Immune Reconstitution following Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation: The Impact of Expanding CD28negative CD8+ T Cells on Relapse

AbstractAllogeneic stem cell transplantation has become standard therapy for hematologic malignancies through the positive immunologic graft-versus-leukemia effect. Initial immune recovery relies on peripheral expansion of infused T cells, which switch to a memory-like phenotype. This study prospectively investigated whether changes in subset composition precedes complications after myeloablative HLA-matched transplantation for hematologic malignancies. Of 80 allograft recipients, 18 were still free of clinical complication throughout 395 to 1564 days of follow-up. Compared with this complication-free subgroup, patients who developed chronic graft-versus-host disease (cGVHD) without relapsing recovered similar numbers of circulating T cells with predominance of CD8+ T cells lacking CC-chemokine receptor-7 and CD28 expression throughout the first year after transplantation. Conversely, poor CD8+ T cell recovery with diminished numbers of CD28neg CD8+ T cells (∼1/4th of that of relapse-free patients) preceded occurrence of malignant relapse. In multivariate analysis, lower CD28neg CD8+ T cell counts by day 60 postallograft were associated with a greater risk of subsequent relapse (hazard ratio [HR] 0.33; 95% confidence interval [CI]: 0.14-0.76; P = .01). Enumeration of CD28neg CD8+ T cells in patients could assist in predicting risk of relapse and help build an algorithm for accelerating the immune recovery by reducing the immunosuppressive treatment and considering the introduction of preemptive donor lymphocyte infusions

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

Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease

BACKGROUND: Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD. METHODS: We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56. RESULTS: A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P<0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P<0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]). CONCLUSIONS: Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy

Etude des mutations des gènes CEBPA, FLT3 et RAS dans les leucémies aiguës myéloïdes de l'adulte (à propos de 224 observations)

LILLE2-BU Santé-Recherche (593502101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Adaptation des doses de médicament des conditionnements de greffe de cellules souches hématopoïétiques dans des populations avec comorbidité : obésité, maladie rénale chronique ou hépatopathie : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

International audienceIn September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th Allogeneic Stem Cell Transplantation Clinical Practices Harmonization Workshop Series. Our work group focused on chemotherapy drug dose adaptation for hematopoietic stem cell transplantation patients presenting a comorbidity. The purpose of this workshop was to provide recommendations on chemotherapy drug dose adaptation for patient populations receiving hematopoietic stem cell transplantation who also had the following comorbidities: obesity, chronic kidney disease and hepatopathy

Hématologie, soins palliatifs et sciences humaines : une rencontre réflexive qui déplace les représentations

La mise en place d’un séminaire d’éthique clinique, « Hématologie et soins palliatifs » a invité autour de la table acteurs de sciences humaines et sociales et cliniciens à réfléchir à l’articulation entre hématologie et soins palliatifs. Méthodologie : seize participants issus des sciences humaines et sociales et de la médecine palliative et hématologique se sont rencontrés dans une démarche d’éthique clinique, autour de cas cliniques vécus et considérés comme complexes d’un point de vue clinique et éthique. Résultats : la réflexion initiale se basait sur des questions organisationnelles entre médecine palliative et hématologie. Elle s’est déplacée au cours du séminaire, invitant à un questionnement d’ordre identitaire sur deux types de médecine, dites curative ou palliative. L’attention à la subjectivité des cliniciens et l’apport des sciences humaines et sociales dans la réflexion ont proposé un nouveau paradigme de soin, basé sur l’attention au mouvement de vie du sujet malade. Discussion : la méthodologie de l’éthique clinique a permis d’élaborer des pistes de transformation des pratiques professionnelles

Prise en charge palliative des patients allogreffés : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

International audienceAllogeneic hematopoietic cell transplantation (allo-HCT), the only curative therapy for numerous hematological malignancies, carries a significant risk of morbidity and mortality. The patients and families’ expectations regarding the procedure, the prognosis uncertainties, as well as the existence of potential new therapeutic possibilities, lead to frequent use of intensive care. Even though the transplant physicians are highly skilled in acute care, their knowledge of palliative approach is limited, making the use of palliative care insufficient and often late. By promoting reflection on the proportionality of care and the patients’ quality of life, palliative care may contribute to the allo-HCT patients management. Nevertheless, obstacles to this approach remain. The objective of this work is to propose recommendations to promote the implementation of palliative care into transplant units.L’allogreffe de cellules hématopoïétiques, seule perspective curative pour certaines hémopathies malignes, comporte des risques de morbi-mortalité importants. Les attentes des patients et de leurs proches vis-à-vis de la procédure, les incertitudes pronostiques, ainsi que l’existence de nouvelles possibilités thérapeutiques, engendrent un recours fréquent, onéreux aux soins intensifs. Si les médecins greffeurs maîtrisent parfaitement les soins actifs, leur connaissance en ce qui concerne les soins palliatifs est limitée, rendant l’accès à ces soins très restreint et souvent tardif. Favorisant une réflexion sur la proportionnalité des soins et sur la qualité de vie des patients, les soins palliatifs peuvent contribuer à la prise en charge des patients allogreffés et à l’accompagnement de leurs proches. Néanmoins, des obstacles à cette approche demeurent. Cet article a pour objectif de proposer des recommandations pour favoriser l’intégration de la démarche palliative au sein des unités d’allogreffe

Epigenetic silencing of the tetraspanin CD9 during disease progression in multiple myeloma cells and correlation with survival.

PURPOSE: The purpose of this study was to investigate expression and epigenetic regulation of CD9 in multiple myeloma (MM) cells during disease progression. EXPERIMENTAL DESIGN: CD9 expression was retrospectively analyzed on bone marrow myeloma samples from 81 patients by immunophenotyping. CD9 expression by murine 5TMM cells was detected by flow cytometric staining and quantitative PCR. The methylation status of the CD9 promoter was determined by bisulfite PCR sequencing. RESULTS: Primary plasma cells in the majority of MM patients with nonactive disease (n = 28) showed CD9 expression, whereas most cases with active disease (n = 53) were CD9 negative. CD9 expression in diagnostic bone marrow samples (n = 74) correlated with survival. Moreover, CD9 expression on murine 5T33 and 5T2MM cells was significantly down-regulated during disease development. Treatment of CD9-nonexpressing 5T33MMvt cells with the clinically relevant histone deacetylase inhibitor LBH589 resulted in a significant increase in CD9 expression. In contrast, cells treated with the demethylation agent 5-aza-2'deoxycytidine barely showed any increase. A combination study with both compounds resulted in a strong synergistic reactivation of CD9. CD9-expressing 5T33MMvv cells and 5T33MMvt cells stably transduced with a mCD9 lentiviral transferplasmid were shown to be more susceptible to natural killer cell-mediated cytolysis than CD9-negative 5T33MMvt cells. CONCLUSIONS: CD9 expression correlates with disease status and survival of MM patients. In the murine 5T33MM model, we show that histone modifications, and to a lesser extent CpG methylation, are key epigenetic events in CD9 down-regulation. Furthermore, as CD9 expression becomes down-regulated, 5T33MM cells become less susceptible to natural killer cell-mediated cytolysis

Mise en place d’une consultation infirmière de suivi post-allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Le nombre de patients allogreffés suivis en consultation post-greffe ne cesse d’augmenter. Le médecin n’est plus en capacité d’assurer seul ce suivi. Certains centres ont déjà mis en place une consultation infirmière sous la responsabilité d’un médecin. Un état des lieux des centres SFGM-TC a été effectué par le biais d’un questionnaire qui a confirmé la nécessité de cette consultation afin d’améliorer l’organisation des soins et la qualité de la prise en charge des patients. Au cours de cet atelier, nous avons défini des pré-requis pour la création d’une consultation infirmière jusqu’à j100 post-greffe, sous la responsabilité d’un médecin greffeur. Afin d’accompagner les centres dans cette dynamique, nous proposons des outils pratiques de support à la consultation. La politique de santé actuelle est en faveur d’une plus grande autonomie de l’infirmier(ière) expert(e). La mise en place du statut d’infirmier (ière) de pratiques avancées est une première étape et permet d’envisager cette évolution professionnelle.[A specialist nurse consultation for post-transplant follow-up of patients undergoing allogeneic hematopoietic cell transplantation: Recommendations of the Francophone Society of Marrow Transplantation and Cellular Therapy (SFGM-TC)]. The number of hematopoietic stem cell transplantation is in constant rise. This increase has put in spotlight the lack of physician availability. Some healthcare centers have already organised a nurse's consultation under the supervision of an expert physician. We conducted a survey among nurses and physicians from the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) centers who confirmed the need to create a special transplantation-skilled population of nurses. During this ninth annual workshop of the SFGM-TC, we have defined the required conditions for a transplant nurse consultation until day 100 post-transplant with the responsibility of the transplant expert physician. To help the centers in this dynamic, we provided practical tools to support this consultation. The current heath policy is in favor of an increased autonomy of the expert nurse. The implementation of the status of nurse in advanced practice is the first step in this professional development

Hématologie, soins palliatifs et sciences humaines : une rencontre réflexive qui déplace les représentations

INTRODUCTION : la mise en place d’un séminaire d’éthique clinique, « Hématologie et soins palliatifs » a invité autour de la table acteurs de sciences humaines et sociales et cliniciens à réfléchir à l’articulation entre hématologie et soins palliatifs. Méthodologie : seize participants issus des sciences humaines et sociales et de la médecine palliative et hématologique se sont rencontrés dans une démarche d’éthique clinique, autour de cas cliniques vécus et considérés comme complexes d’un point de vue clinique et éthique. RÉSULTATS : la réflexion initiale se basait sur des questions organisationnelles entre médecine palliative et hématologie. Elle s’est déplacée au cours du séminaire, invitant à un questionnement d’ordre identitaire sur deux types de médecine, dites curative ou palliative. L’attention a la subjectivité des cliniciens et l’apport des sciences humaines et sociales dans la réflexion ont proposé un nouveau paradigme de soin, basé sur l’attention au mouvement de vie du sujet malade. DISCUSSION : la méthodologie de l’éthique clinique a permis d’élaborer des pistes de transformation des pratiques professionnelles [Titre en angalais : Hematology, palliative care, and human sciences: a dialogue that changes portrayals