References of "Baron, Frédéric"
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See detailPost-remission strategies for the prevention of relapse following allogeneic hematopoietic cell transplantation for high-risk acute myeloid leukemia: expert review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Lee, C. J.; Savani, B. N.; Mohty, M. et al

in Bone Marrow Transplantation (in press)

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy generally associated with poor prognosis. Allogeneic hematopoietic cell transplantation (alloHCT) continues to be the most potent ... [more ▼]

Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy generally associated with poor prognosis. Allogeneic hematopoietic cell transplantation (alloHCT) continues to be the most potent anti-leukemia treatment for adult patients with intermediate and high-risk AML. However, disease relapse after alloHCT remains unacceptably high and is the primary cause of treatment failure and mortality following alloHCT. It is therefore that post-transplant early cellular or pharmacologic maintenance or preemptive strategies to enhance the graft-versus-leukemia effect or to eradicate persistent minimal residual disease have been of renewed interest, particularly with the availability of more sensitive technologies to measure residual AML. Although preliminary studies have demonstrated improved outcomes with the use of post-alloHCT remission therapies, prospective randomized trials are required to determine their clinical efficacy and role in the treatment of AML. On behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize the available evidence on the use and efficacy of available pharmacologic post-remission therapies, including hypomethylating agents, deacetylase inhibitors, and tyrosine kinase inhibitors, as well as cellular therapies, including preemptive and prophylactic donor lymphocyte infusions for the prevention of relapse of AML. © 2018, Springer Nature Limited. [less ▲]

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See detailInfusion of third-party mesenchymal stromal cells after kidney transplantation: a phase I-II, open-label, clinical study.
ERPICUM, Pauline ULiege; WEEKERS, Laurent ULiege; DETRY, Olivier ULiege et al

in Kidney International (2019), 95

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year ... [more ▼]

Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs ( approximately 2 x 10(6)/kg) on day 3 +/- 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m(2), compared to 32.5 ml/min/1.73m(2)in controls and 29.3 ml/min/1.73m(2)in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied. [less ▲]

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See detailComparison of Mesenchymal Stromal Cells From Different Origins for the Treatment of Graft-vs.-Host-Disease in a Humanized Mouse Model.
Gregoire, Celine; Ritacco, Caroline ULiege; Hannon, Muriel et al

in Frontiers in immunology (2019), 10

Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies ... [more ▼]

Mesenchymal stromal cells (MSCs) have potent immunomodulatory properties that make them an attractive tool against graft- vs.-host disease (GVHD). However, despite promising results in phase I/II studies, bone marrow (BM-) derived MSCs failed to demonstrate their superiority over placebo in the sole phase III trial reported thus far. MSCs from different tissue origins display different characteristics, but their therapeutic benefits have never been directly compared in GVHD. Here, we compared the impact of BM-, umbilical cord (UC-), and adipose-tissue (AT-) derived MSCs on T-cell function in vitro and assessed their efficacy for the treatment of GVHD induced by injection of human peripheral blood mononuclear cells in NOD-scid IL-2Rgamma(null) HLA-A2/HHD mice. In vitro, resting BM- and AT-MSCs were more potent than UC-MSCs to inhibit lymphocyte proliferation, whereas UC- and AT-MSCs induced a higher regulatory T-cell (CD4(+)CD25(+)FoxP3(+))/T helper 17 ratio. Interestingly, AT-MSCs and UC-MSCs activated the coagulation pathway at a higher level than BM-MSCs. In vivo, AT-MSC infusions were complicated by sudden death in 4 of 16 animals, precluding an analysis of their efficacy. Intravenous MSC infusions (UC- or BM- combined) failed to significantly increase overall survival (OS) in an analysis combining data from 80 mice (hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.32-1.08, P = 0.087). In a sensitivity analysis we also compared OS in control vs. each MSC group separately. The results for the BM-MSC vs. control comparison was HR = 0.63 (95% CI 0.30-1.34, P = 0.24) while the figures for the UC-MSC vs. control comparison was HR = 0.56 (95% CI 0.28-1.10, P = 0.09). Altogether, these results suggest that MSCs from various origins have different effects on immune cells in vitro and in vivo. However, none significantly prevented death from GVHD. Finally, our data suggest that the safety profile of AT-MSC and UC-MSC need to be closely monitored given their pro-coagulant activities in vitro. [less ▲]

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See detailUmbilical cord blood versus unrelated donor transplantation in adults with primary refractory or relapsed acute myeloid leukemia: a report from Eurocord, the Acute Leukemia Working Party and the Cord Blood Committee of the Cellular Therapy and Immunobiology Working Party of the EBMT.
Baron, Frédéric ULiege; Labopin, Myriam; Ruggeri, Annalisa et al

in Blood Cancer Journal (2019), 9(4), 46

The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated ... [more ▼]

The role of umbilical cord blood transplantation (CBT) in acute myeloid leukemia (AML) patients with active disease at allogeneic hematopoietic cell transplantation (allo-HCT) remains poorly investigated. In this study, we compared transplantation outcomes of 2963 patients with primary refractory or relapsed AML given CBT, 10/10 HLA-matched UD, or 9/10 HLA-matched UD allo-HCT from 2004 to 2015 at EBMT-affiliated centers. Neutrophil engraftment and complete remission rates in CBT, UD 10/10, and UD 9/10 recipients were 75 and 48%, 93 and 69%, and 93 and 70%, respectively. In multivariate Cox analyses, in comparison with CBT (n = 285), UD 10/10 recipients (n = 2001) had a lower incidence of relapse (HR = 0.7, P = 0.001), a lower incidence of non relapse mortality (HR = 0.6, P < 0.001), better GVHD-free and leukemia-free survival (GRFS, HR = 0.8, P < 0.001) and better survival (HR = 0.6, P < 0.001). Further, in comparison with CBT, 9/10 UD recipients (n = 677) also had a lower incidence of relapse (HR = 0.8, P = 0.02), a lower incidence of nonrelapse mortality (HR = 0.7, P = 0.008), better GRFS (HR = 0.8, P = 0.01) and better survival (HR = 0.7, P < 0.001). In summary, these data suggest that in AML patients with active disease at transplantation, allo-HCT with UD results in better transplantation outcomes than CBT. [less ▲]

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See detailIn Vitro Th17-Polarized Human CD4(+) T Cells Exacerbate Xenogeneic Graft-versus-Host Disease.
Delens, Loïc ULiege; Ehx, Gregory; SOMJA, Joan ULiege et al

in Biology of Blood and Marrow Transplantation (2019), 25

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this ... [more ▼]

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4(+) T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rgamma null (NSG) mice. Naive human CD4(+) T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A(+)IFNgamma(+) profile in vivo. Importantly, cotransfer of Th17-polarized cells (1x10(6)) with PBMCs (1x10(6)) exacerbated xGVHD compared with transplantation of PBMCs alone (2x10(6)). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4(+) T cells stimulated in nonpolarizing conditions (Th0 cells, 1x10(6)+1x10(6) PBMCs) or with Th1-polarized cells (1x10(6)+1x10(6) PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model. [less ▲]

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See detailGrowth hormone (GH) deficient mice with GHRH ablation are severely deficient in vaccine and immune responses against Streptococcus pneumoniae
Farhat, Khalil; Bodart, Gwennaëlle ULiege; Charlet-Renard, Jeanne de Chantal ULiege et al

in Frontiers in Immunology (2018), 9

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene ... [more ▼]

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh−/−) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh−/− mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh−/− mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh−/− mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh−/− mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh−/− mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh−/− mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae. [less ▲]

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See detailObesity induces metabolic and phenotypic variations in blood monocytes and NK cells.
Colonval, Megan ULiege; Iovino, Margaud ULiege; Esser, Nathalie et al

Poster (2018, June 26)

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See detailLa souris, le patient, et le faux expert. Décryptage d'une mystification.
Bakker, Julie ULiege; Balthazart, Jacques ULiege; Baron, Frédéric ULiege et al

Article for general public (2018)

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les ... [more ▼]

La recherche sur animaux est actuellement encadrée de façon stricte en Wallonie comme dans toute l'Union Européenne (voir l'article de Marc Vandenheede publié dans le Vif). Cette législation et les contrôles qui y sont associés induisent de nombreuses contraintes pratiques, des charges administratives et des coûts financiers importants que les chercheurs seraient certainement heureux d'éviter s'il existait une alternative à l'expérimentation animale. [less ▲]

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See detailGHRH-deleted Mice Are Severely Deficient in Vaccine And Immunological Responses Against Streptococcus Pneumoniae
Farhat, Khalil ULiege; Bodart, Gwennaëlle ULiege; Desmet, Christophe ULiege et al

Conference (2018, March 20)

Background and objective of the work. Ghrh-/- mice with a severe deficiency of their somatotrope GHRH/GH/IGF1 axis (1) are resistant to experimental allergic encephalomyelitis (2). In basal conditions ... [more ▼]

Background and objective of the work. Ghrh-/- mice with a severe deficiency of their somatotrope GHRH/GH/IGF1 axis (1) are resistant to experimental allergic encephalomyelitis (2). In basal conditions, thymus and T-cell development are not severely affected but a marked spleen atrophy and B-cell lymphopenia were constantly observed (3). Therefore, we investigated vaccinal and anti-infectious responses of Ghrh-/- mice against S.pneumoniae, a T-independent pathogen. Results. Transgenic mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, Pnx23) or protein-PPS conjugate (Prev13). GH treatment of Ghrh-/- mice restored IgM response to Pnx23 vaccine but not to Prev13 suggesting that GH exerts a significant impact on the spleen marginal zone that is strongly implicated in T-independent immunological response to pneumococcal polysaccharides. After intranasal instillation of a non-lethal dose of S.pneumoniae, Ghrh-/- mice exhibited a dramatic susceptibility with a time-dependent increase in lung bacterial load, a bacteremia already after 24h, and a survival limit of 48-72h. In marked contrast, WT and heterozygote mice completely cleared S.pneumoniae infection after 24h. Lungs of infected Ghrh-/- mice were massively infiltrated by inflammatory macrophages, while lung B cells were markedly decreased. Transcription of Ifng, Il10, Cd40, and Cxcl9 was highly increased in the lungs of infected Ghrh-/- mice, whereas Tgfb and Iggj transcripts were unchanged. Resistance of Ghrh-/- mice to infection by influenzavirus H1N1 (a T-dependent antigen) was normal or slightly decreased. Conclusion. This animal model shows that the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in the vaccine and immunological defense against S.pneumoniae. [less ▲]

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See detailNeuronal surface antibody-mediated encephalopathy as manifestation of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Pirotte, Michelle ULiege; Forte, Florence ULiege; Lutteri, Laurence ULiege et al

in Journal of Neuroimmunology (2018), 323

Although it remained controversial for a long time, central nervous system (CNS) involvement of graft-versus-host disease (GVHD) is now becoming recognized as a real nosological entity. Previous case ... [more ▼]

Although it remained controversial for a long time, central nervous system (CNS) involvement of graft-versus-host disease (GVHD) is now becoming recognized as a real nosological entity. Previous case reports have suggested heterogeneous clinical presentations and it is not excluded that the whole spectrum of manifestations has not yet been fully described. Here, we report the case of a 58-year-old man with chronic GVHD who developed a rapidly ingravescent encephalopathy. There was no evidence for CNS immune-mediated lesions on conventional imaging nor for cellular infiltration in the cerebrospinal fluid. Serum analyses revealed the presence of anti-neuronal antibodies directed against anti-contactin-associated protein 2 (anti-Caspr2), a protein associated with voltage-gated potassium neuronal channels. Functional imaging with 2-deoxy-2-[fluorine-18] fluoro- D-glucose integrated with computed tomography (18F-FDG PET-CT) demonstrated diffuse cortical and subcortical hypometabolism. The patient was treated with a combination of immunosuppressive agents (corticosteroids, cyclophosphamide and rituximab) and progressively recovered normal neurocognitive functions. Taken together, these data suggest that CNS-GVHD may manifest as a reversible antibody-mediated functional encephalopathy. This report suggests for the first time the interest of screening for anti-neuronal antibodies and functional imaging with brain 18F-FDG PET-CT in diagnosing this severe complication of allogeneic hematopoietic cell transplantation (alloHSCT). © 2018 Elsevier B.V. [less ▲]

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See detailBeyond maximum grade: modernising the assessment and reporting of adverse events in haematological malignancies.
Thanarajasingam, Gita; Minasian, Lori M.; Baron, Frédéric ULiege et al

in Lancet. Haematology (2018), 5

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have ... [more ▼]

Tremendous progress in treatment and outcomes has been achieved across the whole range of haematological malignancies in the past two decades. Although cure rates for aggressive malignancies have increased, nowhere has progress been more impactful than in the management of typically incurable forms of haematological cancer. Population-based data have shown that 5-year survival for patients with chronic myelogenous and chronic lymphocytic leukaemia, indolent B-cell lymphomas, and multiple myeloma has improved markedly. This improvement is a result of substantial changes in disease management strategies in these malignancies. Several haematological malignancies are now chronic diseases that are treated with continuously administered therapies that have unique side-effects over time. In this Commission, an international panel of clinicians, clinical investigators, methodologists, regulators, and patient advocates representing a broad range of academic and clinical cancer expertise examine adverse events in haematological malignancies. The issues pertaining to assessment of adverse events examined here are relevant to a range of malignancies and have been, to date, underexplored in the context of haematology. The aim of this Commission is to improve toxicity assessment in clinical trials in haematological malignancies by critically examining the current process of adverse event assessment, highlighting the need to incorporate patient-reported outcomes, addressing issues unique to stem-cell transplantation and survivorship, appraising challenges in regulatory approval, and evaluating toxicity in real-world patients. We have identified a range of priority issues in these areas and defined potential solutions to challenges associated with adverse event assessment in the current treatment landscape of haematological malignancies. [less ▲]

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See detailThe eGVHD App has the potential to improve the accuracy of graft versus host disease assessment: a multicenter randomized controlled trial.
Schoemans, Helene M.; Goris, Kathy; Van Durm, Raf et al

in Haematologica (2018), 103

Graft-versus-host disease assessment has been shown to be a challenge for healthcare professionals, leading to the development of the eGVHD App (www.uzleuven.be/egvhd). In this study, we formally ... [more ▼]

Graft-versus-host disease assessment has been shown to be a challenge for healthcare professionals, leading to the development of the eGVHD App (www.uzleuven.be/egvhd). In this study, we formally evaluated the accuracy of using the App compared to traditional assessment methods to assess graft-versus-host disease. Our national multicenter randomized controlled trial involved seven Belgian transplantation centers and 78 healthcare professionals selected using a two-stage convenience sampling approach between January and April 2017. Using a 1:1 randomization stratified by profession, healthcare professionals were assigned to use either the App ("APP&") or their usual graft-versus-host disease assessment aids ("No APP") to assess the diagnosis and severity score of ten expert-validated clinical vignettes. Our main outcome measure was the difference in accuracy for graft-versus-host disease severity scoring between both groups. The odds of being correct were 6.14 (95% CI: 2.83-13.34) and 6.29 (95% CI: 4.32-9.15) times higher in favor of the "APP" group for diagnosis and scoring, respectively (p<0.001). App-assisted graft-versus-host disease severity scoring was significantly superior for both acute and chronic graft-versus-host disease, with an Odds Ratio of 17.89 and 4.34 respectively (p<0.001) and showed a significantly increased inter-observer agreement compared to standard practice. Despite a mean increase of 24 minutes (95% CI: 20.45-26.97) in time needed to score the whole graft-versus-host disease test package in the"APP" group (p<0.001), usability feedback was positive. The eGVHD App showed superior graft-versus-host disease assessment accuracy compared to standard practice and has the potential to improve the quality of outcome data registration in allogeneic stem cell transplantation. [less ▲]

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See detailImpact of antithymocyte globulin doses in reduced intensity conditioning before allogeneic transplantation from matched sibling donor for patients with acute myeloid leukemia: a report from the acute leukemia working party of European group of Bone Marrow Transplantation.
Devillier, Raynier; Labopin, Myriam; Chevallier, Patrice et al

in Bone Marrow Transplantation (2018), 53

Antithymocyte globulin (ATG) is commonly used for graft-vs.-host disease (GVHD) prophylaxis in unrelated donor allogeneic transplantation (Allo-HSCT). However, its use is still controversial in matched ... [more ▼]

Antithymocyte globulin (ATG) is commonly used for graft-vs.-host disease (GVHD) prophylaxis in unrelated donor allogeneic transplantation (Allo-HSCT). However, its use is still controversial in matched sibling donor (MSD) Allo-HSCT, notably after reduced intensity conditioning (RIC). ATG dose may influence the outcome, explaining in part the discordant conclusions in MSD Allo-HSCT. We, therefore, analyzed the impact of ATG doses in patients with acute myeloid leukemia in first complete remission undergoing RIC Allo-HSCT from a MSD. We analyzed 234 patients from the EBMT registry and compared outcome according to given ATG dose (high dose: >/= 6 mg/kg, n = 39 or low dose: < 6 mg/kg, n = 195). No difference was found in the cumulative incidence of acute (grade 2-4: high dose vs. low dose: 21% vs. 13%, p = 0.334; adjusted hazard ratio (HR): 1.20, p = 0.712) and chronic GVHD (extensive: high dose vs. low dose: 19% vs. 18%, p = 0.897; adjusted HR: 1.01, p = 0.980). In contrast, high dose of ATG significantly increased the incidence of relapse (52% vs. 26%, p = 0.011; adjusted HR: 1.31, p = 0.001) leading to impaired outcome (HR progression-free survival (PFS): 1.23, p = 0.002; HR overall survival (OS): 1.17, p = 0.029; HR GVHD and relapse-free survival (GRFS): 1.20, p = 0.005). We conclude that an ATG dose <6 mg/kg is sufficient for GVHD prophylaxis, while higher doses impair disease control and outcome. [less ▲]

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See detailCytogenetic clonal heterogeneity is not an independent prognosis factor in 15-60-year-old AML patients: results on 1291 patients included in the EORTC/GIMEMA AML-10 and AML-12 trials.
Baron, Frédéric ULiege; Stevens-Kroef, Marian; Kicinski, Michal et al

in Annals of Hematology (2018), 97

The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of ... [more ▼]

The presence of cytogenetic clonal heterogeneity has been associated with poor prognosis in patients with acute myeloid leukemia (AML). Here, we reassessed this association. The study cohort consisted of all patients with an abnormal karyotype randomized in the EORTC/GIMEMA AML-10 and AML-12 trials. Abnormal karyotypes were classified as no subclones present (cytogenetic abnormality in a single clone), defined subclones present (presence of one to three subclones), and composite karyotypes (CP) (clonal heterogeneity not allowing enumeration of individual subclones). The main endpoints were overall survival (OS) and disease-free survival (DFS). Among 1291 patients with an abnormal karyotype, 1026 had no subclones, 226 at least 1 subclone, and 39 a CP. Patients with defined subclones had an OS similar to those with no subclones (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.88-1.26), but CP patients had a shorter OS (HR = 1.58, 95% CI 1.11-2.26). However, in a multivariate Cox model stratified by protocol and adjusted for age, cytogenetic risk group, secondary versus primary AML, and performance status, clonal heterogeneity lost its prognostic importance (HR = 1.10, 95% CI 0.91-1.32 for defined subclones versus no subclones; HR = 0.96, 95% CI 0.67-1.38 for CP versus no subclones). Also, the impact of having a donor on DFS was similar in the three clonal subgroups. In summary, in patients with cytogenetic abnormality, presence of subclones had no impact on OS. The dismal outcome in patients with a CP was explained by the known predictors of poor prognosis. TRIAL REGISTRATION: AML-10: ClinicalTrials.gov identifier: NCT00002549, retrospectively registered July 19, 2004; AML12: ClinicalTrials.gov identifier: NCT00004128, registered January 27, 2003. [less ▲]

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See detailHaploidentical transplantation is associated with better overall survival when compared to single cord blood transplantation: An EBMT-Eurocord study of acute leukemia patients conditioned with thiotepa, busulfan, and fludarabine
Giannotti, F.; Labopin, M.; Shouval, R. et al

in Journal of Hematology and Oncology (2018), 11(1), 110

Background: Thiotepa-busulfan-fludarabine (TBF) is a widely used conditioning regimen in single umbilical cord blood transplantation (SUCBT). More recently, it was introduced in the setting of non-T cell ... [more ▼]

Background: Thiotepa-busulfan-fludarabine (TBF) is a widely used conditioning regimen in single umbilical cord blood transplantation (SUCBT). More recently, it was introduced in the setting of non-T cell depleted haploidentical stem cell transplantation (NTD-Haplo). Whether TBF based conditioning provides additional benefit in transplantation from a particular alternative donor type remains to be established. Methods: This was a retrospective study based on an international European registry. We compared outcomes of de-novo acute myeloid leukemia patients in complete remission receiving NTD-Haplo (n = 186) vs. SUCBT (n = 147) following myeloablative conditioning (MAC) with TBF. Median follow-up was 23 months. Treatment groups resembled in baseline characteristics. Results: SUCBT was associated with delayed engraftment and higher graft failure. In multivariate analysis no statistically significant differences were observed between the two groups in terms of acute or chronic graft-versus-host disease (GvHD) (HR = 1.03, p = 0.92 or HR = 1.86, p = 0.21) and relapse incidence (HR = 0.8, p = 0.65). Non-relapse mortality (NRM) was significantly higher in SUCBT as compared to NTD-Haplo (HR = 2.63, p = 0.001); moreover, SUCBT did worse in terms of overall survival (HR = 2.18, p = 0.002), leukemia-free survival (HR = 1.94, p = 0.007), and GvHD relapse-free survival (HR = 2.38, p = 0.0002). Conclusions: Our results suggest that TBF-MAC might allow for a potent graft-versus-leukemia, regardless of the alternative donor type. Furthermore, in patients receiving TBF-MAC, survival with NTD-Haplo may be better compared to SUCBT due to decreased NRM. © 2018 The Author(s). [less ▲]

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See detailSpontaneous atopic dermatitis due to immune dysregulation in mice lacking Adamts2 and 14.
Dupont, Laura ULiege; Ehx, Grégory; Chantry, Mathilde et al

in Matrix Biology (2018), 70

Since its first description, ADAMTS14 has been considered as an aminoprocollagen peptidase based on its high similarity with ADAMTS3 and ADAMTS2. As its importance for procollagen processing was never ... [more ▼]

Since its first description, ADAMTS14 has been considered as an aminoprocollagen peptidase based on its high similarity with ADAMTS3 and ADAMTS2. As its importance for procollagen processing was never experimentally demonstrated in vivo, we generated Adamts14-deficient mice. They are healthy, fertile and display normal aminoprocollagen processing. They were further crossed with Adamts2-deficient mice to evaluate potential functional redundancies between these two highly related enzymes. Initial characterizations made on young Adamts2-Adamts14-deficient animals showed the same phenotype as that of Adamts2-deficient mice, with no further reduction of procollagen processing and no significant aggravation of the structural alterations of collagen fibrils. However, when evaluated at older age, Adamts2-Adamts14-deficient mice surprisingly displayed epidermal lesions, appearing in 2 month-old males and later in some females, and then worsening rapidly. Immunohistological evaluations of skin sections around the lesions revealed thickening of the epidermis, hypercellularity in the dermis and extensive infiltration by immune cells. Additional investigations, performed on young mice before the formation of the initial lesions, revealed that the primary cause of the phenotype was not related to alterations of the epidermal barrier but was rather the result of an abnormal activation and differentiation of T lymphocytes towards a Th1 profile. However, the primary molecular defect probably does not reside in the immune system itself since irradiated Adamts2-Adamts14-deficient mice grafted with WT immune cells still developed lesions. While originally created to better characterize the common and specific functions of ADAMTS2 and ADAMTS14 in extracellular matrix and connective tissues homeostasis, the Adamts2-Adamts14-deficient mice revealed an unexpected but significant role of ADAMTS in the regulation of immune system, possibly through a cross-talk involving mesenchymal cells and the TGFβ pathways. [less ▲]

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See detailImpact of Induction Regimen and of Allogeneic Hematopoietic Cell Transplantation on Outcome in Younger Adults Patients with Acute Myeloid Leukemia with a Monosomal Karyotype.
Baron, Frédéric ULiege; Stevens-Kroef, Marian; Kicinski, Michal et al

in Haematologica (2018)

Monosomal karyotype (MK) confers a poor prognosis in patients with acute myeloid leukemia (AML). Here, we determined the impact of the type of remission-induction chemotherapy and the impact of having a ... [more ▼]

Monosomal karyotype (MK) confers a poor prognosis in patients with acute myeloid leukemia (AML). Here, we determined the impact of the type of remission-induction chemotherapy and the impact of having a donor in younger AML patients with a MK included in two phase III trials. In the first trial, patients were randomized to receive either daunorubicin (DNR), mitoxantrone (MTX), or idarubicin (IDA) in addition to standard-dose cytarabine (SDAC) and etoposide for induction chemotherapy. In the second trial, patients were randomized between either SDAC or high dose cytarabine (HiDAC) induction, both with DNR and etoposide. In both trials, patients who achieved a complete remission with (CR) or without (CRi) complete hematological recovery received an allogeneic hematopoietic stem cell transplantation (allo-HSCT) if they had a donor or an autologous HSCT (auto-HSCT) otherwise. In comparison to patients with intermediate risk cytogenetics without MK (n=1584) and with adverse cytogenetics without MK (n=218), MK+ patients (n=188) were more likely not to achieve a CR/CRi (odds ratio=2.85, 95% confidence interval, CI: 2.10-3.88) and had shorter overall survival (OS) (hazard ratio, HR=2.44, 95% CI: 2.08-2.88) and OS from CR/CRi (HR=2.73, 95% CI: 2.17-3.45). There was no impact of the type of anthracycline or of SDAC vs HiDAC on outcomes in MK+ patients. Among MK+ patients who achieved a CR/CRi, HLA-identical related donor availability was associated with longer survival from CR/CRi (HR=0.59, 95% CI: 0.37-0.95). In summary, these data suggest no benefit of HiDAC in MK+ patients but better OS associated with allo-HSCT. [less ▲]

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See detailCord blood transplantation is associated with good outcomes in secondary Acute Myeloid Leukemia in first remission.
Baron, Frédéric ULiege; Labopin, Myriam; Ruggeri, Annalisa et al

in Journal of Internal Medicine (2018)

BACKGROUND: We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary ... [more ▼]

BACKGROUND: We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary acute myeloid leukemia (sAML). METHODS: Inclusion criteria consisted of >/= 18 years of age, sAML, first CBT between 2002 and 2016, and either first complete remission (CR) or active disease at CBT. RESULTS: One hundred forty six patients met the study inclusion criteria. Status at transplantation was first CR (n=97), primary refractory sAML (n=30) or relapsed (n=19) sAML. Neutrophil engraftment was achieved in 118 patients while the remaining 25 patients (17%) failed to engraft. This include 13% of patients transplanted in first CR versus 30% of those transplanted with active disease (P=0.008)). Two-year incidences of relapse were 25% in first CR patients versus 36% in those with advanced disease (P=0.06) while 2-year incidences of nonrelapse mortality were 35% and 49% (P=0.03), respectively. At 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse free survival were 42% versus 19% (P<0.001), 40% versus 16% (P<0.001), and 26% versus 12% (P=0.002) in first CR patients versus those with advanced disease, respectively. CONCLUSIONS: We report here the first study of CBT in a large cohort of sAML patients. Main observation was that CBT rescued approximately 40% of patients with sAML in first CR. This article is protected by copyright. All rights reserved. [less ▲]

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See detailConditioning intensity in secondary AML with prior myelodysplastic syndrome/myeloproliferative disorders: an EBMT ALWP study.
Sengsayadeth, Salyka; Gatwood, Katie S.; Boumendil, Ariane et al

in Blood Advances (2018), 2(16), 2127-2135

Patients with secondary AML (sAML) with antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) tend to have high-risk disease based on the older age of patients, high-risk ... [more ▼]

Patients with secondary AML (sAML) with antecedent myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPNs) tend to have high-risk disease based on the older age of patients, high-risk cytogenetics, and higher number of prior treatments. Allogeneic hematopoietic cell transplant (HCT) is the only potentially curative therapy available. Eight hundred and two adults with sAML and prior MDS/MPN who received a first HCT between 2000 and 2016 were included in the European Society for Blood and Marrow Transplant (EBMT) Acute Leukemia Working Party (ALWP) study. Median age of the cohort was 59.6 years (range, 18.6-78.6 years). Myeloablative conditioning (MAC) was given to 40% of patients, and 60% received reduced-intensity conditioning (RIC). Overall, the 2-year cumulative incidence of relapse (RI) was 37%, leukemia-free survival (LFS) was 40%, overall survival (OS) was 46%, nonrelapse mortality (NRM) was 23%, and chronic graft-versus-host disease (cGVHD) was 39%. In univariate analysis, a statistical difference between conditioning regimens 6 months after HCT in favor of the MAC group was noted with regard to RI (hazard ratio [HR], 1.47; P = .03), LFS (HR, 1.43; P = .01), and OS (HR, 1.55; P < .05). There was no difference in the cumulative incidence of NRM (HR, 1.38; P = .15). This effect was similarly seen in multivariate analysis (MVA): cumulative incidence of relapse (HR, 1.79; P < .05), LFS (HR, 1.43; P = .02), and OS (HR, 1.53; P = .005) with no difference in NRM (HR, 1; P = .98). This EBMT ALWP analysis suggests that long-term survival can be achieved in patients with sAML with antecedent MDS/MPN and that MAC is a suitable conditioning regimen in patients with sAML. [less ▲]

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See detailHematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
Giebel, Sebastian; Marks, David I.; Boissel, Nicolas et al

in Bone Marrow Transplantation (2018)

Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL ... [more ▼]

Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials. [less ▲]

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