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)

The safety and potential efficacy of FK506 in combination with a short course of methotrexate (MTX) for the prevention of acute graft-versus-host disease (GVHD) after marrow transplantation from HLA-matched unrelated donors was evaluated in a single-arm Phase II study conducted at two centers. Forty-three patients, 15 to 54 (median 41) years of age, were transplanted for hematologic malignancies. Thirty-seven of 43 evaluable patients had evidence of sustained marrow engraftment. Five patients died before day 17 after transplantation. The median time to an absolute neutrophil count of > 0.5 x 10(5)/L was 21 (range, 14 to 30) days. Nephrotoxicity (serum creatinine concentration > 2 mg/dL or doubling of baseline) occurred in 32 patients (74% cumulative incidence during the first 100 days after transplant). Other adverse effects included hypertension (n = 27), hyperglycemia (n = 27), neurotoxicity (n = 9) and thrombotic thrombocytopenic purpura (n = 2). Severe veno-occlusive disease of the liver occurred in 9 (21%) of the 43 patients. Eighteen patients (42%) developed grades II to IV acute GVHD and five (12%) developed grades III to IV acute GVHD. Twelve of 25 evaluable patients developed extensive chronic GVHD within 1 year of marrow transplantation resulting in an estimate of the probability of developing this complication of 48%. The cumulative incidence of transplant-related mortality during the first 100 days was 37%. Kaplan-Meier estimates of disease-free survival at 2 years for good-risk, poor-risk, and all patients were 65%, 4%, and 32%, respectively. FK506 in combination with a short course of MTX appears active in preventing acute GVHD after marrow transplantation from unrelated donors. Further studies comparing the combination of FK506 and MTX with cyclosporine and MTX for the prevention of acute GVHD are warranted.
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PMID:FK506 in combination with methotrexate for the prevention of graft-versus-host disease after marrow transplantation from matched unrelated donors. 889 34

A 44-year-old woman with Ph-positive CML was treated with TBI, splenic irradiation, Ara-C, and CY. She then received unmanipulated marrow cells from her HLA-identical brother. GVHD prophylaxis was FK506 and MTX. WBC counts reached 1000/microliter on day 28 when all metaphases of marrow cells showed 46XY. However, on day 42, 46XX was detected in two of 20 metaphases, and the percentage of cells with female karyotype subsequently increased. On day 519, all metaphases showed female karyotype. BCR-ABL mRNA and Philadelphia chromosome were never detected throughout her post-transplant course. Fluorescence in situ hybridization (FISH) revealed complete recovery of host-derived hematopoiesis in the bone marrow, however, mixed T cell chimerism in the peripheral blood. This suggests that the persistence of donor-derived T cells may prevent disease recurrence through graft-versus-leukemia effect. The patient remains in a molecular complete remission with host-derived hematopoiesis 749 days post-transplant.
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PMID:Durable molecular remission in a patient with chronic myelogenous leukemia and host-derived hematopoiesis after allogeneic bone marrow transplantation. 889 99

The optimal dose of FK506 on rat limb allograft was investigated across the BN-to-F344 histocompatibility barrier. BN limb allografts were rejected in untreated F344 hosts within 11 +/- 1 days (mean +/- SD) after operation. A single injection of 0.5 mg/kg, 1.0 mg/kg, or 2.0 mg/kg of FK506 on the day of transplantation significantly prolonged graft survival, mean survival times (MST) based on gross sign of skin rejection were 16 +/- 1 days, 19 +/- 1 days, 21 +/- 1 days, respectively. Maintenance doses of 0, 0.25, 0.5, 1.0, or 2.0 mg/kg/week of FK506 after a single administration of 10 mg/kg of FK506 on the day of limb allograft prolonged the graft survival, 63 +/- 10, 68 +/- 20, 87 +/- 23, 98 +/- 30, 136 +/- 20 days, respectively, and showed no evidence of infection or toxic side effects. The regimen of lower maintenance dose of FK506, however, developed chronic GVHD. In the second set of experiments, development of peripheral blood chimeras was studied in PVG-to-ACl limb allograft model. A single injection of 50 mg/kg of the day of transplantation prolonged graft survival and MST was 154 days. The average rates of peripheral blood chimeras were 2 to 6% and there was no relationship between graft survival and peripheral blood chimeras. However, GVHD developed in one of the six recipients at 201 days after operation. In the similar experiments, grafts were irradiated before operation. Peripheral blood chimeras was not observed in there experiments and GVHD was not developed in 300 days after operation. These data suggest that FK506 is quite effective for rat limb allograft survival in dose-dependent manner and GVHD could be prevented by graft irradiation before operation.
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PMID:[Limb allograft in rats: studies on optimal maintenance dose of FK506 and development of graft-versus-host-disease (GVHD)]. 891 57

Between March 1984 and March 1995, 76 patients with advanced acute myelogenous, acute lymphoblastic, or chronic myelogenous leukemia underwent allogeneic marrow transplantation from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received a preparative regimen consisting of busulfan 16 mg/kg and cyclophosphamide 120 mg/kg or busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and etoposide (VP-16) 50 mg/kg. For GVHD prevention, patients received cyclosporine with either methotrexate or steroids or FK506 with methotrexate. Fourteen patients were leukemia-free survivors at a median of 6.5 years (range 1-11 years) following transplantation. For the group as a whole, the estimated leukemia-free survival (LFS) at 5 years is 20% (95% confidence interval 10-30%). Ten of the 14 leukemia-free survivors developed acute GVHD greater than grade II and chronic GVHD and two developed only chronic GVHD. Significantly better relapse rates and disease-free survival were associated with the development of acute and/or chronic GVHD. In the absence of acute GVHD and/or chronic GVHD, patients who underwent transplantation for advanced leukemia, after preparation with Bu/CY or Bu/CY/VP-16, were very likely to experience disease recurrence. Novel strategies designed to promote development of GVHD present a promising area for investigation to improve outcome in patients with leukemia at high risk for relapse.
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PMID:Influence of graft-versus-host disease on outcome following allogeneic transplantation with radiation-free preparative therapy in patients with advanced leukemia. 893 44

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.
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PMID:Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after matched unrelated donor marrow transplantation. 894 76

We have evaluated the use of blood stem cell grafts for rapid hematopoietic recovery and tacrolimus (FK506) as GVHD prophylaxis to reduce early mortality after allogeneic transplantation. Eighty-five adults with advanced leukemia received high-dose thiotepa, busulfan, and cyclophosphamide as a preparative regimen in a prospective Phase II study. All donors were HLA-matched and related. Marrow (BMT) was used for 44 patients and filgrastim-mobilized blood stem cells (SCT) for 41 patients. GVHD prophylaxis consisted of cyclosporine (CsA) or FK506 with methotrexate (MTX) or methylprednisolone (MP). The median time to neutrophil recovery was earlier after SCT than after BMT (day 10 vs. 17, P<0.001), but this was due to the selective use of MTX only in the BMT patients. The risk of grades 2-4 GVHD was lower with FK506 than with CsA (16% vs. 45%, P=0.02) and was the same for SCT recipients as for BMT recipients (33% vs. 34%). Regimen-related toxicity was significantly lower after SCT than after BMT but did not differ between the FK506 and CsA patients. In comparison with those receiving the standard transplant (BMT with CsA and MTX), only the SCT recipients using FK506 and MP had a significantly higher survival at day 180 posttransplant (84% vs. 53%, P=0.014). In multivariate analyses, use of FK506 was associated with a lower risk of treatment-related mortality and a higher survival at day 180, while the diagnosis of acute lymphoblastic leukemia was associated with a higher risk of treatment-related mortality. These data suggest that the use of blood stem cell grafts and FK506 can reduce the early mortality after allogeneic transplantation for advanced leukemia.
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PMID:Allogeneic transplantation for advanced leukemia: improved short-term outcome with blood stem cell grafts and tacrolimus. 899 Mar 68

There have been many advances in the prevention and treatment of GVHD, including cyclosporine, FK506, and combination therapies. This syndrome, however, continues to account for significant morbidity and mortality after allogeneic transplantation. With the expanded use of matched unrelated as well as mismatched related donors, the increase in incidence and severity of GVHD poses a new clinical challenge. Many of the newer agents discussed in this paper may have a role in the future as therapy for acute GVHD. The evaluation of these new agents and the approach to be taken is hampered by the realization that most patients have received and are relatively refractory to standard therapies. Clinical trials must be performed earlier in the course of the syndrome to establish the role of these compounds. Newer strategies are likely to include the use of sequential therapy directed at blocking endogenous cytokines followed by blocking alloreactive donor cells, and immunologic advances such as the induction of tolerance. What impact, if any, such therapy may have on amelioration of a graft-versus-leukemia effect remains unknown.
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PMID:Prevention and treatment of acute graft-versus-host disease: the old and the new. A report from the Eastern Cooperative Oncology Group (ECOG). 908 38

We report our findings in two cases of steroid-resistant severe acute GVHD after allogeneic BMT successfully treated with FK506 (tacrolimus). An 18-year-old female (patient 1) who underwent BMT from an HLA-identical sibling for ALL in first CR, developed generalized erythema and profuse watery diarrhea, which progressed to acute GVHD of grade III severity, resistant to steroid control. After continuous 24-h administration of FK506, the diarrhea improved within 10 days. Patient 2, a 9-year-old girl with AML who underwent unrelated BMT, had skin, gut and liver lesions of acute GVHD grade IV, which did not respond to high-dose steroid therapy. They were controlled, however, by continuous intravenous infusion of FK506. Both patients are still surviving after more than 1 year without any acute GVHD sequelae or signs of chronic illness. The adverse effects of FK506 were mild and tolerable in both cases. Comparison of our findings with those in the literature suggests that it is important to give FK506 at plasma concentrations as high as 25-35 ng/ml by continuous intravenous infusion for extended periods to control steroid-resistant severe acute GVHD.
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PMID:Successful treatment of steroid-resistant severe acute GVHD with 24-h continuous infusion of FK506. 908 43

A 19-year-old male underwent allogeneic BMT for severe aplastic anaemia (SAA) from his HLA- and blood group-identical sister. He was conditioned with cyclophosphamide (CY) and single fraction total lymphoid irradiation (TLI). GVHD prophylaxis consisted of FK506 and a short course of methotrexate. The patient failed to achieve durable trilineage hematopoietic engraftment. There was no significant myeloid response to GM-CSF or G-CSF. Evaluation of FACS-sorted peripheral T cells from the patient by fluorescence in situ hybridization (FISH) revealed mixed chimerism (44% host origin). Fifty-three days after the first BMT, he was treated with G-CSF primed, unmanipulated PBSC transfusions (5.28 x 10(8)/kg mononuclear, 4.28 x 10(6)/kg CD34+, 292.51 x 10(6)/kg CD3+ cells) from his original donor without reconditioning. FK506 was continued at the same dose. Neutrophil recovery to 0.5 x 10(9)/l and platelet engraftment to 20 x 10(9)/l was achieved 11 and 27 days following the first dose of allogeneic PBSC transfusion, respectively. On day 23 a repeat FISH on the patient's sorted peripheral T lymphocytes revealed 91% donor origin T cells. The patient is currently well with a stable engraftment 6 months following allogeneic PBSC transfusion, with no signs of acute of chronic GVHD.
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PMID:Successful engraftment after primary graft failure in aplastic anemia using G-CSF mobilized peripheral stem cell transfusions. 911 16

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.
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PMID:The outcome of unrelated donor bone marrow transplantation in patients with hematologic malignancies using tacrolimus (FK506) and low dose methotrexate for graft-versus-host disease prophylaxis. 920 38


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