Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.69 (BMT)
 2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase II study of the efficacy and safety of FK506, a new potent immunosuppressant, has been conducted in 49 patients with GVHD after allogeneic BMT. Eighteen patients with acute GVHD and 31 with chronic GVHD entered the study. FK506 was administered at an initial dose of 0.05 mg/kg i.v. or 0.15 mg/kg orally twice a day to those whose GVHD had become uncontrollable with cyclosporin and/or other immunosuppressants. The response to FK506 was evaluated in 13 patients with acute and 26 with chronic GVHD. A marked response was observed in 5 and a good response in 2 of 13 patients with acute GVHD. For those with chronic GVHD, the response was marked in 2 patients, good in 10 and poor in 8. The most common adverse effects were renal toxicity (53.1%), followed by nausea and vomiting (30.6%) and a feeding of warmth (18.4%). There was a correlation between renal toxicity and whole blood levels of FK506. The dose should be adjusted to keep a trough level between 15 and 25 ng/ml. FK506 is promising in the treatment of both acute and chronic GVHD, even if it is intractable with other immunosuppressants, and may be most effective if administered early in the course of GVHD.
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PMID:FK506 treatment of graft-versus-host disease developing or exacerbating during prophylaxis and therapy with cyclosporin and/or other immunosuppressants. Japanese FK506 BMT Study Group. 758 Oct 86

Three patients who developed acute onset of cerebral blindness within 5-47 days of BMT using tacrolimus (FK506) as primary GVHD prophylaxis are described. This syndrome has been described with the use of cyclosporin A (CsA) and FK506 in solid organ transplant recipients. CsA-induced cerebral blindness has also been noted in BMT recipients but to date there have been no reports of this complication in BMT patients receiving FK506. We have noted a striking similarity in the clinical and radiographic presentations between these patients and those with CsA-associated cerebral blindness. Reversibility within 1-2 weeks of onset and the potential for substitution of CsA for FK506 in these patients is described.
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PMID:Tacrolimus (FK506)-induced cerebral blindness following bone marrow transplantation. 887 19

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

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 38-year-old man developed idiopathic thrombocytopenic purpura (ITP) 8 months following allogeneic BMT while being treated for cGVHD with corticosteroids and tacrolimus (FK506). He received two courses of high-dose intravenous immunoglobulin (IvIG) which resulted in transient improvement. A single dose of intravenous anti-D immunoglobulin induced a durable response. Anti-D immunoglobulin is better tolerated, less complicated to administer, and less expensive than a course of IvIG.
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PMID:Idiopathic thrombocytopenic purpura following allogeneic bone marrow transplantation--treatment with anti-D immunoglobulin. 911 15

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

Tacrolimus (FK506) is a macrolide lactone effective in the control of graft-versus-host disease (GVHD). An interaction between high-dose methotrexate and a macrolide antibiotic (pristinamycin) leading to prolonged methotrexate exposure has been described. Because a randomized prospective trial comparing tacrolimus with cyclosporine (both in combination with methotrexate) following allogeneic BMT showed the tacrolimus plus methotrexate regimen to be more effective in prevention of GVHD, we assessed methotrexate pharmacokinetics in a subgroup of the participants of this trial to evaluate the possibility that an interaction of FK506 and methotrexate was the explanation for the clinical findings. Mean and median methotrexate levels at various time-points after the day 1 and 6 methotrexate doses were comparable in the tacrolimus and cyclosporine cohorts and were elevated in only three of 70 study patients. Area under the curve (AUC) concentrations were also similar after the day 1 and 6 methotrexate doses. Thus, no significant interaction between tacrolimus and methotrexate is apparent and the differences in efficacy between tacrolimus and cyclosporine are unlikely to be attributable to pharmacologic interactions with methotrexate.
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PMID:Lack of interaction between tacrolimus (FK506) and methotrexate in bone marrow transplant recipients. 923 56

We report the results of a phase III trial comparing tacrolimus (FK506) with cyclosporine for GVHD prophylaxis after allogeneic BMT. From February 1995 to July 1996, 136 patients were enrolled and followed up to September 1997. During the first 100 days post-transplant the incidence of grade II-IV acute GVHD (the primary end-point) was lower in the tacrolimus group (17.5%) compared with the cyclosporine group (48.0%, P < 0.0001). A significant difference was observed between the tacrolimus and cyclosporine groups when subset analyses were performed based on recipients from HLA-matched siblings (13.3% vs 41.3%, P = 0.015) or donors other than HLA-matched siblings (21.4% vs 53.8%, P= 0.0029). The incidence of chronic GVHD (47.3% and 47.8%) and Kaplan-Meier estimate of overall survival (62.9% and 65.2%) were similar between the tacrolimus and cyclosporine groups, respectively. The overall leukemia relapse rate was not significantly different between the tacrolimus and cyclosporine groups (19.6% and 11.4%, respectively). However, the relapse rate among recipients from HLA-matched siblings was significantly higher in the tacrolimus group (30.9%) compared with the cyclosporine group (3.6%, P = 0.013). These results suggest the merit of tacrolimus for the prophylaxis of acute GVHD, but a lack of merit for a graft-versus-leukemia effect among recipients from HLA-matched sibling donors.
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PMID:Phase III study comparing tacrolimus (FK506) with cyclosporine for graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation. 1150 36

Under immunosuppressive conditions after hematopoietic stem cell transplantation (HSCT), even if hepatitis B virus (HBV) antigen is negative but hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb) is presented, HBV reactivates and sometimes causes fulminant hepatitis. However, it remains unclear which patients will develop fulminant hepatitis, or whether fulminant hepatitis is caused by host-related factors or by virus-related factors. A 30-yr-old man with a history of aplastic anemia since 3 yr of age underwent allogenic BMT, when HBsAb and HBcAb were positive but HBs antigen (HBsAg) was negative. The donor was negative for HBsAg, HBsAb and HBcAb. After transplantation, the patient was complicated by acute graft-vs.-host disease (GVHD), cytomegalovirus infection, intestinal thrombotic microangiopathy and aspergillus colitis. Chronic GVHD was well controlled by FK506 and prednisolone. Twenty months after transplantation, the patient was admitted with general fatigue and liver dysfunction and was found to be positive for HBsAg and HBeAg. His serum HBV-DNA level was >8.8 log of the genome equivalent (LGE)/mL. Therefore, he was diagnosed as having hepatitis B caused by HBV reactivation and 100 mg/d lamivudine treatment was started. However, jaundice and hepatic failure deteriorated and became fatal. On analysis of the HBV-DNA, two adjacent gene mutations in the core promoter region (T1762/A1764) were detected. Increased replication of the mutated HBV might have caused HBV reactivation which progressed to fulminant hepatitis.
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PMID:Fulminant hepatitis after allogenic bone marrow transplantation caused by reactivation of hepatitis B virus with gene mutations in the core promotor region. 1692 12


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