170 results on '"Martine Escoffre"'
Search Results
2. The initial molecular response predicts the deep molecular response but not treatment-free remission maintenance in a real-world chronic myeloid leukemia cohort
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Sandrine Saugues, Céline Lambert, Elisabeth Daguenet, Gabrielle Roth-Guepin, Françoise Huguet, Pascale Cony-Makhoul, Hyacinthe Johnson Ansah, Martine Escoffre-Barbe, Ali Turhan, Philippe Rousselot, Andreï Tchirkov, Dalil Hamroun, Eric Hermet, Bruno Pereira, and Marc G. Berger
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at months 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the ELTS score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs second generation TKI, 2G-TKI). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.
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- 2024
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3. P315: TP53 ALTERATIONS AND MRD REFINE PROGNOSIS OF ADULT KMT2A-REARRANGED B-ALL
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Rathana Kim, Hugo Bergugnat, Florence Pasquier, Emmanuel Raffoux, Lise Larcher, Marie Passet, Cedric Pastoret, Grardel Nathalie, Vahid Asnafi, Eric Delabesse, Aurélie Caye-Eude, Claus Meyer, Rolf Masrschalek, Anne Thiebaut-Bertrand, Marie Balsat, Martine Escoffre, Sabine Blum, Michael Baumann, Anne Banos, Nicole Straetmans, Maria Pilar Gallego Hernanz, Yves Chalandon, Carlos Graux, Thibaut Leguay, Mathilde Hunault, Françoise Huguet, Véronique Lhéritier, Jean Soulier, Nicolas Boissel, and Emmanuelle Clappier
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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4. P1407: REMOTE MONITORING OF CAR T-CELL TREATED PATIENTS BY A SPECIALIZED NURSE TO DETECT AND MANAGE LATE COMPLICATIONS: REPORT OF THE CARAMA PROGRAM
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Fanny Colin, Bellec Adeline, Laetitia Le Bars, Magali Granger, Sophie De Guibert, Guillaum Manson, Faustine Lhomme, Tony Marchand, Jean-Baptiste Mear, Martine Escoffre, Olivier Decaux, Thierry Lamy De La Chapelle, Roch Houot, and Aline Moignet
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Kinetics of early and late molecular recurrences after first-line imatinib cessation in chronic myeloid leukemia: updated results from the STIM2 trial
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Stéphanie Dulucq, Franck E. Nicolini, Delphine Rea, Pascale Cony-Makhoul, Aude Charbonnier, Martine Escoffre-Barbe, Valérie Coiteux, Pascal Lenain, Françoise Rigal-Huguet, Jixing Liu, Agnès Guerci-Bresler, Laurence Legros, Jean-Christophe Ianotto, Martine Gardembas, Pascal Turlure, Viviane Dubruille, Philippe Rousselot, Juliana Martiniuc, Henry Jardel, Hyacinthe Johnson-Ansah, Bertrand Joly, Tawfiq Henni, Emilie Cayssials, Patricia Zunic, Marc G. Berger, Bruno Villemagne, Fanny Robbesyn, Stephane Morisset, François-Xavier Mahon, and Gabriel Etienne
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% [36.3-50.4] at 5 years, 40.9% [32.8-47.3] at 7 years and 34.5% [25.6- 43.3] at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).
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- 2022
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6. High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL
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Aurelie Cabannes-Hamy, Eolia Brissot, Thibaut Leguay, Francoise Huguet, Patrice Chevallier, Mathilde Hunault, Martine Escoffre-Barbe, Thomas Cluzeau, Marie Balsat, Stephanie Nguyen, Florence Pasquier, Magda Alexis, Veronique Lheritier, Cedric Pastoret, Eric Delabesse, Emmanuelle Clappier, Herve Dombret, and Nicolas Boissel
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and
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- 2022
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7. Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia
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Hyacinthe Johnson-Ansah, Benjamin Maneglier, Françoise Huguet, Laurence Legros, Martine Escoffre-Barbe, Martine Gardembas, Pascale Cony-Makhoul, Valérie Coiteux, Laurent Sutton, Wajed Abarah, Camille Pouaty, Jean-Michel Pignon, Bachra Choufi, Sorin Visanica, Bénédicte Deau, Laure Morisset, Emilie Cayssials, Mathieu Molimard, Stéphane Bouchet, François-Xavier Mahon, Franck Nicolini, Philippe Aegerter, Jean-Michel Cayuela, Marc Delord, Heriberto Bruzzoni-Giovanelli, and Philippe Rousselot
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imatinib ,therapeutic drug monitoring ,chronic myelogenous leukemia ,Pharmacy and materia medica ,RS1-441 - Abstract
The registered dose for imatinib is 400 mg/d, despite high inter-patient variability in imatinib plasmatic exposure. Therapeutic drug monitoring (TDM) is routinely used to maximize a drug’s efficacy or tolerance. We decided to conduct a prospective randomized trial (OPTIM-imatinib trial) to assess the value of TDM in patients with chronic phase chronic myelogenous treated with imatinib as first-line therapy (NCT02896842). Eligible patients started imatinib at 400 mg daily, followed by imatinib [C]min assessment. Patients considered underdosed ([C]min < 1000 ng/mL) were randomized in a dose-increase strategy aiming to reach the threshold of 1000 ng/mL (TDM arm) versus standard imatinib management (control arm). Patients with [C]min levels ≥ 1000 ng/mL were treated following current European Leukemia Net recommendations (observational arm). The primary endpoint was the rate of major molecular response (MMR, BCR::ABL1IS ≤ 0.1%) at 12 months. Out of 133 evaluable patients on imatinib 400 mg daily, 86 patients had a [C]min < 1000 ng/mL and were randomized. The TDM strategy resulted in a significant increase in [C]min values with a mean imatinib daily dose of 603 mg daily. Patients included in the TDM arm had a 12-month MMR rate of 67% (95% CI, 51–81) compared to 39% (95% CI, 24–55) for the control arm (p = 0.017). This early advantage persisted over the 3-year study period, in which we considered imatinib cessation as a censoring event. Imatinib TDM was feasible and significantly improved the 12-month MMR rate. This early advantage may be beneficial for patients without easy access to second-line TKIs.
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- 2022
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8. Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase Chronic Myelogenous Leukemia patients
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Gaëlle Fossard, Emilie Blond, Marie Balsat, Stéphane Morisset, Stéphane Giraudier, Martine Escoffre-Barbe, Hélène Labussière-Wallet, Maël Heiblig, Arthur Bert, Madeleine Etienne, Jocelyne Drai, Mohamad Sobh, Isabelle Redonnet-Vernhet, Jean-Christophe Lega, François-Xavier Mahon, Gabriel Etienne, and Franck Emmanuel Nicolini
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2016
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9. Health-related quality-of-life in patients with newly diagnosed multiple myeloma in the FIRST trial: lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide
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Michel Delforge, Leonard Minuk, Jean-Claude Eisenmann, Bertrand Arnulf, Letizia Canepa, Alberto Fragasso, Serge Leyvraz, Christian Langer, Yousef Ezaydi, Dan T. Vogl, Pilar Giraldo-Castellano, Sung-Soo Yoon, Charles Zarnitsky, Martine Escoffre-Barbe, Bernard Lemieux, Kevin Song, Nizar Jacques Bahlis, Shien Guo, Mara Silva Monzini, Annette Ervin-Haynes, Vanessa Houck, and Thierry Facon
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
We compared the health-related quality-of-life of patients with newly diagnosed multiple myeloma aged over 65 years or transplant-ineligible in the pivotal, phase III FIRST trial. Patients received: i) continuous lenalidomide and low-dose dexamethasone until disease progression; ii) fixed cycles of lenalidomide and low-dose dexamethasone for 18 months; or iii) fixed cycles of melphalan, prednisone, thalidomide for 18 months. Data were collected using the validated questionnaires (QLQ-MY20, QLQ-C30, and EQ-5D). The analysis focused on the EQ-5D utility value and six domains pre-selected for their perceived clinical relevance. Lenalidomide and low-dose dexamethasone, and melphalan, prednisone, thalidomide improved patients’ health-related quality-of-life from baseline over the duration of the study across all pre-selected domains of the QLQ-C30 and EQ-5D. In the QLQ-MY20, lenalidomide and low-dose dexamethasone demonstrated a significantly greater reduction in the Disease Symptoms domain compared with melphalan, prednisone, thalidomide at Month 3, and significantly lower scores for QLQ-MY20 Side Effects of Treatment at all post-baseline assessments except Month 18. Linear mixed-model repeated-measures analyses confirmed the results observed in the cross-sectional analysis. Continuous lenalidomide and low-dose dexamethasone delays disease progression versus melphalan, prednisone, thalidomide and has been associated with a clinically meaningful improvement in health-related quality-of-life. These results further establish continuous lenalidomide and low-dose dexamethasone as a new standard of care for initial therapy of myeloma by demonstrating superior health-related quality-of-life during treatment, compared with melphalan, prednisone, thalidomide.
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- 2015
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10. A randomized study of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in elderly patients with acute lymphoblastic leukemia: the GRAALL-SA1 study
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Mathilde Hunault-Berger, Thibaut Leguay, Xavier Thomas, Ollivier Legrand, Françoise Huguet, Caroline Bonmati, Martine Escoffre-Barbe, Laurence Legros, Pascal Turlure, Patrice Chevallier, Fabrice Larosa, Frederic Garban, Oumedaly Reman, Philippe Rousselot, Nathalie Dhédin, André Delannoy, Marina Lafage-Pochitaloff, Marie Christine Béné, Norbert Ifrah, and Hervé Dombret
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Background The prognosis of acute lymphoblastic leukemia in the elderly is poor. The GRAALL-SA1 phase II, randomized trial compared the efficacy and toxicity of pegylated liposomal doxorubicin versus continuous-infusion doxorubicin in patients 55 years or older with Philadelphia chromosome-negative acute lymphoblastic leukemia.Design and Methods Sixty patients received either continuous-infusion doxorubicin (12 mg/m2/day) and continuous-infusion vincristine (0.4 mg/day) on days 1–4 or pegylated liposomal doxorubicin (40 mg/m2) and standard vincristine (2 mg) on day 1, accompanied by dexamethasone, followed at day 28 by a second cycle, reinforced by cyclophosphamide. End-points were safety, outcome and prognostic factors.Results Myelosuppression was reduced in the pegylated liposomal doxorubicin arm with shorter severe neutropenia (P=0.05), shorter severe thrombocytopenia (P=0.03), and fewer red blood cell transfusions (P=0.04). Grade 3/4 infections and Gram-negative bacteremia were reduced in the pegylated liposomal doxorubicin arm (P=0.04 and P=0.02, respectively). There was a trend towards fewer cardiac events among the patients who received pegylated liposomal doxorubicin (1/29 versus 6/31). The complete remission rate was 82% and, with a median follow-up of 4 years, median event-free survival and overall survival were 9 and 10 months, respectively. Despite the better tolerance of pegylated liposomal doxorubicin, no differences in survival were observed between the two arms, due to trends towards more induction refractoriness (17 versus 3%, P=0.10) and a higher cumulative incidence of relapse (52% versus 32% at 2 years, P=0.20) in the pegylated liposomal doxorubicin arm.Conclusions With the drug schedules used in this study, pegylated liposomal doxorubicin did not improve the outcome of elderly patients with acute lymphoblastic leukemia despite reduced toxicities.
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- 2011
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11. Interlaboratory development and validation of a HRM method applied to the detection of JAK2 exon 12 mutations in polycythemia vera patients.
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Valerie Ugo, Sylvie Tondeur, Marie-Laurence Menot, Nadine Bonnin, Gerald Le Gac, Carole Tonetti, Veronique Mansat-De Mas, Lydie Lecucq, Jean-Jacques Kiladjian, Christine Chomienne, Christine Dosquet, Nathalie Parquet, Luc Darnige, Marc Porneuf, Martine Escoffre-Barbe, Stephane Giraudier, Eric Delabesse, Bruno Cassinat, and French Intergroup of Myeloproliferative disorders
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Medicine ,Science - Abstract
BACKGROUND: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary. METHODS/FINDINGS: For these reasons we have defined the conditions of a High Resolution DNA Melting curve analysis (HRM) method able to detect JAK2 exon 12 mutations. After having validated that the method was able to detect mutated patients, we have verified that it gave reproducible results in repeated experiments, on DNA extracted from either total blood or purified granulocytes. This HRM assay was further validated using 8 samples bearing different mutant sequences in 4 different laboratories, on 3 different instruments. CONCLUSION: The assay we have developed is thus a valid method, adapted to routine detection of JAK2 exon 12 mutations with highly reproducible results.
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- 2010
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12. Low Non Relapse Mortality and Good Hematological Response after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma Patients with Renal Insufficiency at Transplant: A Prospective Société Francaise De Greffe De Moelle-Thérapie Cellulaire Observational Study
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Laurent Garderet, Hafida Ouldjeriouat, Mohamed-Amine Bekadja, Elisabeth Daguenet, Laure Vincent, Damien Roos Weil, Marguerite Vignon, Mohamad Mohty, Julie Abraham, Martine Escoffre-Barbe, Bruno Lioure, redhouane Ahmed Nacer, Denis Caillot, Clara Mariette, Lionel Karlin, Pierre Morel, Lila Gilis, Emanuelle Leray, Anaise Blouet, Nicole Raus, Marie Robin, jean Jacques Boffa, Pierre Ronco, Marie Thérèse Rubio, Jerome Lambert, and Jérôme Cornillon
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. 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
14. 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
15. Efficacy and safety of nilotinib in chronic myeloid leukaemia patients who failed to achieve a treatment‐free remission period after imatinib discontinuation: Results of the French Nilo post‐ <scp>STIM</scp> study
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Stéphanie Dulucq, Françoise Rigal‐Huguet, Franck E. Nicolini, Pascale Cony‐Makhoul, Martine Escoffre‐Barbe, Martine Gardembas, Laurence Legros, Philippe Rousselot, Jixing Liu, Delphine Rea, Véronique De Mas, Sandrine Hayette, Sophie Raynaud, Caroline Lacoste‐Roussillon, Fanny Robbesyn, Emilie Klein, Stéphane Morisset, François‐Xavier Mahon, and Gabriel Etienne
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Hematology - Published
- 2023
16. Supplementary Data from Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients
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François-Xavier Mahon, Gabriel Etienne, Joëlle Guilhot, Fabrice Larosa, François Guilhot, Emilie Cayssials, Marc G. Berger, Bruno Villemagne, Tawfiq Henni, Patricia Zunic, Bertrand Joly, Henry Jardel, Juliana Martiniuc, Hyacinthe Johnson-Ansah, Pascal Turlure, Jean-Christophe Ianotto, Martine Gardembas, Jixing Liu, Laurence Legros, Agnès Guerci-Bresler, Delphine Rea, Philippe Rousselot, Pascal Lenain, Viviane Dubruille, Bruno Varet, Valérie Coiteux, Françoise Rigal-Huguet, Martine Escoffre-Barbe, Aude Charbonnier, Pascale Cony-Makhoul, Lisa Boureau, Stéphanie Dulucq, and Franck Emmanuel Nicolini
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Supplemental table 1: Sequence of hydrolysis probes and primers used for the ddPCR.
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- 2023
17. Data from Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients
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François-Xavier Mahon, Gabriel Etienne, Joëlle Guilhot, Fabrice Larosa, François Guilhot, Emilie Cayssials, Marc G. Berger, Bruno Villemagne, Tawfiq Henni, Patricia Zunic, Bertrand Joly, Henry Jardel, Juliana Martiniuc, Hyacinthe Johnson-Ansah, Pascal Turlure, Jean-Christophe Ianotto, Martine Gardembas, Jixing Liu, Laurence Legros, Agnès Guerci-Bresler, Delphine Rea, Philippe Rousselot, Pascal Lenain, Viviane Dubruille, Bruno Varet, Valérie Coiteux, Françoise Rigal-Huguet, Martine Escoffre-Barbe, Aude Charbonnier, Pascale Cony-Makhoul, Lisa Boureau, Stéphanie Dulucq, and Franck Emmanuel Nicolini
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Purpose:Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.Patients and Methods:We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.Results:A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively.Conclusions:We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.See related commentary by Yan et al., p. 6561
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- 2023
18. Pomalidomide and dexamethasone until progression after first salvage therapy in multiple myeloma
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Laurent Garderet, Frederique Kuhnowski, Benoit Berge, Murielle Roussel, Laure Devlamynck, Marie Odile Petillon, Martine Escoffre‐Barbe, Ingrid Lafon, Thierry Facon, Xavier Leleu, Lionel Karlin, Aurore Perrot, Anne‐Marie Stoppa, Bruno Royer, Carine Chaleteix, Mourad Tiab, Carla Araujo, Pascal Lenain, Margaret Macro, Karim Belhadj, Souhila Ikhlef, Cyrille Hulin, Herve Avet Loiseau, Michel Attal, and Philippe Moreau
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Hematology - Published
- 2023
19. 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
20. Dasatinib plus Peg-Interferon alpha 2b combination in newly diagnosed chronic phase chronic myeloid leukaemia: Results of a multicenter phase 2 study (DASA-PegIFN study)
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Lydia, Roy, Jean-Claude, Chomel, Joëlle, Guilhot, Agnès, Guerci-Bresler, Martine, Escoffre-Barbe, Stéphane, Giraudier, Aude, Charbonnier, Viviane, Dubruille, Françoise, Huguet, Hyacinthe, Johnson-Ansah, Pascal, Lenain, Shanti, Ame, Gabriel, Etienne, Franck E, Nicolini, Delphine, Rea, Pascale, Cony-Makhoul, Stéphane, Courby, Jean-Christophe, Ianotto, Laurence, Legros, Antoine, Machet, Valérie, Coiteux, Eric, Hermet, Emilie, Cayssials, Stéphane, Bouchet, Francois-Xavier, Mahon, Philippe, Rousselot, and François, Guilhot
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Hematology - Abstract
Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR
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- 2022
21. First-line second generation tyrosine kinase inhibitors in patients with newly diagnosed accelerated phase chronic myeloid leukemia
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Marie Balsat, Vincent Alcazer, Gabriel Etienne, Françoise Huguet, Marc Berger, Emilie Cayssials, Aude Charbonnier, Martine Escoffre-Barbe, Hyacinthe Johnson-Ansah, Laurence Legros, Lydia Roy, Alain Delmer, Jean-Christophe Ianotto, Corentin Orvain, Fabrice Larosa, Mathieu Meunier, Shanti Amé, Annalisa Andreoli, Pascale Cony-Makhoul, Stéphane Morisset, Isabelle Tigaud, Delphine Rea, and Franck Emmanuel Nicolini
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Cancer Research ,Oncology ,Hematology - Published
- 2023
22. 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
23. Health-related quality of life results from the IFM 2009 trial: treatment with lenalidomide, bortezomib, and dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma
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Philippe Moreau, Benjamin Hebraud, Margaret Macro, Josh Weng, Aurore Perrot, Bertrand Arnulf, Sujith Dhanasiri, Denis Caillot, Karim Belhadj, Murielle Roussel, Michel Attal, Cyrille Hulin, Anne-Marie Stoppa, Martine Escoffre, Thierry Facon, Shien Guo, Laurent Garderet, Xavier Leleu, and Lionel Karlin
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Oncology ,Cancer Research ,medicine.medical_specialty ,Newly diagnosed ,Transplantation, Autologous ,Dexamethasone ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Quality of life ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Lenalidomide ,Multiple myeloma ,Health related quality of life ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,humanities ,Treatment Outcome ,030220 oncology & carcinogenesis ,Quality of Life ,Multiple Myeloma ,business ,030215 immunology ,medicine.drug - Abstract
The Intergroupe Francophone du Myelome 2009 trial (NCT01191060) assessed health-related quality of life (HRQoL) in patients with newly diagnosed multiple myeloma (NDMM) receiving lenalidomide/bortezomib/dexamethasone (RVd) induction therapy followed by consolidation therapy with either autologous stem cell transplantation (ASCT) plus RVd (RVd-ASCT) or RVd-alone; both groups then received lenalidomide maintenance therapy for 1 year. Global HRQoL, physical functioning, and role functioning scores significantly improved for both cohorts from baseline to the end of consolidation and were sustained during maintenance and follow-up, with clinically meaningful changes (RVd-alone
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- 2020
24. Recommandations du France Intergroupe des leucémies myéloïdes chroniques (Fi-LMC) pour l’examen des mutations du domaine kinase de BCR-ABL1 dans la leucémie myéloïde chronique
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Franck-Emmanuel Nicolini, Frédéric Millot, Delphine Réa, Gabriel Etienne, Stéphanie Dulucq, Valérie Coiteux, Jean-Claude Chomel, Olivier Nibourel, Pascaline Etancelin, Martine Escoffre-Barbe, Jean-Michel Cayuela, and Sandrine Hayette
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Myeloid leukemia ,Context (language use) ,Hematology ,General Medicine ,Disease ,03 medical and health sciences ,Bcr abl1 ,030104 developmental biology ,0302 clinical medicine ,Protein kinase domain ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Mutation (genetic algorithm) ,Mutation testing ,Medicine ,Radiology, Nuclear Medicine and imaging ,business ,Tyrosine kinase - Abstract
In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.
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- 2020
25. Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients
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Tawfiq Henni, Aude Charbonnier, Martine Escoffre-Barbe, Pascal Turlure, Franck E. Nicolini, Emilie Cayssials, Marc G. Berger, Agnès Guerci-Bresler, Pascale Cony-Makhoul, Juliana Martiniuc, François Guilhot, Jixing Liu, Joelle Guilhot, Gabriel Etienne, Jean-Christophe Ianotto, Patricia Zunic, Bruno Villemagne, Fabrice Larosa, Viviane Dubruille, Lisa Boureau, Henry Jardel, Philippe Rousselot, Laurence Legros, Françoise Rigal-Huguet, Stéphanie Dulucq, Bertrand Joly, Delphine Rea, Martine Gardembas, Francois-Xavier Mahon, Pascal Lenain, Hyacinthe Johnson-Ansah, Valérie Coiteux, Bruno Varet, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,medicine.drug_class ,Fusion Proteins, bcr-abl ,Phases of clinical research ,Drug Administration Schedule ,Article ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Prospective cohort study ,Protein Kinase Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Survival analysis ,Aged ,Gene Expression Regulation, Leukemic ,business.industry ,Remission Induction ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Imatinib ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Confidence interval ,3. Good health ,Discontinuation ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Female ,Neoplasm Recurrence, Local ,business ,030215 immunology ,medicine.drug ,Chronic myelogenous leukemia - Abstract
Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation. Patients and Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML. Results: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively. Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML. See related commentary by Yan et al., p. 6561
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- 2019
26. 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
27. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial
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Matthijs Westerman, Bertrand Arnulf, Frédérique Kuhnowski, Tahamtan Ahmadi, Annemiek Broijl, Lotfi Benboubker, Marie-Christiane Vekemans, Sonja Zweegman, Xavier Leleu, Maria Krevvata, Cyrille Touzeau, Veronique Vanquickelberghe, Hélène Caillon, Denis Caillot, Ke Zhang, Soraya Wuilleme, Pieter Sonneveld, Michel Delforge, Mark-David Levin, Jean-Richard Eveillard, Jill Corre, Aurore Perrot, Philippe Moreau, Mohamad Mohty, Nathalie Meuleman, Anne-Marie Stoppa, Jessica Vermeulen, Kon-Siong Jie, Saskia K. Klein, Tobias Kampfenkel, Fritz Offner, Thierry Facon, Hervé Avet-Loiseau, Chantal Doyen, Frédérique Orsini-Piocelle, Cécile Sonntag, Murielle Roussel, Carla de Boer, Jean-Pierre Marolleau, Reda Garidi, Thomas Dejoie, Mourad Tiab, Cyrille Hulin, Lionel Karlin, Margaret Macro, Jean Fontan, Sanjay Vara, Jérôme J. Lambert, Niels W.C.J. van de Donk, Marie C. Béné, Martine Escoffre-Barbe, Karim Belhadj, Hematology, CCA - Cancer Treatment and quality of life, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Service d'hématologie, and UCL - (SLuc) Service d'hématologie
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Population ,Transplantation, Autologous ,Dexamethasone ,Drug Administration Schedule ,Maintenance Chemotherapy ,Bortezomib ,Young Adult ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Medicine ,Data monitoring committee ,Humans ,education ,Multiple myeloma ,Aged ,education.field_of_study ,business.industry ,Hazard ratio ,Daratumumab ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Interim analysis ,Progression-Free Survival ,Thalidomide ,Europe ,Oncology ,Female ,business ,Multiple Myeloma ,medicine.drug ,Stem Cell Transplantation - Abstract
Background: CASSIOPEIA part 1 showed superior depth of response and significantly improved progression-free survival with daratumumab, bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) as induction and consolidation in patients with autologous stem-cell transplant (ASCT)-eligible newly diagnosed multiple myeloma. In part 2, we compared daratumumab maintenance versus observation only. Methods: CASSIOPEIA is a two-part, open-label, randomised, phase 3 trial of patients aged 18–65 years with newly diagnosed multiple myeloma and Eastern Cooperative Oncology Group performance status 0–2, done in 111 European academic and community practice centres. In part 1, patients were randomly assigned (1:1) to induction and consolidation with D-VTd or VTd. Patients still on study who had a partial response or better were randomly assigned (1:1) by an interactive web-response system to daratumumab 16 mg/kg intravenously every 8 weeks (a reduced frequency compared with standard daratumumab long-term dosing) or observation only for up to 2 years. Stratification factors were induction treatment and depth of response in part 1. The part 2 primary endpoint was progression-free survival from second randomisation. This preplanned interim analysis of progression-free survival was done after 281 events and shall be considered the primary analysis of progression-free survival. Sponsor personnel and designees who were involved in the analysis were masked to treatment group until the independent data monitoring committee recommended that the preplanned interim analysis be considered the main analysis of progression-free survival in part 2. Otherwise, treatment assignments were unmasked. The interaction between induction and consolidation and maintenance was tested at a two-sided significance level of 0·05 by a stratified Cox regression model that included the interaction term between maintenance treatment and induction and consolidation treatment. Efficacy analyses were done in the maintenance-specific intention-to-treat population, which comprised all patients who underwent second randomisation. Safety was analysed in all patients in the daratumumab group who received at least one dose and all patients randomly assigned to observation only. This trial is registered with ClinicalTrials.gov, NCT02541383. Long-term follow-up is ongoing and the trial is closed to new participants. Findings: Between May 30, 2016, and June 18, 2018, 886 patients (458 [84%] of 543 in the D-VTd group and 428 [79%] of 542 in the VTd group) were randomly assigned to daratumumab maintenance (n=442) or observation only (n=444). At a median follow-up of 35·4 months (IQR 30·2–39·9) from second randomisation, median progression-free survival was not reached (95% CI not evaluable [NE]–NE) with daratumumab versus 46·7 months (40·0–NE) with observation only (hazard ratio 0·53, 95% CI 0·42–0·68, p
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- 2021
28. High tumor burden before blinatumomab has a negative impact on the outcome of adult patients with B-cell precursor acute lymphoblastic leukemia. A real-world study by the GRAALL
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Aurelie Cabannes-Hamy, Eolia Brissot, Thibaut Leguay, Francoise Huguet, Patrice Chevallier, Mathilde Hunault, Martine Escoffre-Barbe, Thomas Cluzeau, Marie Balsat, Stephanie Nguyen, Florence Pasquier, Magda Alexis, Veronique Lheritier, Cedric Pastoret, Eric Delabesse, Emmanuelle Clappier, Herve Dombret, and Nicolas Boissel
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Adult ,Lymphoma, B-Cell ,Neoplasm, Residual ,Antineoplastic Agents ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Burkitt Lymphoma ,Tumor Burden ,body regions ,Recurrence ,hemic and lymphatic diseases ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Antibodies, Bispecific ,Humans ,Retrospective Studies - Abstract
Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD (n=35) or at relapse (n=38). Among MRD patients, 91% had MRD >0.01% before blinatumomab, and 89% achieved complete MRD response after blinatumomab. High pre-blinatumomab MRD levels were associated with shorter relapse-free survival (P=0.049) and overall survival (OS) (P=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between MRD 0.1- 1% and
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- 2021
29. Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients
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Martine Escoffre-Barbe, P. Rousselot, Pascale Cony-Makhoul, Stéphane Bouchet, Lambert Busque, Caroline Dartigeas, Franck E. Nicolini, Valérie Coiteux, Françoise Huguet, Laurence Legros, Lydia Roy, Delphine Rea, François Guilhot, Joelle Guilhot, Emilie Cayssials, Francois-Xavier Mahon, Luigina Mollica, Agnès Guerci, Martine Gardembas, Jean-Michel Cayuela, Anne Bergeron, Gabriel Etienne, Viviane Dubruille, Aude Charbonnier, Mathieu Molimard, Centre Hospitalier de Versailles André Mignot (CHV), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hôpital Maisonneuve-Rosemont, 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), Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Léon Bérard [Lyon], Institut Bergonié [Bordeaux], UNICANCER, Hôpital Paul Brousse, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Hôpital Claude Huriez [Lille], CHU Lille, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherche clinique appliquée à l'hématologie (URP_3518), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux Ségalen [Bordeaux 2], CHU de Bordeaux Pellegrin [Bordeaux], Bristol-Myers Squibb, CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, 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 Paris Cité (UPCité), 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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Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Pleural effusion ,Dasatinib ,Antineoplastic Agents ,Gastroenterology ,Tyrosine-kinase inhibitor ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,hemic and lymphatic diseases ,Clinical endpoint ,Humans ,Medicine ,Cumulative incidence ,Prospective Studies ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,030304 developmental biology ,Aged, 80 and over ,Pharmacology ,0303 health sciences ,Dose-Response Relationship, Drug ,medicine.diagnostic_test ,business.industry ,Tyrosine kinases ,Hematology ,Middle Aged ,medicine.disease ,Effective dose (pharmacology) ,3. Good health ,Pleural Effusion ,Treatment Outcome ,Therapeutic drug monitoring ,030220 oncology & carcinogenesis ,Chronic leukaemia ,Female ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Drug Monitoring ,business ,medicine.drug - Abstract
International audience; Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
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- 2021
30. Longer treatment duration and history of osteoarticular symptoms predispose to tyrosine kinase inhibitor withdrawal syndrome
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Sandrine Saugues, Joelle Guilhot, Céline Lambert, Bruno Pereira, Susanne Saussele, Franck-Emmanuel Nicolini, Laurence Legros, Martine Escoffre-Barbe, Agnès Guerci-Bresler, Delphine Rea, Philippe Rousselot, Marc G. Berger, Martine Gardembas, Stéphane Giraudier, Pascale Cony-Makhoul, Francois-Xavier Mahon, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
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Male ,medicine.medical_specialty ,Time Factors ,medicine.drug_class ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Osteoarthritis ,Pharmacovigilance ,medicine ,Humans ,Protein Kinase Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Aged ,Duration of Therapy ,business.industry ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Imatinib ,Hematology ,Middle Aged ,respiratory tract diseases ,3. Good health ,Discontinuation ,Dasatinib ,Nilotinib ,030220 oncology & carcinogenesis ,Relative risk ,Female ,business ,Tyrosine kinase ,030215 immunology ,medicine.drug - Abstract
The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO-SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO-SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02-2·74)] with a 93-month cut-off time, and history of osteoarticular symptoms [RR = 1·84 (1·04-3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre-existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.
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- 2019
31. Prognostic value of involved/uninvolved free light chain ratio determined by Freelite and N Latex FLC assays for identification of high-risk smoldering myeloma patients
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Hervé Avet-Loiseau, Caroline Moreau, Stephane Minvielle, Claude Bendavid, Basile Henriot, Olivier Decaux, Chloé Rousseau, Martine Escoffre, Martine Sebillot, Emmanuel Rouger, CHU Pontchaillou [Rennes], Nutrition, Métabolismes et Cancer (NuMeCan), 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)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), 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), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), 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), Jonchère, Laurent, and 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)
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Male ,[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Prognostic factor ,Clinical Biochemistry ,Paraproteinemias ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Asymptomatic ,Cohort Studies ,Immunoglobulin kappa-Chains ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Risk Factors ,high-risk ,Serum free ,Internal medicine ,medicine ,Humans ,smoldering multiple myeloma ,Multiple myeloma ,Aged ,free light chains ,business.industry ,Biochemistry (medical) ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Free Light Chain ,Predictive value ,3. Good health ,myeloma ,030104 developmental biology ,030220 oncology & carcinogenesis ,Plasma cell disorder ,Disease Progression ,Female ,Immunoglobulin Light Chains ,medicine.symptom ,Multiple Myeloma ,business - Abstract
Background Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder with a high risk of progression to symptomatic multiple myeloma (MM). The serum free light chain (sFLC) ratio is a powerful prognostic factor for SMM: an sFLC ratio ≥8 has been reported to be associated with a high risk of progression to MM, and an sFLC ratio ≥100 has been described as a criterion for ultra-high-risk SMM, and has been integrated into the definition criteria for MM since 2014. However, all recommendations were based on sFLC measured using the first commercialized assay, Freelite™, while other assays are now available. We aimed to evaluate the safety and accuracy of N-Latex sFLC to identify high-risk and ultra-high-risk SMM. Methods The sFLC ratio was measured at diagnosis with both Freelite and N-Latex assays in a cohort of 176 SMM patients on a BN Prospec nephelometer. Demographic, clinical, therapeutic and laboratory data were collected at the time of diagnosis and at follow-up. Results Sixty-two patients (35.2%) progressed to MM within 2 years. Compared to Freelite™ sFLC, N Latex sFLC ratios ≥8 and ≥100 provided similar performances for the identification of high-risk and ultra-high risk SMM patients. Conclusions Our results evidenced that the N-Latex assay could be used for SMM monitoring, like Freelite. However, an N-Latex sFLC ratio ≥70 appears to provide similar performances to a Freelite sFLC ratio ≥100, with a slightly better positive predictive value. Both assays provided accurate identification of high-risk and ultra-high risk SMM patients. These results should be confirmed in an independent study.
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- 2019
32. Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial
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Véronique Dorvaux, Marc Delord, Marc Muller, Melanie Mercier, Hacene Zerazhi, Jacques Chapiro, Eric Jourdan, Laurence Legros, Françoise Rigal-Huguet, Iona Vaida, François Guilhot, Alberto Santagostino, Claude Preudhomme, Joelle Guilhot, Valérie Coiteux, Jean-Michel Miclea, Jean-Jacques Kiladjian, Emmanuel Gyan, Aude Charbonnier, Amélie Penot, Eric Deconinck, Franck E. Nicolini, Gabriel Etienne, Hyacinthe Johnson-Ansah, Jean-Claude Chomel, Kamel Ghomari, Nathalie Cambier, Delphine Lebon, Viviane Dubruille, Sylvie Glaisner, Philippe Rousselot, Loïc Fouillard, Alain Delmer, Bertrand Joly, Pascal Lenain, Claude-Eric Bulabois, Martine Escoffre Barbe, Christian Berthou, Isabelle Plantier, Delphine Rea, Marc G. Berger, Magda Alexis, Francois-Xavier Mahon, Pascale Cony-Makhoul, Ludovic Lhermitte, Lydia Roy, Jean-Michel Cayuela, Denis Caillot, Anne Vekhoff, Martine Gardembas, Bertrand Pollet, Agnès-Paule Guerci-Bresler, Yazid Arkam, Hervé Maisonneuve, Frédéric Maloisel, Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), and Université Clermont Auvergne (UCA)
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Chronic myeloid leukaemia ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Interferon ,Internal medicine ,Medicine ,Adverse effect ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Imatinib ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Hematology ,3. Good health ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Major Molecular Response ,Pegylated interferon alpha 2a ,Toxicity ,Cytarabine ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,medicine.drug - Abstract
The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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- 2021
33. Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation
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Sylvain Chantepie, Cécile Fourrage, Françoise Huguet, Patrice Chevallier, Elizabeth Macintyre, Hervé Dombret, Nicolas Boissel, Emmanuelle Tavernier, Véronique Lhéritier, Stéphane Leprêtre, Loïc Passini, Vahid Asnafi, Sébastien Maury, Martine Escoffre, Carlos Graux, Ludovic Lhermitte, Emmanuel Raffoux, Patrick Villarese, Norbert Ifrah, Yves Chalandon, Thibaut Leguay, Thorsten Braun, Xavier Thomas, Mathilde Hunault, Rathana Kim, Florian Thonier, Aurore Touzart, 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), Recherche clinique appliquée à l'hématologie (URP_3518), Université Paris Cité (UPCité), Service d'hématologie [CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], 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 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 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), Plateforme de Bioinformatique [Paris] (Fondation Imagine), Innate Immunity and Immunotherapy (CRCINA-ÉQUIPE 7), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'hématologie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service d'hématologie biologique [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Groupe de recherche sur la leucémie lymphoblastique aiguë chez l'adulte [Lyon] (CHU HCL - CHLS), Institut d'Hématologie de Basse-Normandie (IHBN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER, Laboratoire d’Hématologie [CHU Henri-Mondor - APHP], CHU Henri Mondor, CHU Pontchaillou [Rennes], Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Université de Genève = University of Geneva (UNIGE), Swiss Group for Clinical Cancer Research [Bern, Switzerland], CHU Dinant-Godinne UCL Namur [Yvoir, Belgique], We thank the Swiss State Secretariat for Education, Research and Innovation (SERI) Switzerland for support. We thank Force Hemato and Association pour la Recherche contre le Cancer (ARC) for support., Bernardo, Elizabeth, Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hematologie [CHU Pontchaillou, Rennes] (Pôle de Biologie), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], University of Geneva [Switzerland], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Université de Paris (UP), CHU Toulouse [Toulouse]-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)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), UCL - (MGD) Service d'hématologie, and UCL - SSS/IREC/MONT - Pôle Mont Godinne
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Neoplasm, Residual ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,medicine.disease_cause ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma ,0302 clinical medicine ,Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/pathology/therapy ,Receptors ,Hematopoietic Stem Cell Transplantation/mortality ,ddc:616 ,Mutation ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,3. Good health ,Gene Expression Regulation, Neoplastic ,Survival Rate ,030220 oncology & carcinogenesis ,Tumor/genetics ,Residual/genetics/pathology/therapy ,Female ,Stem cell ,Adult ,Homologous ,medicine.medical_specialty ,Adolescent ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,Young Adult ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,medicine ,Biomarkers, Tumor ,Transplantation, Homologous ,Humans ,Clinical significance ,Interleukin-7 receptor ,Chemotherapy ,Neoplastic ,Transplantation ,Receptors, Interleukin-7 ,business.industry ,Minimal residual disease ,030104 developmental biology ,Gene Expression Regulation ,Interleukin-7/genetics ,Neoplasm ,business ,Biomarkers ,Follow-Up Studies - Abstract
International audience; The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with TALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/ JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult TALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp mut) TALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp WT) TALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp mut patients whereas it was of marked benefit to IL7Rp WT cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
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- 2020
34. Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial
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Francois, Guilhot, Françoise, Rigal-Huguet, Joëlle, Guilhot, Agnès-Paule, Guerci-Bresler, Frédéric, Maloisel, Delphine, Rea, Valérie, Coiteux, Martine, Gardembas, Christian, Berthou, Anne, Vekhoff, Eric, Jourdan, Marc, Berger, Loïc, Fouillard, Magda, Alexis, Laurence, Legros, Philippe, Rousselot, Alain, Delmer, Pascal, Lenain, Martine, Escoffre Barbe, Emmanuel, Gyan, Claude-Eric, Bulabois, Viviane, Dubruille, Bertrand, Joly, Bertrand, Pollet, Pascale, Cony-Makhoul, Hyacinthe, Johnson-Ansah, Melanie, Mercier, Denis, Caillot, Aude, Charbonnier, Jean-Jacques, Kiladjian, Jacques, Chapiro, Amélie, Penot, Véronique, Dorvaux, Iona, Vaida, Alberto, Santagostino, Lydia, Roy, Hacene, Zerazhi, Eric, Deconinck, Herve, Maisonneuve, Isabelle, Plantier, Delphine, Lebon, Yazid, Arkam, Nathalie, Cambier, Kamel, Ghomari, Jean-Michel, Miclea, Sylvie, Glaisner, Jean-Michel, Cayuela, Jean-Claude, Chomel, Marc, Muller, Ludovic, Lhermitte, Marc, Delord, Claude, Preudhomme, Gabriel, Etienne, François-Xavier, Mahon, and Franck-Emmanuel, Nicolini
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Adult ,Aged, 80 and over ,Male ,Dose-Response Relationship, Drug ,Cytarabine ,Interferon-alpha ,Middle Aged ,Prognosis ,Recombinant Proteins ,Polyethylene Glycols ,Survival Rate ,Young Adult ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Antineoplastic Combined Chemotherapy Protocols ,Imatinib Mesylate ,Humans ,Female ,Prospective Studies ,Aged ,Follow-Up Studies - Abstract
The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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- 2020
35. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group
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Jean-Michel Cayuela, Laurence Legros, Françoise Rigal-Huguet, Martine Gardembas, Philippe Rousselot, Catherine Roche-Lestienne, Franck E. Nicolini, Stéphanie Dulucq, Gabriel Etienne, Martine Escoffre-Barbe, Marc G. Berger, Pascale Cony-Makhoul, Viviane Dubruille, Aude Charbonnier, Delphine Rea, Shanti Ame, Hyacinthe Johnson-Ansah, Agnès Guerci-Bresler, Valérie Coiteux, and Francois-Xavier Mahon
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Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Cancer ,Myeloid leukemia ,medicine.disease ,Tyrosine-kinase inhibitor ,3. Good health ,Discontinuation ,Clinical Practice ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Daily practice ,Medicine ,business ,Intensive care medicine ,Tyrosine kinase ,After treatment ,030215 immunology - Abstract
Background The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. Methods Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucemies Myeloides Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. Results Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. Conclusions This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.
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- 2018
36. 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
37. 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
38. 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
39. 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
40. 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
41. Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study
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Paul G. Richardson, Hervé Avet-Loiseau, Benoit Dupas, Martine Escoffre-Barbe, Aurore Perrot, Eric Frampas, Caroline Bodet-Milin, Lotfi Benboubker, Michel Attal, Thierry Facon, Gerald Marit, Jean-Richard Eveillard, Florence Caillon, Cyrille Hulin, Véronique Dorvaux, Lionel Karlin, Carine Chaleteix, Denis Caillot, Anne-Marie Stoppa, Brigitte Pegourie, Philippe Moreau, Kamel Laribi, Laurent Garderet, Jean-Michel Nguyen, Nikhil C. Munshi, Kenneth C. Anderson, Aurélie Gaultier, Margaret Macro, and Françoise Kraeber-Bodéré
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Cancer Research ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Bortezomib ,Magnetic resonance imaging ,medicine.disease ,3. Good health ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Maintenance therapy ,030220 oncology & carcinogenesis ,Clinical endpoint ,Medicine ,Radiology ,business ,Nuclear medicine ,Survival rate ,Multiple myeloma ,030215 immunology ,medicine.drug ,Lenalidomide - Abstract
Purpose Magnetic resonance imaging (MRI) and positron emission tomography–computed tomography (PET-CT) are important imaging techniques in multiple myeloma (MM). We conducted a prospective trial in patients with MM aimed at comparing MRI and PET-CT with respect to the detection of bone lesions at diagnosis and the prognostic value of the techniques. Patients and Methods One hundred thirty-four patients received a combination of lenalidomide, bortezomib, and dexamethasone (RVD) with or without autologous stem-cell transplantation, followed by lenalidomide maintenance. PET-CT and MRI were performed at diagnosis, after three cycles of RVD, and before maintenance therapy. The primary end point was the detection of bone lesions at diagnosis by MRI versus PET-CT. Secondary end points included the prognostic impact of MRI and PET-CT regarding progression-free (PFS) and overall survival (OS). Results At diagnosis, MRI results were positive in 127 of 134 patients (95%), and PET-CT results were positive in 122 of 134 patients (91%; P = .33). Normalization of MRI after three cycles of RVD and before maintenance was not predictive of PFS or OS. PET-CT became normal after three cycles of RVD in 32% of the patients with a positive evaluation at baseline, and PFS was improved in this group (30-month PFS, 78.7% v 56.8%, respectively). PET-CT normalization before maintenance was described in 62% of the patients who were positive at baseline. This was associated with better PFS and OS. Extramedullary disease at diagnosis was an independent prognostic factor for PFS and OS, whereas PET-CT normalization before maintenance was an independent prognostic factor for PFS. Conclusion There is no difference in the detection of bone lesions at diagnosis when comparing PET-CT and MRI. PET-CT is a powerful tool to evaluate the prognosis of de novo myeloma.
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- 2017
42. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia
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Francois-Xavier Mahon, Martine Gardembas, Agnès Guerci-Bresler, Stéphane Giraudier, Gabriel Etienne, Françoise Huguet, Laurence Legros, Bruno Varet, F. E. Nicolini, Stephane Morisset, Philippe Rousselot, Jean-Christophe Ianotto, Thomas Pagliardini, Irit Touitou, Delphine Rea, Martine Escoffre, and Marie-Pierre Noel
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Cancer Research ,medicine.medical_specialty ,Univariate analysis ,medicine.drug_class ,business.industry ,Myeloid leukemia ,Cancer ,medicine.disease ,Confidence interval ,Tyrosine-kinase inhibitor ,Discontinuation ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Multicenter study ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,In patient ,business ,030215 immunology - Abstract
BACKGROUND Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10. © 2017 American Cancer Society.
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- 2017
43. Evaluation of the Impact of Renal Failure on Correlation and Concordance Between 2 Free Light Chain Assays
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Martine Escoffre, Olivier Decaux, Emmanuel Rouger, Claude Bendavid, Thibault Cavey, Brice Autier, James Norwood, Martine Sebillot, Caroline Moreau, 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 ), Laboratoire de Biochimie et Toxicologie [Rennes] = Biochemistry and Toxicology [Rennes], CHU Pontchaillou [Rennes], Service d’Hématologie Clinique [Rennes], Service de Médecine interne et immunologie clinique [Rennes] = internal medicine and clinical immunology [Rennes], 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 ), and Jonchère, Laurent
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Cancer Research ,medicine.medical_specialty ,Pathology ,Concordance ,Paraproteinemias ,Urology ,Plasma cell dyscrasia ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,030204 cardiovascular system & hematology ,Kidney Function Tests ,free light chain ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Correlation ,Immunoglobulin kappa-Chains ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Cohen's kappa ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Immunoglobulin lambda-Chains ,hemic and lymphatic diseases ,medicine ,Humans ,Renal Insufficiency ,Renal Insufficiency, Chronic ,Stage (cooking) ,Multiple myeloma ,Kidney ,business.industry ,Monoclonal gammopathy ,Reproducibility of Results ,Hematology ,medicine.disease ,[SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,Pearson product-moment correlation coefficient ,3. Good health ,FLC interpretation ,multiple myeloma ,medicine.anatomical_structure ,Oncology ,Immunoglobulin G ,030220 oncology & carcinogenesis ,symbols ,Immunoglobulin Light Chains ,business ,Biomarkers ,chronic kidney disease ,Follow-Up Studies - Abstract
International audience; BACKGROUND:Free light chain (FLC) assays are essential for diagnosis and follow-up of plasma cell dyscrasia. Two assays are available: Freelite (Binding Site) and N Latex FLC (Siemens). The aim of our study was to evaluate the impact of renal failure on concordance and correlation between the 2 FLC assays.METHODS:FLC measurements using both assays were performed on 1215 fresh serum samples from patients with or without monoclonal gammopathy and renal failure. Concordance and correlation were evaluated using Passing-Bablock regression, Pearson correlation coefficient, and the Cohen kappa coefficient, taking into account the renal failure stage (evaluated with Chronic Kidney Disease-Epidemiology Collaboration formulae) and evaluation of treatment response in patients' follow-up.RESULTS:A good correlation was demonstrated between both assays, irrespective of the renal failure stage (Pearson correlation coefficient > 0.90). For FLC ratio interpretation, there remained 7.6% to 20.8% discordances between the 2 methods throughout the whole range of renal impairment. To evaluate FLC evolution in patient follow-up, 41 patients were selected with at least 6 consecutive serum samples being collected during the study period: we observed a concordant evolution of FLC concentrations between both assays. However, few discrepancies were observed with 4 patients.CONCLUSIONS:Despite adjusted reference ranges for Freelite FLC ratio, there are approximately 12.5% discrepancies in interpretation of FLC ratio between the 2 available assays. They are not linked to renal failure stage and neither of the assays performed better than the other: results must be interpreted taking into account clinical data and the same assay must be used for patient follow-up.
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- 2016
44. Switches of tyrosine-kinase inhibitors in chronic phase of chronic myeloid leukemia in real life
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Olivier Allangba, Violaine Doncker, Thierry Lamy, Vincent Launay, Dominique Jacomy, Estelle M. Le Pabic, Philippe Moreau, Isabelle Grulois, Adrien Trebouet, Benoit Bareau, Mathilde Niault, Marie-Laure Boulland, Marie-Françoise Le Coz, Katell Le Du, James D. Norwood, Cedric Pastoret, Odile Luycx, Thierry Fest, Martine Escoffre-Barbe, and Catherine Henry
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0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,business.industry ,Phase (matter) ,Cancer research ,In real life ,Medicine ,Myeloid leukemia ,Hematology ,business ,Tyrosine kinase - Published
- 2018
45. [Recommendations from the French CML Study Group (Fi-LMC) for BCR-ABL1 kinase domain mutation analysis in chronic myeloid leukemia]
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Jean-Michel, Cayuela, Jean-Claude, Chomel, Valérie, Coiteux, Stéphanie, Dulucq, Martine, Escoffre-Barbe, Pascaline, Etancelin, Gabriel, Etienne, Sandrine, Hayette, Frédéric, Millot, Olivier, Nibourel, Franck-Emmanuel, Nicolini, and Delphine, Réa
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Drug Substitution ,Clinical Decision-Making ,DNA Mutational Analysis ,Fusion Proteins, bcr-abl ,Mutation, Missense ,Role ,High-Throughput Nucleotide Sequencing ,Antineoplastic Agents ,DNA, Neoplasm ,Protein Domains ,Drug Resistance, Neoplasm ,Catalytic Domain ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Humans ,Point Mutation ,Molecular Biology ,Protein Kinase Inhibitors - Abstract
In the context of chronic myeloid leukemia (CML) resistant to tyrosine kinase inhibitors (TKIs), BCR-ABL1 tyrosine kinase domain (TKD) mutations still remain the sole biological marker that directly condition therapeutic decision. These recommendations aim at updating the use of BCR-ABL1 mutation testing with respect to new available therapeutic options and at repositioning different testing methods at the era of next generation sequencing (NGS). They have been written by a panel of experts from the French Study Group on CML (Fi-LMC), after a critical review of relevant publications. TKD mutation testing is recommended in case of treatment failure but not in case of optimal response. For patients in warning situation, mutation testing must be discussed depending on the type of TKI used, lasting of the treatment, kinetic evolution of BCR-ABL1 transcripts along time and necessity for switching treatment. The kind and the frequency of TKD mutations occasioning resistance mainly depend on the TKI in use and disease phase. Because of its better sensitivity, NGS methods are recommended for mutation testing rather than Sanger's. Facing a given TKD mutation, therapeutic decision should be taken based on in vitro sensitivity and clinical efficacy data. Identification by sequencing of a TKD mutation known to induce resistance must lead to a therapeutic change. The clinical value of testing methods more sensitive than NGS remains to be assessed.
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- 2019
46. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study
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Bertrand Arnulf, Lotfi Benboubker, Claire Mathiot, Jérôme J. Lambert, Cécile Sonntag, Pieter Sonneveld, Lixia Pei, Aurore Perrot, Jean Paul Fermand, Karim Belhadj, Pascal Lenain, Matthijs Westerman, Saskia K. Klein, Carla de Boer, William Deraedt, Soraya Wuilleme, Anne-Marie Stoppa, Jessica Vermeulen, Frédérique Orsini-Piocelle, Brigitte Kolb, Jordan M. Schecter, Jean-Pierre Marolleau, Cyrille Hulin, Mark-David Levin, Tobias Kampfenkel, Sen Zhuang, Jill Corre, Christopher Chiu, Jean Fontan, Hervé Avet-Loiseau, Thomas Dejoie, Martine Escoffre-Barbe, Murielle Roussel, Michel Delforge, Jean-Richard Eveillard, Cyrille Touzeau, Lionel Karlin, Tahamtan Ahmadi, Philippe Moreau, Niels W.C.J. van de Donk, Marie C. Béné, Marie-Christiane Vekemans, Sonja Zweegman, Xavier Leleu, Reda Garidi, Hélène Caillon, Mourad Tiab, Margaret Macro, Nathalie Meuleman, Elena Smith, Laurent Garderet, Kon-Siong Jie, Thierry Facon, Denis Caillot, Frédérique Kuhnowski, Annemiek Broijl, Michel Attal, Chantal Doyen, Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), 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), Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes] (INCA-DGOS-Inserm), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], 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), 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), Service d'hématologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Universitaire Ziekenhuizen Leuven, Laboratoire de Biochimie [Nantes], CIC CHU ( Lille)/inserm, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Hôpital JeanMinjoz, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service d'Hématologie [Institut Curie], Institut Curie [Paris], Service de biostatistiques et information médicale [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Hôpital de la Milétrie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Universitaire de Caen, Intergroupe francophone du myélome (IFM), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Département d'hématologie et de biologie [CHU Nantes], Amsterdam UMC - Amsterdam University Medical Center, Service d'Hématologie, Centre Hospitalier Universitaire de Reims (CHU Reims), Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Service de Médecine Onco-hématologie [La Roche sur Yon], Centre Hospitalier Universitaire de Nantes, Service clinique des Maladies du Sang, CHU Amiens-Picardie, Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), 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), CHU Pontchaillou [Rennes], CHRU Brest - Service d'Hématologie (CHU-Brest-Hemato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Saint-Quentin, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hematology, CCA - Cancer Treatment and quality of life, UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (MGD) Service d'hématologie, and UCL - (SLuc) Service d'hématologie
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Adult ,Male ,Oncology ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Population ,030204 cardiovascular system & hematology ,Transplantation, Autologous ,Dexamethasone ,Drug Administration Schedule ,Bortezomib ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,030212 general & internal medicine ,education ,Multiple myeloma ,education.field_of_study ,business.industry ,Standard treatment ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Daratumumab ,General Medicine ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Survival Analysis ,Thalidomide ,Transplantation ,Treatment Outcome ,Chemotherapy, Adjuvant ,Female ,Multiple Myeloma ,business ,medicine.drug - Abstract
Background: Bortezomib, thalidomide, and dexamethasone (VTd) plus autologous stem-cell transplantation is standard treatment in Europe for transplant-eligible patients with newly diagnosed multiple myeloma. We evaluated whether the addition of daratumumab to VTd before and after autologous stem-cell transplantation would improve stringent complete response rate in patients with newly diagnosed multiple myeloma. Methods: In this two-part, randomised, open-label, phase 3 CASSIOPEIA trial, we recruited transplant-eligible patients with newly diagnosed multiple myeloma at 111 European sites. Patients were randomly assigned (1:1) to receive four pre-transplant induction and two post-transplant consolidation cycles of VTd alone (VTd group) or in combination with daratumumab (D-VTd group). The primary endpoint of part 1 was stringent complete response assessed 100 days after transplantation. Part 2 (maintenance) is ongoing. The trial is registered with ClinicalTrials.gov, number NCT02541383. Findings: Between Sept 22, 2015, and Aug 1, 2017, 1085 patients were enrolled at 111 European sites and were randomly assigned to the D-VTd group (n=543) or the VTd group (n=542). At day 100 after transplantation, 157 (29%) of 543 patients in the D-VTd group and 110 (20%) of 542 patients in the VTd group in the intention-to-treat population had achieved a stringent complete response (odds ratio 1·60, 95% CI 1·21–2·12, p=0·0010). 211 (39%) patients in the D-VTd group versus 141 (26%) in the VTd group achieved a complete response or better, and 346 (64%) of 543 versus 236 (44%) of 542 achieved minimal residual disease-negativity (10−5 sensitivity threshold, assessed by multiparametric flow cytometry; both p
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- 2019
47. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study
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Michel Attal, Paul G Richardson, S Vincent Rajkumar, Jesus San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A Dimopoulos, Jeffrey Shang-Yi Huang, Jiri Minarik, Michele Cavo, H Miles Prince, Sandrine Macé, Kathryn P Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth C Anderson, Paul G. Richardson, Vincent Rajkumar, Meletios A. Dimopoulos, H. Miles Prince, Kathryn P. Corzo, Kenneth C. Anderson, Simon Harrison, Wojt Janowski, Ian Kerridge, Andrew Spencer, Michel Delforge, Karel Fostier, Philip Vlummens, Ka Lung Wu, Richard Leblanc, Michel Pavic, Michael Sebag, Roman Hajek, Vladimir Maisnar, Ludek Pour, Henrik Gregersen, Lotfi Benbouker, Denis Caillot, Martine Escoffre-Barbe, Thierry Facon, Laurent Frenzel, Cyrille Hulin, Lionel Karlin, Brigitte Kolb, Brigitte Pegourie, Aurore Perrot, Mourad Tiab, Laure Vincent, Dietger Niederwieser, Achilles Anagnostopoulos, Sosana Delimpasi, Marie-Christine Kyrtsonis, Anargyros Symeonidis, Arpad Illes, Gabor Mikala, Zsolt Nagy, Sara Bringen, Paolo Corradini, Ciceri Fabio, Roberto Lemoli, Anna Liberati, Chiara Nozzoli, Renato Zambello, Shinsuke Iida, Takashi Ikeda, Satoshi Iyama, Morio Matsumoto, Chihiro Shimazaki, Kazutaka Sunami, Kenshi Suzuki, Michihiro Uchiyama, Youngil Koh, Kihyun Kim, Jae Hoon Lee, Chang-Ki Min, Hillary Blacklock, Hugh Goodman, Annette Neylon, David Simpson, Sebastian Grosicki, Artur Jurczyszyn, Adam Walter-Croneck, Krzysztof Warzocha, Luis Araujo, Claudia Moreira, Vadim Doronin, Larisa Mendeleeva, Vladimir Vorobyev, Andrej Vranovsky, Adrian Alegre, Mercedes Gironella, Marta Sonia Gonzalez Perez, Carmen Montes, Enrique Ocio, Paula Rodriguez, Mats Hardling, Birgitta Lauri, Ming-Chung Wang, Su-Peng Yeh, Mutlu Arat, Fatih Demirkan, Zafer Gulbas, Sevgi Kalayoglu Besisik, Ihsan Karadogan, Tulin Tuglular, Ali Unal, Filiz Vural, Jonathan Sive, Matthew Streetly, Kwee Yong, Jason Tache, Attal, Michel, Richardson, Paul G, Rajkumar, S Vincent, San-Miguel, Jesu, Beksac, Meral, Spicka, Ivan, Leleu, Xavier, Schjesvold, Fredrik, Moreau, Philippe, Dimopoulos, Meletios A, Huang, Jeffrey Shang-Yi, Minarik, Jiri, Cavo, Michele, Prince, H Mile, Macé, Sandrine, Corzo, Kathryn P, Campana, Frank, Le-Guennec, Solenn, Dubin, Franck, Anderson, Kenneth C, and ICARIA-MM study group
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Male ,medicine.medical_specialty ,Asia ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Antibodies ,Dexamethasone ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,030212 general & internal medicine ,Progression-free survival ,Aged ,Antibodies, Monoclonal ,Europe ,Female ,Middle Aged ,Multiple Myeloma ,Neoplasm Recurrence, Local ,North America ,Progression-Free Survival ,Thalidomide ,Treatment Outcome ,Multiple myeloma ,Lenalidomide ,Isatuximab ,business.industry ,Bortezomib ,General Medicine ,Pomalidomide ,medicine.disease ,Neoplasm Recurrence ,Local ,business ,Isatuximab, pomalidomide, low-dose dexamethasone ,medicine.drug - Abstract
BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma. METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (
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- 2019
48. Ponatinib evaluation and safety in real-life chronic myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: the PEARL observational study
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Maël Heiblig, Stephane Morisset, Franck E. Nicolini, Lucila Sackmann-Sala, Viviane Dubruille, Philippe Rousselot, Lydia Roy, Shanti Ame, Delphine Rea, Gabriel Etienne, Marie-Lorraine Chretien, Françoise Huguet, Aude Charbonnier, Emilie Cayssials, Agnès Guerci-Bresler, Valérie Coiteux, Mohamad Sobh, Eric Hermet, Martine Escoffre-Barbe, Centre Léon Bérard [Lyon], Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7), Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Claude Huriez [Lille], CHU Lille, CHU Pontchaillou [Rennes], Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie [IUCT Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service d'Hématologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Service d'Hématologie Biologique [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Compassionate Use Trials ,Male ,Oncology ,Cancer Research ,Salvage therapy ,Kaplan-Meier Estimate ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Medicine ,Cumulative incidence ,Treatment Failure ,Aged, 80 and over ,Ponatinib ,Imidazoles ,Hematology ,Middle Aged ,Intention to Treat Analysis ,3. Good health ,Pyridazines ,Cardiovascular Diseases ,030220 oncology & carcinogenesis ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Genes, abl ,Young Adult ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Pragmatic Clinical Trials as Topic ,Genetics ,Humans ,Adverse effect ,Protein Kinase Inhibitors ,Molecular Biology ,Survival analysis ,Aged ,Salvage Therapy ,business.industry ,Patient Selection ,Cell Biology ,medicine.disease ,Survival Analysis ,Clinical trial ,chemistry ,Drug Resistance, Neoplasm ,business ,030215 immunology ,Chronic myelogenous leukemia - Abstract
IF 2.436 (2017); International audience; Ponatinib represents a remarkable progress in the treatment of heavily pretreated chronic myelogenous leukemia (CML) and de novo Philadelphia chromosome-positive ALL patients despite significant toxicity in clinical trials. To date, "real-life" data remain few and the use of ponatinib in this setting and its consequences remain mostly unknown. We report, within a national observational study, the use of ponatinib in unselected CML patients who had previously failed ≥2 lines of tyrosine kinase inhibitor (TKI) therapy (or one line if an Abelson (ABL)T315I mutation was identified), in real-life conditions (2013-2014) in a compassionate program. Our analysis has been focused on 48 chronic phase CML patients recorded. With a median follow-up of 26.5 months since ponatinib initiation, the overall survival (OS) rates (80.5% at 3 years) and cumulative incidence of major molecular response (81.8% at 18 months) were similar to those of the phase II study, with no influence of BCR-ABL mutations nor the reason of ponatinib prescription. A specific subanalysis of the preexisting cardiovascular risk factors and events occurring on ponatinib is described. These events occurred after a median time on ponatinib of 5.8 months (excluding hypertension) and were observed in 29/48 patients (47%), even in those already on anti-aggregants/coagulants. The majority were not severe and resolved, but two cases were fatal. Other hematological or nonhematological nonvascular adverse events were similar to those previously described in trials. This observational study reports similar rates of survival, molecular responses, and a slight increase in the cardiovascular toxicity of ponatinib in real-life conditions, prompting improved control of cardiovascular risk factors and selection of patients.
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- 2018
49. 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
50. 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
- Author
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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.
- Published
- 2019
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