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See detailRapamycin Prevents Experimental Sclerodermatous Chronic Graft-versus-Host Disease in mice
Belle, Ludovic ULg; Binsfeld, Marilène ULg; DUBOIS, Sophie ULg et al

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 14

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See detailWhat is the Contribution of Host-Derived CMV Immunity after Allogeneic Transplantation following Non-Myeloablative Conditioning?
MENTEN, Catherine ULg; Castermans, E.; Hannon, Muriel ULg et al

in Haematologica (2012), 97(Supplement 1), 720

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See detailEvidence for Expansion of Host-derived CMV-specific CD8+ T cells after Allogeneic Transplantation with Non-Myeloablative Conditioning
MENTEN, Catherine ULg; Castermans, E.; Hannon, Muriel ULg et al

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 16

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See detailRapamycin prevents experimental sclerodermatous chronic graft-versus-host disease in mice
Belle, Ludovic ULg; Binsfeld, Marilène ULg; DUBOIS, Sophie ULg et al

Conference (2012)

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that ... [more ▼]

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that mortality is relatively low, making difficult to study the impact of potentially therapeutic compounds. Aims: To develop a more severe model of cGVHD and to assess the impact of Rapamycin administration in that model. Results: Lethally irradiated Balb/C mice were injected with 10x106 bone marrow cells and 70x106 splenocytes from B10.D2 donor mice. Twenty-one days later, all mice developed cGvHD. For the severe model, donor B10.D2 mice were injected with 0.5x106 splenocytes from Balb/C twenty-one days before transplantation. All mice from the severe model (n=8) died a median of 32 days while 3 of 7 mice in the classical model survived beyond day 52. Mean survival was decreased in the severe model compared to the classical model (32 days versus 37 days; p=0.0185). Recipient mice in the severe group experienced higher weight loss, hair loss and skin fi brosis. Numbers of T lymphocytes (231.9 ± 151.4 versus 951 ± 532.8; p=0.0032) and CD4+ T cells (63.25 ± 41.93 versus 135.0 ± 14.39; p=0.0018) per microliter of blood at day 21 were lower in the severe group than in the classical model. Moreover, number of regulatory T cells (Tregs) was decreased in the severe model (1.250 ± 0.8864 versus 8.000 ± 6.753; p=0.0151). We then investigated whether rapamycin administration could prevent GVHD in the severe model. All (n=8) mice treated with PBS (placebo) died a median of 32 days after transplantation, while 6 of 8 mice given 1 mg/kg/day i.p. rapamycin survived beyond day 52 (p=0.0012). Number of Tregs/μl was higher at day 21 in rapamycin-treated mice than in mice given PBS (2.000±1.195 versus 1.250±0.8864; p=0.0796). Moreover, number of naïve CD4+T (10.00±4.192 versus 30.25±5.185; p= 0.0089) and effector memory T cells (EMT) (30.67±3.180 versus 67.33±7.881; p= 0.0125) were higher in rapamycin mice. Finally, proliferation of EMT (assessed by fl ow cytometry using Ki-67) was higher in PBS than in rapamycin mice (45.28%±4.084 versus 31.90%± 2.003; p=0.0474). Conclusion: We have developed a mice model of severe cGVHD. Interestingly, rapamycin prevented death from cGVHD in that model, perhaps through in vivo expansion of Treg. [less ▲]

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See detailValue of infliximab (Remicade) in patients with low-risk myelodysplastic syndrome. Final results of a randomized phase II trial (EORTC trial 06023) of the EORTC Leukemia Group
Baron, Frédéric ULg; Suciu, Stefan; Amadori, Sergio et al

in Haematologica (2012), 97(4), 529533

Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade) is an anti-tumor-necrosis factor alpha chimeric ... [more ▼]

Tumor-necrosis factor alpha activity has been correlated to ineffective erythropoiesis in lower risk myelodysplastic syndromes. Infliximab (Remicade) is an anti-tumor-necrosis factor alpha chimeric antibody that is used in the treatment of patients with heumatoid arthritis or Crohn's disease. Forty-six patients with myelodysplastic syndromes and a relatively low risk of developing acute leukemia were included in a randomized phase II study assessing the therapeutic activity of two dosages of infliximab administration (3 mg/kg versus 5 mg/kg). The primary endpoint was the response rate. Responses were observed in 3 of 22 patients (13.1%) randomized to the 3 mg/kg arm, versus 0 of 21 patients randomized in the 5 mg/kg arm. According to the statistical design of the current study, neither of the two infliximab dose schedules tested showed sufficient activity as a single agent in this cohort of unselected patients with early myelodysplastic syndrome. [less ▲]

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See detailBone marrow-derived mesenchymal stromal cells failed to prevent experimental xenogeneic graft-versus-host disease
Bruck, France; de Leval, Laurence; Belle, Ludovic ULg et al

Poster (2012)

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See detailImatinib and Nilotinib Inhibit Hematopoietic Progenitor Cell Growth, but Do Not Prevent Adhesion, Migration and Engraftment of Human Cord Blood CD34+ Cells
Belle, Ludovic ULg; Bruck, France; FOGUENNE, Jacques ULg et al

in PLoS ONE (2012), 7(12), 52564

Background: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to ... [more ▼]

Background: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34+ cells. Design and Methods: After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rc (null) mice. <br />Results: TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34+ cell cycle entry. Adhesion of CD34+ cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1a gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. <br />Conclusions: These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe. [less ▲]

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See detailComparison of Immune Reconstitution after Hematopoietic Stem Cell Transplantation with Flu-TBI versus TLI-ATG Conditioning
Hannon, Muriel ULg; Humblet-Baron, S.; Graux, C. et al

in Haematologica (2012), 97(Supplement 1), 180

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See detailAdaptation of a Murine Chronic GVH Model to Study Graft versus Myeloma Effect after Allogeneic Transplantation
Binsfeld, Marilène ULg; Belle, Ludovic ULg; Hannon, Muriel ULg et al

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 16

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See detailImpact of chronic graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukaemia: A report from the Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation
Baron, Frédéric ULg; Labopin, M.; Niederwieser, D. et al

Conference (2012)

We investigated the impact of occurrence of GVHD on transplantation outcomes in a large cohort of AML pts given allogeneic PBSC after RIC conditioning. Data from 1859 AML pts in fi rst (n=1439) or second ... [more ▼]

We investigated the impact of occurrence of GVHD on transplantation outcomes in a large cohort of AML pts given allogeneic PBSC after RIC conditioning. Data from 1859 AML pts in fi rst (n=1439) or second (n=420) CR transplanted between 2000 and 2009 following a RIC regimen at EBMT affi liated centres were analyzed. Pts were given PBSC from HLA-identical sibling (MRD, n=1208), or from HLA-matched unrelated donors (MUD, n=651). ATG was given in 269 (22%) MRD and in 267 (41%) MUD recipients, respectively, while 151 (13%) MRD and 165 (25%) MUD recipients received in-vivo T cell depletion with alemtuzumab. The impact of chronic GVHD (cGVHD) on outcomes was assessed using time-dependent multivariate Cox models and in a landmark analysis at 18 months after transplant. The 3-y cumulative incidence of cGVHD was 47%. Fifty-three percent of patients with cGVHD had extensive cGVHD, while the remaining 47% had limited cGVHD. In multivariate analyses, occurrence of grade II-IV aGVHD was associated with a lower risk of relapse (HR=0.8; P=0.04), a higher risk of chronic (HR=2.2; P<0.001) and extensive chronic GVHD (HR=2.8; P<0.001), a higher risk of NRM (HR=2.4 P<0.001), a worsened LFS (HR=1.3; P=0.01), and a worsened OS (HR=1.5; P<0.001). In multivariate time-dependent analyses, occurrence of limited cGVHD was associated with a lower risk of relapse (HR=0.7; P=0.05), comparable NRM (HR=1.4; P=0.16), comparable LFS (HR=0.9; P=0.29) and better OS (HR=0.5; P<0.001), while occurrence of extensive cGVHD was associated with a lower risk of relapse (HR=0.6; P=0.01), higher NRM (HR=3.2; P<0.001), a trend for worsened LFS (HR=1.3; P=0.06) and comparable OS (HR=0.9; P=0.34). In a landmark analysis in patients who were leukemia-free at 18 months after transplantation (n=776), 2-year relapse, NRM, LFS and OS were 16±2%, 2.5±1%, 82±2%, and 89±2%, respectively, in patients without cGVHD before the landmark time-point, versus 9±1% (P=0.001), 8±1% (P<0.001), 83±2% (P=0.65), and 86±2% (P=0.38), respectively, in patients with cGVHD before the landmark time-point. In conclusion, in this cohort of AML patients transplanted in remission, occurrence of cGVHD was associated with a lower risk of relapse that translated to better OS in patients with limited cGVHD but not in those with extensive cGVHD who experienced higher long term NRM. These results highlight the role of the GVT effect in RIC allo-SCT, but also the need for improving the prevention of severe cGVHD in pts receiving RIC allo-SCT. [less ▲]

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See detailImpact of alemtuzumab versus anti-thymocyte globulin after unrelated allogeneic stem cell transplantation with reduced-intensity conditioning as treatment for AML in CR1: a survey from the Acute Leukaemia Working Party of the EBMT
Baron, Frédéric ULg; Labopin, M.; Mufti, G. et al

Conference (2012)

In vivo T cell depletion of the graft with anti-thymocyte globulin (ATG) or with alemtuzumab has been frequently used in the setting of RIC allo-SCT from unrelated donors. This survey compared allo-SCT ... [more ▼]

In vivo T cell depletion of the graft with anti-thymocyte globulin (ATG) or with alemtuzumab has been frequently used in the setting of RIC allo-SCT from unrelated donors. This survey compared allo-SCT outcomes between 364 AML patients in first CR given unrelated PBSC after chemotherapy-based RIC and given either ATG (n=213) or alemtuzumab (n=151) in the conditioning regimen. Alemtuzumab patients were more frequently given grafts from HLA-mismatched donors (30% versus 16% having at least 1/10 HLA-mismatch with their donor, P=0.005), and were conditioned more often with melphalan-based RIC (62%), while ATG recipients were more frequently conditioned with busulfan-based RIC (84%). Median time to neutrophil engraftment (>500 ANC) was 16 days in ATG recipients, versus 12 days in alemtuzumab recipients (P<0.001). The incidence of grade II-IV acute GVHD was 28% in ATG recipients (9 patients with grade IV) and 24% (NS) in alemtuzumab recipients (2 patients with grade IV). Two-year incidences of chronic GVHD, relapse and NRM were 45%, 23% and 14%, respectively, in ATG recipients, and 47% (NS), 25% (NS) and 25% (P=0.008), respectively, in alemtuzumab recipients. Two-year OS and LFS were 69% and 63%, respectively, in ATG recipients, versus 55% (P=0.003) and 51% (P=0.02), respectively, in alemtuzumab recipients. Death from infection occurred in 7% of ATG recipients, versus 12% of alemtuzumab recipients. When the analysis was restricted to the 210 patients given grafts from 10/10 HLA-matched unrelated donors, the use of alemtuzumab (n=64) remained signifi cantly associated with higher NRM (22% vs 9%, P=0.007), lower LFS (58% vs 69%, P=0.07), and lower OS (62% vs 74%, P=0.04). In multivariate analyses (performed in patients given grafts from 10/10 HLA-matched donors), in comparison to the use of ATG, the use of alemtuzumab was associated with higher NRM (HR=2.5, P=0.025), a statistically non-signifi cant but higher relapse rate (HR=1.7, P=0.18), and signifi cantly worse LFS (HR=0.5, P=0.013) and OS (HR=0.4, P=0.002). In summary, this homogeneous cohort of AML patients transplanted in fi rst CR and given PBSC grafts from unrelated donors, the use of alemtuzumab in comparison with ATG was associated with worse LFS and OS. [less ▲]

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See detailEORTC Leukemia Group achievements
Willemze, Roel; Suciu, Stefan; Marie, Jean-Pierre et al

in EJC Supplements (2012), I

The EORTC Leukemia Group (LG) has a long history of promoting the study of leukemias and related malignancies and reports here on three of their most significant achievements. In acute myelogenous ... [more ▼]

The EORTC Leukemia Group (LG) has a long history of promoting the study of leukemias and related malignancies and reports here on three of their most significant achievements. In acute myelogenous leukemia (AML), the LG and Italian group GIMEMA started their fruitful collaboration in 1986 with the AML-8 trial with 1519 inclusions. In the AML-8A trial, in patients who reached complete remission, without a HLA identical sibling, autograft provided longer disease-free survival than a second course of consolidation, whereas the best outcome was observed in patients with a donor, who had to be allografted. The AML-10 trial set a new standard of treatment for induction/consolidation with replacement of daunorubicin by either idarubicin or mitoxantrone. The AML-12 trial tested the effect of high-dose cytosinearabinoside during induction (2109 inclusions, data base locked in August 2011 for final analysis). Development of intergroup trials focusing on subgroups of AML bearing specific genetic abnormalities is now mandatory to validate the “targeted approach” of driving molecular events. In high-risk myelodysplastic syndrome (MDS), the phase III trial conducted by the LG in collaboration with the German MDS Study Group showed that the response rate of decitabine versus best supportive care was higher (complete or partial remissions, 19% versus 0%, and hematologic improvement, 15% versus 2%), progression-free survival was significantly prolonged (median 6.6 versus 3 months), cumulative incidence of AML was significantly decreased (22% versus 33% at one year), but the impact on OS was less evident (median 10.1 versus 8.5 months; hazard ratio 0.88). Quality of life had improved significantly in patients in the decitabine arm. The assessment of HDAC inhibitors, such as vorinostat, will probably be tested in the next trial. Also in MDS, relevant genetic lesions involved in the pathogenesis of this disease were identified using single nucleotide polymorphisms array-based genomic profiling and genomic sequencing in 102 patients with MDS. Acquired abnormalities of the TET2 gene were identified in 26% of the cases and in the EZH2 gene in 5−10% of the patients. TET2 mutations were detected in 96% of the bone marrow cells, including CD34+ progenitor cells, suggesting that TET2 mutations could be an early event during disease evolution. In normal bone marrow, TET2 expression was elevated in granulocytes, suggesting a role in myelopoiesis. Conclusion: during the last 25 years the EORTC LG in cooperation with GIMEMA made a considerable contribution to the improvement of treatment results of patients with acute leukemia or MDS. [less ▲]

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See detailMesenchymal stromal cells : a new tool against graft-versus-host disease ?
Baron, Frédéric ULg; Storb, Rainer

in Biology of Blood & Marrow Transplantation (2012), 18(6), 822-840

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti ... [more ▼]

Mesenchymal stromal cells (MSCs) represent a heterogeneous subset of multipotent cells that can be isolated from several tissues including bone marrow and fat. MSCs exhibit immunomodulatory and anti-inflammatory properties that prompted their clinical use as prevention and/or treatment for severe graft-versus-host disease (GVHD). Although a number of phase I-II studies have suggested that MSCs infusion was safe and might be effective for preventing or treating acute GVHD, definitive proof for their efficacy remains lacking thus far. Multicenter randomized studies are ongoing to more precisely assess the impact of MSCs infusion on GVHD prevention/treatment, whereas further research is performed in vitro and in animal models with the aims of determining the best way to expand MSCs ex vivo as well as the most efficient dose and schedule of MSCs administration. After introducing GVHD, MSC biology, and results of MSCs infusion in animal models of allogeneic hematopoietic cell transplantation, this article reviews the results of the first clinical trials investigating the use of MSCs infusion as prevention or treatment of GVHD. [less ▲]

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See detailAllogreffe de cellules souches hématopoïétiques après conditionnements réduits ("minigreffes") comme traitement de certaines pathologies hématologiques malignes
SERVAIS, Sophie ULg; Baron, Frédéric ULg

in Onco Hemato (2012), 6

L’allogreffe de cellules souches hématopoïétiques est un trai¬tement efficace, proposé pour la prise en charge d’un grand nombre de pathologies hématologiques malignes. Le concept des allogreffes de ... [more ▼]

L’allogreffe de cellules souches hématopoïétiques est un trai¬tement efficace, proposé pour la prise en charge d’un grand nombre de pathologies hématologiques malignes. Le concept des allogreffes de cellules souches hématopoïétiques après un conditionnement réduit (appelées «minigreffes») repose sur deux principes essentiels: une toxicité moindre du condi¬tionnement limitant la morbidité et la mortalité reliées à la greffe et l’immunothérapie antitumorale (effet «greffe-ver¬sus-tumeur») comme mécanisme principal de l’éradication des cellules malignes. Les minigreffes ont démontré des résul¬tats encourageants dans de nombreuses pathologies héma¬tologiques malignes. Elles permettent aux patients inéligibles pour une greffe de cellules souches conventionnelle avec un conditionnement myéloablatif de bénéficier de l’effet (poten¬tiellement curatif) de la greffe contre la tumeur. Au travers de cet article, nous proposons une revue de la littérature concernant les fondements conceptuels des minigreffes de cellules souches hématopoïétiques, les particularités de ce type de greffes, les effets secondaires possibles, les résultats obtenus dans plusieurs pathologies hématologiques malignes ainsi que les indications actuellement reconnues. [less ▲]

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See detailRituximab et maladie du greffon contre l'hôte chronique
Baron, Frédéric ULg; SERVAIS, Sophie ULg

in Horizons Hemato (2012), 2(2), 78-81

La maladie du greffon contre l’hôte (« greffe-versus-hôte » – GVH) chronique (GVHc) est une complication fréquente des allogreffes de cellules souches hématopoïétiques (CSH). A l’heure actuelle, à ... [more ▼]

La maladie du greffon contre l’hôte (« greffe-versus-hôte » – GVH) chronique (GVHc) est une complication fréquente des allogreffes de cellules souches hématopoïétiques (CSH). A l’heure actuelle, à l’exception des corticostéroïdes, peu de traitements se sont avérés réellement efficaces pour la prise en charge de la GVHc. Des données récentes suggèrent un rôle important des lymphocytes B (LB) dans la physiopathologie de la GVHc. Elles constituent le rationnel scientifique à une série d’études évaluant l’efficacité du rituximab, un anticorps monoclonal dirigé contre l’antigène CD20 exprimé à la surface des LB, dans la prévention ou le traitement de la GVHc. [less ▲]

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See detailExpression of growth hormone (GH)/insulin-like growth factor (IGF) axis during Balb/c ontogeny and effects of GH upon ex-vivo T-cell differentiation
Kermani, Hamid; Goffinet, Lindsay ULg; Mottet, Marie ULg et al

in Neuroimmunomodulation (2012), 19

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in ... [more ▼]

Aims: We here address the question of expression and role of GH/IGF axis in the thymus. Methods: Using RT-qPCR, the expression profile of various components of the somatotrope GH/IGF axis was measured in different thymic cell types and during thymus embryogenesis in Balb/c mice. Effect of GH on T-cell differentiation was explored through thymic organotypic culture. Results: Transcription of Gh, Igf1, Igf2 and their related receptors predominantly occurred in thymic epithelial cells (TEC), while a low level of Gh and Igf1r transcription was also evidenced in thymic T cells (thymocytes). Gh, Ghr, Ins2, Igf1, Igf2, and Igfr1, displayed distinct expression profiles depending on the developmental stage. The protein concentration of IGF-1 and IGF-2 were in accordance with the profile of their gene expression. In fetal thymus organ cultures (FTOC) derived from Balb/c mice, treatment with exogenous GH resulted in a significant increase of double negative CD4-CD8- T cells and CD4+ T cells, together with a decrease in double positive CD4+CD8+ T cells. These changes were inhibited by concomitant treatment with GH and GHR antagonist pegvisomant. However, GH treatment also induced a significant decrease in FTOC Gh, Ghr and Igf1 expression. Conclusion: These data show that the thymotropic properties of the somatotrope GH/IGF-1 axis involve an interaction between exogenous GH and GHR expressed by TEC. Since thymic IGF-1 is not increased by GH treatment, the effects of GH upon T-cell differentiation could implicate a different local growth factor or cytokine. [less ▲]

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