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)

Many patients receiving allogeneic stem cells develop chronic graft-versus-host disease (cGVHD), which remains as the main cause of morbidity and mortality. Although the first line of therapy is generally with steroids, it is not well known how to manage refractory cases. Those patients are usually treated with alternative experimental agents. Sirolimus (Rapamycin), a new immunosuppressive agent, inhibits signal transduction and cell cycle progression after binding to FKBP12. We report a retrospective analysis with sirolimus in transplant recipients with cGVHD refractory to previous immunosuppressive therapy. Forty-seven patients with refractory or relapsed cGVHD were treated with the combination of sirolimus and calcineurin inhibitors (n = 33), mycophenolate (n = 9), or prednisone (n = 5). Thirty-eight of 47 (81%) patients had clinical responses (complete = 18, partial = 20). The main toxicity was mild renal failure, particularly at the start of therapy. Four patients who presented thrombotic microangiopathy were managed with plasmapheresis and the discontinuation of sirolimus and calcineurin inhibitors. Statistical analysis showed the type of cGVHD onset and presirolimus clinical status as the main variables influencing the response to treatment. The Kaplan-Meier estimate of survival was 57.4% at 3 years. The current study shows the efficacy and safety of sirolimus in refractory cGVHD patients. Further investigation is warranted to elucidate the role of sirolimus in cGVHD, and find the best combination (sirolimus + calcineurin inhibitors versus others) for therapeutic use.
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PMID:Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. 1753 80

Transplant-associated microangiopathy (TAM) is a severe complication following allogeneic hematopoietic stem cell transplantation (HSCT) even after reduced-intensity conditioning (RIC). Data on 112 patients following RIC were analyzed with respect to TAM according to the ASBMT and risk factors, response to well-defined therapy and outcome were determined. TAM occurred in 11 of 112 patients. Univariate analysis determined acute graft-versus-host disease and ABO-incompatibility as risk factors for TAM. Treatment consisted of withdrawal of calcineurin inhibitors and plasma exchange (PE). Response to PE was 64%. PE seems to be an effective therapeutic option that should be assessed in larger patient cohorts.
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PMID:ABO-incompatible allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning: close association with transplant-associated microangiopathy. 1756 87

Calcineurin inhibitors (cyclosporine and tacrolimus) have been used as the mainstay immunosuppressive therapy for solid organ and hematopoietic cell transplantations (HCT) to prevent allograft rejection and for prophylaxis and treatment of the chronic graft-versus-host disease. Adverse effects of these drugs include nephrotoxicity, hepatotoxicity, neurotoxicity, hypertension and gingival hyperplasia. Association of oral non-gingival soft tissue hyperplasia with calcineurin inhibitor therapy has only recently been recognized and is thought to occur infrequently. We present four cases of oral non-gingival inflammatory fibro-vascular hyperplasias attributed to the use of calcineurin inhibitors following solid organ transplantation and HCT. These lesions interfere with function and must be differentiated from other oral lesions, and therefore should be surgically excised.
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PMID:Calcineurin inhibitor-associated oral inflammatory polyps after transplantation. 1785 Apr 43

There are 3 clearly distinct clinical entities that occur after HCT: TMA, idiopathic CKD, and nephrotic syndrome. The potentially independent role of GVHD and chronic inflammation in the development and progression of idiopathic CKD warrants further investigation. CKD after HCT is a relatively common occurrence. As the indications for and number of transplants performed world wide increases, so will the burden of kidney disease. Identifying those patients at risk for the development of CKD will be important for potential intervention and prevention of CKD and progression to end-stage renal disease in this patient population. There are those patients who will develop CKD that is not related to TBI or the conditioning regimen but rather to complications and/or therapy that occur after HCT, specifically aGVHD and cGVHD and prolonged calcinuerin inhibitor use. The burden of management will fall not only to the nephrologists but the oncologist as well to ensure close monitoring of renal function, blood pressure, and urinalyses posttransplant. It may be that our energies have been misdirected in trying to reduce exposure to TBI, and rather we should try to decrease the inflammatory and cytokine effects of GVHD and reduce exposure to calcineurin inhibitors to prevent CKD in this population of patients.
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PMID:Chronic kidney disease after pediatric hematopoietic cell transplant. 1816 26

Prevention of GVHD is one of the most desirable goals of BMT in aplastic anemia (AA). We reviewed the medical records of 24 consecutive patients treated with BMT for acquired AA using two different GVHD prevention strategies. Ten patients were given alemtuzumab-based GVHD prophylaxis (50-60 mg in three divided doses on days -8, -7 and -6), and 14 patients were given conventional GVHD prophylaxis with calcineurin inhibitors plus MTX before the introduction of the alemtuzumab-based protocols. The incidence of acute, chronic and 'serious GVHD' was significantly reduced in alemtuzumab-treated patients compared to conventionally treated patients [11 vs 64% (P=0.03), 0 vs 78% (P=0.002) and 0 vs 57% (P=0.007), respectively]. Engraftment time and rates of graft failure appeared similar in the two groups. A significantly higher proportion of alemtuzumab-treated patients developed CMV reactivation compared to control patients (83 vs 12%; P=0.03); none developed CMV disease. The rates of other infectious complications did not appear significantly different. Our data suggest that 50-60 mg of alemtuzumab given according to the current schedule significantly reduces the risk of GVHD without increasing the risk of graft failure or serious infections.
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PMID:Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies. 1837 7

Calcineurin inhibitors, tacrolimus and cyclosporine, have been widely used to prevent the rejection or graft-versus-host disease after transplantations. Since these drugs have a narrow therapeutic range and show large inter- and intraindividual pharmacokinetic variability, frequent therapeutic drug monitoring is required to control their blood concentrations. Even with blood concentrations within the therapeutic range, some patients still experience acute rejection or infections. Tacrolimus and cyclosporine form a complex with their respective binding proteins, immunophilins, which in turn inhibit the phosphatase activity of calcineurin, a key enzyme in the activation of T lymphocytes. Pharmacodynamic assessment of calcineurin phosphatase activity in combination with the monitoring of blood concentrations has been studied. The inhibitory effects on calcineurin activity in peripheral blood mononuclear cells differed between tacrolimus and cyclosporine in transplant patients. The pharmacodynamics of both drugs shows great inter- as well as intraindividual variation, and acute rejection was associated with calcineurin activity. Calcineurin activity at trough time points was suggested as a single surrogate predictor for overall calcineurin activity throughout dosing periods. Monitoring of calcineurin phosphatase activity might be useful to determine the therapeutic range of tacrolimus and cyclosporine concentrations for an individual patient treated with a calcineurin inhibitor.
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PMID:Pharmacodynamic monitoring of calcineurin phosphatase activity in transplant patients treated with calcineurin inhibitors. 1857 18

Certain leukemias have a high relapse risk even after allo-SCT, and GVHD prophylaxis with calcineurin inhibitors (CNIs) may interfere with a possible GVL effect. Therefore, we replaced CYA by sirolimus in patients with high relapse risk. In contrast to CNIs, sirolimus promotes the generation of regulatory T-cells and has potent antineoplastic activity. Sirolimus has been used in combination with CNI for GVHD prophylaxis in hematopoietic SCT. However, no CNI-free prophylactic regimen with sirolimus has been evaluated so far. Within the FLAMSA-RIC protocol, 15 patients received GVHD prophylaxis with sirolimus and mycophenolate mofetil (MMF). The underlying diagnoses were relapsed or refractory T-ALL (n=3), AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) or mixed-lineage leukemia-partial tandem duplication (MLL-PTD; n=10; 5 with refractory disease) and CML in refractory myeloid blast crisis (n=2). All evaluable patients (n=14) were engrafted. Grades II-IV acute GVHD occurred in 21% and chronic GVHD in 30% of patients. Non-relapse mortality rate was 14%. No thrombotic microangiopathy or sinusoidal obstruction syndrome was observed. Three patients with FLT3-ITD+ AML relapsed after a median of 112 days. At a median follow-up of 10 months after transplantation, 10 patients are alive and in complete remission. In conclusion, sirolimus-based GVHD prophylactic regimens deserve further investigation.
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PMID:Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. 1901 60

Non-malignant late effects after hematopoietic stem cell transplantation (HSCT) are heterogeneous in nature and intensity. The type and severity of the late complications depend on the type of transplantation and the conditioning regimen applied. Based on the most recent knowledge, we discuss three typical non-malignant complications in long-term survivors after HSCT, namely pulmonary, cardiovascular and renal complications. These complications illustrate perfectly the great diversity in respect of frequency, time of appearance, risk factors, and outcome. Respiratory tract complications are frequent, appear usually within the first two years, are closely related to chronic graft-versus-host disease (GVHD) and are often of poor prognosis. Cardiac and cardiovascular complications are mainly related to cardiotoxic chemotherapy and total body irradiation, and to the increase of cardiovascular risk factors. They appear very late after HSCT, with a low magnitude of risk during the first decade. However, their incidence might increase significantly with longer follow-up. The chronic kidney diseases are usually asymptomatic until end stage disease, occur within the first decade after HSCT, and are mainly related with the use of nephrotoxic drugs such as calcineurin inhibitors. We will discuss the practical screening recommendations that could assist practitioner in the follow-up of long-term survivors after HSCT.
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PMID:Late pulmonary, cardiovascular, and renal complications after hematopoietic stem cell transplantation and recommended screening practices. 1907 70

Posterior reversible encephalopathy syndrome (PRES) is one of the serious adverse side effects of calcineurin inhibitors, which are used for the prophylaxis of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). We retrospectively analyzed 12 patients who developed PRES after allo-SCT aiming to clarify the clinical features, risk factors, and prognosis of PRES. Median onset of PRES is 17 days after allo-SCT. The most frequent primary symptom was high blood pressure, followed by headache and visual disturbance. Nine of our patients subsequently developed systemic seizure. Sites of PRES by MRI were detected in the frontal, temporal, and parietal lobes, basal ganglia, and brain stem in addition to occipital lobe. Serum creatinine that had increased two-fold from the baseline value was identified as the only risk factor for developing PRES after allo-SCT. The incidence of acute GVHD (grade II-IV) in patients with PRES and those without were 88.9% and 48.7%; respectively (P<0.001), and most of these patients died of GVHD or GVHD-related causes. The 2-year overall survival of patients with PRES and those without were 16.7% and 72.4%, respectively (P<0.001). These data suggested the importance of early intervention for PRES and exploitation of optimal GVHD prophylaxis after developing PRES.
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PMID:[Retrospective analysis of posterior reversible encephalopathy syndrome after allogeneic stem cell transplantation]. 1922 23

Each year in the US, more than 10 000 patients benefit from allogeneic haematopoietic stem cell transplantation (HSCT), a modality that offers an excellent chance of eradicating malignancy but confers a higher risk of treatment-related mortality. An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment. Although there appears to be a consistent treatment approach to idiopathic thrombotic thrombocytopenic purpura (TTP) using plasma exchange, corticosteroids and rituximab, the treatment strategies for TA-TMA are perplexing, in part, because the literature regarding this complex condition does not provide true consensus for incidence, aetiology, diagnostic criteria, classification and optimal therapy. The classic definition of idiopathic TTP includes schistocytes on the peripheral blood smear, thrombocytopenia and increased serum lactate dehydrogenase. Classic idiopathic TTP has been attributed to deficient activity of the metalloproteinase responsible for cleaving ultra-large von Willebrand factor multimers. This protease is a member of the 'a disintegrin and metalloprotease with thrombospondin type 1 motif' family and is subsequently named ADAMTS-13. Severely deficient ADAMTS-13 activity (<5% of normal) is associated with idiopathic TTP in 33-100% of patients. In constrast to the pathophysiology of idiopathic TTP, patients with TA-TMA have >5% ADAMTS-13 serum activity. These data may explain why plasma exchange, a standard treatment modality for idiopathic TTP that restores ADAMTS-13 activity, is not effective in TA-TMA. TA-TMA has a multifactorial aetiology of endothelial damage induced by intensive conditioning therapy, irradiation, immunosuppressants, infection and graft-versus-host disease. Treatment consists of substituting calcineurin inhibitors with an alternative immunosuppressive agent that possesses another mode of action. One candidate may be daclizumab, especially in those with mild to moderate TMA. Rituximab therapy or the addition of defibrotide may also be beneficial. In general, plasma exchange is not recommended.
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PMID:Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. 1922 75


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