Stavroula Masouridi-Levrat

Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies

Torque teno virus in patients undergoing allogeneic hematopoietic stem cell transplantation for hematological malignancies

NK Cell Functional Impairment after Allogeneic Hematopoietic Stem Cell Transplantation Is Associated with Reduced Levels of T-bet and Eomesodermin

NK cells play a major role in protection against tumor recurrence and infection after allogeneic hematopoietic stem cell transplantation (HSCT). It has been shown that NK cell function after HSCT is impaired, but underlying molecular mechanisms are not well-known. In this report we show that the level of T-bet and Eomesodermin (Eomes), two T-box transcription factors regulating lymphocyte effector functions, is strongly reduced in NK cells from HSCT recipients compared with healthy control subjects. Reduction of T-bet and Eomes expression appeared early and persisted for years after HSCT, affecting all peripheral blood NK cells independently of their differentiation status. Reduced T-bet levels in NK cells from allogeneic HSCT recipients significantly correlated with reduced perforin expression. Acute, but not chronic, graft-versus-host disease, as well as CMV reactivation, was associated with further downregulation of T-bet expression in NK cells. Lower levels of T-bet expression in NK cells were associated with less favorable outcome after HSCT as a result of increased nonrelapse mortality. Collectively, our results provide a possible molecular explanation for the previously reported functional exhaustion of NK cells after allogeneic HSCT and suggest an impact of the NK transcriptional machinery status on HSCT outcome.

High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities.

Unrelated donor searches in Switzerland require high-resolution HLA typing for HLA-A/B/C/DRB1/DRB3,4/DQB1 loci. We evaluated this strategy accepting donors with ⩾9/10 match. Of 802 unrelated donor transplants in 2000–2013, 570 were 10/10 matched, 31 were DRB3/4 mismatched, 261 were single-allele mismatched and 13 had 2 allele mismatches. Of the 261 single-allele disparities, 60 concerned HLA-A/-B, 55 HLA-C and 73 HLA-DRB1/-DQB1 loci. Transplants were reduced intensity conditioning (289, 36%), marrow (187, 23%), EBMT risk score was low in 39, intermediate I in 331, intermediate II in 333 and high in 99 patients. Five-year survival was 48±4%. HLA affected survival in the multivariate model adjusted for risk score. HLA-A/-B and HLA-C mismatches had twice the mortality risks, whereas HLA-DRB1/-DQB1 mismatches were similar to matched transplants. HLA-DRB3/4 mismatches were associated with a nonsignificant increased mortality risk. HLA-DRB3/4 mismatches had higher graft-versus-host disease and transplant-related mortality risks and lower relapse rates compared with matched transplants. We show significant effects of HLA class I, but not HLA class II, mismatches. The lack of impact of DRB1 disparities may be related to the lower immunogenicity of the DRB1*11:01/11:04 and DRB1*14:01/14:54 mismatches, representing 46% of DRB1 incompatibilities. These results support a matching algorithm that prioritizes mismatches considered as more permissive.

Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation

Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure (GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions.

Torque Teno Virus Load and Acute Rejection After Orthotopic Liver Transplantation

decreases from 2.5% of total body weight in young people to about 1.6% in the nonagenarian population, and several morphological changes with aging indicate that the liver cells in advanced old age are in a hyperfunctioning state, possibly trying to compensate for the decline in total cell number. However, it has been suggested that aging has a limited effect on liver functions but more on its response to extrahepatic factors, disease states or increased metabolic demands to which elderly people may have an impaired ability to respond. Atheromatosis usually affects the celiac trunk in old donors but, although this happens rarely, when atheroma occurs distally at the level of the right hepatic artery or at the bifurcation of the gastroduodenal and the common hepatic artery, the liver graft must be discarded for LT. The LT procedure is a scenario in which many donor risk factors may be involved. Thus, in our previous brief communication on octogenarian liver donors, we recommended the use of liver grafts with no age limit but in good preprocurement condition (hemodynamic stability, low doses of vasopressor drugs), short intensive care unit stay, good liver function tests, soft liver consistency, absence of hepatic artery atheromatosis, cold ischemia time less than 9 hours, and macrosteatosis less than 30%. From that time, we have continued applying the same criteria, but in recent years we have added other conditions such as implanting

Outcome of hematopoietic stem cell transplantation is similar for patients with a partial in vitro T-cell-depleted graft compared with a non-T-cell-depleted graft when stratified by the refined disease risk index.

Comparisons of hematopoietic stem cell transplantation (HSCT) methods in retrospective studies are often hampered by the heterogeneity of comparison groups. The refined disease risk index (DRI) is a potentially interesting tool to compare HSCT protocols as it is based on the disease type and burden at transplant and stratifies patients into four prognostic groups for overall survival (OS). We included 265 patients with partial T-cell-depleted graft (TDEP) and 163 non-TDEP patients in a retrospective study and compared outcomes following stratification using the refined DRI. The 2-year OS rate for TDEP patients was 81.6, 60.9 and 43.3% for the low-, intermediate- and high-risk groups, respectively (P<0.001). For non-TDEP patients, the 2-year OS rate was 62.9, 48.8, 44.2 and 7.6% for the low-, intermediate-, high- and very-high-risk groups, respectively (P<0.001). There was no significant difference when comparing OS between TDEP and non-TDEP for the low-, intermediate- and high-risk groups, but TDEP patients had less acute GvHD grades II–IV. In conclusion, we confirm that the refined DRI is a valuable tool to compare the outcomes of different HSCT protocols. We demonstrate also that TDEP did not impact on the outcome of HSCT, but it did reduce the incidence of acute GvHD.

In-Hospital Transfer Is a Risk Factor for Invasive Filamentous Fungal Infection among Hospitalized Patients with Hematological Malignancies: A Matched Case-Control Study

OBJECTIVE Immunocompromised patients now benefit from a longer life expectancy due to advanced medical techniques, but they are also weakened by aggressive treatment approaches and are at high risk for invasive fungal disease. We determined risk factors associated with an outbreak of invasive filamentous fungal infection (IFFI) among hospitalized hemato-oncological patients. METHODS A retrospective, matched, case-control study was conducted between January 1, 2009, and April 31, 2011, including 29 cases (6 proven, 8 probable, and 15 possible) of IFFI and 102 matched control patients hospitalized during the same time period. Control patients were identified from the hospital electronic database. Conditional logistic regression was performed to identify independent risk factors for IFFI. RESULTS Overall mortality associated with IFFI was 20.7% (8.0%-39.7%). Myelodysplastic syndrome was associated with a higher risk for IFFI compared to chronic hematological malignancies. After adjustment for major risk factors and confounders, >5 patient transfers outside the protected environment of the hematology ward increased the IFFI risk by 6.1-fold. The risk increased by 6.7-fold when transfers were performed during neutropenia. CONCLUSION This IFFI outbreak was characterized by a strong association with exposure to the unprotected environment outside the hematology ward during patient transfer. The independent associations of a high number of transfers with the presence of neutropenia suggest that affected patients were probably not sufficiently protected during transport in the corridors. Our study highlights that a heightened awareness of the need for preventive measures during the entire care process of at-risk patients should be promoted among healthcare workers.

Complete and sustained remission of spondyloarthritis after allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome

Joint Bone Spine - In Press.Proof corrected by the author Available online since samedi 27 decembre 2014

Haematopoietic cell transplantation in Switzerland, changes and results over 20 years: a report from the Swiss Blood Stem Cell Transplantation Working Group for Blood and Marrow Transplantation registry 1997–2016

In 1997, the Swiss Blood Stem Cell Transplantation Group (SBST) initiated a mandatory national registry for all haematopoietic stem cell transplants (HCTs) in Switzerland. As of 2016, after 20 years, information was available for 7899 patients who had received an HCT (2781 allogeneic [35%] and 5118 autologous [65%]). As some patients had more than one transplant the total number of transplants was 3067 allogeneic and 6448 autologous. We compared patient characteristics and outcome of the first decade (1997-2006) and second decade (2007-2016) of the registry. There were numerous changes over time. For allogeneic HCT, transplant rates, and therefore use of HCT technology, increased from 14 to 21.8 HCTs per 1 million inhabitants per year from the first to the second decade. Likewise autologous HCTs increased from 24.8 to 37.2 annually corrected for population growth. Allogeneic transplant recipients were older (38.4 vs 48.3 years) and more frequently had unrelated donors in the second decade. Similarly, age increased for recipients of autologous HCT (50.8 vs 56.4 years). Analysis of outcome showed that the probabilities of overall and progression-free survival were stable over time, in spite of the treatment of older and higher risk patients. In multivariate analysis, nonrelapse mortality decreased in recipients of allogeneic HCT (relative risk 0.68, 95% confidence interval 0.52-0.87) over the two decades. Improvement in adjusted nonrelapse mortality compensated for the fact that higher risk patients were treated in more recent years, resulting in similar overall survival. Five-year survival probabilities were 56% (53-59%) in the first and 54% (51-57%) in the second decade for allogeneic HCT, and 59% (57-61%) in the first and 61% (59-63%) in the second decade for autologous HCT. Detailed analyses of changes over time are presented. This study included all HCTs performed in Switzerland during the period of observation and the data are useful for quality assurance programmes, healthcare cost estimation and healthcare planning. Between 50 and 60% of patients were long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care and observation.

Impact of T-cell depletion on outcome of patients undergoing allogeneic hematopoietic cell transplantation for myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) are clonal stem cell disorders usually characterized by cytopenia and dysplasia. MDS are usually diagnosed during the sixth decade and are associated with reduced life expectancy, mainly related to transformation to acute leukemia, infections, or bleeding. Currently, the only potentially curative treatment for MDS is allogeneic hematopoietic stem cell transplantation (HSCT) [1–3]. However, HSCT is associated with significant morbidity and mortality mainly related to acute or chronic graft-vs.-host disease (aGvHD or cGvHD) [4, 5]. In the Geneva Stem Cell Transplant Center we use partial in vitro T-cell-depleted grafts usually for patients in complete remission at transplant to reduce GvHD incidence [6]. Indeed, partial T-cell depletion decreases the number of alloreactive donor T cells triggering GvHD. However, it is hypothesized that this strategy could increase relapse incidence (RI) and decrease overall survival (OS) due to the loss of the graft-vs.-leukemia effect mediated by donor lymphocytes. Impact of partial T-cell depletion was previously investigated in a cohort of patients, including heterogeneous diseases and results had shown no worsening of outcome for partially T-cell-depleted patients [7]. However, the impact of partial T-cell depletion was never specifically investigated for patients undergoing transplantation for MDS. In this retrospective study, we investigated patients allografted for a diagnosis of MDS over a 19 years’ period (from 01 January 1998 to 31 August 2016). Patients aged ≥18 years old at transplant time, who had a diagnosis of MDS according to the 2008 World Health Organization criteria, and who had a first HSCT were included. Patients with haploidentical transplantation, stem cell from identical twins, umbilical cord blood transplantation, or more than two human leukocyte antigen (HLA) locior allelemismatched unrelated donor (MMUD) transplantation were excluded. This study was approved by an ethics committee. Primary outcomes were comparison of 3-year OS, progression-free survival (PFS), GvHD-free/relapse-free survival (GRFS) [8], RI, and non-relapse mortality (NRM) between partially T-cell-depleted patients and non-T-celldepleted ones. Secondary outcomes were impact of partial T-cell depletion on grade 2–4 acute and chronic GvHD. Sixty-two patients were included. Forty-four percent were female, median age at transplant was 48 years (range: 18–70 years) with myeloablative conditioning for 66% and reduced intensity for 34%. Median time from diagnosis to HSCT was 7.5 months (range: 3–86 months). Peripheral blood stem cell (90%) or bone marrow (BM; 10%) grafts were from HLA-identical siblings (45%), HLA-matched unrelated donor (MUD; 42%), or MMUD (13%). Antithymocyte globulin was used for 56% of patients and partial T-cell depletion was performed for 52% of patients. Median follow-up was 4.6 years (range: 0–15). Patients’ characteristics and data on transplantation are shown in Table 1. Myeloablative conditioning usually consisted of cyclophosphamide (120 mg/kg) with either total body irradiation These authors contributed equally: Maude Raboud, Yan Beauverd.