Validation of the disease risk index for outcome of patients undergoing allogeneic hematopoietic stem cell transplantation after T cell depletion.

Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell-depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients.

Dynamics of Expression of Programmed Cell Death Protein-1 (PD-1) on T Cells After Allogeneic Hematopoietic Stem Cell Transplantation.

Immune exhaustion contributes to treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Immune checkpoint blockade, including programmed cell death protein-1 (PD-1) blockade, is a promising strategy to improve the antitumor effect of allogeneic HSCT with high rates of response reported in patients treated for disease relapse. However, severe and sometimes fatal Graft- vs.-Host-Disease (GvHD) has been reported as a complication. Little is known about the dynamics of PD-1 expression on immune effector cells after allogeneic HSCT. In the present study, we analyzed PD-1 expression on T cell subpopulations isolated from 105 allogeneic HSCT recipients. Our analysis revealed a significant increase in proportions of PD-1-expressing CD4 and CD8 T cells early after allogeneic HSCT followed by a progressive normalization of PD-1 expression at CD8 but not CD4 T cell surface. Analysis of co-expression of two other exhaustion markers, 2B4 and CD160, revealed a preferential expansion of PD-1-single positive cells. Moreover, the analysis of granzyme B and perforin expression in PD-1+ and PD-1- CD8 T cells from HSCT recipients did not reveal any impairment in cytotoxic molecules production by PD-1-expressing CD8 T cells. Analyzing the association between clinical factors and the expression of PD-1 on T cells, we identified the use of in vivo and/or ex vivo T-cell depletion as the factor most strongly associated with elevated PD-1 levels on T cells. Our results extend our knowledge of the regulation of PD-1 expression at T cell surface after allogeneic HSCT, a crucial information for the optimization of post-transplantation PD-1 blocking therapies.

Partial T-cell depletion improves the composite endpoint graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic stem cell transplantation.

Graft-versus-host disease (GvHD)-free, relapse-free survival (GRFS) is a recently reported composite endpoint that allows to simultaneously estimate risk of death, relapse and GvHD after allogeneic hematopoietic stem cell transplantation (HSCT). In this retrospective study comprising 333 patients transplanted for hematologic malignancies, we compared GRFS in patients receiving partial T-cell-depleted (pTCD) grafts with patients receiving T-cell-replete grafts (No-TCD). pTCD was associated with a significantly improved GRFS. The beneficial effect of pTCD on GRFS remained highly significant in multivariable analysis taking into account clinical factors differing between patient groups. We observed no effect of pTCD on overall survival, progression-free survival, and relapse cumulative incidence, while non-relapse mortality cumulative incidence was significantly lower in patients receiving pTCD. The results of our retrospective analysis suggest that pTCD could improve GRFS in allogeneic HSCT recipients without significantly affecting OS and PFS, thus improving patients' quality of life without impairing the curative potential of allogeneic HSCT.

[How to manage EBV reactivation and EBV-PTLD, CMV and human herpesvirus 6 reactivation and infection after allogeneic stem cell transplantation: A report of the SFGM-TC (update)]. / Conduite à tenir devant une réactivation EBV et un syndrome lymphoprolifératif à EBV, une réactivation ou infection à CMV et à HHV-6 après allogreffe de cellules souches hématopoïétiques : recommandations de la SFGM-TC (mises à jour).

The French society of bone marrow transplantation and cell therapy (SFGM-TC) organizes annually workshops in the attempt to harmonize clinical practices between different francophone transplantation center. Here, we report our recommendations regarding the management of Epstein Barr virus reactivation and lymphoproliferative disorders, cytomegalovirus (CMV) and human herpes virus 6 (HHV6) after allogeneic stem cell transplantation.

[Modalities for preparation, cryopreservation, thawing of hematopoietic stem cells and precautions for infusion to patient: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Modalités de préparation, cryopréservation, décongélation des cellules souches hématopoïétiques et précautions pour infusion au patient : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

To date, despite an existing regulatory framework and standards, there are no true technical recommendations. A survey of 23 cell processing facilities (France, Belgium and Switzerland) has allowed to overview current practices according to cellular products specifications upon arrival at the facility, with modalities for their preparation prior to cryopreservation, storage, thawing and finally for infusion to patient. Data analysis shows great variability of collected volumes and cell concentrations in cellular products. Despite homogeneous practices for handling cells at the facility, methods vary between centers, especially for the choice of cryoprotective solutions and thawing methods. During the workshop, practices have been discussed and summarized to write of recommendations about the following topics: processing and cryopreservation, thawing, bedside precautions (for infusion). This work identifies some improvements in terms of collection, choice of wash solution of thawed cells and validation of the conditions of carriage.

Comparing Two Types of Rabbit ATG prior to Reduced Intensity Conditioning Allogeneic Hematopoietic SCT for Hematologic Malignancies.

Different rabbit polyclonal antilymphocyte globulins (ATGs) are used in allogeneic hematopoietic stem cell transplantation (alloHSCT) to prevent graft-versus-host disease (GvHD). We compared 2 different ATGs in alloHSCT after reduced intensity conditioning (RIC) for hematological malignancies. We reviewed 30 alloHSCT for hematologic malignancies performed between 2007 and 2010 with fludarabine and i.v. busulfan as conditioning regimen. Patients alternatingly received Thymoglobulin or ATG-F. Median followup was 3.3 (2.5-4.5) years. Adverse events appeared to occur more frequently during Thymoglobulin infusion than during ATG-F infusion but without statistical significance (P = 0.14). There were also no differences in 3-year overall survival (OS), disease-free survival (DFS), relapse incidence, and transplant related mortality (TRM) in the Thymoglobulin versus ATG-F group: 45.7% versus 46.7%, 40% versus 33.7%, 40% versus 33.3%, and 20% versus 33.3%. The same held for graft failure, rejection, infectious complications, immune reconstitution, and acute or chronic GvHD. In patients transplanted for hematologic malignancies after RIC, the use of Thymoglobulin is comparable to that of ATG-F in all the aspects evaluated in the study. However due to the small number of patients in each group we cannot exclude a possible difference that may exist.

A rare case of primary cutaneous follicle centre lymphoma presenting as a giant tumour of the scalp and combined with JAK2V617F positive essential thrombocythaemia.

Primary cutaneous follicle centre lymphoma (PCFCL) is a rare cutaneous B cell lymphoma in middle-age adults with excellent prognosis. Here we present a case of a patient with a PCFCL in the form of a giant tumour of the scalp in combination with a myeloproliferative neoplasm, JAK2V617F positive essential thrombocythaemia. This case may be of interest because of the favourable outcome in spite of the large size of the PCFCL, the rare combination with essential thrombocythaemia and because it contributes to discussion on the role of JAK2 mutation in such patients.

Identification of a novel F11 missense mutation (Ile463Ser) in a family with congenital factor XI deficiency.

We investigated an asymptomatic 19-year-old patient with factor XI deficiency diagnosed in the context of presurgical laboratory screening. The F11 gene was analyzed and a novel missense mutation I463S in exon 12 was identified in heterozygosity in the proband. His mother, also diagnosed with asymptomatic factor XI deficiency, was found to be heterozygous for the same mutation. This novel amino acid substitution in the serine protease catalytic domain appears to be responsible for the low factor XI levels in both individuals.

Mutation of the translation initiation codon in FGA causes congenital afibrinogenemia.

Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Extensive allelic heterogeneity has been found for this disorder and more than 40 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. However, the continuous genetic analysis of additional patients still allows the identification of novel mutations and thus the greater understanding of fibrinogen structure and function. Here we report the identification of a novel missense mutation in FGA exon 1 affecting the translation initiation codon: c.1 A>T (ATG>TTG) M1L, identified in a young boy from Madagascar in compound heterozygosity with a second mutation in FGA exon 4: c.385 C>T (CGA>TGA) R129X. The patient suffered from occasional severe arthralgias (shoulder, knee) most likely caused by intra-articular bleeding with subsequent inflammation.