The effect of cyclosporine initiation time on the outcome of matched allogeneic stem‐cell transplantation following fludarabine‐based conditioning

Cyclosporine (CSA) is the most commonly used medication for GVHD prophylaxis. The initiation time varies from day −4 to day 0. Initially, we gave CSA starting on day −1. However, since 2003 we have changed CSA initiation timing policy in most of our protocols to day −4, to achieve stable and controlled pretransplant CSA levels. Here, we assessed if initiation time impact the outcome of allogeneic stem‐cell transplantation (allo‐SCT). Data of 261 patients who underwent allo‐SCT for hematological malignancies from a fully matched donor, treated with CSA as a single agent for GVHD prophylaxis were prospectively collected. Patients were divided according to CSA initiation time and analyzed for outcome. The acute GVHD severity, cGVHD extent, GVHD‐associated mortality were significantly lower in the CSA −4 group. There was no difference in the rate and timing of acute or chronic GVHD. Overall survival did not differ between the groups. We conclude that the initiation of CSA at day −4 reduced the severity of aGVHD, extent of cGVHD, and GVHD‐associated mortality without impact on overall survival.     

Levels of soluble FasL and FasL gene expression during the development of graft-versus-host disease in DLT-treated patients

Three patients with different clinical symptoms of graft-versus-host disease (GVHD) who had received donor lymphocyte transfusion (DLT) for the treatment of relapsed leukaemia after an allogeneic bone marrow transplantation (BMT) from HLA-matched sibling donors were analysed for the presence of soluble FasL (sFasL) in the sera and for the expression of the Fas ligand (FasL) gene in the peripheral blood mononuclear cells (PBMNC). Two patients who demonstrated liver damage with increased levels of serum bilirubin showed significantly increased levels of serum sFasL. The increase in the sFasL level was observed prior to the increase in the bilirubin during the clinical courses of both patients. The high dose of methyl predonisolone administered to one of these patients greatly reduced the levels of sFasL in the serum. The bilirubin levels were also reduced thereafter. The third patient (without liver damage) did not show any increase in the serum sFasL level. The expression of the FasL gene in the PBMNC of these three patients was examined. All three patients showed increased levels of the FasL gene expression during their clinical courses. However, only one patient showed a parallel alteration of FasL gene expression with sFasL in the serum. These cases provide evidence that the Fas/FasL system is closely associated with human GVHD, especially in the development of liver GVHD.     

Soluble c-kit levels in acute GVHD after allogeneic bone marrow transplantation

Serum soluble c-kit concentrations were measured in 11 patients with or without acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. The serum soluble c-kit levels in the patients with moderate to severe acute GVHD (grade II-IV) were significantly lower than those in the patients with no or mild acute GVHD (grade 0-I) following the onset. The data from this study indicate that measurement of serum soluble c-kit concentration is a useful indicator of severe acute GVHD.     

Continuous pre- and post-transplant exposure to a disease-associated gut microbiome promotes hyper-acute graft-versus-host disease in wild-type mice

ABSTRACT

Objective

The gut microbiome plays a key role in the development of acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. Here we investigate the individual contribution of the pre- and post-transplant gut microbiome to acute GVHD using a well-studied mouse model.     

The HLA System: An Update and Relevance to Patient-Donor Matching Strategies in Clinical Transplantation

In recent years the development of recombinant DNA and sequencing techniques has led to a greatly increased understanding of the genetic complexity, structure and function of the human major histocompatibility complex. This system may be subdivided into the ‘classical' HLA (human leukocyte antigen) class I and II transplantation antigens and novel HLA and non-HLA genes, involved in antigen processing and presentation to T cells. Parallel technological developments in HLA DNA typing in the clinical laboratory have resulted in a more precise awareness of the role of HLA matching for the classical HLA antigens in bone marrow and solid organ transplantation, while alternative strategies and techniques for donor selection are currently under evaluation. This review offers a current perspective on the genetics, structure and function of the HLA system, its relevance to clinical transplantation and future prospects for improvements in donor selection.     

Ancillary and supportive care in chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) continues to be the most important long-term complication of allogeneic HSCT. Responses to immunomodulation are often partial, and patients continue to experience reflares of the disease and symptoms that can significantly impair quality of life. The definition of 'ancillary therapy and supportive care' embraces the most frequent immunosuppressive or anti-inflammatory interventions used with topical intent, and any other interventions directed at organ-specific control of symptoms or complications resulting from GVHD and its therapy. This chapter will focus on ancillary and supportive care for the most frequent manifestations of chronic GVHD, including skin and appendages, eyes, oral mucosa, vagina, and immunologic and infectious complications. The level of recommendation of all interventions is based on an evidence-based system developed by the National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease.     

Acute polymyositis after donor lymphocyte infusion

Polymyositis usually occurred along with other manifestations of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT) had been reported. However, polymyositis with a sole manifestation of acute GVHD following donor lymphocyte infusion (DLI) is rare. We reported a 45-yr-old man of acute lymphoid leukemia post-allogeneic HSCT 6 months developed acute polymyositis after DLI. He did not develop any symptoms, signs of acute or chronic GVHD following allogeneic HSCT, despite withdraw of immuosuppresive agents, cyclosporin A (CsA). As the DNA-STR of bone marrow analysis showed mixed chimerism, he received the DLI for remission on May 16, 2002. Acute polymyositis developed following DLI 22 d later. The clinical presentation of polymyositis is compatible with a manifestation of acute GVHD following DLI. It also responds to the treatment of steroid and CsA.     

Two cases of graft-versus-host disease following transfusion of nonirradiated blood products

Summary Two patients, suffering from AML and AMMoL respectively, experienced acute GVHD after transfusion of nonirradiated blood products. One of the patients, who surprisingly showed normal granulocyte counts during the acute phase of GVHD, survived and is disease-free eight months after initial diagnosis was made.Vorgetragen auf der Sitzung Aktuelle Mitteilungen der 26. Jahrestagung der Deutschen und Österreichischen Gesellschaft für Hämatologie und Onkologie im Oktober 1981 in München     

Human papillomavirus reactivation following treatment of genital graft‐versus‐host disease

Vaginal chronic graft‐versus‐host disease (cGVHD) is a common complication of stem cell transplantation. Human papillomavirus (HPV) disease can reactivate after transplantation, presumably because of immune factors affecting systemic immunity, such as waning antibody titers, impaired T‐ and B‐lymphocyte responses, and the use of immunosuppressive therapies. However, a relationship between the use of local immunosuppressive agents and HPV reactivation and spread has not been previously described, to our knowledge. A 30‐year‐old woman, 2 years post transplant receiving systemic cyclosporine for cGVHD, was treated with vaginal dilators, topical corticosteroids, and estrogen for vaginal cGVHD. Colposcopy and biopsy for abnormal cytology revealed condylomatous cervicitis. Over the next 4 months, while continuing dilator therapy, linear verrucous lesions developed in the vagina and vulva, and were successfully treated with laser therapy. Use of local immunosuppression and dilators for genital GVHD can enhance spread of HPV infection. Integration of HPV screening and treatment into the care of women with genital cGVHD and development of strategies to manage both conditions simultaneously are warranted.     

Retrospective Comparison of CD34-selected Allogeneic Peripheral Blood Stem Cell Transplantation Followed by CD8-depleted Donor Lymphocyte Infusions with Unmanipulated Bone Marrow Transplantation

We have previously reported the feasibility of allogeneic CD34-selected PBSC transplantation followed by pre-emptive CD8-depleted DLI (study group). In this report, we retrospectively compare the clinical outcome of the 24 patients included in this study with an historical group of 35 patients receiving unmanipulated marrow (BMT group). Patients in the study group had significantly faster neutrophil and platelet recovery and were discharged earlier than BMT patients. The actuarial 150-day (after DLI) probability of developing grade II-IV acute GVHD was 28% for the study group versus 62% for the BMT group (p=0.002). The actuarial 2-year probability of developing chronic GVHD was similar (37 versus 36% (NS)) but chronic GVHD was significantly delayed in the study group (p=0.003). The actuarial 2-year probability of relapse was 30% in the study group versus 33% in the BMT group (NS). The actuarial 2-year probability of survival was 45% in the study group versus 43% in the BMT group (NS). We conclude that allogeneic transplantation of CD34-selected PBSC followed by pre-emptive CD8-depleted DLI is feasible with rapid engraftment and minimizes the risk of severe GVHD. Large prospective trials are required to confirm these results.