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)

Graft-versus-host disease (GVHD) is a major obstacle in allogeneic hematopoietic stem cell transplantation (HSCT). Mature donor T-cells present in the graft play a pivotal role in the development of acute GVHD. On the other hand, mature donor T-cells in the graft are also crucial for the elimination of residual tumor cells still present in the patient after HSCT. Whether donor T cells act non-specifically against the patient, including an overlapping GVHD/GVL reactivity, or some donor T cells have GVHD reactivity while other donor T cells have GVL reactivity is still unclear. Some in-vitro data are suggestive that selective T cell depletion techniques are possible by which GVHD-reactive T cells can be eliminated while GVL-reactive T cells are preserved. Here we update some approaches of selective T cell depletion that have been developed in our laboratory.
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PMID:Prevention of acute graft-versus-host-disease by selective depletion of T cells reactive with minor histocompatibility antigens on epithelial cells. 1142 61

Relapse is the major cause of treatment failure after allogeneic stem cell transplantation (SCT) in patients with acute lymphoblastic leukemia. Minimal residual disease (MRD) was analyzed before SCT in 30 patients with acute lymphoblastic leukemia. The aim was to determine whether the level of MRD before transplantation was correlated with outcome. Fifteen patients were found to have high-level MRD (10(-2) to 10(-3)), 10 had low-level MRD (< 10(-3)), and 5 were MRD(-). Among MRD(-) patients the probability of relapse was 0 in 5, which was less than in MRD(+) patients (13 of 25) (P =.05). No major difference was found between the high- and low-level MRD(+) groups. Among the MRD(+) patients, only 2 of 11 with acute and chronic graft-versus-host disease had a relapse, versus 11 of 14 without (P =.005). In conclusion, for patients entering transplantation while they have residual disease, a combination of acute and chronic graft-versus-host disease may be needed to decrease the risk of relapse after SCT.
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PMID:The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. 1153 39

A 9-year-old girl with acute lymphoblastic leukemia in second remission underwent cord blood transplantation (CBT) from an HLA-mismatched (2 loci by serotype, 3 loci by genotype) unrelated donor. The infused nucleated cell count was 1.95 x 10(7)/kg. FK506 and mini-MTX were used to prevent graft-versus-host disease (GVHD), but grade II acute GVHD developed on the skin (stage III). The GVHD subsided after administration of corticosteroid, but marked hyperglycemia developed, which required transient insulin therapy for its control. Minimal residual disease (MRD) was assessed using a clone-specific probe for the JH region. MRD was positive before CBT, but became negative one month after CBT. Now, at 14 months after CBT, the patient is in a disease-free state without detectable MRD. These observations suggest that CBT with two mismatched HLA loci can be performed safely, and that sequential analysis of MRD is useful for evaluation of the disease status after CBT.
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PMID:[Cord blood transplantation with two mismatched HLA loci in a child with acute lymphoblastic leukemia in second remission: follow-up of minimal residual disease using a clone-specific probe]. 1157 3

Allogeneic transplantation of hematopoietic stem cells (HSC) is a curative treatment for hematological malignancies aiming to eradicate the malignant clone using the immunological conflict inherent to donor HSC installation in the recipient. The different possible sources of HSCs (bone marrow, blood, and cord blood) and better knowledge of HLA typing has led to the development of new transplantation techniques and modalities (transplantations after non-myeloablative conditioning, haploidentical transplantations, etc.), which should improve patient survival and extend allograft indications. HSC allografting is subject to immunological reactions stemming from the histocompatibility discrepancy between donor and recipient. For the most part, these are reactions of the graft against the host (graft-versus-host disease: GVHD) and graft rejection (host-versus-graft: HVG). This immunological conflict can also be responsible for recognizing and destroying the recipient's residual tumor cells, which carry specific tumor antigens and/or minor antigens of histocompatibility (graft-versus-leukemia effect, GVL or graft-versus-malignancy effect, GVM). The posttransplantation period can also be riddled with various complications such as veno-occlusive disease, endocrine complications, as well as complications arising from infections and secondary neoplasms because of a more or less substantial and durable immune deficiency. Acute and chronic leukemias are the major indications for HSC allogeneic transplantation, for which the results are variable and closely related to the patient status, the hematological disease, and the transplant procedure. Other hematological diseases are also indications for allogeneic transplantation but are rarer, for which allogeneic transplantation remains nevertheless the only curative treatment, despite an overly high level of toxicity. Improvement in the results of unrelated transplantations, use of peripheral HSC or cord blood cells, development of non-myeloablative conditioning regimens, and techniques of ex vivo manipulation of the graft have allowed HSC allogeneic transplantation indications to be extended. The antitumor efficacy of donor lymphocytes infusion for relapses after transplantation mirrors the GVL effect and is the first stage in a targeted cellular immunotherapy using sensitized lymphocytes or dendritic cells.
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PMID:[Allogeneic hematopoietic stem-cell transplantation for hematological malignancies]. 1160 65

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

Chronic myeloid leukemia in blast crisis (BC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) are associated with extremely poor outcome. Allogeneic transplantation during BC or active leukemia is most often unsuccessful due to high-rates of both treatment-related complications and relapse. Long-term results are significantly better if a second chronic phase or remission can be achieved prior to transplantation. Similarly, DLI given for the treatment of post-transplant relapse is more successful when given during a second remission. In this study we report our results with a previously unreported approach consisting of short-term treatment with imatinib mesylate (formerly, STI571) to induce or maintain remission, followed by allogeneic transplantation or DLI and the impact on transplantation/DLI outcome. Sixteen patients were treated either in preparation for transplantation (n = 12), for DLI (n = 1), or for both (n = 3). Ten had CML in BC; seven myeloid and three lymphoid BC. Six patients had Ph(+) ALL. The donors were matched unrelated (n = 9), matched siblings (n = 5) or haplo-identical (n = 2). Eleven of 15 patients given imatinib pre-transplant were transplanted in complete hematologic response. Engraftment and GVHD rates were not different from expected. Seven patients had grade II-III hepatic toxicity after transplantation. After a median follow-up of 10 months (range, 3-16 months) six remain alive, two after further therapy. The 1-year survival rate was 25%. Four patients were given imatinib prior to DLI, all had complete response. Two remain in remission >6 months from relapse. In conclusion, treatment with imatinib allows transplantation in a more favorable status or maintaining remission with low toxicity until transplantation is feasible. Pre-transplant imatinib seems safe and not associated with excess post-transplant complications. Imatinib may have substantial activity in combination with DLI. Further study of a larger group of patients is required to assess the impact on long-term outcome and the role of post-transplant imatinib in controlling residual disease.
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PMID:Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias. 1259 25

New approaches are needed for maximizing specific responses against tumor cells resistant to chemotherapy. While cytokine therapy may amplify natural resistance against minimal residual disease, more robust anti-leukemia reactivity can be provided by allogeneic bone marrow transplantation (BMT) in conjunction with myeloablative, hence hazardous, conditioning, at the cost of graft-versus-host disease (GVHD). Documentation of the capacity of donor lymphocyte infusion (DLI) given late post BMT, when patients were off immunosuppression, in early 1987, with successful reversal of relapse and cure of patients fully resistant to maximally tolerated doses of chemoradiotherapy, with many patients alive and well >10-15 years later, indicated two important facts. First, resistant tumors are unlikely to be cured with higher doses of chemoradiotherapy that may harm the patient but not eliminate all his clonogenic tumor cells. Second, that under condition of tolerance to donor alloantigens, DLI may provide a cure to otherwise resistant patients. These observations paved the road for clinical application of non-myeloablative stem cell transplantation (NST), in the early 90s, based on a two-step procedure, first involving induction of transplantation tolerance to donor alloantigens by engraftment of donor stem cells, following safe lymphoablative rather than myeloablative conditioning. Second, use of donor lymphocytes for elimination of residual tumor or otherwise abnormal hematopoietic cells by immune-mediated graft-versus-host effects inducible by mobilized blood stem cell allografts containing larger inocula of donor T cells, or supported by post-grafting DLI when patients were off immunosuppressive modalities.
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PMID:Immunotherapy of hematologic malignancies and metastatic solid tumors in experimental animals and man. 1271 59

A 5-year-old boy received CD34-positive HLA haplo-identical bone marrow transplantation from his father as treatment for refractory advanced neuroblastoma. He had residual disease in the para-aortic lymph nodes and multiple bones after the transplant. However, all of his residual disease had disappeared completely 3 years later. He developed grade I acute graft-versus-host disease (GVHD) but had no symptoms of chronic GVHD or any other complications. This case demonstrates the possibility of a graft-versus-tumor effect against neuroblastoma by HLA-mismatched allogeneic hematopoietic stem cell transplantation.
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PMID:Graft-versus-tumor effect in a patient with advanced neuroblastoma who received HLA haplo-identical bone marrow transplantation. 1281 85

The possible advantage of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a graft-versus-lymphoma effect. We explored the feasibility and efficacy of allo-HSCT with reduced-intensity (RI) regimens in advanced malignant lymphoma (ML). A total of 20 patients with indolent (n=9) or aggressive lymphoma (n=11) received allo-HSCT with an RI regimen (RIST). The preparative regimen consisted of a combination of purine analog and alkylating agent with or without antithymocyte globulin. A total of 11 patients had chemorefractory disease, seven had chemosensitive relapsed disease and two had residual disease. All of the patients received G-CSF-mobilized blood stem cells from HLA-matched siblings. Of the 20 patients, 19 achieved engraftment with acceptable regimen-related toxicities. Seven patients developed grade II-IV acute GVHD and 15 developed chronic GVHD. Of the 15 patients with evaluable disease, 12 achieved a complete response. One died of invasive fusariosis, four subsequently died of GVHD complicated with fungal infection and one died of progressive disease. With a median follow-up of 358 days, the Kaplan-Meier estimates for 1-year overall and progression-free survival were both 70%. The high response rate with low relapse observed in this study suggests that RIST may be an effective alternative curative treatment for patients with advanced ML.
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PMID:High complete response rate after allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimens in advanced malignant lymphoma. 1283 76

Minimal residual disease (MRD) assessments were performed retrospectively after allogeneic stem cell transplantation (SCT) in 32 patients (23 children and nine adults) with acute lymphoblastic leukaemia (ALL). Using immunoglobulin and T-cell receptor rearrangements as clonal markers, MRD was detected after SCT in nine patients, eight of whom have relapsed. The median time between first MRD detection and relapse was 5.5 (range 0.5-30) months. In 23 patients without MRD, six have relapsed to date: lower sensitivity, central nervous system relapse and clonal exchange of the leukaemic clone were factors that may explain the failure to detect MRD before relapse in these patients. In univariate analysis, factors associated with decreased risk of relapse were transplantation in first remission (P=0.02), the combination of acute and chronic graft-versus-host disease (P=0.03) and absence of MRD after SCT (P=0.005). In multivariate analysis, only MRD detection after SCT was significantly associated with increased risk of relapse (P=0.05). In conclusion, MRD detection after SCT is correlated with relapse and provides the opportunity for initiating immunotherapeutic intervention at an early stage when the tumour cell burden is still low.
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PMID:Minimal residual disease detection after allogeneic stem cell transplantation is correlated to relapse in patients with acute lymphoblastic leukaemia. 1293 Mar 90


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