GI GVHD Research Articles

Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen

Allogeneic hematopoietic cell transplantation (HCT) in patients with Hurler's syndrome can improve survival and ameliorate many aspects of Hurler's syndrome including neurologic decline and cardiac compromise. Unfortunately, the toxicity of traditional preparative regimens to organs affected by the syndrome may have deleterious effects. Additionally, despite the intensity of these regimens, achieving stable donor chimerism can be difficult. We report transplant outcomes following a reduced intensity, highly immunosuppressive preparative regimen consisting of alemtuzumab, fludarabine and melphalan prior to HCT in seven patients with Hurler's syndrome treated at two centers. Six patients received grafts from unrelated donors and one received a sibling donor graft. The preparative regimen was well tolerated. All patients had initial donor engraftment at 100 days; one patient had delayed loss of donor chimerism. There was no severe acute GVHD (no GI GVHD of grade II or more, no grade IV skin GVHD). Six of the seven children are surviving at a median of 1014 (726-2222) days post transplant. This reduced intensity preparative regimen has the potential to support engraftment and improve survival and outcome in patients with Hurler's syndrome undergoing HCT.

399: Choice of diet as part of treatment for GI GVHD

399: Choice of diet as part of treatment for GI GVHD

Infliximab for the Treatment of Chronic Graft Versus Host Disease.

Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic stem cell transplantation. Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of GVHD. Infliximab is a murine-human chimeric monoclonal antibody that binds TNF-α, preventing interaction with its receptor and its ability to mediate the development of GVHD. Infliximab is active in the treatment of steroid refractory acute GVHD, particularly for patients with GI GVHD (Couriel et al Blood. 2004 Aug 1;104(3):649–54).We performed a retrospective analysis to evaluate the activity of infliximab in 22 patients with AML/MDS (n=5), lymphoma (n=8), ALL (n=3), and others (n=6) with steroid refractory chronic extensive GVHD. Response was measured according to standard response criteria (Pavletic et al. Biology of Blood and Marrow Transplantation 2006 Mar;12(3):252–66). The median age of the patients was 50 years (range 20 – 64). Fourteen (64%) patients had matched sibling donors, 8 (36%) had matched unrelated donors, 9 (41%) underwent nonmyeloablative conditioning, one patient had a bone marrow transplant and the other 21 patients had peripheral blood stem cell transplants. All patients were given standard doses of tacrolimus or cyclosporine for GVHD prophylaxis with either short course methotrexate or mycophenolate mofetil. All patients were treated with systemic steroids at the onset of GVHD. Fifty percent of the patients initially presented with acute GVHD that progressed to chronic extensive GVHD. The other half presented with late onset or de novo chronic extensive GVHD. Nineteen had skin involvement (86%), 15 (68%) had gastrointestinal involvement, and 10 (45%) had liver involvement at the time of treatment with infliximab. All patients were considered refractory to tacrolimus/cyclosporine and systemic steroids, had intolerable side effects from steroids or could not be successfully tapered off steroids prior to infliximab administration. Median time from transplant to infliximab administration was 337days (range 122 to 932 days). The patients received a median of 4 weekly courses (range 1–20 courses) of infliximab at 10mg/kg. The overall response rate was 64% (n=14); 11 (50%) experienced a complete response (CR); 3 (14%) experienced a partial response (PR); 8 (36%) had progressive GVHD. The response rate for skin GVHD was 68%, GI was 60% and liver was 50%. One patient suffered an acute infusion reaction after the first infliximab dose and had no further drug administered. Median survival of all patients following initiation of infliximab was 223 days. Median survival of all responders was 625 days after infliximab, while median survival of the non-responders was 70 days after infliximab. Six patients remain alive at a median follow-up of 55 months (27%). Three of six survivors are on minimal immunosuppression with limited cGVHD and three are off all immunosuppression with no evidence of cGVHD. Of the patients who died, 7 (32%) died from infectious complications, 5 (23%) died from complications of progressive cGVHD, 4 (18%) died from hemorrhagic or embolic strokes, 2 died from complications of post-transplant lymphoproliferative disorder (PTLD), and one patient from relapse. In conclusion, infliximab has activity for cGVHD. Prospective trials investigating the activity of infliximab, the infectious risks, predictive measures responding patients and optimal timing of administration are needed.

Rituximab Infusion Two Months after Nonmyeloablative Transplantation Maintains B-Cell Disease Control with Minimal GVHD.

B cells are implicated in the pathophysiology of chronic GVHD, as evidenced by the association of Ab production against minor histocompatibility Ags with chronic GVHD, and rituximab efficacy in chronic GVHD. We hypothesize that anti-B cell therapy beginning 56 days after nonmyeloablative total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) transplantation reduces chronic GVHD. Cognizant of possible GVL loss with B cell depletion, we treated patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) because any loss of GVL may be offset by rituximab's direct anti-B cell tumor efficacy.Patients were conditioned with TLI (80 cGy in 10 fractions, d-11 to d-1) and ATG (1.5mg/kg/day, d-11 to d-7, total 7.5mg/kg). PBSC were infused on day 0. Primary GVHD prophylaxis was MMF from day 0 until d28 for MRD, d100 for URD and cyclosporine (CSA) tapered off by 6 months. To diminish donor B cell alloimmunity, rituximab (375 mg/m2) was infused on days 56, 63, 70, and 77 post-transplant.Fourteen patients have received HCT, and 11 (median age 57, range 46–65 yrs) have received four rituximab infusions (5 fludarabine-refractory, unmutated immunoglobulin heavy-chain variable region gene (IgVH) CLL; 6 MCL). Median follow-up is 290 days (108–381 days). No infusion related toxicities occurred. Transient leukopenia in all patients and frank neutropenia in one patient was noted as early as 30 days post-rituximab. There was one graft loss at day 50 in a patient with MCL progression. Only 3/11 patients had peripheral blood CD3 donor chimerism >95% before rituximab infusion day 56, but 6/7 patients achieved full donor chimerism post-rituximab day 180, showing rituximab has no detrimental effect on engraftment. Peripheral blood CD19+ B cells were undetectable in all patients days 90–270, and 2/2 evaluable patients at one year now have CD27+ CD19+ donor B cell reconstitution. Infections post-transplant include early CMV reactivation (5), influenza B (1), aspergillus sinusitis (1), ecthyma gangrenosum (1), VZV (1). All infections resolved. Non-relapse mortality at 100 days and currently is 0%. Four of the 5 unmutated IgVH CLL patients with diffuse lymphadenopathy and marrow involvement by 4-color flow and IgVH quantitation prior to HCT have achieved molecular CR by IgVH PCR. One CLL patient progressed 9 months after HCT and has received DLI. Four MCL patients were transplanted in PR; one achieved CR, 3 progressed before rituximab infusion and 2 subsequently died. The third progressed MCL patient responded to salvage chemotherapy with development of chronic GVHD and achieved CR. No patients developed acute GVHD. One patient developed chronic GI GVHD that resolved with six weeks of steroids.Rituximab infused 56–77 days after TLI-ATG is well tolerated and able to modulate donor B cell reconstitution without detrimental effect on engraftment or infection incidence. No acute GVHD occurred. This novel approach of rituximab infusion two months after TLI-ATG HCT provides safe in vivo peripheral donor B cell depletion with low chronic GVHD incidence thus far. Importantly, GVL is maintained with four CLL and two MCL patients achieving molecular CR after HCT.CLL/MCLMed AgeMed f/uMRD/URDGVHDCD3>95% Donor ChimerismDisease status pre-HCT»last f/u5/657 yrs290 days9/2aGVHD- none cGVHD- one,d257D56 pre-rituximab: 3/11 pts>95%; D180: 6/7 pts>95%CLL: 4 PR»CR; 1PR»PD–DLI; MCL: 1PR»CR; 3PR»PD-2 deaths; 2CR»CR

Prospective evaluation for upper gastrointestinal tract acute graft-versus-host disease after hematopoietic stem cell transplantation.

The incidence and clinical significance of upper gastrointestinal tract acute graft-versus-host disease (upper GI GVHD) were prospectively evaluated in 44 Japanese patients who underwent allogeneic (n = 26) or autologous (n = 18) stem cell transplantation. Endoscopic examination was routinely performed between days 20 and 50 post-transplant and when symptoms of upper GI and/or acute GVHD of other organs were present. The results were compared with the historical records of 49 allograft and 20 autograft recipients. The diagnosis of upper GI GVHD was confirmed by histologic findings of GVHD and persistent upper GI tract symptoms. The incidence of upper GI GVHD was 46% in the prospective allograft group, higher than in the retrospective group. Upper GI GVHD was not diagnosed in any autograft patients. Twelve of 19 patients with upper GI GVHD had skin GVHD, and two of the 12 had concurrent lower GI GVHD. Upper GI GVHD was successfully treated with steroids and did not progress to symptomatic lower GI GVHD. In addition, upper GI GVHD completely resolved without specific alteration in immunosuppressant therapy in six patients. No risk factors for upper GI GVHD could be identified. The presence of upper GI GVHD did not significantly affect early death rate, incidence of chronic GVHD, and overall survival. In conclusion, by the prospective evaluation of the upper GI tract by endoscopy we could accurately diagnose upper GI GVHD in half our allogeneic recipients. However, upper GI GVHD was successfully controlled with or without additional steroids in all cases and had little impact on transplant outcome.

Single Cell Necrosis in Upper GI GVHD

Single Cell Necrosis in Upper GI GVHD

The immunopathology of upper gastrointestinal acute graft-versus-host disease. Lymphoid cells and endothelial adhesion molecules.

Acute graft-versus-host disease is a common complication of allogeneic bone marrow transplantation, but the mechanisms resulting in tissue injury are uncertain. In order to probe the effector phase of upper gastrointestinal acute GVHD, we performed immunopathologic studies of duodenal biopsies obtained from patients with or without GVHD. We evaluated the infiltrating mononuclear cells in both epithelium and lamina propria for expression of CD2, CD4, CD8, CD25, T alpha/beta and gamma/delta receptors, CD16, CD56, CD57 and also studied the distribution of cell adhesion molecules (ELAM-1, VCAM-1, ICAM-1, PECAM-1). In the epithelium, only a minimal T cell infiltrate was observed. In the lamina propria, GVHD tissue (vs. control) had an infiltrate of CD2+ (17.7 +/- 2.9% vs. 7.2 +/- 1.8%; P < 0.04), CD8+ (15.5 +/- 4.4% vs. 4.8 +/- 1.9%, P < 0.04) T lymphocytes. GVHD-positive and control tissues contained similar numbers of CD4+ T cells and natural killer cells (CD56+ or CD57+). ICAM-1 staining of endothelial cells was prominent in GVHD tissues (13.5 +/- 1.1 capillaries/field) and was significantly increased over non-GVHD specimens (7.5 +/- 1.8; P < 0.02). ELAM-1, VCAM-1, and PECAM-1 were similarly distributed in both biopsy groups. These data suggest that effectors of upper GI GVHD include CD2+, CD8+, T lymphocytes infiltrating the lamina propria. Inflammatory cell activation and resultant secretion of cytokines might directly damage the mucosa, but may also upregulate ICAM-1 on local endothelium leading to perpetuation of inflammation by recruitment of additional cytotoxic lymphocytes.

SIMULTANEOUS UPPER AND LOWER ENDOSCOPIC BIOPSY IN THE DIAGNOSIS OF INTESTINAL GRAFT-VERSUS-HOST DISEASE

Graft-versus-host disease in the upper gastrointestinal tract presents with anorexia, vomiting, and abdominal discomfort. Because these symptoms are not specific, we have proposed that a diagnosis of upper GI GVHD requires histologic confirmation. However, the utility of upper endoscopy in the diagnosis of upper GI GVHD has not been examined. We report a retrospective analysis of 77 allogeneic bone marrow transplantation recipients who received simultaneous upper and lower GI tract biopsies. Upper GI GVHD was found in 44% of patients, of whom 59% also had a positive lower GI tract biopsy (P less than 0.001). Thirty-five percent of the patients with no clinical evidence of lower GI tract GVHD had symptomatic upper GI GVHD confirmed histologically. Patients with and without upper GI GVHD had no significant difference in their clinical symptoms or in their endoscopic findings. We found an association between upper GI and skin GVHD greater than stage I (P = 0.05), a trend to concordance between upper GI GVHD and clinical GVHD in the lower GI tract (P = 0.08), and with the overall clinical GVHD grade (P = 0.08) but no association with clinical liver involvement. Of these 77 patients, 16% had their treatment for acute GVHD changed to include systemic immunosuppression as a result of the upper GI endoscopic biopsy. In addition, 71% had other enteric pathology identified that required specific therapy. These data suggest that upper GI GVHD cannot be diagnosed accurately from its clinical presentation nor inferred from lower GI symptoms or from extraintestinal GVHD. Upper GI endoscopy with biopsy is an important tool in the diagnosis of intestinal GVHD.

Nutritional management of patients with intestinal graft-versus-host disease

Gastrointestinal Graft-Versus-Host Disease (GI GVHD) may occur following bone marrow transplantation for the treatment of acute leukemia or aplastic anemia. The resulting GI damage leads to symptoms including altered intestinal mobility, malabsorption, and protein losing enteropathy. A five-phase nutritinal regimen has been developed to supply adequate nutrient support, promote intestinal healing, reduce GI symptoms, and satisfy individual dietary preferences. The patient and family are integrally involved in the dietary planning and care. Dietary compliance is promoted through the use of nutrition education materials which explain GI GVHD and provide nutritional guidelines and their rationale.