Pharmacogénétique de l'Imatinib dans la Leucémie Myéloïde Chronique etDonnées Censurées par Intervalles en présence de Compétition

Imatinib in the treatment of chronic myeloid leukemia is a success of targeted therapy in oncology. The aim of this therapy is to block the biochemical processes leading to disease development. This strategy results in a reduction of the risk of disease progression and allows patients to avoid extensive and hazardous treatments such as hematologic stem cell transplantation.However, even if imatinib efficacy has been demonstrated in a clinical setting, a significant part of patients do not achieve suitable levels of molecular response. The objective of this thesis, is to test the hypothesis of a correlation between polymorphisms of genes implied in drug absorption an metabolism and the molecular response in chronic myeloid leukemia in chronic phase treated by imatinib.In order to evaluate patients molecular response, blood biomarker assessments are performed every 3 months. This type of follow up produces interval censored data. As patients remain at risk of disease progression, or may interrupt their treatments due to poor tolerance, the response of interest may not be observable in a given setting. This situation produces interval censored competing risks data.To properly handle such data, we propose a multiple imputation based method.The main idea is to convert interval censored data into multiple sets of potentially right censored data that are then analysed using multiple imputation rules.Le traitement de la leucémie myéloïde chronique (LMC) par imatinib est un succès de thérapie ciblée en oncologie. Le principe de cette thérapie est de bloquer les processus biochimiques à l'origine du développement de la maladie, et de permettre à une majorité de patients de réduire leurs risques de progression mais aussi d'éviter des traitements lourds et risqués comme la greffe de cellules souches hématopoïétiques.Cependant, même si l'efficacité de l'imatinib à été prouvée dans un contexte clinique, il n'en demeure pas moins qu'une proportion non négligeable de patients n'obtient par de niveaux de réponse moléculaire jugés optimale. Le but de cette thèse est de tester l'hypothèse d'un lien entre des polymorphismes de gènes impliqués dans l'absorption des médicaments et de leurs métabolisme, et la réponse moléculaire dans la leucémie myéloïde chronique en phase chronique traitée par imatinib.Dans le but d'évaluer la réponse moléculaire des patients, des prélèvements sanguins sont réalisés tout les 3 mois afin de pratiquer le dosage d'un biomarqueur. Ce type particulier de suivi produit des données censurées par intervalles. Comme par ailleurs, les patients demeurent à risque de progression ou sont susceptible d'interrompre leurs traitements pour cause d'intolérance, il est possible que la réponse d'intérêt ne soit plus observable sous le traitement étudié. Les données ainsi produites sont censurées par intervalles dans un contexte de compétition (risques compétitifs).Afin de tenir compte de la nature particulière des données collectées, une méthode basée sur l'imputation multiple est proposée. L'idée est de transformer les données censurées par intervalles en de multiples jeux de données potentiellement censurées à droite et d'utiliser les méthodes disponibles pour l'analyser de ces données. Finalement les résultats sont assemblés en suivant les règles de l'imputation multiple

Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse

Compared with T-ALL diagnosis samples, samples obtained at relapse or after xenograft into immunodeficient mice exhibit additional genomic lesions in oncogenes and/or tumor suppressor genes; these lesions contribute to leukemia-initiating activity

Splicing factor and exon profiling across human tissues

It has been shown that alternative splicing is especially prevalent in brain and testis when compared to other tissues. To test whether there is a specific propensity of these tissues to generate splicing variants, we used a single source of high-density microarray data to perform both splicing factor and exon expression profiling across 11 normal human tissues. Paired comparisons between tissues and an original exon-based statistical group analysis demonstrated after extensive RT-PCR validation that the cerebellum, testis, and spleen had the largest proportion of differentially expressed alternative exons. Variations at the exon level correlated with a larger number of splicing factors being expressed at a high level in the cerebellum, testis and spleen than in other tissues. However, this splicing factor expression profile was similar to a more global gene expression pattern as a larger number of genes had a high expression level in the cerebellum, testis and spleen. In addition to providing a unique resource on expression profiling of alternative splicing variants and splicing factors across human tissues, this study demonstrates that the higher prevalence of alternative splicing in a subset of tissues originates from the larger number of genes, including splicing factors, being expressed than in other tissues

Intratumoral pan-ErbB targeted CAR-T for head and neck squamous cell carcinoma: interim analysis of the T4 immunotherapy study

Background: Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues. // Methods: We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion. // Results: Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product. // Conclusions: These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study

BACKGROUND We recently reported that peroxisome proliferator‐activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add‐on therapy to imatinib would impact CML residual disease, as assessed by BCR‐ABL1 transcript quantification. METHODS CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR4.5) defined by BCR‐ABL1/ABL1 IS RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR4.5 over 12 months. RESULTS Twenty‐four patients were included (age range, 24‐79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR4.5 was 56% (95% confidence interval, 37%‐76%) by 12 months, despite a wide range of therapy duration (1.9‐15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR4.5 by 48 months. The cumulative incidence of MMR to MR4.5 spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients. CONCLUSION Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009‐011675‐79). Cancer 2017;123:1791–1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Pharmacogenetics of Imatinib in Chronic Myeloid Leukemia etInterval Censored Competing Risks Data

Le traitement de la leucémie myéloïde chronique (LMC) par imatinib est un succès de thérapie ciblée en oncologie. Le principe de cette thérapie est de bloquer les processus biochimiques à l'origine du développement de la maladie, et de permettre à une majorité de patients de réduire leurs risques de progression mais aussi d'éviter des traitements lourds et risqués comme la greffe de cellules souches hématopoïétiques.Cependant, même si l'efficacité de l'imatinib à été prouvée dans un contexte clinique, il n'en demeure pas moins qu'une proportion non négligeable de patients n'obtient par de niveaux de réponse moléculaire jugés optimale. Le but de cette thèse est de tester l'hypothèse d'un lien entre des polymorphismes de gènes impliqués dans l'absorption des médicaments et de leurs métabolisme, et la réponse moléculaire dans la leucémie myéloïde chronique en phase chronique traitée par imatinib.Dans le but d'évaluer la réponse moléculaire des patients, des prélèvements sanguins sont réalisés tout les 3 mois afin de pratiquer le dosage d'un biomarqueur. Ce type particulier de suivi produit des données censurées par intervalles. Comme par ailleurs, les patients demeurent à risque de progression ou sont susceptible d'interrompre leurs traitements pour cause d'intolérance, il est possible que la réponse d'intérêt ne soit plus observable sous le traitement étudié. Les données ainsi produites sont censurées par intervalles dans un contexte de compétition (risques compétitifs).Afin de tenir compte de la nature particulière des données collectées, une méthode basée sur l'imputation multiple est proposée. L'idée est de transformer les données censurées par intervalles en de multiples jeux de données potentiellement censurées à droite et d'utiliser les méthodes disponibles pour l'analyser de ces données. Finalement les résultats sont assemblés en suivant les règles de l'imputation multiple.Imatinib in the treatment of chronic myeloid leukemia is a success of targeted therapy in oncology. The aim of this therapy is to block the biochemical processes leading to disease development. This strategy results in a reduction of the risk of disease progression and allows patients to avoid extensive and hazardous treatments such as hematologic stem cell transplantation.However, even if imatinib efficacy has been demonstrated in a clinical setting, a significant part of patients do not achieve suitable levels of molecular response. The objective of this thesis, is to test the hypothesis of a correlation between polymorphisms of genes implied in drug absorption an metabolism and the molecular response in chronic myeloid leukemia in chronic phase treated by imatinib.In order to evaluate patients molecular response, blood biomarker assessments are performed every 3 months. This type of follow up produces interval censored data. As patients remain at risk of disease progression, or may interrupt their treatments due to poor tolerance, the response of interest may not be observable in a given setting. This situation produces interval censored competing risks data.To properly handle such data, we propose a multiple imputation based method.The main idea is to convert interval censored data into multiple sets of potentially right censored data that are then analysed using multiple imputation rules

[Systèmes de production et politiques agricoles]

International audienceLa politique agricole est définie comme un compromis entre groupes sociaux pour la gestion publique de la coordination au sein du secteur agricole, et entre les activités agricoles et non agricoles. En Amérique Latine et en Europe, sont examinés les rapports entre l'évolution des politiques agricoles et les recherches sur les systèmes de production, ces derniers y apparaissent comme un moyen de comprendre l'évolution des politiques. Une typologie des relations entre ces deux processus est ensuite proposée : recherches sur des systèmes de production organisées ou non par les pouvoirs publics afin d'améliorer l'efficacité de politiques agricoles, recherches visant explicitement à contester certaines politiques et enfin recherches qui ont permis de faciliter l'établissement d'un nouveau compromis social et d'en interpréter le contenu. Il n'en reste pas moins que de nombreux acteurs non-agricoles interviennent dans l'évolution des politiques agricoles et que les recherches sur les systèmes de production sont alors peu éclairantes