Rejection Graft Failure Research Articles

Optimal Outcomes after Second Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Recurrence Following Graft Failure/Rejection of the First Graft

Introduction. Graft failure/rejection (GF/R) is a significant complication following HCT in non- malignant diseases. The risk of GF/R in patients with thalassemia is particularly high as a consequence of alloimmunization related to transfusion exposures and hyperproliferative marrow. Although the GF/R rate after myeloablative HLA-matched sibling transplants for thalassemia has been reduced, its incidence still remains high following alternative donor transplantation. Typically, GF/R after HCT for thalassemia is accompanied by autologous hematopoietic recovery, but occasionally patients develop GF with prolonged marrow aplasia. Given great variability in conditioning regimens and outcomes after second HCT for GF/R, it is important to develop a uniform treatment approach to patients receiving second transplantation for GF/R with autologous recovery.Methods. We report on 21 consecutive patients with median age of 9 years (range, 4-24 years) with thalassemia who underwent a second HCT for GF/R with autologous recovery. Ten patients had primary and 11 patients secondary GF/R following the first BMT. Median time to second transplant was 41 months (range, 8- 204). Treatment protocol consisted of preconditioning cytoreduction/immunosuppression with hydroxyurea (30 mg/kg/day) and azathioprine (3 mg/kg/day) from day −45 pre-transplant, and fludarabine (30 mg/m2/day) from day −16 through day −12. Conditioning regimen included oral or intravenous (i.v.) busulfan, thiotepa 10 mg/kg/day, cyclophosphamide 200 mg/kg total dose, and thymoglobulin 12.5-10 mg/kg total dose. Cyclosporine, methylprednisolone and methotrexate were given for GVHD prophylaxis. All but 4 patients received second HCT from the same donor. Thirteen patients received bone marrow (BM), and 8 patients PBSC. One patient was in class 1, 7 patients in class 2, and 13 patients in class 3 of risk. Most patients had moderately severe iron overload with median serum ferritin of 2692 ng/ml (range, 500-10126 ng/ml). The median liver fibrosis score 1 (range 0-5).Results. All but 1 patient achieved sustained engraftment with a 5 year overall and disease-free survival (DFS) of 85% (95% CI, 59-95%). DFS was 92% (95% CI, 54-99%) in patients receiving BM and 75% (95% CI, 32-93%) in those given PBSC, although the difference was not statistically significant (p=0.27) (Figure 1).One patient had primary GF with the cumulative incidence of 5% (95% CI, 0-13%). The incidence of grade 2-4 acute GVHD was 50% (95% CI, 0-75%) in the PBSC and 8 % (95% CI, 0-24%) in the BM group (p=0.025). Respective incidences of moderate to severe chronic GVHD were 43% (95% CI, 0-70%) and 0% (p=0.012). The high incidence of both acute and chronic GVHD after PBSC transplantation prompted us to abandon its use for second transplantation since 2006. At the time of survival analysis, 18 patients were alive, with median follow-up duration of 10 years (range, 1.2-12.8 years). At present all patients are off immunosuppressive medication. There were 3 deaths due to pneumonia, postsplenectomy sepsis and rejection with cerebral bleeding. The most frequently observed toxicities were grade 2 elevations in AST and ALT, followed by grade 2 oral mucositis. Few patients experienced grade 3 liver and gut toxicities. None of the patients developed liver VOD. Three patients had pneumonia, and 4 patients developed grade 2-3 late onset BK virus -related hemorrhagic cystitis. None of the patients developed lymphoproliferative disorder.Conclusions. We demonstrate the excellent DFS in patients with thalassemia treated with second transplantation for GF/R following the first graft. Importantly, the intensified treatment protocol was not associated with increased nonhematological toxicity, even though most patients suffer from pre-existing organ damage due to iron overload and/or hepatitis. This study clearly showed that the same donor could be successfully used for second transplantation in these patients. Due to significantly high incidence of both acute and chronic GVHD after PBSC, bone marrow graft is preferred source for second transplantation in patients with thalassemia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The histological changes in immunologically tolerant lymphoid tissue.

SummaryThe histological features of the regional lymph node draining a skin homograft have been examined in normal and tolerant recipients. The response of this node was morphologically identical in normal and specifically tolerant hosts, the most important feature being the appearance of medullary cords packed with intensely pyroninophilic cells. Furthermore, a similar response was observed in the regional lymph nodes of (DA × Lewis)F1 hybrids bearing DA skin grafts of which they were “genetically tolerant”. It was concluded that the failure of graft rejection in tolerant rats could not be attributed to an absence of reactivity to the grafts on the part of the lymphoid tissue of the host.

Treatment of Ulcerative Colitis with Antimetabolites

Ulcerative colitis is a disease of widely varying severity. The course in any patient is difficult to predict. In this community repeated episodes commonly lead to a chronic active stage, in which the sufferer becomes an invalid unless the process is relieved by colectomy. In this phase exacerbations and com plications are common, and not infrequently lead to death. It is with patients in this group that the present trial has been concerned. While ulcerative colitis as representative of an autoimmune disorder fails to fill all the criteria enumerated by McKay and Burnet (1963) for autoimmune disease, there remains strong evidence for immunological disturbance. This evidence has been reviewed by Kirsner (1961). I do not propose to discuss at length whether this disturbance represents a normal response to modified tissue or a defect of the immune mechanism. I consider the action of antimetabolites, together with observa tions made during this therapy, supports the view of primary tissue damage or modification. With the exception of steroid hormones, the most powerful suppressants of the immune response, as measured by failure of graft rejection, are all agents developed for the treatment of cancer. These agents may be considered in their main groupings?nitrogen mustard and its derivatives, the sulphur mustards, the antimetabolites, and antibiotics. There is prob ably some selectivity of action of these agents, antagonism occurring between the antimetabolites, mercaptopurine, and the folic-acid antagonists. In our early trials we used the anti metabolites mercaptopurine and 6-thioguanine. More recently the sulphur mustard busulphan has been employed.