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 field of BMT has entered a new phase based on insights into basic molecular and cellular biology. The mechanism of cure mediated by allogeneic HSCT is now believed to be at least partially mediated by cellular attack against tumor-associated antigens. Better understanding of these cellular targets and the means of targeting them specifically will allow a more precise application of cellular therapy than is currently possible. This in turn may make it possible to design therapies that are increasingly selective without the collateral toxicities of GVHD, infection, and direct organ damage that currently are the limiting features of allogeneic HSCT as practiced until recently. However, it remains a challenge to demonstrate that disease-control using reduced intensity preparative regimens is at least comparable to that achieved by traditional myeloablative HSCT. This will require carefully controlled studies in each the major diseases that have shown sensitivity to the immune-mediated effects of HSCT. The chapters below will highlight progress towards the goals of elucidating the role of NST.
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PMID:Development of allogeneic hematopoietic stem cell transplantation (HSCT). 1190 93

NST is becoming a widely accepted method for allogeneic HSCT. Much experience has been gained, and the biology, indications and limitations are becoming clearer. Nonmyeloablative conditioning allows consistent engraftment of allografts from matched related, unrelated, and even partially matched donors. NST has been able to reduce the toxicity of allogeneic HSCT. The better immediate outcome produces better overall DFS. NST was feasible in elderly patients with almost no upper age limit, and in patients with organ dysfunction or other comorbidities precluding standard ablative conditioning. NST has also reduced the regimen-related toxicity of allogeneic HSCT in high-risk setting such as HSCT in heavily pretreated patients or following failure of a prior transplant procedure and in the unrelated setting. NST is rapidly becoming the treatment of choice in these indications where toxicity of standard ablative therapy is unacceptable. In certain malignancies such as in NHL, Hodgkin's disease and multiple myeloma, standard ablative NST has been reported to result in exceptionally high treatment related mortality, and NST is being investigated as a more reasonable alternative. NST may reduce the toxicity of the procedure even in younger patients who are eligible for ablative HSCT as well, however the long-term impact on patient outcome in this group is not yet established, and NST merits further investigation in prospective comparative trials. As described above, the known susceptibility of the underlying malignancy to GVT, the response to prior chemotherapy and bulk of residual disease, and the type of donor are other factors to consider when considering NST, and when selecting a regimen. The optimal preparative regimen needs to be defined. Ultimately less chemotherapy will be used and more specific immune-modulation, rather than intense nonspecific immunosuppression, will be used to achieve HVG tolerance. Preliminary animal models using costimulation blockade for specific induction of tolerance are promising steps towards achievement of this goal. Although much progress has been achieved with consistent achievement of engraftment with NST, GVHD and disease recurrence remain major obstacles to successful treatment. Existing clinical data suggest that NST does limit the incidence and severity of GVHD. Limitation of regimen-related toxicity, and bilateral transplantation tolerance afforded by mixed chimerism, are believed to have a major role in limiting GVHD. However GVHD remains the primary cause of treatment-related mortality. The development of techniques to separate GVHD and GVL are essential for further improvement of NST outcome. Better understanding of the biology and targets of GVHD and GVL may allow the elimination of alloreactive T-cells responsible for GVHD from the graft while retaining T-cells with GVL and infection control potential. Recurrence of the underlying malignancy is a major complication when NST is attempted in patients with chemo-refractory diseases and with high tumor bulk. Reduced toxicity regimens such as the FB/ATG regimen have been somewhat more successful in controlling disease progression until a potent GVT effect is established. However novel approaches are urgently required. NST serves as a platform for cellular immunotherapy. Judicious use of pre-emptive DLI needs to be explored. DLI may be amplified by activation of donor lymphocytes with IL-2 or in vivo administration of IL-2. Identification of tumor antigens will lead the way to ex-vivo generation and expansion of tumor specific cytotoxic T-lymphocytes to be used as potent immunotherapy without the hazards of GVHD. Allogeneic transplantation is rapidly changing from administration of supralethal doses of chemotherapy and radiation, trying to physically eliminate the 'last tumor cell', to the more subtle and tolerated sophisticated immunotherapy. This effort will focus on specific induction of HVG tolerance followed by induction of tumor-specific GVT effect to cure the underlying malignancy.
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PMID:Non-myeloablative hematopoietic stem cell transplantation (NST) in the treatment of human malignancies: from animal models to clinical practice. 1190 95

Reduced intensity (non-myeloablative) stem cell transplant (NST) preparative regimens are being increasingly used to exploit the curative potential of allogeneic stem cell transplantation without the morbidity and mortality associated with conventional transplantation. Growing confidence in the power of the allogeneic graft-versus-malignancy (GVM) effect makes such an approach attractive. Lower intensity transplants increase the degree of mixed chimerism, both in T cell and myeloid cell lineages. Currently a variety of NST treatment approaches are being developed and in this chapter their safety profile and the immunological characteristics of the mixed chimeric state are described. Results of NST in specific disease categories are still limited but the NST approach appears to have promise in the treatment of both haematological and non-haematological malignancies because of the benefit of low toxicity coupled with a strong graft-versus-malignancy effect. NST regimens are also being explored in high-risk patients with non-malignant disorders. However, at present, there is insufficient data to determine whether NST should replace standard myeloablative transplants in specific disease groups. With their low toxicity, NST are well placed as platforms for future developments in transplant immunology to avoid GVHD and enhance the allograft effect against malignant diseases.
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PMID:Allogeneic transplantation using non-myeloablative transplant regimens. 1192 17

Bone marrow transplantation (BMT) which represents an important clinical tool for treatment of patients with a wide variety of malignant and non-malignant diseases, however, the procedure is associated with procedure-related toxicity and mortality as well as unavoidable late complications. Many of the undesirable consequences of BMT are caused directly or indirectly by the intensive conditioning administered during the pre-transplant period. However, if the main goal of the BMT procedure is to enable immunotherapy by alloreactive donor lymphocytes, the conditioning prior to BMT needs to be reconsidered, because transplantation tolerance across major histocompatibility complex (MHC) occurs spontaneously in nature, as evidenced by the fact that pregnant females do not reject their conceptus. In fact, as shown by Owens in the 1940s, placental parabiosis in utero leads to permanent mixed chimerism and bilateral transplantation tolerance. These observations followed by experiments carried out in the 1950s by Billingham et al. suggested that infusion of parental stem cells into neonates with no exogenous immunosuppressive treatment resulted in mixed chimerism and permanent transplantation tolerance to donor alloantigens. Thus, a window of opportunity provided shortly after delivery, was sufficient for induction of tolerance without the need for heavy conditioning. Tolerant recipients were shown to be chimeras with only a small proportion of donor cells. However, without corroborating evidence that transplantation tolerance could be intentionally induced, the approach could not be applied in clinical practice for immunocompetent recipients. Starting in 70s, we documented the feasibility of establishing bilateral transplantation tolerance by mixed chimerism following non-myeloablative conditioning in immu. nologically mature recipients across MHC in mice, rats and dogs. Several studies have shown that reduced intensity conditioning can be very useful for immunoregulation whereas more intensive the pre-grafting immunosuppression resulted in more aggressive the GVHD. These and other findings suggested that lower intensity conditioning may be sufficient for engraftment of donor stem cells, thus suggesting that immunosuppression without myeloablation may be sufficient for prevention of allograft rejection. Following engraftment of donor stem cells, donor lymphocytes infused with bone marrow or mobilized blood stem cells can eradicate residual hematopoietic cells of host origin, occasionally non-hematopoietic tumor cells of host origin as well. Whenever indicated, donor lymphocytes infusion (DLI) can be used at a later stage post BMT to eradicate residual malignant cells of host origin or for the treatment of residual or recurrent disease. Taken together, ongoing clinical studies suggest that high-dose, myeloablative chemoradiotherapy, could be safely replaced with non-myeloablative conditioning (NST).
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PMID:Maternal-fetal relationship, natural chimerism and bilateral transplantation tolerance as the basis for non-myeloablative stem cell transplantation. 1243 Aug 49

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Non ablative or reduced intensity preparative regimens for allogeneic stem cell transplantation (NST) have been proposed as a strategy that would allow exploiting the graft versus tumor effect of allogeneic transplantation without the toxicity of myeloablative therapy. After more than five years of cumulative clinical experience, it is now well established that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and may allow to extend indications of stem cell transplantation in the future.
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PMID:Update on non-myeloablative stem cell transplantation for hematologic malignancies. 1243 Aug 50

Allogeneic stem cell transplantation is an established treatment modality for a variety of hematologic malignancies. Unfortunately it carries a high risk of complications and toxicities related to the intensive preparative regimen which is traditionally used for pre-transplant myeloablation and the graft versus host disease, which may be life threatening. Thus allogeneic stem cell transplantation has been used only for younger patients with a good performance status, excluding many other potential candidates due to advanced age or comorbid conditions. Non ablative or reduced intensity preparative regimens for allogeneic stem cell transplantation (NST) have been proposed as a strategy that would allow exploiting the graft versus tumor effect of allogeneic transplantation without the toxicity of myeloablative therapy. After more than five years of cumulative clinical experience, it is now well established that NST is a feasible treatment option for patients with suboptimal performance status and is mostly effective in slow proliferating malignancies, which gives time for a graft versus malignancy effect to take place. Additionally achievement of stable donor cell engraftment with NSTs provides a platform for adoptive immune cell treatments and may allow to extend indications of stem cell transplantation in the future.
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PMID:Update on non-myeloablative stem cell transplantation for hematologic malignancies. 1243 Aug 84

In order to investigate the clinical efficacy of non-myeloablative allogeneic stem cell transplantation (allo-NST) and related technology in patients with hematologic malignancies, twenty-six cases of hematological malignancies (10 AL, 14 CML, 2 MM patients) received NST following conditioning regimens with fludara + cyclophosphamide + ATG (14 cases) and busulfan or melphalan + cyclophosphamide + ATG (12 cases), G-CSF (600 micro g/d) or G-CSF (300 micro g/d) + GM-CSF (300 micro g/d) were used for mobilizing peripheral blood stem cell. A combination of cyclosporine A (CsA) and methotrexate (MTX) was administered for GVHD prophylaxis. Patients will be eligible for donor lymphocyte infusion (DLI) or donor stem cell infusion (DSI) given in graded increments according to the chimeric formation and clinical reaction. Generally the dose of the first infusion was 1 x 10(7)/kg at 4th week post-transplantation. The engraftment analysis included the detection of microsatellite short tandem repeats (STRs), Bcr/Abl fusion gene, Philadelphia chromosome, HLA-locus analysis, sex chromosome and ABO blood type or blood subtype. The results showed that 22 patients (84.62%) were engrafted, among which 18 patients were full donor chimerism (FDC) up to now. Acute GVHD occurred in 3/26 cases (11.54%). Chronic GVHD was diagnosed in 6 of 26 (23.07%) evaluable patients. The incidence of infection and hemorrhage was low and slight. It is concluded that allo-NST is a safe and effective therapeutic method for hematologic malignancies, but the related technology such as selection of indication, conditioning regimen and transplantation immunotherapy should be studied further.
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PMID:[Non-myeloablative allogeneic stem cell transplantation in patients with hematologic malignancies]. 1498 71

The conditioning prior to allogeneic stem cell transplantation was originally designed as a myeloablative conditioning, designed to eliminate malignant or genetically abnormal cells and then use the transplant procedure for rescue of the patients or to replace missing bone marrow products. However, allografts can induce effective graft vs. malignancy effects and can also eliminate undesirable hematopoietic stem cells in patients with genetic disorders and autoimmune diseases, thus documenting that alloreactive effects mediated by donor lymphocytes post-grafting can play a major role in eliminating hematopoietic cell of host origin, as well as provide effective immunotherapy for the treatment of disease recurrence. The efficacy of donor lymphocyte infusion (DLI) could be improved by activation with rIL-2 or by donor immunization. The cumulative experience over the years suggesting that alloreactive donor lymphocytes were most effective in eliminating tumor cells of host origin resulted in an attempt to reduce the intensity of the conditioning in preparation for the transplant procedure used for the treatment of hematological and other malignancies as well as life-threatening non-malignant disorders for which allogeneic stem cell transplantation may be indicated. Our working hypothesis proposed that the myeloablative conditioning which is hazardous and may be associated with early and late side effects, may not be required for treatment of patients with any indication for allogeneic stem cell transplantation. Instead, nonmyeloablative conditioning based on the use of reduced intensive preparatory regimen, also known as nonmyeloablative stem cell transplantation, may be sufficient for engraftment of donor stem cells while avoiding procedure-related toxicity and mortality, followed by elimination of undesirable cells of host origin by post-transplant effects mediated by alloreactive donor lymphocytes infused along with donor stem cells or administered subsequently as DLI. Improvement of the immediate outcome of stem cell transplantation using NST due to a significant decrease in transplant related mortality has broadened the spectrum of patients eligible for allogeneic stem cell transplantation, including elderly patients and other patients with less than optimal performance status. Likewise, the safer use of stem cell transplantation prompted expanding the scope of potential indications for allogeneic stem cell transplantation, such as metastatic solid tumors and autoimmune disorders, which now are slowly becoming much more acceptable. Current strategies focus on the need to improve the capacity of donor lymphocytes to eliminate undesirable malignant and non-malignant hematopoietic cells of host origin, replacing abnormal or malignant stem cells or their products with normal hematopoietic stem cells of donor origin, while minimizing procedure-related toxicity and mortality and improving the quality of life by reducing the incidence and severity of hazardous acute and chronic GVHD.
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PMID:Nonmyeloablative stem cell transplantation and cell therapy for malignant and non-malignant diseases. 1598 65

The purpose of this study was to investigate the efficacy of non-myeloablative allogeneic stem cell transplantation (allo-NST) and its related technologies in hematological malignancies. 26 patients with hematological malignancies (acute leukemia 10, chronic myeloid leukemia 14, multiple myeloma 2) received allo-NST following conditioning regimens with fludarabine/cyclophosphamide/ATG in 14 cases or busulfan or melphalan/cyclophosphamide/ATG in 12 cases prior to infusion of 2 or 3 collections of G-CSF (600 microg/d) or G-CSF (300 microg/d) plus GM-CSF (300 microg/d) mobilized blood stem cell on the fifth day. A combination of cyclosporine A (CsA) and methotrexate (MTX) was administered for GVHD prophylaxis. Patients were eligible for donor lymphocyte infusion (DLI) (or donor stem cell infusion (DSI)) given in graded increments according to the chimeric formation and clinical feature. Generally, the dose of the first infusion was 1 x 10(7)/kg in 4th week post-transplantation. The engraftment analyses included the detection of microsatellite short tandem repeats (STRs), bcr/abl fusion gene, Philadelphia chromosome, HLA-locus analysis, sex chromosome and ABO blood type or blood subtype. The results showed that out of 26 patients, 22 (84.62%) were engrafted, 18/22 were full donor chimerism (FDC) up to now. Acute GVHD occurred in 3/26 (11.54%), while chronic GVHD was diagnosed in 6 out of 26 (23.07%) patients. The incidence and degree of infection and hemorrhage were low and slight. It is concluded that NST is a safe and effective therapy for hematological malignancies, whereas related technologies such as adaptation selected, conditioning regimen and transplantation immunotherapy should be studied further.
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PMID:Nonmyeloablative allogeneic hematopoietic stem cell transplantation in 26 cases of hematological malignancies. 1692 19

The development of reduced intensity or non-myeloablative conditioning (NST) in preparation for allogeneic stem cell transplantation (SCT) revolutionized the field and led to reconsideration of the dogma of upper age limit that was set up by the transplant centers as an eligibility parameter. Analysis of the literature data showed that NST regimens are associated with decreased transplant related mortality, and graft-versus-host disease, in comparison with standard myeloablative conditioning, in patients above the age of 50-55 years, or in younger patients with significant comorbidities. However we have to mention, that our considerations are based on the retrospective analysis of the literature data, and that well controlled prospective randomized studies are needed in order to definitely assess the role of NST. Comorbidity indices might be proved as the most important parameters for the choice of the most proper regimen for each patient in need and should be included in future trials.
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PMID:Allogeneic hematopoietic stem cell transplantation in the elderly. 1730 34


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