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

CD34 has been widely used as a stem and progenitor cell marker, and clinical CD34+ stem cell transplantation (CD34+ SCT) has been performed for tumor purging and for prevention of graft-versus-host disease. Recently, CD34-negative hematopoietic stem cells (CD34 HSCs) were identified in mice and humans. Xenogeneic chimera engraftment assays with immunodeficient mice or preimmune fetal sheep resulted in identification of human CD34- HSCs in cord blood, bone marrow, and granulocyte colony-stimulating factor-mobilized peripheral blood, although no significant clonogenic activity was detected in vitro. These characteristics of CD34- HSCs make the assessment of clinical samples difficult. The generation of CD34+ HSCs from CD34 cells in vitro may be a surrogate assay for detecting CD34- HSC activity. This approach was used in recipients of CD34+ SCT and revealed the absence of a CD34 precursor population. The identification of a positive marker in CD34- HSCs and the development of a simpler and more efficient in vivo assay for CD34- HSCs may allow the diagnostic evaluation of human CD34- HSCs in various clinical procedures and diseases.
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PMID:Human CD34- hematopoietic stem cells: basic features and clinical relevance. 1204 66

We present a 60-year-old patient with primary refractory non-Hodgkin's lymphoma and a 58-year-old patient with multiple myeloma with relapse after first autologous stem cell transplantation (ASCT), who underwent ASCT followed by allogeneic stem cell transplantation (alloSCT) with reduced intensity conditioning consisting of fludarabine and a single dose of total body irradiation. For graft-versus-host disease prophylaxis cyclosporine and mycophenolate mofetyl were given. Complete donor chimaerism was observed on d 28 after SCT. Both patients achieved sustained complete haematological and molecular remission of the immunoglobulin kappa light chain (Igkappa) rearrangement and are alive and well 17 and 16 months after SCT respectively.
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PMID:Continuous complete clinical and molecular remission in two patients with refractory lymphoid malignancies after autografting followed by allogeneic stem cell transplantation with reduced intensity conditioning. 1210 Jan 37

Since graft-versus-leukemia (GVL) is the main weapon for disease eradication after reduced intensity conditioning (RIC) allogeneic SCT, the availability of sensitive and specific techniques to monitor changes in tumor load after transplant are especially helpful. These minimal residual disease techniques would allow an early intervention in the event of low tumor burden, for which immunotherapy is highly effective. Some authors have found an association between persistence of MRD, mixed chimerism and risk of relapse. Nevertheless, data from the literature remain contradictory and further correlations should be established, especially in RIC transplants. In this study we have analyzed the impact of MRD and chimerism monitoring on the outcome of 34 patients undergoing RIC allogeneic SCT who were considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions. At day +100 25 (75%) patients reached complete remission (CR), there were five (15%) partial responses and three patients progressed. Incidence of grade 2-4 aGVHD and extensive cGVHD were 35% and 58%, respectively. Sixteen percent of patients developing aGVHD relapsed as compared to 47% in those without aGVHD (P = 0.03) and also 10% of patients developing cGVHD relapsed as compared to 50% relapses in those without cGHVD (P = 0.03). Four patients (12%) died due to early (n = 1) and late (n = 3) transplant-related mortality. After a median follow-up of 15 months, 24 out of the 34 patients remain alive. Projected overall survival and disease-free survival at 3 years are 68% and 63%, respectively. Early chimerism analysis showed 67% of patients with complete chimerism (CC) in bone marrow (BM), 86% in peripheral blood (PB), 89% in granulocytes and 68% in T lymphocytes. On day +100, these figures were 68%, 79%, 90% and 73%, respectively, and on day +180 there were 83% patients with CC in BM, 100% in PB, 100% in granulocytes and 100% in T lymphocytes. We observed a trend to a higher incidence of relapse in patients with mixed chimerism (MC) as compared to patients with CC. MRD monitoring by flow cytometry and/or RT-PCR analysis was performed in 23 patients. MRD assessment on days +21 to +56 after transplant allowed identification of patients at risk of relapse. In this sense, seven out of 12 patients (58.3%) who had positive MRD on days +21 to +56 relapsed as compared to none out of 11 patients who had negative MRD (P = 0.002). Of the seven patients with criteria to monitor MRD who relapsed after transplant, all but one remained MRD positive until relapse. By contrast, 10 patients remained MRD negative and all of them are in continuous CR. In nine additional patients, persistence of MRD or mixed chimerism was observed after transplant and withdrawal of cyclosporin with or without DLI was performed. Only two out of these nine patients relapsed. MRD clearance was preceded by CC and GVHD. In conclusion, in our study we found that RIC allogeneic transplantation can be used in patients considered poor candidates for conventional transplantation due to advanced age or other concurrent medical conditions with both low toxicity and low transplant-related mortality. Simultaneous studies of both chimerism and MRD are a useful tool in order to predict risk of relapse in patients undergoing RIC transplants and so can be helpful for individualizing treatment strategies after transplant.
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PMID:Chimerism and minimal residual disease monitoring after reduced intensity conditioning (RIC) allogeneic transplantation. 1214 80

Many hematologic disorders, leukemias and lymphomas in particular, can be cured with allogeneic hematopoietic stem cell transplantation (allo-SCT). However, chronic graft-versus-host disease (cGVHD) appears to remain as a major determinant of long term outcome and quality of life following allo-SCT. The gradual increase in the incidence of cGVHD over the past decade has recently gained another momentum along with the use of blood as a source of stem cells. Donor lymphocyte infusion (DLI) is also associated with a progressive form of cGVHD, mostly refractory to treatment. Prediction of the outcome of patients with newly diagnosed chronic GVHD may be important in identifying those who are likely to benefit from reduced treatment and patients who are unlikely to have a sustained response to standard treatment. In addition, a reliable predictive model could allow us to design better clinical trials and facilitate the communication among the centers. Although it is highly reproducible, the current system of grading in cGVHD is of limited utility since it does not stratify patients for outcome. It divides patients into those needing treatment (extensive cGVHD) and those who do not (limited cGVHD). Therefore, a new clinical grading system is needed to classify all patients based on their prognosis so like patients with similar features can be grouped for study and clinical management purposes. Using multivariate analysis, we recently identified three independent risk factors affecting the survival without recurrent malignancy. These factors are extensive skin involvement (>50% BSA), thrombocytopenia, and progressive-type onset of cGVHD. We are in the process of validating this prognostic model in three other cohorts from different institutions. We expect that the new grading system, based on this model, may allow us to identify the diversity of outcome within "extensive stage" cGVHD.
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PMID:Clinical grading in chronic graft-versus-host disease: is it time for change? 1215 88

The use of mycophenolate mofetil (MMF) for prophylaxis of aGVHD and/or for treatment of acute or chronic GVHD is increasing. However, the benefit of MMF as an alternative to commonly used immunosuppressive agents still needs to be assessed. We ran a retrospective study on 21 consecutive patients (median age, 36 years; range, 20-63) with aGVHD or extensive cGVHD following related (17) or unrelated (4) matched donor SCT (BM, 16; PBSC, 5) who received MMF (2 g/day) because of intolerance to or failure of CsA-containing combinations. Four of the six patients with aGVHD responded, and the response rate was 69% in cGVHD patients. We observed neither significant differences in terms of response rate for skin, liver and bowel nor dissociated response in cases of multiple organ involvement (67% of the patients). Response was the same for lichenoid and sclerodermatous skin cGVHD subtypes. No adverse effects, except diarrhea (three patients), were observed. However, 22 opportunistic or serious viral or bacterial infections occurred in 10 patients. Analysis of trough plasma levels showed a trend for a higher mean MPA concentration in patients responding to MMF. Our study highlights the high risk of infectious complications induced by the administration of MMF, an otherwise efficient and well-tolerated treatment for GVHD.
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PMID:Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients. 1220 50

Because of progress in supportive therapies, the upper limit of age for conventional allogenic stem cell transplantation (allo-SCT) is rising. We retrospectively evaluated the impact of age on transplant outcomes in patients older than 50 years of age who underwent conventional allo-SCT in 8 institutions in Japan. The median age was 52-years old (range 50 to 65). The underlying diseases included severe aplastic anemia (n = 3), acute myelogenous leukemia (n = 20), acute lymphoblastic leukemia (n = 10), chronic myelogenous leukemia (n = 11), myelodysplastic syndrome (n = 18), and non-Hodgkin lymphoma (n = 3). Forty two patients (67%) with hematological malignancies received allo-SCT in an advanced disease stage at the time of transplant. The two-year overall survival and disease-free survival rate were 50.1% and 43.6%, respectively. In patients with hematological malignancies, the two-year probability rates of survival were 54.3% with standard risk patients, and 45.9% with poor risk patients. The severity of acute GVHD, the kind of grafts, and age (> or = 55) were related to poor prognosis. Our data suggest that prophylaxis of acute GVHD and selection of the graft is more important for older patients, and that patients less than 55-years old can be candidates for conventional allo-SCT.
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PMID:[Outcome of allogeneic stem cell transplantation in patients older than 50 years of age]. 1246 25

In allogeneic hematopoietic cell transplantation, donor lymphocytes play a central therapeutic role in both graft-versus-leukemia and immune reconstitution. However, their use is limited by the risk of severe graft-versus-host disease (GVHD). Different strategies have been investigated to obtain all the benefits derived from donor lymphocytes while avoiding the risk of GVHD. Infusions of donor lymphocytes transduced with the herpes simplex virus thymidine kinase (HSV-tk) suicide gene resulted in anti-tumor activity in a substantial number of patients. Acute GVHD could be effectively controlled by ganciclovir-induced elimination of the transduced cells. Haplo-identical stem cell transplantation (haplo-SCT) is a promising therapeutic option for patients with high-risk hematologic malignancies lacking an HLA-matched donor. However, the intensive T-cell depletion required to overcome the risk of lethal GVHD has been associated with a delayed immune recovery with a prolonged risk of posttransplantation viral, fungal, and other opportunistic infections. Donor lymphocyte infusions of HSV-tk represent a promising tool for preventing disease relapse and promoting immune reconstitution after haplo-SCT, and a unique tool for the control of GVHD. The genetic manipulation of donor lymphocytes with a suicide gene is a promising strategy to increase feasibility and safety of allogeneic bone marrow transplantation.
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PMID:Suicide-gene-Transduced donor T-cells for controlled graft-versus-host disease and graft-versus-tumor. 1246 92

Invasive aspergillosis (IA) is common in allogeneic SCT recipients, with an incidence of 4-10%. The majority of these infections are diagnosed several months after SCT and they are frequently associated with GVHD. The diagnosis is difficult and often delayed. Established IA is notoriously difficult to treat with a death rate of 80-90%. This review summarises recent data on this problem to assess whether there has been any progress. Effective prophylactic measures are still lacking. Severe immunosuppression is the main obstacle to the success of therapy. Recent and ongoing developments in diagnostic measures and new antifungal agents may improve treatment results to some extent, but Aspergillus infections still remain a formidable problem in allogeneic transplantation. Further studies in this field will focus on the role of various cytokines and combinations of antifungal agents.
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PMID:Aspergillus infections in allogeneic stem cell transplant recipients: have we made any progress? 1247 86

Allogeneic stem cell transplantation (allo-SCT) is an effective therapeutic option for a wide range of hematological malignancies. The toxicity of the conditioning regimen and graft-versus-host disease (GVHD) occurring after the infusion of the graft remain the most important factors leading to high morbidity and mortality. Reduced-intensity conditioning regimens have recently been developed in an effort to reduce the toxicity associated with conventional allo-SCT while preserving the curative potential of the graft-versus-tumor (GVT) effect. Most patients with lymphoproliferative disorders are not ideal candidates for allo-SCT due to higher age at diagnosis, which together with the advanced stage of disease at the time of transplantation can lead to a high transplant-related mortality (TRM). Preliminary experience indicates that reduced-intensity allo-SCT is feasible in such patients. The immediate TRM is low in comparison with conventional procedures and overall results seem promising, thus indicating the existence of a GVT effect. Nevertheless, all series are still low in numbers and follow-up is too short to draw definitive conclusions. Acute and chronic GVHD remain a significant problem with incidences comparable to the conventional setting in some series. Thus, therapeutic strategies must be sought to decrease GVHD without abrogating the GVT effect.
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PMID:Allogeneic stem cell transplantation after reduced-intensity conditioning in lymphoid malignancies. 1257 57

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus-related (EBV) clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. In the setting of hematopoietic stem cell transplantation, PTLD is an often-fatal complication occurring relatively early after transplant. Risk factors for the development of PTLD are well established, and include HLA-mismatching, T-cell depletion, and the use of antilymphocyte antibodies as conditioning or treatment of graft-versus-host disease. Early recognition of PTLD is particularly important in the SCT setting, because PTLD in these patients tends to be rapidly progressive. Familiarity with the clinical features of PTLD and a heightened level of suspicion are critical for making the diagnosis. Surveillance techniques with EBV antibody titers and/or polymerase chain reaction (PCR) may have a role in some high-risk settings. Immune-based therapies such as monoclonal anti-B-cell antibodies, interferon-alpha, and EBV-specific donor T cells, either as treatment for PTLD or as prophylaxis in high-risk patients, represent promising new directions in the treatment of this disease.
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PMID:Post-transplant lymphoproliferative disorder: a review. 1262 74


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