, 1 na), 11 pts. died in CR (6 after HSCT), 34 are in ongoing CR. Based on Kaplan Meier analysis, EFS (events being resistant disease, relapse or death) at 12 months was 74%, with median follow-up of 39 (24-66) months for surviving pts., EFS and OS at 4 years was 42%, and 47%, respectively. By landmark analyses using median time to HSCT as cutoff, cumulative incidence of relapse in transplanted vs. non-transplanted pts. was 32% and 47%, OS at 4 years was 61% and 39%, median OS was not reached versus 3.6 years, respectively (p=ns). The proportion of pts. with a BCR-ABL1/ABL1 ratio ≤0.1% increased from 41% after induction to 86% after consolidation 2; that of pts. with undetectable or non-quantifiable BCR-ABL1 transcripts (sensitivity ≥10-4) increased from 14% to 58%. Conclusions. Nilotinib combined with low-intensity chemotherapy is well tolerated and highly effective in elderly pts. with Ph-positive ALL. OS and EFS compare favorably with previous similar studies testing imatinib or dasatinib. With 32% of pts. undergoing allogeneic HSCT and 61% survival at 4 years, transplantation is a viable option in this elderly cohort of pts.. Disclosures Ottmann: Celgene: Consultancy, Research Funding; Novartis: Consultancy; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Fusion Pharma: Consultancy, Research Funding. Pfeifer:Novartis: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Sanhes:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goekbuget:Pfizer: Consultancy, Other: Travel support, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Celgene: Consultancy; Kite / Gilead: Consultancy; Amgen: Consultancy, Other: Travel support, Research Funding. Dombret:Jazz Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; Ambit (Daiichi Sankyo): Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Ariad (Incyte): Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Shire-Baxalta: Consultancy, Honoraria; Immunogen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Cellectis: Consultancy, Honoraria, Other: Travel expenses; Otsuka: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau.
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- 2018
19. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study
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Bruno Villemagne, Martine Escoffre-Barbe, Michel Tulliez, Valérie Coiteux, Francois-Xavier Mahon, Gaelle Guillerm, Marie-Pierre Noel, Laurence Legros, François Guilhot, Joelle Guilhot, Franck E. Nicolini, Martine Gardembas, Jean-Christophe Ianotto, Philippe Rousselot, Agnès Guerci-Bresler, Hyacinthe Johnson-Ansah, Jean-Michel Pignon, Aude Charbonnier, Gabriel Etienne, Delphine Rea, Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), INSERM CIC 0802 (INSERM - CHU de Poitiers), Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Laboratoire d'hématologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'hématologie (Labo Hémato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Institut de Biologie Valrose (IBV), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hématologie clinique [CH La Roche-sur-Yon], Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon (CHD Vendée), CHU Pontchaillou [Rennes], CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), CIC Brest, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Cavale Blanche, Pathologie et virologie moléculaire (PVM (UMR_7151)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Université de Poitiers, Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre Hospitalier Départemental - Hôpital de La Roche-sur-Yon, Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7)
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Adult ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Immunology ,Dasatinib ,Fusion Proteins, bcr-abl ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biochemistry ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,RNA, Messenger ,Protein Kinase Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Aged ,Aged, 80 and over ,Univariate analysis ,business.industry ,Incidence ,Myeloid leukemia ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Interim analysis ,Confidence interval ,3. Good health ,Surgery ,Discontinuation ,Leukemia ,Pyrimidines ,Treatment Outcome ,Nilotinib ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,030215 immunology ,medicine.drug - Abstract
STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.
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- 2016
20. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial
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Mathieu Puyade, Karim Belhadj, Brigitte Kolb, Carla Araujo, Arnaud Jaccard, Michel Attal, Odile Luycx, Thomas Dejoie, Bruno Royer, Laurent Garderet, Sylvie Glaisner, Pascal Lenain, Denis Caillot, Anne-Marie Stoppa, Karim Laribi, Hélène Caillon, Jean-Claude Eisenmann, Hervé Avet-Loiseau, Lucie Planche, Pascal Godmer, Jean-Paul Fermand, Philippe Rodon, Murielle Roussel, Marc Wetterwald, Jean-Valère Malfuson, Gerald Marit, Martine Escoffre, Laetitia Biron, Philippe Moreau, Mamoun Dib, Jean Fontan, Thierry Facon, Driss Chaoui, Brigitte Pegourie, Carine Chaleteix, Borhane Slama, Cyrille Hulin, Mourad Tiab, Sabine Brechignac, Margaret Macro, Olivier Allangba, and Véronique Dorvaux
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Adult ,Male ,endocrine system ,medicine.medical_specialty ,Neutropenia ,Immunology ,Urology ,Biochemistry ,Dexamethasone ,law.invention ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Randomized controlled trial ,law ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Cyclophosphamide ,Multiple myeloma ,Aged ,business.industry ,Anemia ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Thrombocytopenia ,Surgery ,Thalidomide ,030220 oncology & carcinogenesis ,Female ,business ,Multiple Myeloma ,030215 immunology ,medicine.drug - Abstract
The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.
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- 2016
21. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia
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Urs Hess, Jean-Pierre Marolleau, Patrice Chevallier, Kheira Beldjord, Martine Escoffre-Barbe, Sylvie Chevret, Norbert Ifrah, Véronique Lhéritier, Thorsten Braun, Norbert Vey, Dominik Heim, Marie C. Béné, Mathilde Hunault, Nicolas Boissel, Xavier Thomas, Jean-Yves Cahn, Françoise Huguet, Thibaut Leguay, Jean-Michel Pignon, Sébastien Maury, Yves Chalandon, Hervé Dombret, Service greffe de moelle osseuse, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Recherche en Cancérologie de Lyon ( 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 ), Laboratoire d'Hématologie [Purpan], Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service d'Hémato-oncologie [CHU Saint-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], CHU Pontchaillou [Rennes], European Society for Blood and Marrow Transplantation ( EBMT ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Study Group Perinatal Programming [Charité Campus Virchow-Klinikum], Charité Campus Virchow-Klinikum (CVK)-Department of Obstetrics [Charité Campus Virchow-Klinikum], Division of Experimental Obstetrics [Charité Campus Virchow-Klinikum], Charité Campus Virchow-Klinikum (CVK)-Charité Campus Virchow-Klinikum (CVK)-Division of Experimental Obstetrics [Charité Campus Virchow-Klinikum], Charité Campus Virchow-Klinikum (CVK), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre hospitalier universitaire de Nantes (CHU Nantes), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Society for Blood and Marrow Transplantation (EBMT), 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), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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), Department of Obstetrics [Charité Campus Virchow-Klinikum], Charité Campus Virchow-Klinikum (CVK)-Charité Campus Virchow-Klinikum (CVK), and Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)
- Subjects
Oncology ,Male ,Lymphoma ,Survival ,analysis ,medicine.medical_treatment ,administration & dosage ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/immunology ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,immunology ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Philadelphia Chromosome ,CD20 ,ddc:616 ,Leukemia ,biology ,Rituximab/administration & dosage/adverse effects ,Incidence ,Hazard ratio ,Remission Induction ,General Medicine ,Middle Aged ,Prognosis ,3. Good health ,drug therapy ,Survival Rate ,030220 oncology & carcinogenesis ,Rituximab ,Female ,France ,Switzerland ,medicine.drug ,Adult ,medicine.medical_specialty ,Patients ,Adolescent ,Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease-Free Survival ,03 medical and health sciences ,Young Adult ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Asparaginase ,Humans ,Antigens ,Survival rate ,Chemotherapy ,business.industry ,medicine.disease ,Antigens, CD20 ,Surgery ,therapeutic use ,Multivariate Analysis ,Adult Acute Lymphoblastic Leukemia ,biology.protein ,adverse effects ,Antigens, CD20/analysis ,business ,030215 immunology ,Follow-Up Studies - Abstract
International audience; Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .)
- Published
- 2016
22. Salvage Therapy Post Pomalidomide-Based Regimen in Relapsed/Refractory Myeloma
- Author
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Hervé Avet-Loiseau, Murielle Roussel, Michel Attal, Philippe Moreau, Philippe Rodon, Gerald Marit, Brigitte Kolb, Mamoun Dib, Olivier Decaux, Bruno Royer, Brigitte Pegourie, Marc Wetterwald, Marie-Odile Petillon, Anne Banos, Denis Caillot, Lionel Karlin, Mourad Tiab, Anne-Marie Stoppa, Sabine Brechignac, Guillemette Fouquet, Cyrille Hulin, Xavier Leleu, Margaret Macro, Laurent Garderet, Jean-Paul Fermand, Thierry Facon, Laurence Legros, Bertrand Arnulf, Lotfi Benboubker, Martine Escoffre, Claire Mathiot, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Universitaire de Caen, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Laboratoire d'Hématologie biologique, Institut Curie, Service d'Hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Universitaire de Bobigny, Hôpital Général de La Roche sur Yon, Hôpital de Bayonne, CH de la Côte Basque, Hôpital Général de Dunkerque, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Universitaire de Tours, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Service d'Hématologie Clinique, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Hématologie [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Hôpital Claude Huriez [Lille], CHU Lille, 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), Institut Curie [Paris], 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), Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], INSTITUT CURIE, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Universitaire de Vandoeuvre les Nancy, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier de la Côte Basque (CHCB), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'Hématologie Clinique (CHU de Dijon), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire [Grenoble] (CHU), Intergroupe francophone du myélome (IFM), Service d'Hématologie [Bordeaux], CHU Bordeaux [Bordeaux], Service d'hématologie [Reims], Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'hématologie clinique (CHU d'Avicenne), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Hopital de Périgueux (CH Périgueux), Hopital de Périgueux, Service d'hématologie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Médecine Onco-hématologie [La Roche sur Yon], Centre Hospitalier Universitaire de Nantes, Service hématologie Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'hématologie (CH de la Côte Basque), Service d'hématologie (CH de Dunkerque), Centre Hospitalier Dunkerque, Laboratoire d'Hématologie [CHU Amiens], CHU Amiens-Picardie, Service d'Hématologie [CHRU Nancy], Département d’Hématologie Clinique [CHU Tours], Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Service d'hématologie adulte [Hôpital de Saint Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hématologie [Nantes], CIC - Poitiers, Université de Poitiers-Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Direction Générale de l'Organisation des Soins (DGOS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncologie hématologique et Thérapie Cellulaire (CHU Poitiers), Centre hospitalier universitaire de Poitiers (CHU Poitiers), 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 Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Avicenne, Le CHCB, Centre Hospitalier de la Côte Basque, Service d'Hématologie Clinique [CHU Amiens], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, CHU Saint Louis [APHP], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,0301 basic medicine ,Oncology ,Palliative care ,Survival ,[SDV]Life Sciences [q-bio] ,Salvage therapy ,Disease ,Biochemistry ,Dexamethasone ,0302 clinical medicine ,Stable Disease ,Recurrence ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Multiple myeloma ,Aged, 80 and over ,0303 health sciences ,Hematology ,General Medicine ,Middle Aged ,Thalidomide ,3. Good health ,030220 oncology & carcinogenesis ,Female ,Multiple Myeloma ,medicine.drug ,Bendamustine ,Adult ,medicine.medical_specialty ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,Humans ,030304 developmental biology ,Aged ,Salvage Therapy ,[ SDV ] Life Sciences [q-bio] ,business.industry ,Disease progression ,Cell Biology ,Pomalidomide ,medicine.disease ,Regimen ,030104 developmental biology ,Relapsed refractory ,business ,030215 immunology - Abstract
Background. The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) has been proven effective and safe in patients with end-stage relapsed/refractory multiple myeloma (RRMM), otherwise characterized by a very poor outcome and short survival of less than a year. However, multiple myeloma remains incurable and relapses are inevitable even with pomalidomide-based regimen. It is thought that patients are back to unmet medical need after pomalidomide exposure, although the outcome after pomalidomide remains unknown. We sought to analyse the line of therapy in RRMM after Pom-Dex treatment, the response to further treatment line and survival post pomalidomide era. Methods. We included 134 patients from the 2 IFM studies (IFM2009-02 in end stage RRMM, n=84, median therapy 5 lines and IFM2010-02 in del17p and/or t(4;14) RRMM, n=50, median therapy 2 lines) treated with Pom-Dex. In both studies, patients received pomalidomide (oral 4mg daily) given either 21 days out of 28 or continuous and dexamethasone (oral 40mg weekly, but 20mg if >75 years old in the IFM 2010-02), given until progression. Overall, 95/135 patients (70%) received further therapy post Pom-Dex, 57/84 (68%) and 38/50 (76%) in IFM2009-02 and IFM2010-02 studies, respectively; the remaining patients had palliative care. Results. As a whole for the 95 patients, the median age was 60 (range 31-82), the M/F ratio was 1.5, t(4;14) was observed in 26/50 (52%) and del17p in 14/47 (30%). The post Pom-Dex regimens were very diverse, and varied significantly across the 2 trials; however, the regimens contained alkylating agents in 54% and 60% of patients in IFM2009-02 and IFM2010-02, respectively. The most prescribed alkylator was cyclophosphamide (60%) in IFM2010-02 while similar prescription of cyclophosphamide and bendamustine was observed in about 40% of patients in the IFM2009-02 study (p=0.032). Alkylating agents were administered primarily in a 3 drugs-based combination (or more) in IFM2010-02, 70%, versus in combination solely to dexamethasone for most patients in IFM2009-02, 60% (p=0.034). Amongst the combinations of alkylating agents, novel agents were considered in 55% versus 17.5% in the 2 studies, as expected considering that IFM2010-02 included patients exposed but not refractory to lenalidomide, while IFM2009-02 recruited essentially patients double refractory to lenalidomide and bortezomib (p When no alkylating agent was used, bortezomib plus dexamethasone, dexamethasone alone, or clinical trials were favoured, the latter in a lesser instance. An intensification was proposed in 8% of patients (n=8), with allogeneic transplantation in 3 patients. 27% and 29% responded to the post Pom-Dex regimen, with an extra 35% and 34% having stable disease in the 2 studies, respectively. With a median follow-up of 49 months (IFM2009-02) and 24 months (IFM2010-02), 77% and 52% of patients have died. The median PFS on Pom-Dex was approximately 5 months (CI95% 2.5;6.5) across the studies, with 20% of patients free of relapse beyond a year, similar to the post Pom-Dex phase, 5 months (2.9;7.0) and 4 months (2.2;5.7) in 2010-02 and 2009-02, with 29% and 13% of patients progression-free beyond one year, respectively. Importantly, the median OS of IFM2009-02 study (end stage RRMM, median 5 lines) for patients that had a post pomalidomide regimen was 20 months (14;26), with 30% of patients beyond 3 years, versus 13 months for the study as a whole (Leleu et al. Blood 2013) including patients considered in palliative care after Pom-Dex was stopped. This difference was not observed in IFM2010-02 to the same extent, in patients treated earlier with Pom-Dex but characterized with poor risk cytogenetic features, del17p and/or t(4;14), median OS of 14 months (9;18) across the 2 subgroups versus a median OS of 12 months and 9.8 months for the 2 subgroups in the study as a whole (Leleu et al. Blood 2015). Conclusion. Pom-Dex changed the paradigm in advanced RRMM with a prolonged PFS that translated into a prolonged OS. Importantly, OS was further improved when patients were offered a post pomalidomide therapy particularly in advanced RRMM with no poor risk cytogenetic features. Future studies might confirm the survival impact of pomalidomide used earlier in the disease course. The IFM2009-02 and 2010-02 trials were conducted with the support of Celgene Disclosures Karlin: BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Arnulf:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Stoppa:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Legros:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau. Garderet:Bristol-Myers Squibb: Consultancy. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avet-Loiseau:Janssen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Leleu:Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; LeoPharma: Honoraria; Chugai: Honoraria.
- Published
- 2015
23. A Multicenter Open Label Phase II Study of Pomalidomide, Cyclophosphamide and Dexamethasone in Relapse Multiple Myeloma Patients Initially Treated with Lenalidomide, Bortezomib and Dexamethasone
- Author
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Lofti Benboubker, Herve Avet Loiseau, Mourad Tiab, Carla Araujo, Eric Voog, Margaret Macro, Philippe Moreau, Martine Escoffre-Barbe, Claire Mathiot, Jean Yves Mary, Gerald Marit, Murielle Roussel, Olivier Allangba, Eric Jourdan, Jean-Pierre Marolleau, Anne-Marie Stoppa, Frédérique Kuhnowski, Ingrid Lafon, Lionel Karlin, Thierry Facon, Michel Attal, Aurore Perrot, Pascal Lenain, Laurent Garderet, Mohamad Mohty, and Carine Chaleteix
- Subjects
medicine.medical_specialty ,Cyclophosphamide ,Bortezomib ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Pomalidomide ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Progressive disease ,Dexamethasone ,Multiple myeloma ,030215 immunology ,medicine.drug ,Lenalidomide - Abstract
Introduction: The rate of response (partial remission and better) to pomalidomide and low dose dexamethasone in myeloma patients who had previously received lenalidomide and bortezomib was 33% (Richardson PG, et al. Blood 2014;123:1826). In view of improving the response rate of pomalidomide based therapy, we conducted a phase II trial to evaluate the efficacy and safety of the addition of weekly oral cyclophosphamide to pomalidomide and dexamethasone (PCD) in patients in first relapse following initial treatment in the IFM 2009/DFCI trial (Attal M, et al. NEJM 2017;376:1311). Since the combination of lenalidomide, bortezomib and dexamethasone (RVD) is becoming the standard of care in the frontline setting with or without autologous stem cell transplantation (ASCT), our goal was also to find an effective salvage regimen to induce new remission in patients relapsing after exposure to lenalidomide and bortezomib so as to be able to proceed to ASCT (ClinicalTrials.gov identifier: NCT02244125). Patients / Methods: Eligible patients had relapsed myeloma after one line of treatment according to the IFM 2009/DFCI trial. All patients had received RVD as induction and consolidation therapy plus lenalidomide maintenance for 1 year (Arm A). Half of them had undergone upfront ASCT after the induction phase as part of the initial protocol (Arm B). At first relapse, all patients received oral pomalidomide 4 mg on D1-21, oral cyclophosphamide 300 mg on D1, 8, 15 and 22 and oral dexamethasone 40 mg D1-4 and D15-18 of a 28 day cycle (PCD). Four reinduction cycles were administered to all patients. Those who had not been transplanted initially (Arm A) and who were responding underwent ASCT and received two additional cycles of PCD while those who had already been transplanted (Arm B) received 5 cycles of PCD. All were subsequently treated with pomalidomide plus dexamethasone maintenance until disease progression. The primary endpoint was the rate of partial response or better after the initial 4 cycles of PCD. Responses were assessed using the IMWG criteria. Results: Between April 2014 and February 2017, 100 patients were enrolled. The cut-off date for this intermediate analysis was 4th July 2017. At inclusion in the relapse trial, the median age was 62 years (range 39-70), and 62% of the patients were male. The median time from diagnosis of myeloma to current therapy was 3.6 years (3.1-4.3, 1st and 3rd quartile) and 97% had a PS of 0 or 1. The myeloma isotype was IgG (72%), IgA (17%), light chain (9%) or IgD (2%). Five patients had a plasmacytoma and 15% high risk cytogenetics (t(4-14) and/or del 17p and/or t(14-16)). The ISS was I (78%), II (15%) or III (7%). In 90 evaluated patients after 4 cycles of PCD, objective responses were obtained in 82 (91%): CR: 2 (2.2%), VGPR: 29 (32%) and PR: 51 (57%). Stable disease was observed in 3 patients (3%) and progressive disease in 5 (5.6%). Adverse events (AE) of grade 3-4 occurred in 72 patients (72%) including hematological toxicities (61%) (53% neutropenia, 36% lymphopenia, 6% anemia, 5% thrombocytopenia), infection (8%) (63% pneumonia), asthenia (7%), hyperglycemia (6%), gastrointestinal disorders (3%), allergic skin reactions (2%) and cardiovascular disorders (3%) (1 pulmonary embolism, 1 myocardial infarction and 1 syncope). There was no grade 3 or 4 peripheral neuropathy. Six patients (6%) discontinued one of the study drugs (P, C or D). Dose reductions were recorded in 38% of the patients for pomalidomide, in 35% for cyclophosphamide and in 46% for dexamethasone, the reasons being AE/SAE (77%, 70% and 71%), omission (13%, 13% and 9%) and other (10%, 17% and 20%) (P, C and D, respectively). Four of the 50 patients in Arm A could not have the planned ASCT at relapse while 7 of the 50 in Arm B received a second ASCT. PFS (PFS1 and PFS2) and OS will be reported during the meeting. Conclusion: In this first planned relapse trial, the all oral combination of pomalidomide, cyclophosphamide and dexamethasone was very efficacious at first relapse following lenalidomide, bortezomib and dexamethasone treatment. After 4 cycles, the rate of partial response or better was 91% and 92% of the patients could proceed to ASCT. Toxicity was mostly hematological and manageable. These results should be compared to those of other pomalidomide and dexamethasone-based second line therapies. Disclosures Garderet: Amgen: Honoraria; Takeda: Honoraria. Roussel: JANSSEN: Honoraria, Research Funding. Facon: Amgen, Celgene: Speakers Bureau. Karlin: Janssen: Honoraria, Other: Travel expenses. Perrot: Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau: Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceutical: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Macro: JANSSEN: Honoraria. Benboubker: Takeda, Celgene, Janssen, Amgen: Consultancy. Jourdan: NOVARTIS: Consultancy, Honoraria. Mohty: Sanofi: Honoraria, Speakers Bureau. Attal: Sanofi: Consultancy; Amgen: Consultancy, Research Funding; JANSSEN: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.
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- 2017
24. Nilotinib Versus Nilotinib Combined to Pegylated-Interferon Alfa 2a in First-Line Chronic Phase Chronic Myelogenous Leukemia Patients. Interim Analysis of a Phase III Trial
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Françoise Huguet, Laurence Legros, Gabriel Etienne, Vérane Schwiertz, Franck E. Nicolini, Delphine Rea, Martine Gardembas, Stephane Morisset, Jean-Christophe Ianotto, Lydia Roy, Shanti Ame, Martine Escoffre-Barbe, Pascal Turlure, Fabrice Larosa, Eric Hermet, Viviane Dubruille, Simona Lapusan, Pascale Cony-Makhoul, Agnès Guerci-Bresler, Stéphanie Dulucq, Denis Caillot, Philippe Rousselot, Francois-Xavier Mahon, Aude Charbonnier, Pascal Lenain, Hyacinthe Johnson-Ansah, Philippe Quittet, Valérie Coiteux, Stéphane Courby, Madeleine Etienne, and Denis Guyotat
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0301 basic medicine ,medicine.medical_specialty ,Intention-to-treat analysis ,Anemia ,business.industry ,Incidence (epidemiology) ,030106 microbiology ,Immunology ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Interim analysis ,Biochemistry ,Chronic phase chronic myelogenous leukemia ,Pulmonary embolism ,03 medical and health sciences ,Nilotinib ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015). Aims Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82). Methods Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Results Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1. Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid). Conclusion The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting. Disclosures Nicolini: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne: Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux: Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul: BMS: Speakers Bureau. Rousselot: Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat: BMS: Speakers Bureau. Ianotto: Novartis: Other: Grant. Rea: BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon: Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.
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- 2017
25. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results
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Anne-Marie Stoppa, Brigitte Kolb, Sabine Brechiniac, Gerald Marit, Mamoun Dib, Marie Odile Petillon, Bruno Royer, Brigitte Onraed, Philippe Rodon, Lionel Karlin, Anne Banos, Philippe Moreau, Beatrice Thielemans, Claire Mathiot, Olivier Decaux, Brigitte Pegourie, Laurent Garderet, Thierry Facon, Denis Caillot, Mourad Tiab, Laurence Lacotte, Jean-Gabriel Fuzibet, Michel Attal, Margaret Macro, Jean Paul Fermand, Martine Escoffre-Barbe, Cyrille Hulin, Laurence Legros, Marc Wetterwald, Xavier Leleu, Bertrand Arnulf, Lotfi Benboubker, Hervé Avet-Loiseau, Murielle Roussel, Service d'immunologie, 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), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes], Service d'hématologie biologique, Service des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Laboratoire d'Hématologie biologique, Institut Curie [Paris], Service d'hématologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Foie, métabolismes et cancer, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'hématologie clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire d'Hématologie [Rangueil], Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hôpital Claude Huriez [Lille], CHU Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UR)-Hôpital Pontchaillou, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut Curie, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (HOTE GREFFON), Université de Franche-Comté (UFC)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Hôpital de Rangueil, CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), INSTITUT CURIE, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -hopital Jean Minjoz, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Université de Franche-Comté ( UFC ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Toulouse III - Paul Sabatier ( UPS ), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), and Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille )
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Male ,Oncology ,Refractory period ,[SDV]Life Sciences [q-bio] ,Chromosomal translocation ,Biochemistry ,Dexamethasone ,Translocation, Genetic ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Multiple myeloma ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,Hematology ,Middle Aged ,Prognosis ,Thalidomide ,3. Good health ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,Chromosomes, Human, Pair 4 ,Multiple Myeloma ,medicine.drug ,Adult ,medicine.medical_specialty ,Immunology ,Population ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,education ,Aged ,Neoplasm Staging ,030304 developmental biology ,Chromosomes, Human, Pair 14 ,[ SDV ] Life Sciences [q-bio] ,Dose-Response Relationship, Drug ,business.industry ,Cytogenetics ,Cell Biology ,medicine.disease ,Pomalidomide ,Surgery ,Regimen ,Drug Resistance, Neoplasm ,Neoplasm Recurrence, Local ,business ,Gene Deletion ,Chromosomes, Human, Pair 17 ,Follow-Up Studies - Abstract
International audience; The combination of pomalidomide and low-dose dexamethasone (Pom-Dex) can be safely administered to patients with end-stage relapsed/refractory multiple myeloma (RRMM). However, we observed a shorter median progression-free survival (PFS) and overall survival (OS) in these patients when characterized with adverse cytogenetics (deletion 17p and translocation [4;14]) in the Intergroupe Francophone Myélome (IFM) 2009-02 trial. We then sought to determine whether MM with adverse cytogenetics would benefit more from Pom-Dex if exposed earlier in the multicenter IFM 2010-02 trial. The intention-to-treat population included 50 patients, with a median age of 63 years (38% were ≥65 years). Interestingly, there was a striking difference in time to progression (TTP), duration of response, and overall response rate (ORR) according to the presence of del(17p) compared with t(4;14) (TTP, 7.3 vs 2.8 months; duration of response, 8.3 vs 2.4 months; and ORR, 32% vs 15%). OS was prolonged after Pom-Dex, particularly in t(4;14), given the short TTP, suggesting that patients were rescued at relapse with further lines of therapy. Pom-Dex, a doublet immunomodulatory drug-based regimen, is active and well tolerated in adverse cytogenetic patients with early RRMM, particularly in those with del(17p), who are characterized by a high and rapid development of a refractoriness state and known for their poor prognosis. Future studies will determine the underlying mechanisms of Pom-Dex activity in del(17p). This trial is registered at www.clinicaltrials.gov as #NCT01745640.
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- 2015
26. Time to Spare Newly Diagnosed Non Transplant Eligible Myeloma (eNDMM) from Thalidomide
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Hélène Demarquette, Stéphanie Guidez, Artur J. Jurczyszyn, Denis Caillot, Brigitte Pegourie, Marie Lorraine Chretien, Charles Lancesseur, Lionel Karlin, Cristina M. Joao, Claire Bories, Laurence Legros, Laurent Garderet, Souhila Ikhlef, Martine Escoffre, Bruno Royer, Laurent Voillat, Cyrille Hulin, Anne Banos, Eric G. Voog, Anne-Marie Stoppa, Lofti Benboubker, Niels Abildgaard, Katell Le Du, Philippe Moreau, Thierry Facon, Sonja Zweegman, Margaret MACRO, Francesca Gay, Evangelos Terpos, Xavier Leleu, Hematology, CCA - Disease profiling, CCA - Innovative therapy, and CCA - Quality of life
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myeloma *American *society *hematology *transplantation human patient relapse disease course survival therapy aged diagnosis follow up exposure plasmacytoma kidney failure drug dose reduction arm multiple myeloma health care quality electrocorticography *thalidomide bortezomib lenalidomide prednisone melphalan pomalidomide lactate dehydrogenase ,hemic and lymphatic diseases ,Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Background. Thalidomide is one of the most prescribed regimens upfront in eNDMM, e.g. elderly myeloma, essentially as melphalan-prednisone-Thalidomide (MPT). Several options are offered at 1st and 2nd relapse to patients initially exposed to Thalidomide with either bortezomib or lenalidomide-based therapy. On the other hand, the second most prescribed drug in elderly myeloma upfront is Bortezomib, primarily as Bortezomib-melphalan-prednisone (VMP), the 2nd standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation. Interestingly, lenalidomide is the drug of choice at first relapse in the vast majority of cases in most countries where lenalidomide is approved at first relapse and beyond. In this situation, it is likely that the patients would not receive thalidomide throughout the disease course of myeloma. We sought to analyse whether patients not exposed to thalidomide upfront, and that were solely exposed to the 2 drugs, bortezomib-based regimen and lenalidomide-based therapy would have a lower survival than patients exposed to all 3 drugs, e.g. thalidomide, lenaldiomide and bortezomib. Method. A total of 145 patients were recruited in this multicentric study, 46,2% were in the thalidomide upfront exposed arm and 53,8% had never been exposed to thalidomide. Patients were required to be aged ≥65 years, NDMM treated with either thalidomide upfront or never been exposed to thalidomide upfront or later in the myeloma disease course. If not exposed to thalidomide, the patients were to have received bortezomib upfront and lenalidomide first relapse or vice versa. In the thalidomide group, all patients had MPT initially for a median of 8 cycles (range 3 - 12), at a median dose of thalidomide of 100mg/day (50-200), with 11% dose reduction. In the non-exposed thalidomide group, all patients had bortezomib upfront, patients received Vd, VCd or VMP upfront; lenalidomide was then given at first relapse to all patients. The median dose administered of bortezomib was 1.3mg/m², for a median of 5 cycles (2-9). Results. Overall, the median age was 73 years (range, 65 - 85), with 35% aged >75. The M/F ratio was 1.1, 38% were ISS 3, the median b2m was 5.5mg/L, 26% had an ECOG score ≥ 2, 42% had renal insufficiency, 11% had elevated LDH, 8% presence of plasmacytoma, and 14% had adverse FISH (del17p, t(4;14) and or t(14;16)). There was no difference in patients' characteristics across studied groups, according to exposure or not to thalidomide. With a median follow-up of 5 years, 60% have died overall; 69% in the thalidomide exposed group versus 52% in the thalidomide non-exposed group (p=0.027). The median OS of thalidomide exposed patients was 55.7 months (46;65) versus 44 months (35;53) in the thalidomide non exposed patients (p=0.079). In the thalidomide exposed group, the median PFS of the thalidomide, bortezomib then lenalidomide lines were 27 months (24;30), 11 months (8;13) and 13 months (10;15). In the thalidomide non-exposed group, the median PFS of bortezomib then lenalidomide lines were 17 months (13;21) and 13 months (6;20). We then studied the survival of patients from onset of first relapse in the thalidomide exposed group, e.g. upon treatment with bortezomib, followed by lenalidomide at subsequent relapse, 22.5 months (10;34) compared to patients in the thalidomide non-exposed group that received bortezomib upfront and lenalidomide at first relapse, 44 months (35;53), p=0.005. Conclusion. Overall, thalidomide exposed versus non exposed groups had similar OS, while OS was significantly lower in the thalidomide exposed patients at first relapse onset versus in the thalidomide non exposed patients from diagnosis. This data seems to recommend use of bortezomib- and lenalidomide-based regimens as early as possible in the myeloma disease course, but not to abandon thalidomide. Study of the impact of thalidomide in the post bortezomib, lenalidomide and pomalidomide era might thus be important to study and optimize. Disclosures Karlin: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Legros:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Garderet:Bristol-Myers Squibb: Consultancy. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Stoppa:Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Moreau:Janssen: Other: Adboard; Novartis: Other: Adboard; Takeda: Other: Adboard; Amgen: Other: Adboard; Celgene: Honoraria, Other: Adboard. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Terpos:Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Research Funding. Leleu:LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Chugai: Honoraria.
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- 2015
27. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS
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Philippe Bertrand, Vincent Delwail, Patrick Michenet, Annick Le Pourhiet-Le Mevel, Martine Escoffre-Barbe, Noel Milpied, Antoine Thyss, Remy Gressin, Jean-Pierre Vilque, Eric Legouffe, Bernard Desablens, Roselyne Delepine, Eric Deconinck, Philippe Colombat, Pascale Cornillet-Lefebvre, Jean-François Ramée, Arash Jenabian, Philippe Travade, Charles Foussard, Jérôme Jaubert, and Hervé Maisonneuve
- Subjects
Adult ,Male ,Oncology ,medicine.medical_specialty ,Cyclophosphamide ,medicine.medical_treatment ,Immunology ,Follicular lymphoma ,Transplantation, Autologous ,Biochemistry ,Recurrence ,Internal medicine ,Humans ,Medicine ,Lymphoma, Follicular ,Survival rate ,Neoplasm Staging ,Chemotherapy ,business.industry ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Chemotherapy regimen ,Surgery ,Survival Rate ,Transplantation ,Regimen ,Doxorubicin ,Disease Progression ,Feasibility Studies ,Female ,France ,business ,Follow-Up Studies ,Stem Cell Transplantation ,Teniposide ,medicine.drug - Abstract
Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.
- Published
- 2005
28. The p16(INK4A)/pRb pathway and telomerase activity define a subgroup of Ph+ adult Acute Lymphoblastic Leukemia associated with inferior outcome
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Nathalie Klein, Wei W. Chien, Martine Ffrench, Norbert Ifrah, Fabrice Larosa, Régine Catallo, Gilles Salles, Sandrine Hayette, Agnès Chassevent, Françoise Huguet, Marie-Christine Béné, Kheira Beldjord, Adriana Plesa, Aline Schmidt, Amel Chebel, Xavier Thomas, Thibaut Leguay, Laurence Baranger, Luc M. Gerland, Hervé Dombret, and Martine Escoffre-Barbe
- Subjects
Adult ,Male ,Cancer Research ,Poor prognosis ,Telomerase ,Adolescent ,Blotting, Western ,Biology ,Real-Time Polymerase Chain Reaction ,Retinoblastoma Protein ,Immunophenotyping ,Young Adult ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Philadelphia Chromosome ,Lymphocytes ,RNA, Messenger ,Phosphorylation ,neoplasms ,Cells, Cultured ,Cyclin-Dependent Kinase Inhibitor p16 ,Neoplasm Staging ,Reverse Transcriptase Polymerase Chain Reaction ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,In vitro ,Survival Rate ,Oncology ,Case-Control Studies ,Immunology ,Cytogenetic Analysis ,Lymphocyte activation ,Adult Acute Lymphoblastic Leukemia ,Cancer research ,Female ,Cell activation ,Cell aging ,Follow-Up Studies - Abstract
Adult Acute Lymphoblastic Leukemia (ALL) therapies have been improved by pediatric-like approaches. However, treatment failures and relapses are common and new markers are needed to identify patients with poor prognosis in prospective trials. The p16(INK4A)/CDK4-6/pRb pathway and telomerase activity, which are implicated in cell activation and aging, were analyzed to identify new prognostic markers. Proteins of the p16(INK4A)/CDK4-6/pRb pathway and telomerase activity were analyzed in 123 adult B-cell precursor (BCP) ALL cases included in the GRAALL/GRAAPH trials. We found a significantly increased expression of p16(INK4A) in BCP-ALLs with MLL rearrangement. Telomerase activity was significantly lower in Philadelphia chromosome-negative/IKAROS-deleted (BCR-ABL1(-)/IKAROS(del)) cases compared to Philadelphia chromosome-positive (BCR-ABL1+) BCP-ALLs. In BCR-ABL1+ ALLs, high CDK4 expression, phosphorylated pRb (p-pRb) and telomerase activity were significantly associated with a shorter disease-free survival (DFS) and event-free survival (EFS). Enhanced p16(INK4A) expression was only related to a significantly shorter DFS. In vitro analyses of normal stimulated lymphocytes after short- and long-term cultures demonstrated that the observed protein variations of poor prognosis in BCR-ABL1+ ALLs may be related to cell activation but not to cell aging. For these patients, our findings argue for the development of therapeutic strategies including the addition of new lymphocyte activation inhibitors to current treatments.
- Published
- 2014
29. Second TKI Discontinuation in CML Patients That Failed First Discontinuation and Subsequently Regained Deep Molecular Response after TKI Re-Challenge
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Stéphane Giraudier, Stephane Morisset, Franck E. Nicolini, Agnès Guerci-Bresler, Philippe Rousselot, Martine Escoffre, Bruno Varet, Gabriel Etienne, Françoise Huguet, Laurence Legros, Thomas Pagliardini, and Francois-Xavier Mahon
- Subjects
medicine.medical_specialty ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Discontinuation ,Dasatinib ,03 medical and health sciences ,0302 clinical medicine ,Nilotinib ,030220 oncology & carcinogenesis ,Internal medicine ,Cohort ,medicine ,Re challenge ,business ,Survival rate ,Accelerated phase ,030215 immunology ,medicine.drug - Abstract
Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients, long-term undetectable molecular disease (UMD). Several studies have now demonstrated that TKIs could be safely discontinued in those patients previously treated with imatinib (STIM, TWISTER, EUROSKI) and more recently with nilotinib and dasatinib (STOP 2G-TKI). All these studies show a Treatment-Free Remission (TFR) rate reaching ~50%. However, a major issue needs to be resolved for the ~50% of patients that fail such TFR strategies. Methods: We have previously reported the possibility of a second imatinib discontinuation in 16 patients who obtained a second UMD state according to the STIM criteria (RE-STIM observational study, Legros et al. Blood 2012). Here, we report a larger cohort of patients who attempt twice TKI-discontinuations with enlarged inclusion criteria: Adults CML patients without prior allogeneic transplantation or progression to advanced phase CML undergoing a 2nd attempt of TKI discontinuation for sustained deep molecular response after a 1st failure. All patients were followed in CML reference centers and according to the EUTOS-ELN accreditation criteria for BCR-ABL assessments with minimal numbers of 32,000 ABL copies/sample. Results: At the time of analysis (1st July 2016), 67 patients (median age: 51 years (range: 25-80 years)) were included. At CML diagnosis, 64 patients were in chronic phase (CP) and 3 patients in accelerated phase (AP). The Sokal risk and the EUTOS long-term survival scores (ELTS) were respectively low in 47% and 68%, intermediate in 36% and 16%, high in 11% and 2% and unknown in 6% and 14% of patients. All patients were treated initially with imatinib and 16% of patients switch to nilotinib (6/11) or to dasatinib (5/11) for intolerance/resistance reasons prior to the 1st TKI discontinuation. The median time on TKI prior to the 1st discontinuation was 63 months (range: 30-146) and the median duration of 1st CMR was 35 months (range: 20-85). The 1st molecular relapse occurred with a median of 2.5 months (range: 0-22) and the second UMD after TKI re-challenge was obtained with a median of 4.4 months (0-40). The reason of the TKI re-challenge was loss of UMD in 43%, loss of MMR in 55% and unknown in 1%. The TKI re-challenge (imatinib 73%, nilotinib 16%, dasatinib 11%) was then administered during a median of 31 months (range: 9-72 months) before the 2nd attempt of discontinuation. At 2nd TKI cessation, 85% of patients were in UMD, 3% in MR4.5, 6 % in MR4, 3% in MMR and 3% unknown. Thirty out of sixty-eight (44%) patients remained treatment-free after a median follow-up of 21.5 months (1-106), see figure. Similarly to 1st attempts, the majority of loss of MMR occurred during the first 6-12 months in this 2nd attempt cohort. Gender, age, disease phase, prognosis scores, prior interferon exposure, initial TKI type, and duration of UMD were not found to have any impact on the outcome after the 2nd attempt in a multivariate analysis. In contrast, a longer time to obtain the first UMD before the 1st attempt was associated with a significantly lower molecular disease-free survival rate after the 2nd discontinuation (p = 0.048). All patients are alive at last follow-up except one who died from an unrelated CML reason (heart attack under imatinib). Conclusion: TKIs could safely and successfully be discontinued a second time in CML pts despite a 1st failure. Figure. Figure. Disclosures Nicolini: BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Etienne:BMS: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Speakers Bureau; novartis: Consultancy, Speakers Bureau. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Guerci-Bresler:Pfizer: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; ARIAD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
- Published
- 2016
30. The Upper Age Limit for a Pediatric-Inspired Therapy in Younger Adults with Ph-Negative Acute Lymphoblastic Leukemia (ALL)? Analysis of the Graall-2005 Study
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Philippe Rousselot, Patrice Chevallier, Yves Chalandon, Marie C. Béné, Vahid Asnafi, Elizabeth Macintyre, Agnès Buzyn, Caroline Bonmati, Thomas Pabst, Véronique Lhéritier, Martine Escoffre-Barbe, Norbert Ifrah, Thibaut Leguay, Jean-Pierre Marolleau, Stéphane Leprêtre, Hervé Dombret, Eric Delabesse, Mathilde Hunault, Xavier Thomas, Nicolas Boissel, Norbert Vey, Jean-Yves Cahn, and Françoise Huguet
- Subjects
medicine.medical_specialty ,Vincristine ,Chemotherapy ,Randomization ,Cyclophosphamide ,business.industry ,Surrogate endpoint ,medicine.medical_treatment ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Acute lymphocytic leukemia ,Clinical endpoint ,Medicine ,Rituximab ,business ,030215 immunology ,medicine.drug - Abstract
Background: Treatment of younger adults with Ph-negative ALL has markedly evolved since the early 2000s. Survivals have substantially improved using pediatric or pediatric-inspired protocols with higher doses of steroids, vincristine (VCR), methotrexate (MTX) and L-asparaginase (L-Aspa), as was done in the GRAALL-2003 trial (Huguet et al. JCO 2009). However, the upper age limit for a pediatric-like strategy remained undetermined. In the GRAALL-2005 study (NCT00327678), we aimed to address this age issue in a larger trial and to randomly evaluate a reinforced hyper-fractionated (hyperC) vs standard (standardC) dose of cyclophosphamide (CPM) during induction and late intensification. Patients with CD20-positive B-cell precursor (BCP) ALL were also randomized in the rituximab GRAALL-2005/R study, as specifically reported last year (Maury et al. ASH 2015). Patients and Methods: Patients aged 18-59 years old with newly-diagnosed Ph-negative ALL were eligible. Chemotherapy comprised a steroid prephase, a 5-drug induction, two 3-block dose-dense consolidation phases, a late intensification, a third consolidation phase, CNS irradiation, and a 2-year maintenance (Beldjord et al. Blood 2014). Allogeneic transplantation was offered in first complete remission (CR) to patients with conventional high-risk factors (Dhédin et al. Blood 2015). During induction and late intensification, CPM was given at 750 mg/m2 on day 1 followed by 750 mg/m2 on day 15 (standardC) or 300 mg/m2/12h on day 15 to 17 (hyperC), according to randomization arm. The primary endpoint was event-free survival (EFS). Secondary endpoints were cumulative incidences of failure (CIF, including primary refractoriness and relapse) and CI of non-refractoriness/relapse mortality (CINRM, including toxic death during induction and death in first CR), overall survival (OS), compliance and safety. Compliance was assessed by comparing the median doses of specific drugs actually received by patients who completed specific treatment phases. Results: Between 2006 and 2014, 787 evaluable patients were randomized (398 standardC, 389 hyperC; 525 BCP-ALL, 262 T-ALL). Median age was 36y, with 200, 172, 171, 151 and 93 patients in the 18-24y, 25-34y, 35-44y, 45-54y and 55y+ age subgroups, respectively. Overall CR rate was 91.9% and 278 patients were transplanted in first CR. With a median follow-up of 5.2 years, 5y-EFS and OS were 52% (48-56) and 58% (55-62), respectively, confirming previous GRAALL-2003 results. No difference in outcome was observed in T- vs BCP-ALL patients. At 5 years, EFS was 60%, 58%, 54%, 50% and 26% in the youngest to the oldest age subgroup, respectively (HR, 2.2 [1.7-2.8]; p Conclusions: Taken together, these results indicate that 55 years is likely to be the upper age limit for a pediatric-like strategy in younger adults with ALL, because of excessive toxicity and worse treatment compliance observed above this age. Older adults could probably benefit from alternative front-line approaches such as hyper-fractionated CPM or new agents such asinotuzumabozogamicin. Disclosures Rousselot: BMS: Research Funding; Ariad: Research Funding; Pfizer: Research Funding.
- Published
- 2016
31. Evaluation of the Concordance of Two Free Light Chains Assays to Identify High Risk Smoldering Myeloma Patients
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Caroline Moreau, Herve Avet Loiseau, Olivier Decaux, Martine Escoffre, Martine Sebillot, Emmanuel Rouger, Thierry Lamy, Stephane Minvielle, and Basile Henriot
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Oncology ,030213 general clinical medicine ,medicine.medical_specialty ,Spectinomycin ,business.industry ,Anemia ,Concordance ,Immunology ,Cancer ,Cell Biology ,Hematology ,030204 cardiovascular system & hematology ,medicine.disease ,Immunoglobulin light chain ,Biochemistry ,03 medical and health sciences ,Leukemia ,0302 clinical medicine ,Internal medicine ,medicine ,business ,Multiple myeloma ,medicine.drug - Abstract
Background Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM). According to 2003 classification, the IMWG (International Myeloma Working Group) recommended only to treat patients with end organ damage - often referred as CRAB criteria (hypercalcemia, renal failure, anemia and radiological bone lesions). The standard of care for SMM was to postpone treatment until progression to symptomatic disease occurred. The average annual risk of progression of SMM to MM was 10%/year. In 2014 IMWG proposed a revised classification including 3 new criteria that enable early diagnosis of MM before organ damage. The new criteria of MM needs the presence of more than 10% clonal bone marrow plasma cells combined with either the presence of end organ damage (CRAB criteria) or one of following new biomarkers of malignancy: bone marrow plasma cells ≥60%, serum free light chains (FLC) ratio ≥100 and ≥2 focal lesions on MRI. The FLC criteria were established with Freelite™ assay (The Binding Site Company) and have not been validated with other available assays. Freelite™ assay which used polyclonal antibodies was available since 2001. More recently N Latex assay (Siemens Healthyneers) using monoclonal antibodies has been commercialized in Europe. It is now well know that there is a good correlation between the 2 assays even though results in absolute values are not numerically identical. In this context, the aim of this study was to evaluate the concordance between the two assays to identify high risk SMM, when considering the biomarker of malignancy FLC ratio ≥100. Methods This is a retrospective study including 185 patients with SMM according to 2003 IMWG criteria. FLC concentration and ratio were evaluated in frozen sera with both assays in a BN Prospec and evolution status was collected. Results The average age was 62.5 (± 10.2) years old. Results revealed poor correlation between the 2 assays with a Slope Passing-Bablok value of 0.63 (0.57-0.67) for the FLC κ and of 0.44 (0.35-0.62) for the κ/ λ ratio ≥ 100, and concordance in determining the level of FLC λ with a Slope Passing-Bablok 1.16 (0.99-1.40). A Freelite™ratio ≥ 100 was found in 27 patients (14.3%), and a N Latex ratio ≥ 100 was found in 10 patients (5.3%). All but one patients with an N Latex ratio ≥ 100 had also a Freelite™ ratio ≥ 100. Mean of follow up was 2.4 years. A progression toward MM was observed in 77 (40.7%) patients. Among the 27 patients with Freelite™ ratio ≥ 100, 14 patients (55.5%) have evolved toward MM (figure 1A). Specificity and sensitivity for a Freelite™ ratio ≥ 100 were respectively 88.7% (95% CI 81.8 to 94.0%) and 20.3% (95% CI 11.8 to 31.2%). With the N Latex Assay, only 10 patients had a FLC ratio ≥ 100, in which 7 patients have evolved towards MM. Specificity and sensitivity for a N-Latex ratio ≥ 100 were respectively be 67.0% (95% CI 57.4 to 75.6%) and 53.2% (95% CI 41.5 to 64.7%). Given the poor predictive performance of a N-Latex ratio ≥ 100 we determined that a N-Latex ratio ≥ 70 have adequate specificity of 95.5% (95% CI 89.9 to 98.5%) and a sensitivity of 13.0% (95% CI 6.4 to 22.6%) (figure 1B). 15 patients (8.1%) patients had a N-Latex ratio ≥ 70. Among these, 10 patients (66.6%) have evolved toward MM. Conclusion Our study shows poor correlation between the two FLC assays in SMM patients. A Freelite™ ratio ≥ 100 had a lesser specificity than previously described (specificity 95% in Larsen study [1]). The 100 cut-off value was not performant enough for N-Latex assay. A new ratio is thus needed and was found to be 70 to have sufficient specificity and sensitivity. This result need to be validated in an independent cohort. However, with a Freelite™ ratio ≥ 100 or an N Latex ratio ≥ 70, a significant number of patients would have been overtreated. Physicians should be aware of the limits of both assays. 1.Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free light chain ratio as a biomarker for high-risk smoldering multiple myeloma. Leukemia. 2013;27:941-6. Figure 1 probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Figure 1. probability of progression to overt multiple myeloma (A) according to Freelite™ ratio (cut-off 100) (B) according to N-Latex ratio (cut-off 70) Disclosures Moreau: The Binding Site: Other: supply of free light chain assays ; SIEMENS: Other: supply of free light chain assays , Research Funding. Decaux:The Binding Site: Other: supply of free light chain assays , Research Funding; SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding.
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- 2016
32. Frontline Therapy with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Induction Followed By Autologous Stem Cell Transplantation, Krd Consolidation and Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Primary Results of the Intergroupe Francophone Du MyéLome (IFM) Krd Phase II Study
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Hervé Avet-Loiseau, Laurent Garderet, Murielle Roussel, Philippe Moreau, Karim Belhadj, Martine Escoffre, Valérie Lauwers-Cances, Lotfi Benboubker, Thierry Facon, Michel Attal, Denis Caillot, Cécile Fohrer, Nelly Robillard, Brigitte Pegourie, and Xavier Leleu
- Subjects
Melphalan ,medicine.medical_specialty ,Immunology ,Phases of clinical research ,Biochemistry ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,Multiple myeloma ,Lenalidomide ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Carfilzomib ,Surgery ,Regimen ,chemistry ,030220 oncology & carcinogenesis ,business ,Progressive disease ,030215 immunology ,medicine.drug - Abstract
Background: Autologous Stem Cell Transplantation (ASCT) is a standard of care for eligible NDMM pts. Current induction and consolidation regimen associate a proteasome inhibitor (PI), immunomodulatory drug (IMiD) and dexamethasone (Dex). Efforts to further improve outcomes are still needed, mainly by increasing the depth of tumor reduction and the duration of response. As response rate improves with time, we may need to extend cycles numbers. The benefit of bortezomib could be hampered by its neurological side effects. The IFM decided to evaluate, in the transplant setting, Carfilzomib (Carf), a non neurotoxic PI, with Lenalidomide (Len) and Dex as prolonged induction and consolidation regimen followed by Len maintenance. Methods: This open-label, single arm, phase II study was conducted at 10 IFM transplant centers, with enrollment between 03-11/2014. Pts under 66 with symptomatic NDMM received four 28-day induction cycles of KRd= Carf 20/36mg/m2 (D1-2, 8-9, 15-16), Len 25 mg (D1-21), Dex 20 mg (D1-2, 8-9, 15-16, 22-23). Stem cell collection was planned for all pts after high dose (HD) cyclophosphamide. All pts proceeded to HD melphalan (200 mg/m2) followed by ASCT. Two months after hematological recovery, pts received four 28-day consolidation cycles of KRd (at last tolerated dose) followed by 1 year of Len maintenance (10 mg, D1-21). The primary objective was sCR rates at the completion of consolidation. Secondary objectives reported here included response rates after induction, ASCT and consolidation; PFS and safety profile of the KRd combination as induction and consolidation. Responses (Central Lab Dr Puissant, Toulouse) were assessed according to International Uniform Response Criteria. Flow cytometric analysis of plasma cells for Minimal Residual Disease MRD (Central Lab Dr Robillard, Nantes) was performed at each step of the program for pts at least in VGPR. For informative pts, MRD by Next Generation Sequencing NGS (Central Lab Pr Avet-Loiseau, Toulouse) was also analysed. Adverse events (AEs) were graded using the CTCAE v4.03. Patients: Forty-eight pts with symptomatic MM were screened, 46 were enrolled and received at least 1 dose of treatment. Baseline characteristics of the treated pts were: median age = 56 years (range 40-65); ISS= 1 in 46%, 2 in 48% and 3 in 6% of pts. Adverse cytogenetics (17p deletion and/or t(4;14); central Lab Pr Avet-Loiseau, Toulouse) were observed in 9 of 43 (21%) assessable pts. Results: All pts but 4 pts remain on study at data cut-off. Forty-three patients completed induction, 42 underwent ASCT, 41 completed consolidation and 27 patients are currently on maintenance phase. Considering efficacy, at the completion of consolidation, 23 sCR pts or more were required to claim activity of the program with prolonged KRd induction and consolidation. Among 42 evaluable pts, 27 were in sCR. Overall Response Rate (ORR) was 97.5%, including 23.5% VGPR, 69% CR or better and 32/36 pts (89%) were MRD negative by flow. For pts tested by NGS, 13/22 (59%) were MRD negative. CR or better rates improved at each step of the program. Description of responses is given in table 1. With a median follow-up of 20 months from start of therapy, 4 events were reported: 2 pts had progressive disease (PD) and 2 pts died without PD. Median PFS was not reached. Considering safety, there was no KRd related death, 4 pts permanently discontinued combined treatment due to AEs: 3 during induction (1 cardiac failure, 1 pneumonia, 1 jugular vein thrombosis ) and 1 post ASCT ( lethal septic choc). Overall, 44 serious AEs were reported in 30 pts (65%) including 8 cardiovascular events (2 cardiac failures, 1 bradycardia, 2 pulmonary embolisms and 3 thrombosis despite adequate prophylaxis). Overall, 20 cardiovascular events were reported: 7 cardiac disorders and 13 thrombosis. Other SAEs included infections in 12 pts (26%) and musculoskeletal disorders in 8 pts (17%). The 2 most common grade 3/4 AEs (>10%) related to KRd were hematological toxicities and infections, mainly post ASCT, during consolidation safety period. There was no grade 3/4 sensory peripheral neuropathy. Conclusion: 8 cycles of KRd as induction and consolidation in the transplant setting produce high quality responses in NDMM pts. Safety profile seems acceptable but cardiovascular AEs if confirmed in other studies might impact results. Updated efficacy and safety data will be presented during the meeting including complete MRD analysis by NGS. Table 1 Table 1. Disclosures Roussel: BMS: Other: lecture fees; sanofi: Other: lecture fees; AMGEN: Consultancy, Other: lecture fees, Research Funding; celgene: Consultancy, Other: lecture fees, Research Funding; janssen: Consultancy, Other: lecture fees. Belhadj:janssen: Consultancy; novartis: Consultancy. Facon:celgene: Consultancy; janssen: Consultancy; sanofi: Consultancy; BMS: Consultancy; novartis: Consultancy; amgen: Consultancy. Garderet:Novartis: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS: Consultancy, Honoraria. Fohrer:celgne: Consultancy; amgen: Consultancy. Moreau:Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Avet-Loiseau:celgene: Consultancy; amgen: Consultancy; sanofi: Consultancy; janssen: Consultancy. Attal:amgen: Consultancy, Research Funding; celgene: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy.
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- 2016
33. BCR-ABL1 molecular remission after 90Y-epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B-ALL: proof of principle
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Thierry Guillaume, Nelly Robillard, Caroline Bodet-Milin, Patrice Chevallier, David M. Goldenberg, Françoise Kraeber-Bodéré, T. Eugène, Jacques Delaunay, William A. Wegener, Claire Le Houerou, Martine Escoffre-Barbe, and Audrey Ménard
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Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Lymphoblastic Leukemia ,medicine.medical_treatment ,Sialic Acid Binding Ig-like Lectin 2 ,Fusion Proteins, bcr-abl ,Antibodies, Monoclonal, Humanized ,Immunophenotyping ,Bcr abl1 ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Medicine ,Humans ,Yttrium Radioisotopes ,B Acute Lymphoblastic Leukemia ,business.industry ,CD22 ,Remission Induction ,Hematology ,General Medicine ,Middle Aged ,Radioimmunotherapy ,Phenotype ,Treatment Outcome ,Immunology ,Female ,Allogeneic hematopoietic stem cell transplant ,business ,Tetraxetan ,Epratuzumab ,medicine.drug - Abstract
Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with (90) yttrium ((90) Y)-labeled anti-CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. (90) Y-Epratuzumab tetraxetan may be a promising therapeutic option for CD22(+) B-ALL patients.
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- 2013
34. Pomalidomide plus low-dose dexamethasone is active and well tolerated in bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myélome 2009-02
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Nathalie Meuleman, Laurent Garderet, Philippe Moreau, Sabine Brechignac, Brigitte Kolb, Gerald Marit, Margaret Macro, Hervé Avet-Loiseau, Michel Attal, Bruno Royer, Mauricette Michallet, Murielle Roussel, Marie Odile Petillon, Claire Mathiot, Beatrice Thielemans, Martine Escoffre-Barbe, Olivier Decaux, Intergroupe Francophone du Myelome, Xavier Leleu, Cyrille Hulin, Bertrand Arnulf, Lotfi Benboubker, Jean Paul Fermand, Catherine Traullé, Bernadette Hennache, Brigitte Pegourie, Anne-Marie Stoppa, Thierry Facon, Denis Caillot, university hospital, University Hospital, Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), 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), Hématologie et oncologie pédiatrique, Department of Hematology, Hospices Civils de Lyon (HCL), Service des maladies du sang, CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Groupe Hospitalier Sud, Laboratoire d'Hématologie biologique, Institut Curie [Paris], Service d'Hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Laboratoire de Biochimie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (UMR_S567 / UMR 8104), 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 Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Médecine interne et immunologie clinique [Rennes] = internal medicine and clinical immunology [Rennes], CHU Pontchaillou [Rennes], Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Service d'hématologie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Claude Huriez [Lille], CHU Lille, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire d'Hématologie [Purpan], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Service d'hématologie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Curie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de médecine interne, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Hôpital Claude Huriez, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Toulouse III - Paul Sabatier ( UPS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hospices Civils de Lyon ( HCL ), INSTITUT CURIE, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Cochin ( UMR_S567 / UMR 8104 ), 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 Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou, Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut Mondor de Recherche Biomédicale ( IMRB ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
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Drug Resistance ,Medical Oncology ,Biochemistry ,Dexamethasone ,law.invention ,Bortezomib ,0302 clinical medicine ,Randomized controlled trial ,law ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Treatment Failure ,Lenalidomide ,Multiple myeloma ,Societies, Medical ,Aged, 80 and over ,Hematology ,Middle Aged ,Boronic Acids ,3. Good health ,Thalidomide ,Treatment Outcome ,030220 oncology & carcinogenesis ,Pyrazines ,France ,Drug ,Multiple Myeloma ,medicine.drug ,Adult ,medicine.medical_specialty ,Immunology ,Urology ,Dose-Response Relationship ,03 medical and health sciences ,Medical ,medicine ,Humans ,Aged ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Dose-Response Relationship, Drug ,business.industry ,Cell Biology ,medicine.disease ,Pomalidomide ,Surgery ,Regimen ,Drug Resistance, Neoplasm ,Neoplasm ,business ,[ SDV.GEN ] Life Sciences [q-bio]/Genetics ,Societies ,030215 immunology - Abstract
International audience; The combination of pomalidomide and dexamethasone can be safely administered to patients with multiple myeloma (MM) and has significant efficacy, although the optimal regimen remains to be determined. Patients with MM whose disease progressed after multiple lines of therapy have limited treatment options. We designed a multicenter, phase 2 randomized study assessing two different dose regimens of pomalidomide and dexamethasone in advanced MM. Treatment response was assessed centrally. Pomalidomide (4 mg) was given orally on days 1 to 21 (arm 21/28) or continuously (arm 28/28) over a 28-day cycle, plus dexamethasone given weekly. Eighty-four patients (43, arm 21/28 and 41, arm 28/28) were randomized. The median number of prior lines was 5. Overall response rate was 35% (arm 21/28) and 34% (arm 28/28), independent of the number of prior lines and level of refractoriness. Median duration of response, time to disease progression, and progression-free survival was 7.3, 5.4, and 4.6 months, respectively, which was similar across cohorts. At 23 months follow-up, median overall survival was 14.9 months, with 44% of the patients alive at 18 months. Toxicity consisted primarily of myelosuppression, which was manageable. The efficacy and safety data presented here, along with data from other phase 2 trials, suggest that pomalidomide 4 mg per day on days 1 to 21 of 28 with dexamethasone should be investigated in future trials. This trial is registered at ClinicalTrials.gov (No. NCT01053949).
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- 2013
35. Bortezomib, Thalidomide and Dexamethasone (VTD) Is Superior to Bortezomib, Cyclophosphamide and Dexamethasone (VCD) Prior to Autologous Stem Cell Transplantation for Patients with De Novo Multiple Myeloma. Results of the Prospective IFM 2013-04 Trial
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Kamel Laribi, Driss Chaoui, Mourad Tiab, Sabine Brechignac, Philippe Moreau, Lucie Planche, Pascal Godmer, Laetitia Biron, Margaret Macro, Cyrille Hulin, Hervé Avet-Loiseau, Karim Belhadj, Murielle Roussel, Marc Wetterwald, Hélène Caillon, Arnaud Jaccard, Gerald Marit, Thomas Dejoie, Brigitte Pegourie, Odile Luycx, Thierry Facon, Denis Caillot, Pascal Lenain, Mamoun Dib, Jean Fontan, Carine Chaleteix, Borhane Slama, Anne-Marie Stoppa, Olivier Allangha, Mathieu Puyade, Véronique Dorvaux, Jean-Paul Fermand, Michel Attal, Martine Escoffre, Carla Araujo, Brigitte Kolb, Bruno Royer, Jean Claude Eisenmann, Laurent Garderet, Sylvie Glaisner, and Philippe Rodon
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medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,law.invention ,Thalidomide ,Clinical trial ,Regimen ,Autologous stem-cell transplantation ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Clinical endpoint ,Progression-free survival ,business ,Multiple myeloma ,medicine.drug - Abstract
Background Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537). Methods Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0. Results From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate (> partial response [PR]) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively. Conclusion This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD. Disclosures Moreau: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.
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- 2015
36. Personalized Daily Doses of Imatinib By Therapeutic Drug Monitoring Increase the Rates of Molecular Responses in Patients with Chronic Myeloid Leukemia. Final Results of the Randomized OPTIM Imatinib Study
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François Guilhot, Stéphane Bouchet, Laurent Sutton, Laure Morisset, Camille Pouaty, Wajed Abarah, Valérie Coiteux, Jean-Michel Cayuela, Françoise Huguet, Laurence Legros, Francois-Xavier Mahon, Sorin Visanica, Martine Gardembas, Philippe Rousselot, Jean Michel Pignon, Benjamin Manéglier, Bénédicte Deau, Bachra Choufi, Martine Escoffre-Barbe, Pascale Cony-Makhoul, and Hyacinthe Johnson-Ansah
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medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Imatinib mesylate ,Therapeutic drug monitoring ,Dose adjustment ,Internal medicine ,Major Molecular Response ,medicine ,Chronic phase CML ,In patient ,business ,Sokal Score ,medicine.drug - Abstract
[Graphic][1] Background Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007). We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17). Patients and Methods Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months. Results One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 ( p
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- 2015
37. Addition of Rituximab Improves the Outcome of Adult Patients with CD20-Positive, Ph-Negative, B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL): Results of the Randomized Graall-R 2005 Study
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Dominik Heim, Véronique Lhéritier, Mathilde Hunault, Xavier Thomas, Sébastien Maury, Hervé Dombret, Thibaut Leguay, Norbert Ifrah, Patrice Chevallier, Norbert Vey, Jean-Pierre Marolleau, Nicolas Boissel, Françoise Huguet, Sylvie Chevret, Marie-Christine Béné, Yves Chalandon, Urs Hess, Kheira Beldjord, Thorsten Braun, and Martine Escoffre-Barbe
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medicine.medical_specialty ,Randomization ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,Chemotherapy regimen ,Minimal residual disease ,law.invention ,Surgery ,Transplantation ,Regimen ,Randomized controlled trial ,law ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Rituximab ,Cumulative incidence ,business ,medicine.drug - Abstract
Purpose: The use of rituximab, a chimeric monoclonal antibody to CD20, has led to significant improvement in the treatment of B-cell non-Hodgkin's lymphoma and mature B-cell ALL. CD20 is expressed in 30 to 50% of adult BCP-ALL patients. Although some single arm studies suggested that adding rituximab to chemotherapy could improve the outcome of these patients, no randomized study has been reported so far. Methods: To evaluate the potential benefit of adding rituximab, we conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab, in patients aged 18-59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts. Rituximab (375 mg/m2) was given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7) and first year of maintenance (6 infusions) for a total of 16 to 18 infusions. Allogeneic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The primary study objective was event-free survival (EFS). A study sample size of 220 patients was estimated in order to detect a 20% gain in EFS at 2 years (two-sided test, power 85%, type 1 error 5%). A sensitivity analysis was performed after censoring patients allografted in first CR at transplant time. This trial was registered at http://www.clinicaltrials.gov as #NCT00327678. Results: From 2005 to 2014, 220 patients from 56 centers were randomized. Eleven patients had non-eligibility criteria (n=5 Ph+ ALL; n=3 CD20-negative ALL; n=1 HIV infection) or withdrew their consent (n=2) and were accordingly excluded from this modified ITT analysis that dealt with 209 patients (105 in the rituximab arm and 104 in the control arm). Median age was 40 years. Both randomization arms were well balanced for pretreatment characteristics including age, ECOG status, WBC, and central nervous system (CNS) involvement (6% of the whole cohort). After induction ± salvage reinduction, CR rate was 92% and 91% in rituximab and control arm, respectively. In patients who reached CR after first induction and were evaluated for Ig/TCR minimal residual disease level (MRD), the rates of patients with MRD Conclusions: In adults with CD20-positive, Ph-negative, BCP-ALL, the addition of rituximab to the pediatric-inspired GRAALL protocol improves EFS; it also prolongs OS when ignoring patient's outcome after transplantation in first CR. Disclosures Off Label Use: Rituximab is not currently approved for this indication.. Chalandon:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2015
38. Osteoarticular Pain after Discontinuation of Tyrosine Kinase Inhibitors (TKI): A French Cohort
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Charlotte Oris, Marie Zenut, Agnès Guerci, Martine Escoffre-Barbe, Martine Gardembas, Joelle Guilhot, Delphine Rea, Bruno Pereira, Francois-Xavier Mahon, Marc G. Berger, Pascale Cony-Makhoul, Sandrine Saugues, Laurence Legros, Philippe Rousselot, Franck E. Nicolini, and Stéphane Giraudier
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medicine.medical_specialty ,business.industry ,Immunology ,Context (language use) ,Cell Biology ,Hematology ,Biochemistry ,Discontinuation ,Surgery ,Clinical trial ,Nilotinib ,Internal medicine ,Pharmacovigilance ,Cohort ,Medicine ,Medical history ,business ,Sokal Score ,medicine.drug - Abstract
Context: The Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) increasing dramatically the survival of CML patients and leading to a residual disease with a sustained and deep molecular response. In this subset of very good responder patients, the attempts of stopping treatment in different clinical trials were successfully achieved without relapse. The Swedish team in the EURO-SKI protocol already reported cases of musculoskeletal pain occurring after cessation of TKI (Richter et al., JCO, 2014). Since several clinical trials regarding TKI discontinuation have been also run in France, we decided to retrospectively collect data using the pharmacovigilance system of the different Trials collected prospectively. Method: 428 patients from STIM2 (n=204) and EURO-SKI (n=224) trials were systematically analyzed from the case report from each trial. For the EURO-SKI only French patients were included. Statistical analysis was performed using Stata 13 software (StataCorp LP, College Station, TX, US). Comparisons between the independent groups were realized using the Chi-squared or Fisher's exact tests for categorical variables, and using Student t-test or Mann-Whitney test for quantitative. Multivariate analyses were performed to take into account adjustment on covariates fixed according to univariate results and clinically relevance. Results: Among the 428 patients the main characteristics were as follow i,e; 208 (48.6%) men and 220 (51.4%) women, with a median age of 77.5 years (24-93). Sokal scores (n=449) were low in 187 (41.6%) patients, intermediate in 188 (41.9%) patients and high in 74 (16.5%) patients. A withdrawal TKI syndrome (WS) was reported for 102 (23.8%) patients (100 after imatinib and 2 after nilotinib). 2). The WS consists in bone and articular pains and arthritis and affects the upper limbs, shoulders and cervical rachis, with a grade 1 or 2 in most patients and grade 3 in 22% of patients . The prevalence of WS depends on the trials, 34.8% in EURO-SKI group and 13.8% in STIM2 group (p We did not observe any difference between WS group and the group without painful syndrome in terms of sex ratio (p=0.92), age (p=0.33), sokal score (p=0.15), BCR-ABL transcript (p=0.42) or duration of CML (p=0.24). However the median duration of TKI therapy appeared longer in this subgroup (median: 88.8 months vs 79.8 months (p=0.02). There was no biological inflammatory syndrome and the results of medical imaging were inconclusive. However, a medical history of osteoarticular pains or disease appeared as predisposing to withdrawal syndrome (22.9% in WS group vs 9.8% in control group; p=0.002). Finally the two factors, duration of treatment and medical history were confirmed using multivariate analysis (RR=1.73 and 1.76 respectively). Among 19 exploitable cases suffering CML relapse and requiring further TKI treatment, pain disappeared in 7 patients (37%) within a median period of 3.5 weeks. Conclusion: About 23% of patients who stopped TKIs experienced a TKI WS and all TKI seems to be concerned. The predisposing factors were a medical history of osteoarticular pain or disease, and the duration of treatment. So patients and physicians should be aware and recommendations should be proposed for patients who have treated longtime with a history of arthritis. Disclosures Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rousselot:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.
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- 2015
39. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma
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Jean-Gabriel Fuzibet, Marc Wetterwald, Bruno Lioure, Carla Araujo, Thierry Facon, Philippe Moreau, Catherine Sebban, Anne-Marie Stoppa, Laurent Garderet, Carine Chaleteix, Christian Berthou, Claire Mathiot, Hervé Avet-Loiseau, Brigitte Kolb, Olivier Decaux, Cyrille Hulin, Jean-Luc Harousseau, Lotfi Benboubker, Pascal Lenain, Michel Attal, Mourad Tiab, Denis Caillot, Martine Escoffre, Catherine Traullé, Gerald Marit, Mamoun Dib, Brigitte Pegourie, Jean Fontan, Edouard Randriamalala, Gérard Lepeu, and Chantal Doyen
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Immunology ,Urology ,Biochemistry ,Transplantation, Autologous ,Dexamethasone ,Bortezomib ,Autologous stem-cell transplantation ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Survival analysis ,Multiple myeloma ,Dose-Response Relationship, Drug ,business.industry ,Induction chemotherapy ,Cell Biology ,Hematology ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Boronic Acids ,Combined Modality Therapy ,Survival Analysis ,Surgery ,Thalidomide ,Peripheral neuropathy ,Treatment Outcome ,Pyrazines ,Female ,business ,Multiple Myeloma ,medicine.drug ,Stem Cell Transplantation - Abstract
The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction before high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally randomly assigned to receive VD or vtD. After 4 cycles, the complete response (CR) rate was the same in both groups (13% in the vtD arm, 12% in the VD arm, P = .74). However, the CR plus very good partial response (VGPR) rate was significantly higher in the vtD arm (49% vs 36%, P = .05). After ASCT, the CR plus VGPR rate was significantly higher in the vtD arm (74% vs 58%, P = .02). The reduced doses of bortezomib and thalidomide translated into a reduced incidence of peripheral neuropathy (PN): grade ≥ 2 PN were reported in 34% in the VD arm versus 14% in the vtD arm (P = .001). vtD, including reduced doses of bortezomib and thalidomide, yields higher VGPR rates compared with VD and can be considered a new effective triplet combination before HDT/ASCT. This study was registered with www.clinicaltrials.gov as #NCT00910897 and EudraCT as #2007-005204-40.
- Published
- 2011
40. When can real-time quantitative RT-PCR effectively define molecular relapse in acute promyelocytic leukemia patients? (Results of the French Belgian Swiss APL Group)
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Martine Escoffre-Barbe, Bruno Cassinat, Emmanuel Raffoux, Marie-Hélène Schlageter, A Parry, Jean-Luc Harousseau, Fabien Zassadowski, Philippe Rousselot, Sylvie Chevret, André Baruchel, Chantal Himberlin, Pierre Fenaux, Christine Chomienne, Jean-Yves Cahn, Hervé Dombret, Oumedaly Reman, Denis Guyotat, Didier Bouscary, Olivier Legrand, Isabelle Guillemot, Stéphane de Botton, Martine Gardembas, Charikleia Kelaidi, and Lionel Ades
- Subjects
Oncology ,Acute promyelocytic leukemia ,Cancer Research ,medicine.medical_specialty ,Positive sample ,Oncogene Proteins, Fusion ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Hematology ,medicine.disease ,Minimal residual disease ,Article ,Real-time polymerase chain reaction ,Leukemia, Promyelocytic, Acute ,Recurrence ,Internal medicine ,Immunology ,Cohort ,medicine ,Humans ,business ,Survival rate - Abstract
10–20% of APL patients relapse and the challenge remains to early identify these patients to improve survival rate. We report PML-RARα transcript detection by RQ-PCR in 260 consecutive APL patients ( n = 970 samples). 223 patients with samples of sufficient RNA quality to demonstrate they reached molecular remission were monitored for MRD. During follow-up, 38 of these patients were tested positive for PML-RARα mRNA. 13 out of the 38 patients (34%) effectively developed hematological relapse. In the first positive sample, specific PML-RARα NCN thresholds over which, or under which, patients could effectively be predicted to relapse or not, were identified and subsequently validated in a second cohort.
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- 2008
41. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience
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Marie-Thérèse Daniel, Keith Bourgeois, Lionel Mannone, Valérie Bardet, L. Aljassem, Stéphane Cheze, Beatrice Mahe, Charikleia Kelaidi, Lionel Ades, Sophie Park, Geneviève Leroux, Norbert Vey, Martine Escoffre-Barbe, Odile Beyne-Rauzy, Pascale Lepelley, Christophe Ravoet, Augustin Ferrant, Peter L. Greenberg, Hervé Dombret, François Dreyfus, Pierre Fenaux, Sophie Grabar, Aspasia Stamatoullas, Valérie Coiteux, and Françoise Picard
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Oncology ,Male ,medicine.medical_specialty ,Time Factors ,Immunology ,Biochemistry ,Disease-Free Survival ,Cohort Studies ,Predictive Value of Tests ,Internal medicine ,Granulocyte Colony-Stimulating Factor ,medicine ,Humans ,Survival rate ,Erythropoietin ,Aged ,Epoetin beta ,Hematology ,business.industry ,Cell Biology ,Granulocyte colony-stimulating factor ,Survival Rate ,International Prognostic Scoring System ,Myelodysplastic Syndromes ,Cohort ,Female ,business ,Blast Crisis ,Erythrocyte Transfusion ,Cohort study ,medicine.drug - Abstract
We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin α, epoetin β, or darbepoetin α (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as “nonresponders” or “responders” according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.
- Published
- 2007
42. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study
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Elizabeth Macintyre, Francis Witz, Eric Delabesse, Arnaud Pigneux, Martine Escoffre, Philippe Rousselot, Véronique Lhéritier, Jean-Michel Cayuela, Yves Chalandon, M C Vekemans, Delphine Rea, Oumedaly Reman, Norbert Ifrah, Xavier Thomas, Jean-Paul Vernant, Sébastien Maury, Adrienne de Labarthe, Francoise Huguet-Rigal, Hervé Dombret, and Agnes Buzyn
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Oncology ,Male ,Neoplasm, Residual ,Cytarabine/therapeutic use ,Biochemistry ,Piperazines ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Philadelphia Chromosome ,ddc:616 ,Remission Induction ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Middle Aged ,Chemotherapy regimen ,Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/mortality ,Mitoxantrone/therapeutic use ,Residual ,Benzamides ,Imatinib Mesylate ,Female ,medicine.drug ,Adult ,Homologous ,medicine.medical_specialty ,Vincristine ,Adolescent ,Immunology ,Philadelphia chromosome ,Internal medicine ,Transplantation, Homologous ,Humans ,Pyrimidines/administration & dosage ,Mitoxantrone ,Transplantation ,business.industry ,Consolidation Chemotherapy ,Imatinib ,Piperazines/administration & dosage ,Cell Biology ,medicine.disease ,Survival Analysis ,Surgery ,Pyrimidines ,Adult Acute Lymphoblastic Leukemia ,Neoplasm ,Antineoplastic Combined Chemotherapy Protocols/therapeutic use ,business - Abstract
The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.
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- 2007
43. Spontaneous megakaryocytic colony formation does not discriminate between essential thrombocythemia and polycythemia vera
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Olivier Fardel, Pascale Beaucournu, Martine Escoffre-Barbe, Thierry Lamy, Thierry Fest, Bernard Grosbois, Laurence Amiot, Patrick Jego, Isabelle Grulois, Marc Bernard, Service d'hématologie clinique, Université de Rennes (UR)-Hôpital Pontchaillou, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes (UR), Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service de médecine interne, hôpital Sud, Service de Médecine interne et immunologie clinique [Rennes] = internal medicine and clinical immunology [Rennes], CHU Pontchaillou [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
- Subjects
Male ,MESH: Polycythemia Vera ,0302 clinical medicine ,Polycythemia vera ,Megakaryocyte ,Reactive thrombocytosis ,MESH: Aged ,0303 health sciences ,Hematology ,MESH: Middle Aged ,Middle Aged ,MESH: Predictive Value of Tests ,MESH: Megakaryocytes ,medicine.anatomical_structure ,Female ,essential thrombocytemia ,Megakaryocytes ,Thrombocythemia, Essential ,Adult ,medicine.medical_specialty ,Adolescent ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Colony-Forming Units Assay ,03 medical and health sciences ,Myeloproliferative Disorders ,polycythemia vera ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,MESH: Colony-Forming Units Assay ,030304 developmental biology ,Aged ,MESH: Adolescent ,MESH: Humans ,business.industry ,Essential thrombocythemia ,MESH: Adult ,colony-forming unit megacaryocytes ,medicine.disease ,MESH: Male ,endogenous growth ,Colony formation ,Immunology ,MESH: Thrombocythemia, Essential ,Bone marrow ,business ,MESH: Female ,030215 immunology - Abstract
International audience; Laboratory detection of spontaneous growth of colony-forming unit-megacaryocytes (CFU-MK), allowing us to distinguish essential thrombocythemia (ET) from reactive thrombocytosis, is therefore useful for the diagnostic of this myeloproliferative disorder. Whether CFU-MK assays allow us to discriminate at least partly between ET and other myeloproliferative disorders such as polycythemia vera (PV) remains, however, to be established. To gain insights about this point, we have performed CFU-MK cultures from bone marrow cells of patients diagnosed with ET (n = 42) or PV (n = 50) using a standardized collagen-based serum-free method. Spontaneous growth of CFU-MK was similarly detected in both 40/42 patients with ET and 47/50 patients with PV. These data suggest clearly that the CFU-MK assay is useful to detect not only ET, but also PV, but fails to discriminate, even partly, between these two myeloproliferative disorders.
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- 2006
44. Hyperhomocysteinemia and High Doses of Nilotinib Favour Cardio-Vascular Events in Chronic Phase Chronic Myelogenous Leukemia (CML) Patients
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Jocelyne Drai, Emilie Blond, Franck E. Nicolini, Martine Escoffre-Barbe, Isabelle Redonnet-vernhet, Maël Heiblig, Mauricette Michallet, Jeremy Ruby, Stephane Giraudier, Madeleine Etienne, Mohamad Sobh, Jean-Christophe Lega, Hélène Labussière-Wallet, Gabriel Etienne, Stephane Morisset, and Gaelle Fossard
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medicine.medical_specialty ,Univariate analysis ,Hyperhomocysteinemia ,business.industry ,Immunology ,Imatinib ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Sudden death ,Surgery ,Imatinib mesylate ,Nilotinib ,Internal medicine ,medicine ,Cumulative incidence ,Myocardial infarction ,business ,medicine.drug - Abstract
Despite its high efficacy on CML, long-term exposure to nilotinib, a second generation tyrosine kinase inhibitor (TKI2), has been reported to increase the onset of arterial cardiovascular events (CVE) in chronic phase (CP) CML patients (pts), especially in pts with cardiovascular risk factors. However, some pts without any cardiovascular risk factors may experience arterial thrombotic events and the pathogenesis of this phenomenon remains obscure. Homocystein (HC) is a key sulphured amino-acid derived from methionin, independently associated with increased frequencies of thrombo-embolic events, early arteriosclerosis and increased cardiovascular mortality (Nygard NEJM 1997). In addition, in vitro, this amino-acid induces the proliferation of smooth muscle cells, endothelial cell dysfunction, increased collagen synthesis and exerts pro-inflammatory rearrangements within the arterial wall. In the present study, we wanted to determine if hyperhomocysteinemia might influence the onset of cardio-vascular events in a series of 114 CP CML pts on nilotinib. We have prospectively analysed in a multicentric study, on-nilotinib cohorts of CP CML pts between September 2011 and July 2014 with standard clinical assessments [height, weight, body mass index (BMI)], onset of any CV events, and basic routine blood metabolic laboratory assessments (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, glycosylated haemoglobin, homocysteinemia (Biorad kit on HLPC on Summit Dionex system, Thermo Fischer scientific, France), vitamines B9 and B12. All the 114 pts were in CP-CML on nilotinib [43 as first-line, 71 as second-line or more, since a median of 51.5 (3-164) months], 49 were males, with a median age of 51.7 (18-81) at CML diagnosis and 58 (82-20) at nilotinib initiation. Twenty-eight (24.5%) pts presented some CV risk factors prior to nilotinib initiation, and 24 (21%) had an active tobacco abuse at assessment (4 patients unknown). Median weight was 69 (44-149) kg and median BMI was 24.5 (16.5-46) kg/m2 (8 patients >30). Overall, 21 (18.5) pts presented new or worsened pre-existing CVE on nilotinib after a median follow-up of 51.5 months since TKI2 initiation. These CVE occurred after a median of 47 (7.5-82.3) months with a regular increase along the years (Cumulative incidence (CI) 3% at 1 year, 4.12% at 2, 5.15% at 3, 9.30 at 5 and 20.62% at 8.3 years). In total, 3 pts died, 2 from brain stroke, 1 from sudden death in a pt with a history of myocardial infarction. In an univariate analysis we compared our cohort of nilotinib pts to a similar cohort of 17 pts on imatinib as control [median age 56 years since CML diagnosis (p=ns), median duration of imatinib 39 months (p=ns), median weight 70.5 kg (p=ns), BMI 25.9 kg/m2 (p=ns)]. None of these imatinib pts had shown any CVE during follow-up. HC was significantly lower in imatinib-treated pts (p=0.029), in female pts (p=0.018) and increased with age (p Figure 1 Cumulative incidence of CVE on nilotinib according to the level of HC. Figure 1. Cumulative incidence of CVE on nilotinib according to the level of HC. The CI of CVE was significantly higher in pts on nilotinib 800 mg daily (38% at latest follow-up) versus pts on ≤600 mg daily, (10%, p=0.005, Gray test). Finally multivariate analysis identified age [p In conclusion, nilotinib seems to favour CVE in the long-term in CP CML pts, especially in patients with CV risk factors, and these CVE are specifically linked to higher doses of nilotinib and high levels of homocysteinemia. This marker could represent a useful tool to detect pts at risk of arterial CVE on nilotinib. Whether hyperhomocysteinemia is one of the causes of CVE of a consequence of nilotinib treatment remains to be determined. Disclosures Michallet: Genzyme: Consultancy; Oseus: Consultancy; BMS: lectures, lectures Other; Novartis: lectures, lectures Other; MSD: lectures Other. Etienne:Novartis: Consultancy; BMS: lectures, lectures Other. Nicolini:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
- Published
- 2014
45. Prospective Analysis of the Quality of Life of Chronic Phase CML Patients on Second Generation Tyrosine Kinase Inhibitors after Imatinib Failure. an Observational Study
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Gabriel Etienne, Martine Gardembas, Annelore Le Maux, Stephane Giraudier, Emmanuel Gyan, Mohamad Sobh, Hélène Labussière-Wallet, Agnès Guerci-Bresler, Hyacinthe Johnson-Ansah, Hesham Mohamed, Laurent Sutton, Claude-Eric Bulabois, Denis Caillot, Martine Escoffre-Barbe, Pascale Cony-Makhoul, Lydia Roy, Maël Heiblig, Eric Jourdan, Franck E. Nicolini, Nicolas Vantard, Laurence Legros, and Carine Guinard-Azadian
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Pediatrics ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Proportional hazards model ,Immunology ,Population ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Dasatinib ,Transplantation ,Nilotinib ,Quality of life ,Medicine ,Sokal Score ,business ,education ,medicine.drug - Abstract
Imatinib (IM) failure in chronic phase CML patients is a peculiar situation where the quality of life (QoL) of patients has rarely been appreciated and assessed. A majority of patients is rescued by second generation tyrosine kinase inhibitors (TKI2) licensed in this setting. In the retrospective and prospective national observational POSTIM study we have already reported the value of the Hammersmith score in this population of patients. In the same population, we have also have prospectively analysed the QoL and the compliance of these IM-resistant or intolerant patients, on TKI2 (i. e. Nilotinib and Dasatinib) as a secondary objective, using a series of scores currently used to assess such characteristics (Morisky score, Functional Assessment of Cancer Therapy (FACT) subdivided in Physical Well Being (PWB), Social/Family Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), Social/Family well being (SAC), (FACT+SAC=FACT-total), and FACT-Leu) calculated at 6 months and 12 months following first TKI2 initiation. These scores have been correlated to general characteristics of the patients, cytogenetic and molecular responses to TKI2 at one year of TKI2, and to survival. Among the 174 patients enrolled in the POSTIM study, 76 patients have been enrolled in this QoL study in 16 university and non-university academic institutions between 2009 and 2012, and their data collected after informed consent. There were 36 males (47%) and 40 females with a median age at enrolment of 62 (25-86) years and a median duration of CML of 6.5 (3-18) years. Sokal score was low for 37%, intermediate for 28% and high for 35 % (6 pts unknown). IM was stopped because of IM-resistance in 41% (n=29) of the patients, IM-intolerance in 40% (n=28), IM-intolerance + resistance in 19% (n=13) of the patients (6 patients unknown). None of the patients had been allotransplanted previously. Eleven % (n=6) of the patients had a high Hammersmith score (HS), 20% (n=11) an intermediate HS, and 69% (n=37) a low HS of evaluable patients (22 patients non evaluable). Sixty-one percent of the patients (n=46) had Dasatinib and 39% (n=30) had nilotinib as a first TKI2. The first TKI2 has been stopped for first TKI2 resistance (7 patients), intolerance (13 patients) and for resistance and intolerance (3 patients). Eleven patients went from Dasatinib to Nilotinib and 18 from Nilotinib to Dasatinib. The median follow-up after initiation of the first TKI2 is 4.5 (2.5-7) years. There was no difference in PWB, SWB, EWB, FWB, and FACT between Dasatinib and Nilotinib groups (p=0.56, 0.36, 0.53, 0.70, 0.66 respectively). Only one patient died, therefore the overall survival analysis was not relevant. Thirty-four patients (45%) failed the TKI2 treatment. We went on analysing the failure free survival [(FFS), failure defined as no hematologic or cytogenetic response, CHR, CCyR, PCyR MMR or MR4.5 loss, death, progression to AP/BC, definitive TKI2 cessation for resistance or intolerance, allogeneic stem cell transplantation]. Cox model analysis demonstrated that FFS was significantly longer in patients with a high FACT score since TKI2 initiation (median not reached for high FACT versus 28 months for low FACT score, p=0.02, see figure 1) and since CML diagnosis (median 161 months for high FACT versus 66 months for low FACT score, p=0.002; median 162 months for high FACT-total versus 87.5 months for low FACT-total score, p=0.012). In addition, the FFS since diagnosis was significantly better for patients with a high PWB score (median 161 months for high PWB versus 66 months for low PWB score, p=0.032). No difference in cytogenetic and molecular responses to TKI2 observed at 1 year have been influenced by any of the scores individually, or grouped (= FACT, FACT-total), neither the Morisky score. In conclusion, this prospective analysis performed on a large population of patients failing imatinib, on TKI2, demonstrated that maintaining a good QoL for these patients evaluated through the FACT scores, can effectively improve failure-free survival on these drugs, and this needs to be a matter of concern for improving the long-term follow-up and the compliance to treatments of such patients. Figure 1: FFS since TKI2 initiation according to the FACT questionnaire result (Patients have been split into 2 groups according to the median value of the score). Figure 1:. FFS since TKI2 initiation according to the FACT questionnaire result (Patients have been split into 2 groups according to the median value of the score). Disclosures Nicolini: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Roy:Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis, BMS, Pfizer: Honoraria. Legros:Novartis, BMS: Honoraria. Gardembas:BMS: Honoraria. Le Maux:BMS: Employment. Guinard-Azadian:BMS: Employment. Mohamed:BMS: Employment. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria.
- Published
- 2014
46. Hevylite® to Monitor Response to Therapy in Multiple Myeloma
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Marie-Odile Petillon, Lofti Benboubker, Marc Wetterwald, Mauricette Michallet, Philippe Rodon, Susanna Schraen, Claire Mathiot, Brigitte Onraed, Xavier Leleu, Lionel Karlin, Jean-Luc Faucompré, Brigitte Kolb, Bertrand Arnulf, Martine Escoffre-Barbe, Laurence Legros, Mourad Tiab, Sabine Brechignac, Bruno Royer, Margaret Macro, Cyrille Hulin, Olivier Decaux, Guillemette Fouquet, Jean-Gabriel Fuzibet, Jean-Paul Fermand, Laurent Garderet, Anne Banos, Thierry Facon, Hervé Avet-Loiseau, Denis Caillot, Murielle Roussel, Gerald Marit, Philippe Moreau, Mamoun Dib, Michel Attal, Anne-Marie Stoppa, and Brigitte Pegourie
- Subjects
Immunofixation ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,Myeloma protein ,business.industry ,Immunology ,Cell Biology ,Hematology ,Gel electrophoresis of proteins ,medicine.disease ,Pomalidomide ,Biochemistry ,Gastroenterology ,Measurable Disease ,Internal medicine ,Immunoassay ,medicine ,biology.protein ,Antibody ,business ,Multiple myeloma ,medicine.drug - Abstract
Background. Protein electrophoresis and immunofixation in the serum (SPEP - SIF) and urine (UPEP – UIF) have been routinely used for decades for characterizing and quantifying the M protein in Multiple Myeloma (MM). However, these techniques are notoriously tarnished with inaccuracy, despite improvements in recent years. The most important breakthrough in the field in recent years was the discovery of the Serum Free Light Chain Assay (sFLC), a routine quantitative and automated assay that measures kappa and lambda sFLC, however this was added to / rather than replaced traditional tests in the diagnostic armamentarium of MM. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to replace SPEP / IFE during MM patient monitoring Materials and methods. 110 Myeloma treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end stage RRMM and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille, France and results compared to traditional measurements. Along with SPEP, SIF, UPEP, UIF, and sFLC, we have also measured IgA HLC (IgA k and IgA l) and IgG (IgG k and IgG l) and the corresponding difference (clonal - non clonal) and ratio (clonal/non clonal). Results. Overall, 80% were measurable on SPEP with a median serum level of 31g/L (CI95% 19;42), and the remaining also had UPEP measurable myeloma with a median serum level of 0.66g/24h (CI95% 0.4;1.3). The median involved HLC level was 29.7g/L (CI95% 17.6;43.3), the median involved HLC difference clonal - non clonal was 28.8g/L (CI95% 15.6;42.7), the median involved HLC ratio clonal / non clonal was 51.9 (CI95% 18.3;203.9). Since all patients had a measurable intact immunoglobulin-based disease according to IMWG criteria, we have first confirmed that patients had also a measurable disease by HLC. All patients had an abnormal HLC ratio but one patient, who was measurable with an abnormal IgG L involved HLC test. Approximately 32% of patients had an M-spike below 20g/L and/or an electrophoretic migration in beta region meaning in the range of lack of sensitivity of the techniques used, all of whom had a measurable disease using involved HLC level and/or a measurable HLC ratio. We then sought to study the response rate according to HLC, and for that purpose we applied the exact same criteria as to the sFLC-based response criteria recommended by IMWG (e.g. normal ratio is CR and if abnormal ratio, then 90% reduction is VGPR). The ORR in the 2 studies as a whole using traditional measurements was 32%, including 29% PR rate, absence of CR, and 44% had SD (SD and MR). Using HLC, the ORR was 36%, including 26% PR rate and 4.0% CR, and 33% had SD (r² 0.823, p Conclusion. HLC is a new routine quantitative and automated assay that measures Immunoglobulin heavy chain/light chain pairs immunoassay, allowing diagnosis, prognosis and precise assessment of the response to treatment and disease progression in all cases with Myeloma treated with pomalidomide and dexamethasone in 2 different clinical trials. Our study indicates that HLC may be used as a replacement for traditional tests and may offer greater sensitivity in some instances. Furthermore, obviating the need for interpretation may standardize assessments of patients during trials. Future studies might confirm this data analysis in larger trials. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Hulin:Celgene: Honoraria. Stoppa:Celgene Jansen: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.
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- 2014
47. Dasatinib or Nilotinib Discontinuation in Chronic Phase (CP)-Chronic Myeloid Leukemia (CML) Patients (pts) with Durably Undetectable BCR-ABL Transcripts: Interim Analysis of the STOP 2G-TKI Study with a Minimum Follow-up of 12 Months – on Behalf of the French CML Group Filmc
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Franck E. Nicolini, Agnès Guerci, Michel Tulliez, Gabriel Etienne, Laurence Legros, Bruno Villemagne, Gaelle Guillerm, Francois-Xavier Mahon, Philippe Rousselot, Stephane Giraudier, Delphine Rea, Jean Michel Pignon, Valérie Coiteux, Martine Gardembas, Aude Charbonnier, Martine Escoffre, and François Guilhot
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medicine.medical_specialty ,Pediatrics ,business.industry ,Immunology ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,Interim analysis ,Biochemistry ,Discontinuation ,Dasatinib ,Risk groups ,Nilotinib ,Internal medicine ,Landmark analysis ,medicine ,business ,medicine.drug - Abstract
Background: Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL have revolutionized the prognosis of pts suffering from CML but these drugs are considered as non-definitively curative and current recommendation is to treat pts during their entire lifespan. However, prospective trials such as STIM, TWISTER and EUROSKI suggest that imatinib may be successfully stopped in pts with deep and sustained molecular responses. Here, we report on the feasibility of second generation TKIs discontinuation in the setting of the French STOP 2G-TKI study. Methods: Adult CP-CML pts on dasatinib or nilotinib first line or after imatinib without prior allogeneic transplantation or progression to advanced phase CML were proposed TKI discontinuation when presenting: (1) b2a2 or b3a2 BCR-ABL transcripts subtype, 2) TKI treatment duration for at least 36 months, (3) CMR4.5 achieved and maintained for at least 24 months. The primary objective was treatment-free survival without loss of major molecular response (MMR). After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 12 months, every 3 months during the 2ndyear and every 3 to 6 months thereafter. Molecular relapse was defined by MMR loss on a single occasion and triggered TKI reintroduction. Data as of August 1, 2014 are reported in pts with at least 12 months of follow-up (n=52) and median follow-up was 32 months (12-56). Results: Median age was 60 years (34-81) and 61.5% of pts were female. Sokal risk group was low in 58%, intermediate in 23%, high in 13% and unknown in 6%. 2G-TKIs were given after imatinib intolerance in 67% of pts, suboptimal response or resistance to imatinib in 23% and upfront in 10%. Median duration of CML, TKI treatment, 2G-TKI treatment and CMR4.5 was 83 months (36-218), 78 months (36-136), 39 months (19-72) and 28 months (24-64), respectively. Twenty four pts lost MMR after a median time of 4 months (1-38) at last follow-up. Importantly, no loss of CHR or progression to advanced phase CML was observed. The 12- and 24-month probabilities of treatment-free survival without MMR loss were 61.4% (95% CI, 48.1-74.6) and 57% (95% CI, 43.3-70.6), respectively. The majority of relapses occurred within 6 months and in a landmark analysis, pts who were still in MMR without therapy at 6 months had 12- and 24-month probabilities of treatment-free survival without MMR loss of 91.2% (95% CI, 81.6-100) and 84.7% (95% CI, 72.2-97.1), respectively. All pts but 1 who lost MMR restarted 2G-TKI treatment and regained MMR after a median time of 3 months (1-8). Pts in MMR without any therapy (n=28) displayed varying patterns of spontaneous molecular response including stable CMR4.5 in 7 and fluctuations between CMR4.5 and MR4.5, CMR4.5 and MR4, CMR4.5 and MMR in 9, 4 and 4 pts, respectively. Gender, age, prior interferon exposure, 2G-TKI type, treatment duration and duration of CMR4.5 were not found to have any impact on outcome. By contrast, prior history of suboptimal response or resistance to imatinib was associated with a significantly lower chance of successful treatment discontinuation, with a 12-month probability of treatment-free survival without MMR loss of 41.7% (95% CI; 13.8%-69.6%), compared to 67.3% (95% CI, 52.6%-81.8%) in other patients (p=0.04). Conclusions: 2G-TKI could be safely and successfully discontinued in CP-CML pts with long-lasting undetectable BCR-ABL transcripts, especially in those without prior history of suboptimal response or resistance. Most of molecular relapses had an early onset and all were sensitive to 2G-TKI resumption. The recurrence of low levels of detectable residual disease below MMR after 2G-TKI withdrawal did not automatically herald CML relapse and did not preclude the possibility to remain treatment-free. Disclosures Nicolini: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Rousselot:Novartis: Research Funding. Gardembas:BMS: Honoraria. Legros:Novartis, BMS: Honoraria. Etienne:Novartis, BMS,Pfizer, ARIAD Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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- 2014
48. Hevylite® to Monitor Hypogammaglobulinemia, a Predictor of Response to Therapy in Multiple Myeloma
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Jean-Gabriel Fuzibet, Marie Odile Petillon, Philippe Rodon, Marc Wetterwald, Claire Mathiot, Susanna Schraen, Guillemette Fouquet, Brigitte Kolb, Hervé Avet-Loiseau, Gerald Marit, Anne Banos, Mamoun Dib, Murielle Roussel, Olivier Decaux, Sabine Brechiniac, Xavier Leleu, Laurence Legros, Brigitte Onraed, Bruno Royer, Brigitte Pegourie, Mourad Tiab, Margaret Macro, Michel Attal, Anne-Marie Stoppa, Bertrand Arnulf, Lotfi Benboubker, Laurent Garderet, Martine Escoffre-Barbe, Philippe Moreau, Thierry Facon, Denis Caillot, Stephen E. Harding, Cyrille Hulin, Lionel Karlin, Jean-Luc Faucompré, and Jean Paul Fermand
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medicine.medical_specialty ,biology ,business.industry ,Myeloma protein ,medicine.medical_treatment ,Immunology ,Immunosuppression ,Cell Biology ,Hematology ,medicine.disease ,Pomalidomide ,Biochemistry ,Gastroenterology ,Isotype ,Hypogammaglobulinemia ,medicine.anatomical_structure ,Internal medicine ,medicine ,biology.protein ,Bone marrow ,Antibody ,business ,Multiple myeloma ,medicine.drug - Abstract
Background. The depth of Hypogammaglobulinemia has been related to adverse prognosis in myeloma for decades, but most importantly, it has been suggested that its recovery following treatment was associated with good outcome and prolonged survival. However, none of the traditional techniques has allowed a precise measurement of isotype-matched (i.e. concentrations of IgGκ in an IgGλ myeloma patient) hypogammaglobulinemia. Recently, a new test quantifying paired clonal and non-clonal immunoglobulins (heavy/light chains HLC i.e. IgGκ/IgGλ) in serum was developed. Here we aim to assess the new HLC assays as tools to measure Hypogammaglobulinemia, and potentially replace traditional techniques for the monitoring of patients with myeloma. Materials and methods. 107 (59 IgGκ, 29 IgGλ, 12 IgAκ, 7 IgAλ) myeloma patients treated with pomalidomide and dexamethasone in two IFM studies (IFM 2009-02 in end-stage RRMM, and IFM 2010-02 in del17p and t(4;14) RRMM ) were included. The criteria for selection were that patients had measurable intact immunoglobulin myeloma according to IMWG criteria (M spike ≥10g/L), using serum and/or urine protein electrophoresis, with exclusion of patients solely measurable on UPEP and sFLC. All sera were collected centrally before initiation of treatment and sequentially every cycle until progression. Hevylite® (HLC) was measured in the biology laboratory of CHRU of Lille (France). For each patient we have measured the clonal isotype HLC level, and the corresponding non-clonal paired isotype HLC level, e.g. for IgAκ myeloma, the IgAλ non-clonal paired isotype. (Normal ranges: IgGκ 3.84-12.07, IgGλ 1.91-6.74 and IgGκ/IgGλ 1.12-3.21; IgAκ 0.57-2.08, IgAλ 0.44-2.04 and IgAκ/IgAλ 0.78-1.94 g/L). Results. Overall, 98 (92%) patients had an abnormal suppressed uninvolved HLC level at baseline with suppression being more common in IgG than IgA patients (95% v 73%, p IgA 77%), meaning that the vast majority of patients had not recovered from hypogammaglobulinemia at the time of best response. The median uninvolved IgG and IgA HLC concentrations at baseline were 0.62 and 0.2 g/L respectively (range: 05-6.9; 0.01-5.6). At best, response levels reached were 0.53 and 0.24g/L respectively (0.01-5.6; 0.01-7.4). Interestingly, more patients had recovered in the IFM 2009-02 study compared to the IFM2010-02 study, essentially different in the number of prior lines of therapy (3 and 9, respectively). We then sought to understand the relationship with response to therapy. We noted that very few patients’ hypogammaglobulinemia levels normalized completely, nor did their uninvolved paired isotype HLC levels normalize. However, we found that 55% of responders (IMWG) had improved levels (by at least 20%) of the uninvolved paired isotype HLC compared to 18.5% of the non-responders (p=0.001). Similarly, an improvement of at least 50% in the levels of uninvolved paired isotype HLC was achieved by 35% of responders compared to 13% of non-responders, respectively (p=0.013); an improvement of 75% was reached by 22.5% of responders and 7.4% of non-responders (p=0.028). This data strongly correlated to the depth of response, since, for example, 75% of patients in VGPR or better had improved levels of uninvolved paired isotype HLC by 50% at the time of greatest response, compared to 31% for PR and 13% for SD (p=0.005). Similar correlations were seen for 20% (p Conclusion. The mechanism of immunosuppression in myeloma patients is poorly understood. Here we have shown for the first time that isotype-matched hypogammaglobulinemia correlates to depth of response. Hypogammaglobulinemia is important to assess not only because of its greater risk of infectious complications, often severe in myeloma, but also as it plays a predictive role in occurrence of response and more importantly depth of response. Future studies are needed to unravel the relationship between debulking of tumor cells and correction of hypogammaglobulinemia; in other words, is repopulating of the marrow with normal B cells associated to better outcome, and how does this affect the homeostasis of the bone marrow in its ability to support tumour cells. Disclosures Stoppa: Celgene Jansen: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.
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- 2014
49. Subcutaneous Bortezomib, Melphalan and Prednisone in Elderly Newly Diagnosed Multiple Myeloma Patients
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Charles Herbaux, Cristina M. Joao, Alexia Plocque, Valentine Richez, Francesca Gay, Loic Renaud, Laurence Legros, Laurent Garderet, Souhila Ikhlef, Brigitte Pegourie, Martine Escoffre-Barbe, Bruno Royer, Laurent Voillat, Cyrille Hulin, Anne Banos, Eric G. Voog, Lionel Karlin, Anne-Marie Stoppa, Lotfi Benboubker, Sonja Zweegman, Eva De Jongh, Niels Abildgaard, Katell Le Dû, Artur J. Jurczyszyn, Philippe Moreau, Thierry Facon, Denis Caillot, Evangelos Terpos, and Xavier Leleu
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Melphalan ,medicine.medical_specialty ,business.industry ,Bortezomib ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,Log-rank test ,Transplantation ,Regimen ,Prednisone ,Internal medicine ,medicine ,business ,Dexamethasone ,Multiple myeloma ,medicine.drug - Abstract
Background. Bortezomib-melphalan-prednisone (VMP) is a standard of care upfront in Multiple Myeloma (MM) ineligible for transplantation, where bortezomib was given twice weekly intra veinously. Based on the VISTA study, the median TTP was 24.0 months, the median OS 56.4 months, the ORR (IMWG) 71% and the CR rate 30%. This regimen was then improved with a weekly administration of bortezomib starting at cycle 1 (called Palumbo design) or cycle 2 (called Mateos design). In the once-weekly schedule, the median PFS was 33.1 months, the median OS was not reached, the ORR 85% and the CR rate 30%. Recently, subcutaneous bortezomib was approved in association to dexamethasone in relapsed MM that proved non-inferior to standard intravenous administration in terms of efficacy, with an improved safety profile, particularly with regard to the rate of neuropathy. As a consequence, physicians have switched to Bortezomib subcutaneous administration in the VMP regimen in many countries. We aimed to study the impact of subcutaneous bortezomib in the VMP regimen (VscMP) in elderly MM newly diagnosed (NDMM). Method. A total of 40 patients were recruited for the current study. Patients were required to be aged ≥65 years, NDMM treated with subcutaneous Bortezomib, Melphalan and Prednisone. Patients had VscMP either according to VISTA schedule or to Palumbo (weekly) schedule. Response rate was determined according to IMWG. All survival endpoints were evaluated using Kaplan-Meier estimates and compared with the log-rank test. Results. The median age was 79 years (range, 67 - 90), with 28 patients (70%) aged >75 and 18 patients (45%) aged >80. The m:f ratio was 1.2, 77% of the patients were ISS 2 or 3, 32% had an ECOG score ≥ 2, and 10% had adverse FISH (del17p and/or t(4;14)). 15 patients were treated in the VISTA schedule and 25 in the weekly schedule (Palumbo design). No patients have had Mateos design. For the cohort as a whole, the median TTP was 32 months, the median OS is not reached with 81% 5-years estimate, the ORR 75% and the CR rate 17,5%; that demonstrated that subcutaneous bortezomib is non-inferior to IV data reported in historical studies for the VMP regimen. Similarly, there was not much difference in terms of efficacy between patients that had bortezomib subcutaneous weekly versus twice a week: weekly: the median OS is not reached, the ORR 80% and the CR rate 13%; twice a week: the median OS is not reached, the ORR 84% and the CR rate 20%. With regards to the safety profile of VMP given with bortezomib subcutaneous, it seemed to offer an improved safety profile: 12.5% of grade 3 or 4 hematologic toxicity versus 47% in the literature. It does not seem to be any difference in neurological toxicity, with 5% of grade ≥2 peripheral neuropathy in our study, as to the VISTA study. Interestingly, we have seen no clear difference in terms of safety profile between the two schedule designs, VMP twice a week versus weekly using bortezomib sub cutaneous, which tend to confirm the improved safety profile of VMP with bortezomib used subcutaneously. Conclusion. The use of subcutaneous bortezomib in the standard of care bortezomib-melphalan-prednisone regimen in elderly MM newly diagnosed had comparable efficacy than the intravenous administration. Importantly, the subcutaneous administration is associated to improved safety profile in comparison with previously published data. This dataset might encourage the use of the twice weekly subcutaneous bortezomib in the VMP regimen for patients considered fit. Disclosures No relevant conflicts of interest to declare.
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- 2014
50. Characteristics and Outcomes of Unselected Adolescents and Young Adults Patients with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era
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Marc G. Berger, Pierre-Simon Rohrlich, Pascale Cony-Makhoul, Gabriel Etienne, Anne Corby, Mael Haiblig, Martine Escoffre-Barbe, Martine Gardembas, Stéphane Giraudier, Lydia Roy, Françoise Huguet, Laurence Legros, Agnès Guerci-Bresler, Valérie Coiteux, Delphine Rea, Stéphanie Bernardin, and Franck E. Nicolini
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Pediatrics ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Immunology ,Ponatinib ,Imatinib ,Cell Biology ,Hematology ,Biochemistry ,Chemotherapy regimen ,Tyrosine-kinase inhibitor ,Discontinuation ,Dasatinib ,chemistry.chemical_compound ,Nilotinib ,chemistry ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years (Hoglund M 2013). However, little is known about outcomes in CML in adolescents and young adults. In the literature there are few reports involving only patients enrolled in trials aged from 15 to 30 years (Cortes J 2012, Kalmanti L 2013). We report here the characteristics and outcomes in 78 unselected adolescents and young adults ranging from 18 to 25 years with newly diagnosed CML in chronic (n=73) or in accelerated phase (n=5) in the tyrosine kinase inhibitor (TKI) era from 13 Fi-LMC centers being in possession with local databases. The median follow-up is 56 months (0-144) after diagnosis. Sokal scores were low in 41 (56%) patients, intermediate in 10 (13%), and high in 13 (17%) and unknown in 9 (14%) patients. Five patients had a CCA/Ph+ but were in CP cytologically, at diagnosis. Initial TKI were imatinib alone (n=55) or in combination with IFN (n=3), nilotinib alone (n=5) or in combination (n=1), dasatinib alone (n=10) or in combination (n=1) or ponatinib (n=1). One patient died before treatment initiation from brain hemorrhage, and initial treatment is unknown in one patient. Only 38/76 (50%) of patients remained under TKI first-line at latest follow-up. The reasons of first-line discontinuation were blast crisis (n=3); according to ELN criteria, cytogenetic failures (n=10), molecular failures (n=5), molecular warnings (n=8), mutation (n=1); intolerance (n=6), FDA notification in EPIC study (n=1). The second-line therapies were imatinib (n=2), IFN in combination with aracytine (n=1), nilotinib (n=13), dasatinib (n=13), high-dose chemotherapy alone (n=1) or followed by allogeneic bone marrow transplantation (n=4). 13 patients discontinued their second line TKI for blastic transformations (n=2), cytogenetic failures (n=4), molecular failures (n=2), molecular warning (n=1), mutation (n=1) and intolerance (n=3). The third-line therapies were imatinib (n=1), nilotinib (n=2), dasatinib (n=5), ponatinib (n=1), chemotherapy alone (n=1), allo-transplantation (n=1). Only 25/78 (32%) of patients were included in a trial. Only one patient experimented a 4th line of TKI (ponatinib). We compared characteristics and outcome of the 2 groups of patients, enrolled in first line versus unenrolled (Table 1). There were significantly more men included than women. Accelerated phases and CCA/Ph+ were observed only in the unenrolled group. The overall survival is shown in Figure 1A. Blastic transformation, failure of TKI defined as ELN 2013 recommendations and death were used to calculate the EFS curve (Figure 1B). Finally, we designed a curve representing the probability to remain under first-line TKI: 2nd line TKI-Free Survival (Figure 1C). A complete analysis comparing characteristics and outcome between the 2 groups of patients, will be available for ASH presentation. Table 1: Characteristics of patients Total patients n=78 Enrolled patients n=24 Unenrolled patients n=54 P value Ratio H/F (n) 50/28 18/5 22/32 0.0025 Median age (years) 22 23 22 NS CCA/Ph+ (n) 5 0 5 - Phase (C/A) (n) 73/5 24/0 49/5 NS Sokal (L/I/H/U) (n) 41/10/13/9 16/2/5/1 25/8/8/8 NS Median FU (months) (Range) 56 (0-144) 41 (2-114) 63 (0-144) - Interval from D to 1st line TKI (days) 27 29 24 - 1st line TKI (I/N/D/P/NA)(n) 58/6/11/1/2 9/4/10/1/0 49/2/1/0/2 NS Median 1st line TKI duration (months) 27 26 28 - Discontinuations (n) 38 8 30 0.069 Discontinuation reasons (n) Blastic phase Cytogenetic failure Molecular failure Molecular warning Intolerance Pregnancy Sustained CMR FDA notification Mutation 3 10 5 8 6 2 2 1 1 0 3 3 0 0 0 1 1 0 3 7 2 8 6 2 1 0 1 TKI line Number (1/2/3/4)(n) 38/19/10/1 17/5/2/0 24/12/8/1 - Abbreviations: U unknown; FU follow up; D diagnosis; I imatinib; N Nilotinib; D dasatinib; P Ponatinib; TKI Tyrosine Kinase Inhibitor Figure 1: (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Figure 1:. (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Disclosures Nicolini: Novartis: Consultancy. Gardembas:BMS: Honoraria. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Guerci-Bresler:Novartis, BMS, Pfizer: Honoraria. Roy:Novartis: Honoraria; BMS: Honoraria. Legros:Novartis, BMS: Honoraria.
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- 2014
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