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)

A 54-year-old woman developed polymyositis 6 months after allogeneic bone marrow transplantation (BMT) for acute myelogenous leukemia transformed from myelodysplasia. At the onset of myositis, the patient had oral dryness, and the histology of oral mucosa was compatible with chronic graft-versus-host disease (GVHD). Muscle biopsy revealed focal muscle necrosis with massive lymphocytic infiltration. She was diagnosed with polymyositis, and the dose of cyclosporine was increased. Three months later, a complete resolution of myositis had been obtained, and the cyclosporine was tapered off. However, 51 months after the first episode of myositis, she again noted severe myalgia and was diagnosed with a recurrence of polymyositis based on high serum creatinine kinase (CK) and the findings of magnetic resonance imaging (MRI). At that time, chronic GVHD in other organs was not present. She achieved a second remission of polymyositis with cyclosporine, and has remained in remission for 4 years. The pathogenesis of myositis can be attributed to the immunologic imbalance characteristic of the post-allogeneic BMT setting.
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PMID:Recurrent acute myositis after allogeneic bone marrow transplantation for myelodysplasia. 1218 1

Cyclosporine-based immunosuppression is common after allogeneic hematopoietic stem cell transplantation (HSCT). Elevated cyclosporine concentrations are associated with significant toxicity and often result in the temporary cessation or discontinuation of cyclosporine. Low blood concentrations also result in significant immunologic risks, primarily graft-versus-host disease and loss of stem cell graft. The pharmacokinetics of cyclosporine are highly complex, and maintaining therapeutic and safe cyclosporine concentrations are challenging. Several clinical factors are known to independently influence in vivo cyclosporine pharmacokinetic behavior. However, in the critically ill patient, several of these clinical factors are generally present simultaneously. Unfortunately, there are no studies that have evaluated the combined effects of these clinical factors on cyclosporine disposition in HSCT. The objective of our study is to determine the population pharmacokinetic parameters of intravenous and oral cyclosporine, evaluate the effects of clinical covariates on cyclosporine pharmacokinetics, and develop a model that estimates clearance (Cl) and dose requirements for an individual HSCT patient with these clinical covariates. The authors analyzed 740 cyclosporine steady-state whole blood concentrations in 129 adult patients obtained between day 0 and discharge or 60 days posttransplant, whichever came first. Patients received intravenous cyclosporine at 2.5 mg/kg every 12 hours if body weight was greater than 50 kg, 2.5 mg/kg every 8 hours if less than 50 kg, or 5 to 7.5 mg/kg/d given as a continuous infusion, beginning on day-3. Patients were converted to oral therapy as tolerated. The influence of clinical covariates on the Cl of cyclosporine was tested with a nonlinear mixed effects model (NONMEM). The tested clinical covariates were age, height, body weight on admission, body surface area, sex, type of hematologic malignancy, transplant type, preparative regimen, baseline serum creatinine, T-cell depletion of graft, number of methotrexate doses, day of onset, and maximum grade of acute graft-versus-host disease. The route and frequency of cyclosporine administration, day posttransplant, total bilirubin level, serum creatinine level, actual body weight, presence of concurrent CYP450 enzyme inhibitors and inducers, or nephrotoxins on the day of the cyclosporine blood measurement were also evaluated. Cyclosporine Cl significantly decreased each week posttransplant. The authors found no significant effect of any of the other tested covariates including total bilirubin on Cl. The final regression model for the estimation of Cl is: Cl (L/hr) = ([body weight in kg - 70] * 0.183 + 22.3) * (day posttransplant factor). The corresponding day posttransplant factor estimates are 1.46, 1.32, 1.20, and 1.0 during days 0 to 7, 8 to 14, 15 to 21 and greater than 21 posttransplant, respectively. The interindividual variability in Cl was 27.7%. The dose of intravenous or oral cyclosporine can be calculated using the estimated Cl. Understanding cyclosporine pharmacokinetics and the clinical events that lead to alterations in Cl and exposure is critical in optimizing immunosuppressive therapy. The authors found that cyclosporine Cl significantly decreased posttransplant until day 21. A pharmacokinetics model was developed that incorporates the day posttransplant to predict cyclosporine Cl. Cyclosporine dose requirements in an individual HSCT patient to achieve the desired therapeutic blood target can be estimated using this model.
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PMID:Posttransplant day significantly influences pharmacokinetics of cyclosporine after hematopoietic stem cell transplantation. 1276 80

We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n=54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1-167.4) was significantly (P<0.0001) lower than that in patients (n=49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9-235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.
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PMID:Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation. 1462 75

Acute and chronic renal dysfunction are common after hematopoietic stem cell transplantation (HSCT). Although the pathology of chronic HSCT nephropathy is well described, the histologic changes that accompany acute renal dysfunction after HSCT are less well known because renal biopsies are rarely undertaken in the peritransplantation period. Archival renal tissue from consecutive HSCT recipients who died and underwent autopsy at a single center during an 8-year period was studied. Abnormalities of renal pathology were described, and associations of histologic abnormalities with clinical events were systemically studied. Abnormalities of renal histology were common among the 26 patients in this study. The 3 most common histologic abnormalities were glomerular sclerosis (19/26; 73%), tubular epithelial atypia (19/26; 73%), and tubular calcification (18/26; 69%). Tubulitis (16/24; 67%) and interstitial fibrosis (16/26; 62%) were also frequently observed. Clinical veno-occlusive disease was not associated with histologic evidence of thrombotic microangiopathy in the kidney at autopsy. Also, clinical graft-versus-host disease was not associated with renal tubulitis. Unexpectedly, the proportion of patients with tubular atrophy (54%) or interstitial fibrosis (62%) was high, considering the young age of the patients at transplantation and their normal pretransplantation creatinine clearance. Well-recognized histologic abnormalities are common in the kidneys of patients who die after HSCT. Although we did not demonstrate associations of these histologic changes with clinical variables before death, larger studies with prospectively collected renal tissue are warranted.
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PMID:Renal pathology at autopsy in patients who died after hematopoietic stem cell transplantation. 1465 51

Improving survival rates following pediatric bone marrow transplantation (BMT) will likely result in greater numbers of children progressing to end-stage renal disease (ESRD) because of prior chemotherapy, irradiation, sepsis, and exposure to nephrotoxic agents. Renal transplantation remains the treatment of choice for ESRD; however, the safety of renal transplantation in this unique population is not well established. We report our experience with living related renal transplantation in three pediatric patients with ESRD following prior BMT. Two patients with neuroblastoma and ESRD because of BMT nephropathy, and one patient with Schimke immuno-osseous dysplasia and ESRD because of immune complex mediated glomerulonephritis and nephrotic syndrome. Age at time of BMT ranged from 2 to 7 yr. All patients had stable bone marrow function prior to renal transplantation. Age at renal transplant ranged from 8 to 14 yr. All three patients have been managed with conventional immunosuppression, as no patient received a kidney and BMT from the same donor source. These patients are currently 7 months to 6 yr status post-living related transplant. All have functioning bone marrow and kidney transplants, with serum creatinine levels ranging 0.6-1.2 mg/dL. There have been no episodes of rejection. One patient with a history of grade III skin and grade IV gastrointestinal-graft-vs.-host disease (GI-GVHD) prior to transplantation, had a mild flare of GI-GVHD (grade I) post-renal transplant and is currently asymptomatic. The incidence of opportunistic infection has been comparable with our pediatric renal transplant population without prior BMT. One patient was treated for basal cell carcinoma via wide local excision. Renal transplantation is an excellent option for the treatment of pediatric patients with ESRD following BMT. Short-term results in this small population show promising patient and graft survival, however long-term follow-up is needed. Pre-existing immune system impairment and bone marrow function should be taken into consideration when weighing different immunosuppressive agents for renal transplantation. Patients who have undergone renal transplantation following BMT are at high risk for opportunistic infections and malignancy, and need life-long medical surveillance.
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PMID:Successful renal transplantation following prior bone marrow transplantation in pediatric patients. 1536 89

We conducted a phase II trial in 19 chronic graft-versus-host disease (cGVHD) patients with rapamycin, calcineurin inhibitors, and prednisone with the goals of controlling cGVHD, reducing prednisone use, and defining the safety of this regimen. Rapamycin was begun as second-line (n = 9) or more than second-line (n = 10) therapy. With a median follow-up of 42 months, 16 patients were evaluable for response. Nine patients discontinued rapamycin because of poor compliance/patient request (n = 2) or an adverse event (n = 7), 3 of whom were not evaluable because of withdrawal at < or =1 month or noncompliance. The adverse events included serum creatinine > or =2.4 mg/dL (n = 4), hemolytic uremic syndrome (n = 2), and relapse of malignancy (n = 1). Fifteen of 16 evaluable patients had a clinical response. Five of the 16 discontinued the drug, and 1 died of relapsed leukemia. Of the 10 patients who continued rapamycin, 2 discontinued and 1 successfully tapered all systemic immunosuppression. Three of the 10 developed progressive cGVHD with tapering immunosuppression; all responded to resumption of prior medications. Four of the 10 patients required alternate therapy for persistent or progressive cGVHD while receiving rapamycin; prednisone was discontinued (n = 2) or tapered at the time of progressive disease (n = 2). Seventeen of 19 original patients were alive. One death was due to relapsed malignancy, and 1 was due to congestive heart failure. In this report of rapamycin as cGVHD therapy, there is evidence of rapamycin's efficacy. Given the significant toxicities described, investigation of altered administration of rapamycin and calcineurin inhibitors should be pursued in future cGVHD trials.
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PMID:Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. 1604 15

Caspofungin (CAS) is the first of a new class of antifungal agents, the echinocandins, that interfere with fungal cell wall synthesis by inhibition of glucan synthesis. Here, we report the results of 31 patients treated with CAS following allogeneic SCT. CAS was administered as a second-line agent to patients with invasive fungal infection (IFI) (n=15) or fever of unknown origin (n=16) who were recalcitrant to or intolerant of prior antifungal therapy. Unsuccessful first-line regimes included amphotericin B (n=17), liposomal amphotericin B (n=5), fluconazole (n=3), itraconazole (n=1), and voriconazole (n=2). All patients received concomitant immunosuppressive therapy for graft-versus-host disease. In 23 patients, cyclosporin A (CSA) and CAS were administered concurrently without any major side effects detected. Observed increases in GPT were not clinically significant. Normalization of serum creatinine and significant reductions in C-reactive protein were observed in response to CAS. Favorable outcome to CAS were documented in eight of 15 patients with IFI and in 15 of 16 patients with fever of unknown origin. CAS is a promising alternative in patients with IFI and fever of unknown origin in the setting of allogeneic SCT.
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PMID:Caspofungin as second-line therapy for fever of unknown origin or invasive fungal infection following allogeneic stem cell transplantation. 1575 83

Thrombotic microangiopathy (TMA) may occur after allogeneic hematopoietic stem cell transplantation (HSCT) and is related in part to calcineurin inhibitor toxicity. We observed a higher-than-expected rate of TMA when calcineurin inhibitors were combined with sirolimus. To determine the incidence of and risk factors for TMA after HSCT, we performed a retrospective cohort analysis of myeloablative allogeneic HSCT recipients between 1997 and 2003. TMA diagnosis required the simultaneous occurrence of (1) creatinine increase >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) increased lactate dehydrogenase, and (4) no evidence of disseminated intravascular coagulopathy. A total of 111 sirolimus-exposed subjects were compared with 216 nonexposed subjects after HSCT. TMA occurred in 10.8% of the sirolimus group and 4.2% in the nonsirolimus group (odds ratio, 2.79; P=.03). Sirolimus exposure was associated with TMA earlier than in nonsirolimus patients (25 versus 58 days; P=.04). Only the use of sirolimus (exact odds ratio, 3.49; P=.02) and grade II to IV acute graft-versus-host disease (exact odds ratio, 6.60; P=.0002) were associated with TMA in regression analyses. Treatment of TMA varied among affected individuals. Renal recovery was complete in 92% of sirolimus-treated patients. Overall survival after TMA diagnosis was better for sirolimus subjects than for nonsirolimus subjects (58.3% versus 11.1%; P=.02). Sirolimus seems to potentiate the effects of calcineurin inhibitors on TMA after HSCT. TMA associated with sirolimus seems reversible and has a favorable prognosis when compared with TMA associated with calcineurin inhibitors alone. A careful monitoring strategy for TMA should be used with a sirolimus-containing graft-versus-host disease prophylaxis regimen.
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PMID:Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. 1598 55

It is unknown whether imatinib prior to myeloablative haematopoietic stem cell transplantation (HSCT) increases transplant-related toxicity. Among the side effects induced by imatinib, myelosuppression and liver injury might worsen HSCT outcomes. We retrospectively analysed engraftment, liver toxicity, acute graft-versus-host disease (aGVHD) incidence and 100-day mortality in 30 patients with BCR/ABL-positive leukaemias who received imatinib before HSCT and compared results of 48 age-matched controls who did not receive preceding imatinib. Both neutrophil and platelet engraftment occurred more rapidly among imatinib patients but the differences adjusted for Gratwohl scale were not statistically significant (P = 0.18 and 0.22, respectively). The adjusted hazards of having liver function tests (LFTs) >1.5 normal increased and the adjusted durations of elevated LFTs were not significantly different. The estimated adjusted difference in mean peak bilirubin values was also not significantly different (P = 0.48). However, the adjusted hazard of increased creatinine >1.5 normal was significantly higher in the imatinib group (HR = 4.09, P = 0.02). The adjusted odds of grades II-IV aGVHD were similar in both groups (OR = 0.86, P = 0.78), and while the adjusted odds of 100-day mortality were lower among imatinib patients, the difference was not significant (OR = 0.65, P = 0.60). These data do not provide any evidence that imatinib preceding HSCT increases acute transplant-related toxicities.
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PMID:Imatinib therapy prior to myeloablative allogeneic stem cell transplantation. 1600 5

A total of 85 allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis treated with amphotericin B lipid complex (ABLC) were identified from the Collaborative Exchange of Antifungal Research (CLEAR) database. Of these patients, 78% (66/85) presented with pulmonary aspergillosis. Graft-versus-host disease (GVHD) was present in 24 of 85 patients. The response rate to ABLC was 31% (26/85) overall and 21% (5/24) in patients with GVHD. The overall response rate to first-line ABLC treatment was 41% (11/27). Four of nine (44%) patients with GVHD responded to first-line treatment with ABLC, while only one of 13 (8%) responded to ABLC as second-line therapy. Five of 18 (28%) and four of 14 (29%) patients, respectively, responded to sequential or concurrent treatment with ABLC and itraconazole. None of seven patients responded who continued receiving itraconazole after the start of ABLC therapy. At the end of ABLC therapy, serum creatinine had doubled in 12% of patients (10/85), and 2% (2/85) had developed a requirement for dialysis. These data suggest that ABLC, especially when administered as first-line therapy, can result in clinical response even in the most immunocompromised patients, that is, HCT recipients with GVHD, with minimal effects on renal function.
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PMID:Effectiveness of amphotericin B lipid complex (ABLC) treatment in allogeneic hematopoietic cell transplant (HCT) recipients with invasive aspergillosis (IA). 1611 63


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