Partial selective T cell depletion of periphral blood stem cell is efficiency and safety : alloreactivity study, anti-infectious and anti-tumoural response of the CD4+T lymphocyte sub-population

Véritable immunothérapie adoptive, l’allogreffe de Cellules Souches Hématopoïétiques (CSH) est destinée à prévenir la rechute d’une hémopathie maligne grâce au combat immunologique du greffon contre la maladie (effet GVL, Graft Versus Leukemia), dans lequel les lymphocytes T apportés par le greffon sont déterminants. Ils peuvent aussi compromettre le résultat escompté, en induisant une réaction du greffon contre l'hôte (GVH, Graft Versus Host) qui reste une complication redoutée de l’allogreffe. Dans une précédente étude prospective portant sur 62 couples donneur/receveur nous avons pu étudier l'impact de la composition du greffon en cellules T de phénotypes naïfs et mémoires sur le devenir des receveurs d’allogreffes à partir d'un donneur HLA-identique apparenté ou non; et nous avons pu démontrer qu’une proportion élevée de lymphocytes T CD4+CCR7+ dans le greffon était un facteur de risque de la survenue, la précocité et la sévérité de la GVH aiguë, sans influence sur la GVH chronique ou la rechute. Dans le but de séparer l’effet GVL de la GVH, nous avons voulu à travers des travaux de cette thèse, étudier le concept d’une T déplétion partielle et sélective du greffon en lymphocytes T CD4+CCR7+. Nous travaux se sont scindés en trois parties :1) Au plan clinique, nous avons pu confirmer nos précédents résultats sur une cohorte additionnelle de 137 patients. Non seulement, nous avons confirmé qu’une proportion élevée de lymphocytes T CD4+CCR7+ dans le greffon était un facteur de risque de la survenue, de la GVH aiguë, mais également, nous avons observé un effet préférentielle de la sous-population naïve des lymphocytes T CD4+ sur l’incidence de la GVH aiguë. Bien entendu, aucun impact sur l’incidence de la rechute post-allogreffe n’a été enregistré.2) Dans un modèle expérimental utilisant des cultures lymphocytaires en présence des cellules dendritiques provenant des six couples (frère/sœur) HLA-identiques, nous avons pu démontrer que les lymphocytes T CD4+ naïfs déclenchaient la réponse allogénique la plus importante et avec un degré moindre les cellules mémoires centrales par rapport aux effecteurs mémoires T CD4+. Ces résultats non seulement, valident in vitro les constatations cliniques mais aussi mettent l’accent sur le rôle prépondérant des lymphocytes T naïfs dans l’alloréactivité, notamment en situation de compatibilité HLA.3) Nous avons dans la troisième partie pu démontrer qu’une déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+ n’altère pas la réponse immunologique secondaires vis-à-vis des virus.La suite de nos travaux se focalise sur l’effet de la déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+ sur la réaction anti-tumorale du greffon dans la situation HLA compatibilité chez l’homme.Nos résultats constituent une pierre angulaire dans le concept de déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+, ex vivo chez l’homme, en vue de réduire l’incidence de la GVHD sans altérer la réponse anti-infectieuse ou tumorale du greffon notamment chez les donneurs présentant un taux élevé de lymphocytes T CD4+ naïfs et/ou mémoire centrale .A genuine adoptive immunotherapy, Haematopoietic Stem Cell (HSC) allotransplantation aims to prevent the recurrence of a malignant blood disease via an immunological action of the graft against disease (GVL or Graft Versus Leukaemia effect), in which the T lymphocytes supplied by the transplant play a key role. They may also compromise the targeted result, by triggering a GVH (Graft Versus Host) reaction, which remains a serious complication of allotransplantation. In a previous prospective study conducted in 62 donor/recipient pairings, we examined the impact of the transplant\\\'s naive and memory phenotype T cell composition on the fate of recipients of allotransplants from an HLA-identical donor, related to the recipient or otherwise. We demonstrated that a high proportion of CD4+CCR7+ T lymphocytes in the transplant was a risk factor for the development, early onset and severity of acute GVHD, with no influence on chronic GVHD or recurrence. With the objective of separating the GVL effect from the GVH effect, we wanted to investigate the concept of partial and selective CD4+CCR7+ T cell depletion of the graft in the studies conducted as part of this research. Our studies were split into three parts:1) Clinically, we confirmed our previous results in an additional cohort of 137 patients. In addition to confirming that a high proportion of CD4+CCR7+ T lymphocytes in the transplant was a risk factor for the development of acute GVH, we also observed a preferential effect of the naive CD4+T lymphocyte sub-population on the incidence of acute GVHD. Obviously, no impact on the incidence of post-allotransplantation recurrence was recorded.2) In an experimental model using lymphocyte cultures in the presence of dendritic cells taken from six HLA-identical pairings (brother/sister), we demonstrated that naive CD4+ T lymphocytes triggered the greatest allogenic response and, to a lesser degree, central memory cells compared to effector memory CD4+ T cells. Not only do these results validate the clinical observations made in vitro, they also highlight the dominant role of naive T lymphocytes in alloreactivity, particularly in situations of HLA incompatibility.3) In the third part, we demonstrated that selective partial CD4+CCR7+ T cell depletion of the transplants does not impair the secondary immunological response to viruses.The next phase of our research focuses on the effect of selective partial CD4+CCR7+ T cell depletion of grafts on the transplant's anti-tumoural reaction in situations of HLA compatibility in humans.Our results represent a cornerstone in the concept of partial selective T CD4+CCR7+ T cell depletion of transplants, ex vivo in humans, with a view to reducing the incidence of GVHD, without impairing the anti-infectious or anti-tumoural response of the graft, particularly in donors with high levels of naive and/or central memory CD4+ T lymphocytes

Efficacité et innocuité d’une déplétion partielle et sélective des greffons de cellules souches hématopoïétiques : étude de l’alloréactivité, et des réponses antiinfectieuses et anti-tumorales des sous-populations lymphocytaires T4 naïves et mémoires

A genuine adoptive immunotherapy, Haematopoietic Stem Cell (HSC) allotransplantation aims to prevent the recurrence of a malignant blood disease via an immunological action of the graft against disease (GVL or Graft Versus Leukaemia effect), in which the T lymphocytes supplied by the transplant play a key role. They may also compromise the targeted result, by triggering a GVH (Graft Versus Host) reaction, which remains a serious complication of allotransplantation. In a previous prospective study conducted in 62 donor/recipient pairings, we examined the impact of the transplant\\\'s naive and memory phenotype T cell composition on the fate of recipients of allotransplants from an HLA-identical donor, related to the recipient or otherwise. We demonstrated that a high proportion of CD4+CCR7+ T lymphocytes in the transplant was a risk factor for the development, early onset and severity of acute GVHD, with no influence on chronic GVHD or recurrence. With the objective of separating the GVL effect from the GVH effect, we wanted to investigate the concept of partial and selective CD4+CCR7+ T cell depletion of the graft in the studies conducted as part of this research. Our studies were split into three parts:1) Clinically, we confirmed our previous results in an additional cohort of 137 patients. In addition to confirming that a high proportion of CD4+CCR7+ T lymphocytes in the transplant was a risk factor for the development of acute GVH, we also observed a preferential effect of the naive CD4+T lymphocyte sub-population on the incidence of acute GVHD. Obviously, no impact on the incidence of post-allotransplantation recurrence was recorded.2) In an experimental model using lymphocyte cultures in the presence of dendritic cells taken from six HLA-identical pairings (brother/sister), we demonstrated that naive CD4+ T lymphocytes triggered the greatest allogenic response and, to a lesser degree, central memory cells compared to effector memory CD4+ T cells. Not only do these results validate the clinical observations made in vitro, they also highlight the dominant role of naive T lymphocytes in alloreactivity, particularly in situations of HLA incompatibility.3) In the third part, we demonstrated that selective partial CD4+CCR7+ T cell depletion of the transplants does not impair the secondary immunological response to viruses.The next phase of our research focuses on the effect of selective partial CD4+CCR7+ T cell depletion of grafts on the transplant's anti-tumoural reaction in situations of HLA compatibility in humans.Our results represent a cornerstone in the concept of partial selective T CD4+CCR7+ T cell depletion of transplants, ex vivo in humans, with a view to reducing the incidence of GVHD, without impairing the anti-infectious or anti-tumoural response of the graft, particularly in donors with high levels of naive and/or central memory CD4+ T lymphocytes.Véritable immunothérapie adoptive, l’allogreffe de Cellules Souches Hématopoïétiques (CSH) est destinée à prévenir la rechute d’une hémopathie maligne grâce au combat immunologique du greffon contre la maladie (effet GVL, Graft Versus Leukemia), dans lequel les lymphocytes T apportés par le greffon sont déterminants. Ils peuvent aussi compromettre le résultat escompté, en induisant une réaction du greffon contre l'hôte (GVH, Graft Versus Host) qui reste une complication redoutée de l’allogreffe. Dans une précédente étude prospective portant sur 62 couples donneur/receveur nous avons pu étudier l'impact de la composition du greffon en cellules T de phénotypes naïfs et mémoires sur le devenir des receveurs d’allogreffes à partir d'un donneur HLA-identique apparenté ou non; et nous avons pu démontrer qu’une proportion élevée de lymphocytes T CD4+CCR7+ dans le greffon était un facteur de risque de la survenue, la précocité et la sévérité de la GVH aiguë, sans influence sur la GVH chronique ou la rechute. Dans le but de séparer l’effet GVL de la GVH, nous avons voulu à travers des travaux de cette thèse, étudier le concept d’une T déplétion partielle et sélective du greffon en lymphocytes T CD4+CCR7+. Nous travaux se sont scindés en trois parties :1) Au plan clinique, nous avons pu confirmer nos précédents résultats sur une cohorte additionnelle de 137 patients. Non seulement, nous avons confirmé qu’une proportion élevée de lymphocytes T CD4+CCR7+ dans le greffon était un facteur de risque de la survenue, de la GVH aiguë, mais également, nous avons observé un effet préférentielle de la sous-population naïve des lymphocytes T CD4+ sur l’incidence de la GVH aiguë. Bien entendu, aucun impact sur l’incidence de la rechute post-allogreffe n’a été enregistré.2) Dans un modèle expérimental utilisant des cultures lymphocytaires en présence des cellules dendritiques provenant des six couples (frère/sœur) HLA-identiques, nous avons pu démontrer que les lymphocytes T CD4+ naïfs déclenchaient la réponse allogénique la plus importante et avec un degré moindre les cellules mémoires centrales par rapport aux effecteurs mémoires T CD4+. Ces résultats non seulement, valident in vitro les constatations cliniques mais aussi mettent l’accent sur le rôle prépondérant des lymphocytes T naïfs dans l’alloréactivité, notamment en situation de compatibilité HLA.3) Nous avons dans la troisième partie pu démontrer qu’une déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+ n’altère pas la réponse immunologique secondaires vis-à-vis des virus.La suite de nos travaux se focalise sur l’effet de la déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+ sur la réaction anti-tumorale du greffon dans la situation HLA compatibilité chez l’homme.Nos résultats constituent une pierre angulaire dans le concept de déplétion partielle sélective des greffons en lymphocytes T CD4+CCR7+, ex vivo chez l’homme, en vue de réduire l’incidence de la GVHD sans altérer la réponse anti-infectieuse ou tumorale du greffon notamment chez les donneurs présentant un taux élevé de lymphocytes T CD4+ naïfs et/ou mémoire centrale

Ibrutinib Treatment through Nasogastric Tube in a Comatose Patient with Central Nervous System Localization of Mantle Cell Lymphoma

Nowadays, mantle cell lymphoma is considered to have one of the worst prognostic profiles among lymphoid malignancies. Mantle cell lymphoma rarely affects the central nervous system (CNS) as it represents about 0.9% of diagnosis and 4% among recurrent cases. Here, we present the case of a 69-year-old male patient who was diagnosed with mantle cell lymphoma in 2006. The patient relapsed three times, without affecting the CNS, then was treated accordingly, and achieved complete remission three times. Four years after his last complete remission, upon receiving his last dose of treatment, the medical team noted a rapid worsening of the patient’s neurological status followed by a deep coma state causing MCL neurological recurrence by exclusion diagnosis. The patient then received ibrutinib via a nasogastric tube at a dose of 560 mg daily. Two days after receiving his last dose of ibrutinib, the patient regained full consciousness, and 10 days later, he was discharged from the hospital. The patient achieved complete remission and showed no signs of neurological damages for 24 months following his ibrutinib treatment. We believe that the administration of ibrutinib through the nasogastric tube was a determinant factor in this patient’s remission and survival

Gene Expression in Human Acute Cutaneous and Hepatic Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

International audienceHematopoietic stem cell (HSC) allograft can be performed with cells of peripheral or medullar origin. Currently, it is the best therapy for certain malignant diseases. The curative power of allografts is based on conditioning and on the graft versus leukemia (GVL) effect. This effect is always associated with a toxic reaction called graft-versus-host disease (GVHD). Numerous studies have been carried out on mouse models, but the pathophysiology of GVHD remains unknown. To evaluate the variation in gene expression during GVHD, a prospective study was performed on two patients with GVHD, using the donors as controls. Blood lymphocytes were isolated by Ficoll gradient. The gene expression levels in total RNA were determined using the Taqman method. The gene expressions of cytokines (TNFα, INFγ, IL4, IL10), major histocompatibility complex class II (MHC II) and class III (BAT2), an adhesion molecule (VCAM) and granzyme M were studied. INFγ, TNFα, BAT2 and IL4 were up-regulated whereas IL10 and VCAM1 were down-regulated

Durable Resolution of Severe Psoriasis in a Patient Treated with Pentostatin for Hairy Cell Leukemia: A Case Report

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>.</b> <a href="https://link.springer.com/article/10.1007/s13555-017-0216-z">https://link.springer.com/article/10.1007/s13555-017-0216-z</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

Chemotherapy Treatment Doesn't Beneficiate to a Group of Elderly AML Patients with Absence of Complex Karyotype and Circulating Blasts

60th Annual Meeting of the American-Society-of-Hematology (ASH), San Diego, CA, DEC 01-04, 2018International audienceIntroductionAlthough the median age at diagnosis of acute myeloid leukemia (AML) is 67 years, with approximately one third of patients aged 75 years or older, limited treatment options are available for the elderly. There is no standard of care for older patients with AML unfit for intensive chemotherapy. In this case, despite specific treatment such as low-dose cytarabine (LDA) and 5 azacytidine (5AZA), outcome remains extremely poor, without cure (Thomas X, Current Treat Options Oncol 2017, 18(1):2). The goal of our study is to establish a prognostic model of survival in order to identify whether the absence of specific treatment may not be harmful in a subset of patients.Patients and MethodsThe French Hauts-de-France AML observatory is a population-based database reporting AML cases diagnosed and supported in 9 Hospital Centers from the French region Haut-de-France. From January 2008 to December 2016, 572 patients older than 75 years were included in the observatory. Among them 324 patients received best supportive care (BSC) alone, 142 hypomethylating agents, 82 low doses aracytine, and 24 other treatments. As a general consensus accepted in all participating centers, BSC was proposed in unfit patients, after performance status and comprehensive geriatric assessment according to results of a preliminary fast geriatric assessment oncodage G8 (Bellera CA, Ann Oncol 2012, 23(8):2166-72). Clinical data were collected in each center. The study was conducted according to the Declaration of Helsinki and was approved by the Human Research Committee of Lille and the internal review board of the Lille University Hospital Tumor Bank (certification NF 96900-2014/65453-1).ResultsIn the BSC group, median age at diagnosis was 82 years (interquartile range [IQR] 78-86). Median WBC count was 7.3 x10^3/mL (IQR 2.18-42.5) with a median peripheral blood blasts percentage of 21% (IQR 6-59.5). Median bone marrow blasts was 51% (IQR 30-75). Karyotype was available for 181 patients. Two patients were in the favorable, 111 patients (61%) were in the intermediate, 68 patients (38%) were in the unfavorable cytogenetics group and 58 patients (32%) had a complex karyotype.For the BSC group, median survival was 3.2 months (IC 2.3- 4) with a 18% 12-months survival estimate.In univariate Cox models, WBC count (p 75 years), 18% are alive at 12 months without any chemotherapy. Our results indicate that the absence of chemotherapy may not be detrimental in a small subset of unfit patients identified by the absence of both complex karyotype and circulating blasts. However further studies are mandatory for characterizing most of patients alive at 12 months with BSC

Comprehensive molecular landscape in patients older than 80 years old diagnosed with acute myeloid leukemia: A study of the French Hauts-de-France AML observatory

International audienceNo abstract availabl

Imatinib Optimized Therapy Improves Major Molecular Response Rates in Patients with Chronic Myeloid Leukemia

International audienceThe 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 &lt; 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, BC