Autologous Graft-versus-host Disease Research Articles

GRAFT VERSUS HOST DISEASE IN AUTOLOGOUS STEM CELL TRANSPLANT: AN UNCOMMON ENTITY

Identify in literature the graft versus host disease (GVHD) incidence after autologous hematopoietic stem cell transplantation (HSCT). We searched the PubMed database using a broad search strategy to identify studies related to GVHD complication after autologous stem cell transplant. The primary search was conducted using the terms: “GVHD in autologous transplant”, and publication date less than 5 years. 91 free full articles were identified, but 7 were better related to the purpose of the study. Two articles present cases of gastrointestinal tract (GIT) GVHD in recipients of autologous HSCT. Two patients with multiple myeloma had GVHD and the clinical and endoscopic presentations were distinct. Another patient developed severe acute GVHD 93 days post autologous HSCT for Hodgkin's lymphoma. PET and CT findings included characteristic patterns of bowel inflammation with bowel wall thickening, mural stratification, and enhancement with high FDG-uptake of the involved regions, as well as typical extra intestinal findings such as ascites, engorgement of the vasa recti and stranding of the mesenteric fat. A case report of membranous nephropathy succeeding autologous HSCT described that this is a rarely entity (3% post-autologous vs . 97% post-allogeneic HSCT). In autologous HSCT populations, there have been reports of associated glomerular disease, because of any type of immune dysregulation. Based on literature, 6% of all patients with glomerulonephritis after HCT had received Autologous transplants. And the last case report presents a 4-year-old girl with metastatic neuroblastoma who spontaneously developed AGVHD after autologous HSCT. One article said the risk of GVHD in an autologous transplant is zero and the last one related the skin cancer with the delayed immune recovery and persistent immunodeficiency in GVHD. GVHD following stem cell transplantation (SCT) is a common complication in patients that have undergone allogenic SCT but rare in recipients of autologous SCT. With the emergence of autologous HSCT, GVHD and its complications were expected to be eliminated. However, autologous GVHD has been described in some patients, and your prophylaxis mainly consists of post-transplant administration of immunosuppressive drugs and may impair the post-transplant immunologic reconstitution. After the sixth month, immune recovery occurs progressively towards complete recovery, but GVHD may develop. In chronic case, patients with only liver and skin involvement have a better prognosis. Patients with extensive involvement of multiple organs the prognosis may be poor. Recent studies have indicated that two major factors are necessary for the induction of autologous GVHD: the first factor was a disruption of thymic-dependent immune reconstitution and the second one was a failure to reestablish peripheral self-tolerance. On another hand, autologous GVHD has been thought of as an autoimmune syndrome and a milder form of GVHD than its counterpart in allogeneic transplantation, the presence of autoantibodies in relation to the HSCT provides evidence for the involvement of the B cell. The difficulty of finding articles related to the study shows GVHD in autologous HSCT is an uncommon entity, but although this fact, these cases are important to further the understanding of the various presentation of this manifestation and be awake to the possibilities of differential diagnoses.

Invasive Intestinal Aspergillosis in the Setting of Autologous Graft Versus Host Disease after Hematopoietic Cell Transplant for Multiple Myeloma

Autologous stem-cell transplant is used to treat a variety of neoplastic syndromes such as multiple myeloma, chronic myeloid leukemia, and non-Hodgkin's lymphoma. In spite of its efficacy compared to other treatments, it predisposes patients to opportunistic infections and in rare cases, autologous graft versus host disease. In recent years, one opportunistic infection in particular, invasive aspergillosis, has become increasingly more common although survival rates remain low due to difficulty in diagnosis.

Baseline Immune Dysregulation in Autologous Stem Cell Transplant Recipients Is Associated with a ‘Graft Versus Host‘-like Syndrome and Results in Poor Outcomes

Introduction: Acute Graft Versus Host Disease (GVHD) is caused by the recognition of recipient antigens by donor T lymphocytes following allogeneic stem cell transplantation (SCT). The development of clinical and histo-pathological changes similar to GVHD after autologous SCT (ASCT) is a poorly understood and controversial phenomenon. Given the controversy around this topic, we aimed to: 1) analyze outcomes and clinical correlatives for the development of GVHD in ASCT recipients and 2) analyze baseline T and Natural Killer (NK) cell functions in patients that developed GVHD after ASCT, compared to matched controls.Methods: This is a retrospective analysis of patients that received ASCT at Mayo Clinic between January 2006 and December 2016. The study was approved by the Institutional Review Board. ‘Autologous GVHD’ was defined as the development of clinical and histo-pathological findings indicative of GVHD in ASCT recipients, as confirmed by pathology review. Data regarding baseline characteristics, prior treatments, presentation, treatment and outcomes were collected and analyzed. Patients and controls with available cryopreserved PBMCs at baseline and at time of GVHD development were identified. Controls were matched for age, disease status, prior therapies and conditioning regimen. Samples were analyzed for T cell functions, expression of activation and inhibitory receptors, T cell subsets and natural killer (NK) cell functions. Unpaired t-test was used to compare T-cell subset frequencies. Survival was estimated using the Kaplan Meier and Log Rank tests.Results: Between 2006 and 2016, 3,891 consecutive patients underwent ASCT. Of these, 35 (0.9%) developed symptoms suggestive of GVHD warranting biopsies. In 19 of these 35 patients (54%), the histopathological changes were consistent with GI and/or skin GVHD. The most common underlying disease was multiple myeloma (14 patients, 73.7%) and the most common conditioning regimen was melphalan (16 patients, 84.2%). The median age at ASCT was 62 (range 49-73) years. Most patients (14, 73.7%) had grade 3 or 4 GVHD. Delay in steroid initiation beyond 1 week led to lower response rates (30.8% vs 69.2%, p=0.03), longer duration of symptoms (median 28 vs 4 days, p=0.02) and a trend towards worse 1-year OS (64.5% vs. 83.3%, p=0.1). Patients that received at least 1 mg/kg of prednisone had better response to treatment (76.9% vs. 23.1%, p=0.5), although the difference was not statistically significant. The median overall survival (OS) from the time of ASCT was not reached and 53% of patients were alive at 3 years. Five of the 19 patients (26.3%) died due to complications of this immunological phenomenon.We then performed immune profiling of the available cryopreserved samples in the Mayo Clinic transplant biobank. We identified 4 patients with ‘autologous GVHD’ and 7 ASCT recipients as controls, matched for age and underlying disease. The percentage of NK cells (defined as CD3−CD56+)/total live cells was higher in patients compared to controls (34.2% vs 4.3%, p=0.009). T-cell subset analysis revealed higher levels of central memory T-cells (Tcm, defined as CCR7+CD45RA-, 27.4% in patients vs 2% in controls, p=0.02). This is consistent with what has been reported in murine models of allogeneic GVHD where Tcm induce GVHD, due to their TCR's ability of recognizing more alloantigens and their better capacity of undergoing clonal expansion. Furthermore, expression of immune checkpoint receptors was higher in patients compared to controls (CD3+PD1+/CD3+ 15.7% vs 5.7%, p=0.048 and CD3+TIM3+/CD3+ 25.4% vs 2.3% p=0.0003 respectively). This is in line with studies showing upregulation of PD1 and TIM3 on T-cells of allogeneic SCT recipients that develop GVHD and linking higher TIM3 levels with more severe gut GVHD.Conclusions:Our analyses indicate that the development of GVHD-like syndrome after ASCT is associated with baseline immune dysregulation, similar to what is reported in allogeneic GVHD models. This is associated with poor prognosis if prompt steroid treatment is not initiated. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Membranous nephropathy in autologous hematopoietic stem cell transplant: autologous graft-versus-host disease or autoimmunity induction?

With the increasing utility of hematopoietic stem cell transplantation (SCT) as a treatment for cancer and noncancerous disorders, more challenges and complications associated with SCT have emerged. Renal injury immediately after transplant is common and well understood, but long-term renal injury is becoming more evident. Chronic graft-versus-host disease (GVHD) is a known long-term complication of SCT, and membranous nephropathy (MN) is emerging as the most common cause of SCT-associated glomerular pathology. In this case report, we present a patient who developed features of anti-PLA2R antibody-negative MN following autologous SCT. The renal injury responded well to steroids and further response to rituximab therapy was noted, suggesting antibody-mediated autoimmune glomerular disease. We also present a review of the literature on autologous GVHD and the role of T and B cells in induction of autoimmunity by SCT.

Autologous Graft‐Versus‐Host Disease in a Child with Stage IV Neuroblastoma

Graft-versus-host disease (GVHD) is an underappreciated complication of autologous hematopoietic stem cell transplantation (AHSCT) that can affect the skin, gastrointestinal tract, and liver. The development of this rare condition is probably due to an impairment of immunologic tolerance that can occur spontaneously through T-cell dysregulation, possibly from intensive conditioning chemotherapy regimens, or intentionally through administration of cyclosporine in the hopes of promoting an antitumor response. We present the case of a 2-year-old boy with metastatic neuroblastoma who spontaneously developed autologous GVHD after AHSCT. Severe pruritus and an inability to taper his oral steroids without a disease flare marked his disease. Eventually partial relief was achieved with initiation of cyclosporine and a strict soak and smear protocol using topical triamcinolone 0.1% ointment.

Autologous Graft Versus Host Disease: An Emerging Complication in Patients with Multiple Myeloma

Autologous graft versus host disease (autoGVHD) is a recently recognized, rare transplant complication with significant morbidity and mortality. Pathogenesis and risk factors for autoGVHD are poorly understood. We hypothesized that patients with multiple myeloma might be predisposed to autoGVHD through disregulation of immune response resulting from their treatment with immunomodulatory agents (IMiDs) and chemotherapeutic mobilization regimens. We identified 8 patients with multiple myeloma treated between 2005- 2013 with biopsy-proven autoGVHD after transplant. We identified 2 non-autoGVHD controls per autoGVHD patient matched by the time of hematopoietic progenitor cell (HPC) collection (within 15 days). Reference samples from HPC products of autoGVHD, non-autoGVHD myeloma patients, and 7 healthy controls were thawed and examined for cell surface marker expression of CD3, CD4, CD8, CD25, and CD56 and intracellular expression of FoxP3 by multicolor flow cytometry. Information on the following variables was collected: number of transplants prior to developing autoGVHD, mobilization regimens, exposure to a proteosome inhibitor, bortezomib, and IMiDs (thalidomide, lenalidomide and pomalidomide), and human leukocyte class I antigens (HLA A and B). Myeloma patients with and without autoGVHD were well matched for age (60 ± 5.3 and 62.1 ± 7.8 years) and sex (50% and 43.8% male). Regulatory T-cells were decreased, but not significantly, in patients with autoGVHD (1.6 ± 1.4%) compared to non-autoGVHD patients (2.1 ± 1.7%).There was no difference in the NK cell population in the 2 groups. CD3+ cell percentage was significantly lower in autoGVHD (46.6 ± 12.4%) than the non-autoGVHD patients (59.1 ± 14.4%, p = 0.047). On subset analysis of CD3+ cells, CD8+ cells were found to be significantly lower in patients with autoGVHD (12.9 ± 6.9% versus 24.4 ± 13.7%, p = 0.038) but not CD4+ cells. There was a trend towards higher number of transplants in patients who developed autoGVHD (2.1 ± 0.4%) compared to those who did not (1.6 ± 0.7%, p= 0.072). There was no difference between these groups with respect to mobilization regimens, exposure to bortezomib and the IMiDs. HLA B55 positivity was significantly associated with the development of autoGVHD (p=0.028). While there was a trend towards a higher number of transplants being associated with the development of autoGVHD in myeloma patients, no differences were seen in the use of bortezomib, IMiDs and mobilization regimens. However, lower percentages of CD3+ and CD8+ T-cells in HPC products were significantly associated with autoGVHD, suggesting that increased immunosuppression following mobilization may be a predisposing factor for developing autoGVHD in myeloma patients, particularly in the setting of HLA B55 positivity.

Skin Graft-versus-host Disease Following Autologous Stem Cell Transplantation for Multiple Myeloma

Graft-versus-host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT). However, a similar syndrome has been reported in autologous stem cell transplantation (ASCT) as well. The target organs of GVHD in ASCT are the skin, liver and gastrointestinal (GI) tract, which are consistent with those in allo-SCT. Histologic findings from the skin and the mucosa of the GI tract also show similar features. Here we describe a case of autologous GVHD involving the skin of a patient who underwent ASCT for multiple myeloma. In this patient, the response to a total prednisone dose of 0.5 mg/kg/day was unsatisfactory, and the patient required more intensive and prolonged immunosuppressive therapy with slow tapering.

Spontaneous Autologous Graft-versus-Host Disease in Plasma Cell Myeloma Autograft Recipients: Flow Cytometric Analysis of Hematopoietic Progenitor Cell Grafts

Nine plasma cell myeloma patients spontaneously developed histologically proven autologous graft-versus-host disease (GVHD) limited predominantly to the gastrointestinal tract within 1 month of initial autologous hematopoietic cell transplantation (AHCT) using high-dose melphalan conditioning. All recipients responded promptly to systemic and nonabsorbable oral corticosteroid therapy. All patients previously received systemic therapy with thalidomide, lenalidomide, or bortezomib before AHCT. Using enzymatic amplification staining-enhanced flow cytometry, we evaluated expression of selected transcription regulators, pathway molecules, and surface receptors on samples of the infused hematopoietic cell grafts. We demonstrated significantly enhanced expression of GATA-2, CD130, and CXCR4 on CD34(+) hematopoietic progenitor cells of affected patients compared with 42 unaffected AHCT controls. These 3 overexpressed markers have not been previously implicated in autologous GVHD. Although we did not specifically evaluate T cells, we postulate that exposure over time to the various immunomodulating therapies used for induction treatment affected not only the CD34(+) cells but also T cells or relevant T cell subpopulations capable of mediating GVHD. After infusion, the affected hematopoietic progenitor cells then encounter a host that has been further altered by the high-dose melphalan preparative regimen; such a situation leads to the syndrome. These surface markers could be used to develop a model to predict development of this syndrome. Autologous GVHD potentially is a serious complication of AHCT and should be considered in plasma cell myeloma patients with otherwise unexplained gastrointestinal symptoms in the immediate post-AHCT period. Prompt recognition of this condition and protracted treatment with nonabsorbable or systemic corticosteroids or the combination may lead to resolution.

Recurrent Spontaneous Gastrointestinal Graft-Versus-Host Disease in Autologous Hematopoietic Stem Cell Transplantation

Acute graft-versus-host disease (GVHD) is a major complication after allogeneic stem cell transplantation (SCT). A similar manifestation involving skin, gastrointestinal (GI) mucosa, and liver can occur after autologous hematopoietic SCT (autoHSCT), either spontaneously or after treatment with cyclosporine or interferon. Severity of spontaneous GI GVHD among patients treated with autoHSCT is variable. Recurrent spontaneous GI GVHD induced by succeeding cycles of chemotherapy has rarely been reported and is poorly understood. Enteric-coated budesonide has been studied extensively in Crohn's disease, and beclomethasone has been studied in GI GVHD. There are no comparative studies between these drugs for GI GVHD. Furthermore, GI GVHD has to be considered when microbiologic workup remains negative during the workup of persistent diarrhea in autoHSCT. Endoscopic appearances can be normal, and pathologic diagnosis is essential. Further research into risk factors involving type of chemotherapy, interval between chemotherapies, and gene polymorphisms have to be considered for better understanding of autologous GVHD. We report for the first time a patient with spontaneous recurrent GI GVHD after autoHSCT for multiple myeloma with predominant lower GI symptoms and excellent response to enteric-coated budesonide therapy.

Reconstitution of self-tolerance after hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow or hematopoietic stem cell transplantation. GVHD is thought to be primarily due to the response of mature T cells transferred along with the bone marrow graft to foreign histocompatibility antigens expressed on host tissues. Recent studies, however, have challenged this paradigm set forth in the 1960s and have suggested that self-MHC class II antigens can be recognized in GVHD. Many questions still remain unanswered particularly in regard to the role of immune reconstitution, the ability to recognize and discriminate self and the re-establishment of self-tolerance. In fact, the failure to re-establish tolerance to self can lead to systemic autoimmunity that may exacerbate or even mimic GVHD. The present review summarizes our studies in autologous GVHD characterizing the underlying immune mechanisms and their potential impact in allogeneic hematopoietic stem cell transplantation.

Diagnosis and Management of Recurrent Gastrointestinal Graft Versus Host Disease in Autologous Hematopoietic Stem Cell Transplantation

Purpose: Graft versus host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation. Among patients who undergo autologous hematopoietic stem cell transplantation (ASCT), a similar syndrome involving the skin, gastrointestinal (GI) tract and liver has been reported. Recurrent GI-GVHD among ASCT patients has not been reported and is poorly understood as well. In recent years, there has been an increase in the incidence of autologous GVHD. We report a patient with recurrent autologous GI-GVHD following ASCT for multiple myeloma. Biopsies showed active colitis with numerous ‘apoptotic epithelial cells’ in the colon (Figure 1). With predominant lower GI symptoms, patient had excellent response to budesonide therapy (Figure 2). Budesonide has been studied extensively in Crohn's disease while beclomethasone in GVHD. There are no comparative studies between these drugs for GI-GVHD. Conceivably budesonide works better for lower GI and beclomethasone for upper GI tract involvement. Systemic corticosteroids for GI-GVHD following ASCT can suppress a compromised immunity. GI-GVHD has to be considered when microbiological workup remains negative during workup of persistent diarrhea in ASCT (Table 1). Biopsies should be obtained despite normal endoscopic appearance. GI-GVHD can be recurrent, early initiation of nonabsorbable corticosteroids after diagnosis if proven by biopsy is indicated. Further research into risk factors involving type of chemotherapy, interval between chemotherapies and gene polymorphisms have to be considered for better understanding of autologous GVHD.Table 1: Differential diagnosis for diarrhea following myeloablative chemotherapy and ASCT

Rapid Immune Recovery and Graft-versus-Host Disease–like Engraftment Syndrome following Adoptive Transfer of Costimulated Autologous T Cells

Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant. In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26). The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients). Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.

Incidence and Risk of Postherpetic Neuralgia after Varicella Zoster Virus Infection in Hematopoietic Cell Transplantation Recipients: Hokkaido Hematology Study Group

To assess the incidence of and risk factors associated with postherpetic neuralgia (PHN) after hematopoietic cell transplantation (HCT) varicella zoster virus (VZV) infection, we conducted a retrospective chart review of 418 consecutive patients who underwent HCT between April 2005 and March 2007. The male/female ratio was 221/197, median age at HCT was 47 years (range: 0-69 years), and autologous/allogeneic/syngeneic HCT ratio was 154/263/1. Seventy-eight patients developed VZV infection after HCT. Sixty-two patients had localized zoster, 11 patients had disseminated zoster (rash like chicken pox), and 4 patients had visceral zoster. All cases were treated with acyclovir (ACV) or valacyclovir (VACV), and there was no VZV infection-related death. Twenty-seven (35%) of the 78 patients with VZV infection suffered PHN after resolution of VZV infection. Multivariate analysis showed that advanced age is the only risk factor in autologous HCT (P = .0075; odds ratio [OR] = 1.14; 95% confidence interval [CI], 0.97-1.33). On the other hand, advanced age (P = .0097; OR = 1.06; 95% CI, 1.01-1.12), male gender (P = .0055; OR = 12.7; 95% CI, 1.61-100.1), and graft-versus-host disease (GVHD) prophylaxis with a tacrolimus-based regimen (P = .0092; OR = 9.56; 95% CI, 1.44-63.3) were associated with increased risk of PHN in allogeneic HCT. This study for the first time clarified the risk of PHN in HCT recipients.

Eruption of lymphocyte recovery or autologous graft‐versus‐host disease?

Maculopapular exanthemas have a particular high incidence among patients treated with autologous hematopoietic stem cell transplantation (HSCT). In most cases, a viral or drug induced origin is easily identified. However, the transplantation itself may also induce similar skin changes. These exanthemas are known under various names, such as autologous graft-versus-host disease (GVHD), engraftment syndrome (ES) or eruption of lymphocyte recovery (ELR). Given the clinical and histopathological similarities of these disorders, it can prove difficult to establish a diagnosis. Here, we describe a patient who developed a maculopapular exanthema after autologous stem cell transplantation for multiple myeloma, diagnosed as autologous GVHD. We also briefly review the current knowledge of the pathogenesis of autologous GVHD, ES, and ELR. Based on these data we would like to suggest that the latter two do not reflect own disease entities but rather different presentations of autologous GVHD.

Brain Sparing Conditioning Regimen and Umbilical Cord Blood Transplantation for Inherited High Risk Neurologic Metabolic Diseases.

In addition to the well established role of hematopoietic stem cell transplantation (HSCT) in the treatment of malignancies, HSCT is utilized for a number of neurologic metabolic diseases (typically, enzyme deficiencies) due to the ability of donor graft to provide an ongoing source of enzyme that can be taken up by recipient's cells. Many of these diseases damage the white matter of the brain, and after onset of symptoms are characteristically progressive and lethal. Major limitations to the success of HSCT as therapy for these diseases are graft failure and toxicity to the brain from conditioning, resulting in disease progression. Thus, we reasoned that it would be advantageous to develop a less intensive conditioning regimen that minimally contributed to central nervous system toxicity while providing sufficient immunosuppressive to permit engraftment from unrelated cord blood donors. We are testing a reduced intensity regimen including Campath 1H (1.5 mg/kg), clofarabine (200 mg/m2), melphalan (140 mg/m2), and low dose total body irradiation (200 cGy) for this patient population. To gain insight into the persistence of Campath 1H, we measured serum levels within 30 hours prior to the cord blood infusion. We report outcomes in three adults and three children:DiagnosisAge (years)UCB Graft; HLA matchNC dose (×108/kgCD34+ dose (×106/kg)Campath 1H serum level*Donor Engraftment1MLD44dUCB; 4/6, 5/60.440.68Undectectable0%2ALD9dUCB; 5/6, 5/60.901.43699100%3ML1dUCB; 5/6, 5/61.433.041,575100%4TS1sUCB; 6/60.971.332,250100%5MLD42dUCB; 5/6, 6/60.760.942,72860%6MLD42dUCB; 5/6, 5/60.220.24Not done100%Legend: MLD, metachromatic leukodystrophy; ALD, adrenoleukodystrophy; ML, mucolipidosis type II; TS, Tay-Sachs disease; NC, nucleated cell; dUCB, double unit umbilical cord blood; sUCB, single unit umbilical cord blood; ND, not detected; Eng, engraftment; HLA matching is reported for antigen level HLA-A, B and allele level DRB1. *Campath 1H levels (nanograms/mL) are reported as an average of two measurements of samples diluted 10x. Cumulative doses for both UCB units are shown. The most recent donor chimerism is reported. To decrease the risk of graft rejection and prevent graft versus host disease (GvHD) patients received cyclosporine and mycophenolate mofetil. Patient 2 developed grade II skin and gastrointestinal acute GvHD, treated successfully with systemic and topical steroids. All patients are alive; none experienced progressive deterioration of neurologic function in the peri-transplant period. Our data suggest that this conditioning regimen is minimally toxic to the brain. The two subjects with the lowest Campath 1H concentrations had autologous recovery (patient 1) and GvHD (patient 2), suggesting that in vivo T cell depletion with Campath 1H may be beneficial. These results suggest that novel modifications in the transplant process may provide opportunities to decrease neurologic toxicity and maintain optimal neurologic function in this high risk population.

Induction of Autologous Graft-versus-Host Disease: Results of a Randomized Prospective Clinical Trial in Patients with Poor Risk Lymphoma

The results of blood or marrow transplantation in patients with chemorefractory aggressive lymphoma, that is, those not responding to conventional-dose chemotherapy at the time of transplant, have been poor. The relapse rate has been high after autologous bone marrow transplant, whereas allogeneic transplantation has been associated with excessive transplant-related toxicity. Administration of cyclosporine after autologous transplantation can induce an autoreactive syndrome that resembles graft-versus-host disease (GVHD). This syndrome, named autologous graft-versus-host disease, has clear antitumor activity in animal models that can be enhanced by the addition of cytokines such as γ-interferon and interleukin-2. A randomized, prospective study was conducted to evaluate the antitumor effect of autologous graft-versus-host disease induced with cyclosporine, and augmented by the administration of γ-interferon and interleukin-2 in patients with chemorefractory Hodgkin and aggressive non-Hodgkin lymphomas. Fifty-one patients were randomized, 24 to the autologous GVHD induction arm, and 27 to the noninduction arm after autologous transplant using mobilized peripheral blood stem cell (PBSC) grafts. There were no differences in treatment-related mortality, overall and event-free survival (OS, EFS) between both groups; however, in the induction arm, GVHD developed only in 4 patients. The administration of oral cyclosporine followed by interleukin-2 and γ-interferon is generally not well tolerated, and does not appear to be an effective method to induce autologous GVHD in patients receiving autologous PBSC grafts.

Is autologous graft versus host disease (AutoGVHD) really reactivation of Epstein-Barr virus (EBV)?

17526 Background: AutoGVHD is a rare complication following autologous bone marrow transplantation(ABMT). It has been described as an autoimmune syndrome initiated by auto-effector T cells that recognize self-major histocompatibility complex class II antigens. AutoGVHD can be induced with immunosuppresives such as cyclosporine and alemtuzumab. Methods: We wish to report two patients among 17 patients who underwent ABMT this year of what was intially thought to be AutoGVHD but in both instances was really reactivation of EBV. Results: A 70 year old white man underwent ABMT for relapsed AML M2 in second CR. The conditioning regimen was cyclophosphamide and busulfan (BuCy). His hospital was uneventful and the prophylatic antibiotics used were ciprofloxacin, fluconazole, and valacyclovir. Neutropenic fever occured on day +11 and prophylatic antibiotics were discontinued and replaced with intravenous vancomycin, piperacillin&tazobactam, and caspofugin. Engraftment occured on day +15 and the patient was discharged on day + 20 on oral valacyclovir and fluconazole. An AutoGVHD rash occurred on day+29. The second patient was a 67 year old white with a stage IIIAE mantle cell lynphoma who underwent ABMT in first CR with the BEAM+rituximab regimen. His hospital course was uneventful; he received the identical prophylatic antibiotic regimen. Engraftment occured on day +12 and he was discharged on valacyclovir and fluconazole. On day +14 he developed an AutoGVHD rash. The first patient underwent a skin biopsy which showed a spongiotic dermatitis with intraepithelial vesicular formation and dermal perivascular lymphocytes. The immunostains of the lymphocytes showed a predominance of CD4 T cells. Immunostains for CMV, EBV, HSV1 and 2 were nonreactive. Serum antibodies to the Early EBV antigen and EBV capsid (IgG) and EBV nuclear (IgG) were elevated. Serologies for Human Herpes Virus 6, 7, and 8 were negative. The second patient had elevated antibodies to the Early EBV antigen, EBV capsid antigen, and the EBV nuclear antigen. He had elevated antibodies to Human Herpes Virus 6. Conclusions: These two patient suggests that what clinically is thought to be AutoGVHD may indeed be reactivation of EBV. The incidence of reactivation of EVB in ABMT needs to be studied prospectively. No significant financial relationships to disclose.

Diagnostic Challenge in Recurrent Skin Rash After Autologous Bone Marrow Transplantation

Engraftment syndrome, autologous graft-versus-host disease (GVHD), and infection after autologous hematopoietic cell transplantation can have similar clinical presentations. Here, we describe a patient with refractory Ewing sarcoma who had recurrent skin rash after autologous hematopoietic cell transplantation. Although the rash was diagnosed as GVHD histologically, this case illustrates the diagnostic dilemma of distinguishing engraftment syndrome, autologous GVHD, or concomitant viral infection. Because therapy for these entities is different, distinguishing them is important. Establishment of diagnostic criteria and understanding of the pathophysiology of these entities may lead to better management and to improved therapy of refractory cancer.

The Effects of Interleukin 10 and Interferon γ Cytokine Gene Polymorphisms on Survival after Autologous Bone Marrow Transplantation for Patients with Breast Cancer

Several clinical trials evaluating the induction of autoimmune graft-versus-host disease (GVHD) after autologous bone marrow transplantation (BMT) as antitumor immunotherapy have shown that autologous GVHD is associated with increased production of interleukin (IL)-10. The induction of autologous GVHD also segregated with single nucleotide polymorphisms in the IL-10 promoter region (IL-10 -592 and IL-10 -1082 ) and with CA repeats in the first intron of the interferon (IFN)-gamma gene. Polymorphisms within these promoter regions can significantly modify the cytokine response because of differential transcription factor efficiency. This study evaluated the relationship between inheritance of polymorphisms within the IL-10 promoter and in the IFN-gamma gene and the overall survival of patients who received autologous BMT for metastatic breast cancer. Peripheral mononuclear cells from 87 women enrolled in 3 autologous BMT (plus induction of autologous GVHD) clinical trials were examined. By using a Cox proportional hazard model, trends in survival after autologous BMT were analyzed. The model included inheritance polymorphisms of IL-10 -592 , IL-10 -1082 , CA repeats within the first intron of the IFN-gamma gene, estrogen and progesterone receptor status, and stage of disease. Increased survival was significantly associated with patients having the IL-10 -592 promoter allele associated with high IL-10 production (hazard ratio, 0.23; 95% confidence interval, 0.09-0.55; P = .001). The effect of the strong IL-10 promoter allele on survival seems to be independent of the development of clinical autologous GVHD. However, decreased survival was significantly associated with patients having CA repeats associated with higher IFN-gamma transcription (hazard ratio, 2.34; 95% confidence interval, 1.21-4.54; P = .011). Inheritance of specific alleles that modify IL-10 and IFN-gamma production may have unexpected effects on the efficacy of immune-based strategies after autologous BMT. Additional studies are necessary to further define the influence of IL-10 and IFN-gamma on the immune response after BMT.

Cytolytic effector mechanisms and gene expression in autologous graft-versus-host disease: distinct roles of perforin and Fas ligand.

The administration of cyclosporin A (CsA) after autologous stem cell transplantation (SCT) paradoxically elicits a systemic autoimmune syndrome that resembles graft-versus-host disease (GVHD); this is termed autologous GVHD (autoGVHD). Although dominated by activated CD8+ cytotoxic T lymphocytes, the complex cellular reaction also includes CD4+ T cells and involves multiple effector mechanisms. To determine the temporal development and relative importance of these mechanisms in autoGVHD, perforin/granzyme, Fas ligand (FasL), interferon-gamma (IFN-gamma), tumor necrosis factor (TNF)-alpha, and interleukin-18 gene expression in peripheral blood mononuclear cells was examined in 36 patients treated with CsA after SCT. Quantitative real-time polymerase chain reaction analysis revealed that perforin/granzyme B, TNF-alpha, and interleukin-18 messenger RNA (mRNA) levels in peripheral blood mononuclear cells from patients in whom autoGVHD developed were markedly higher (and temporally associated with the onset of autoaggression) compared with the levels detected in healthy individuals and in control, non-CsA-treated SCT patients. It is interesting to note that patients in whom autoGVHD did not develop also demonstrated increased mRNA levels for these cytokines: however, expression was substantially lower compared with that in patients with autoGVHD. It is important to note that IFN-gamma mRNA levels were selectively increased in CD8+ cells only from patients in whom autoGVHD developed. The development of autocytolytic T cells in autoGVHD correlated with increased expression of perforin, IFN-gamma, and TNF-alpha mRNA. Furthermore, enhanced autoreactive T-cell activity and the induction of autoGVHD was also concordant with perforin and TNF-alpha mRNA upregulation in CD4+ cells. Surprisingly, FasL mRNA levels were significantly decreased, with a progressive loss of FasL mRNA expression as autocytolytic activity increased. These findings suggest that IFN-gamma/perforin-based CD8+ cytotoxic T lymphocytes seem to play a dominant role in autoGVHD and that TNF-alpha/perforin-based CD4+ cells may amplify this autoaggressive syndrome. The FasL pathway may play an important role in the regulation of this immune syndrome.