Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. Both the disease and the medications used to treat it are associated with significant morbidity and mortality. The manifestations of chronic GVHD often resemble those of autoimmune disorders. Hydroxychloroquine (HCQ) is a 4-aminoquinoline antimalarial drug used for the treatment of autoimmune diseases. HCQ interferes with antigen processing and presentation, cytokine production, and cytotoxicity and is synergistic with cyclosporine and tacrolimus in vitro. Forty patients with steroid-resistant or steroid-dependent chronic GVHD were enrolled in a phase 2 trial of HCQ 800 mg (12 mg/kg) per day. Three complete responses and 14 partial responses were seen in 32 evaluable patients (53% response rate). All responders tolerated a >50% reduction in their steroid dose while receiving HCQ. Clinical response occurred at a median of 8 weeks (range, 4 to 24 weeks). No hematologic, hepatic, renal, or retinal toxicity was associated with HCQ. In light of its mechanisms of action, clinical activity for GVHD, and low toxicity profile, HCQ may be useful in a multiagent approach for the treatment of extensive chronic GVHD.
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PMID:Hydroxychloroquine for the treatment of chronic graft-versus-host disease. 1090 70

Fifty three patients (pts) received an allogeneic hematopoietic transplant using peripheral blood progenitor cells (PBPC). Diagnosis were acute myeloid leukemia (AML) in 16 pts, acute lymphoblastic leukemia (ALL) in 15, chronic myeloid leukemia (CML) in first chronic phase in 12, aplastic anemia in 4, myelodysplasia in 3 and Hodgkin's disease, major thalasemia and Hunter's syndrome in one each. Mean age was 20 years-old (2-55), 28 males and 25 females. Conditioning regimens were total body irradiation with 1200 cGy and cyclophosphamide 120 mg/kg in 38 pts, busulfan 16 mg/kg and cyclophosphamide 120 mg/kg in 10 pts, total lymphoid irradiation and cyclophosphamide in 3, 2 pts received other chemotherapy based conditionings. PBPC were infused unmanipulated through a central catheter. Graft versus host disease (GVHD) prophylaxis was cyclosporin and short course methotrexate. Donors were 6/6 HLA compatible siblings in 52 cases and 5/6 match in one case. PBPC mobilization was done with G-CSF at a dose of 10 micrograms/kg/day subcutaneously for four days, pheresis started on day 5. Bone marrow harvest was also done in the first thirty cases. Mean cellularities for CD34, CD3, CD4, CD8, CD56, CD19 (cel x 10(6)/kg) were 4.12; 4.59; 2.57; 1.9; 0.55 and 0.68, respectively. Mean recovery of neutrophils > 500/microL was obtained on day +11 and platelets > 20,000/microL on day +13. Patients were hospitalized for a mean period of 26 days (range 18-39) and days with parenteral antibiotics were 12.2 (5-45). Two pts had venoocclusive disease of the liver. Transplant related mortality was 15%. Acute graft versus host disease (GVHD) was observed in 43.4% of pts, only 5 pts had acute GVHD III or IV. Mean time for aGVHD diagnosis was +23 (8-76). Forty three pts were evaluable for chronic GVHD with a mean follow-up of 18 months (4-39). Chronic GVHD was observed in 26.4% by day +240, only 2 pts developed severe cGVHD. The present experience demonstrates an acceptable incidence for cGVHD; however, taking into account recent reports showing an increase of this complication, it seems reasonable not to perform this procedure for non-malignant diseases in which graft versus malignancy effect is not to be expected.
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PMID:[Allogeneic hematopoietic transplantation with stem cells extracted from peripheral blood]. 1096 6

Six patients with advanced Hodgkin's disease in which multiple conventional treatments (median prior chemotherapy regimens: seven), radiation therapy, and a prior autologous stem cell transplantation (SCT) had failed underwent allogeneic SCT following a fludarabine-based conditioning regimen. Median age was 29 years (22-30). Median time to progression after autologous SCT was 6 months (4-21). Disease status at transplant was refractory relapse (n = 3) and sensitive relapse (n = 3). Cell source was filgrastim-mobilized peripheral blood stem cells from an HLA-identical sibling (n = 4) or matched unrelated donor marrow (n = 2). Conditioning regimens were fludarabine-cyclophosphamide-antithymocyte globulin (n = 4), fludarabine-melphalan (n = 1) and fludarabine-cytarabine-idarubicin (n = 1). Myeloid recovery was prompt, with an absolute neutrophil count > or =500/microl on day 12 (11-15). Median platelet recovery to > or =20000/microl was on day 9 (0-60). Chimerism studies on day 30 indicated 100% donor-derived hematopoiesis in 4/5 evaluable patients (4/4 non-progressors). All responders (3/3) have ongoing 100% donor-derived chimerism. Acute graft-versus-host disease (GVHD) was diagnosed in 4/6 evaluable patients. Chronic GVHD was present in 2/4 evaluable patients. There were no regimen-related deaths. Overall day 100 transplant-related mortality was 2/6 (33%). Three patients have expired and three are alive and progression-free with a median follow-up of 9 months (6-26) post transplant. We conclude that allogeneic stem cell transplantation with fludarabine-based preparative regimens is feasible in these high-risk, heavily pretreated HD patients.
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PMID:Allogeneic stem cell transplantation with fludarabine-based, less intensive conditioning regimens as adoptive immunotherapy in advanced Hodgkin's disease. 1104 66

Chronic graft-versus-host disease (GVHD) refractory to standard immunosuppressive therapy remains a major cause of morbidity and mortality after allogeneic bone marrow transplantation (BMT). Thalidomide may be effective in some patients with high-risk or refractory chronic GVHD. We report a single-institution study of thalidomide in 37 BMT patients with extensive chronic GVHD refractory to standard immunosuppressive therapy. Acute GVHD occurred in 34 (91%) of patients and evolved progressively into chronic GVHD in 23 (62%) patients. Thalidomide was added to standard immunosuppressive therapy a median of 11 months (range 0-105 months) after the diagnosis of chronic GVHD. Fourteen of 37 (38%) patients responded after introduction of thalidomide (one complete, 13 partial). Ten of 21 (46%) children and four of 16 (25%) adults responded. Responses were seen in eight of 17 (47%) recipients of related donor marrow and six of 20 (30%) recipients of unrelated donor marrow. Eight of 23 (34%) patients with progressive onset of chronic GVHD showed a response. There were no deaths among the responders. The remaining 23 patients (62%) did not respond and of these only two survive, one with progressive scleroderma, and the other with bronchiolitis obliterans. Chronic GVHD with associated infection (most commonly disseminated fungal infection) was a major contributor to mortality in all cases. Overall, after initiation of thalidomide, the 2-year Kaplan-Meier survival was 41% (95% C.I. 24%-59%). We conclude that thalidomide is a useful and well-tolerated therapy for patients with previously treated refractory chronic GVHD, including those with progressive onset of chronic GVHD, recipients of unrelated donor marrow, and children. Earlier introduction of thalidomide as an adjunct to standard immunosuppressive therapy may lead to more frequent responses and possible better survival.
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PMID:Response to thalidomide therapy in refractory chronic graft-versus-host disease. 1108 86

Chronic graft-versus-host disease (GVHD) affects 30% to 50% of allogenic bone marrow transplant (BMT) recipients surviving the acute phase. We describe the clinical features and the anesthetic management of a child with a systemic form of GVHD resulting in severe restrictive pulmonary dysfunction.
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PMID:Anesthesia in a child with severe restrictive pulmonary dysfunction caused by chronic graft-versus-host disease. 1109 Jul 36

Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic disease in patients with skin, mouth, and eye involvement. We observed 14 patients in whom chronic GVHD of the liver presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. Onset of liver dysfunction was at 294 days (range, 74-747 days) after allogeneic hematopoietic cell transplantation and coincided with a recent cessation or taper of immunosuppressive drugs. Median peak serum alanine transaminase (ALT) was 1,640 U/L (698-2,565 U/L), and median bilirubin was 12.3 mg/dL (0.9-55.9 mg/dL). All biopsies showed characteristic features of GVHD with damaged and degenerative small bile ducts. Other features included a marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, and many acidophilic bodies scattered throughout the lobule. When high-dose immunosuppressive therapy was instituted soon after presentation, progressive improvement and eventual normalization of liver enzymes and bilirubin levels were observed. However, in cases in which the diagnosis was not made and therapy was delayed, a progressive cholestatic picture emerged with histologic evidence of loss of small bile ducts and portal fibrosis. We conclude that a distinct syndrome of chronic liver GVHD presenting as an acute hepatitis can be recognized in a patient at risk who is receiving no, or minimal, immunosuppressive medications. Liver biopsy is necessary to exclude viral causes of liver dysfunction and to confirm characteristic abnormalities of small bile ducts. Institution of high-dose immunosuppression can prevent progressive bile duct destruction and effect resolution of jaundice if given early.
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PMID:Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis. 1109 33

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.
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PMID:Changing from cyclosporine to tacrolimus as salvage therapy for chronic graft-versus-host disease. 1112 11

This report summarizes the experience with a conditioning regimen of cyclophosphamide and antithymocyte globulin in patients with severe aplastic anemia given HLA-matched related marrow grafts at 4 transplantation centers. Enrolled were 94 consecutive patients, of whom 87 had received multiple transfusions and 38 had failed immunosuppressive therapy. Their ages ranged from 2 to 59 years. After transplantation, 89 patients received a methotrexate/cyclosporine regimen for graft-versus-host disease (GVHD) prevention. Cyclosporine with or without prednisone was given in 4 patients, and no immunosuppression was given in 1 patient. Ninety-six percent of patients had sustained grafts, whereas 4% rejected grafts between 2 and 7 months after transplantation. Of the 4 rejecting patients, 3 are alive with successful second engraftments. Acute grade II GVHD was seen in 21% of patients, grade III in 7%, and grade IV in 1% of patients. Chronic GVHD was seen in 32% of patients, most of whom responded completely to immunosuppressive therapy. With a median follow-up of 6.0 years (range, 0.5-11.6 years), the survival rate was 88%. No unusual long-term side effects have been seen with the regimen. We conclude that the cyclophosphamide/antithymocyte globulin regimen combined with methotrexate/cyclosporine after transplantation is well tolerated and effective in heavily pretreated patients with aplastic anemia.
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PMID:Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. 1121 97

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA(+) naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4(+) and CD8(+) cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.
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PMID:Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. 1122 94

In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBTs) or bone marrow transplants, 541 children with acute leukemia (AL) transplanted with umbilical cord blood (n = 99), T-cell-depleted unrelated bone marrow transplants (T-UBMT) (n = 180), or nonmanipulated (UBMT) (n = 262), were analyzed in a retrospective multicenter study. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference between the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMTs (P <.001). Other significant differences were observed in pretransplant disease characteristics, preparative regimens, graft-versus-host disease (GVHD) prophylaxis, and number of cells infused. Nonadjusted estimates of 2-year survival and event-free survival rates were 49% and 43%, respectively, in the UBMT group, 41% and 37% in the T-UBMT group, and 35% and 31% in the UCBT group. After adjustment, differences in outcomes appeared in the first 100 days after the transplantation. Compared with UBMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR] = 0.37; 95% confidence interval [95CI]: 0.27-0.52; P <.001), increased 100 day transplant-related mortality (HR = 2.13; 95CI: 1.20-3.76; P <.01) and decreased acute graft-versus-host disease (aGVHD) (HR = 0.50; 95CI: 0.34-0.73; P <.001). T-UBMT recipients had decreased aGVHD (HR = 0.25; 95CI: 0.17-0.36; P <.0001) and increased risk of relapse (HR = 1.96; 95CI: 1.11-3.45; P =.02). After day 100 posttransplant, the 3 groups achieved similar results in terms of relapse. Chronic GVHD was decreased after T-UBMT (HR = 0.21; 95CI: 0.11-0.37; P <.0001) and UCBT (HR = 0.24; 95CI: 0.01-0.66; P =.002), and overall mortality was higher in T-UBMT recipients (HR = 1.39; 95CI: 0.97-1.99; P <.07). In conclusion, the use of UCBT, as a source of hematopoietic stem cells, is a reasonable option for children with AL lacking an acceptably matched unrelated marrow donor.
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PMID:Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia. 1134 18


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