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-leukemia (GVL) effect is an immunologically important phenomenon which decreases the relapse rate of leukemia after allogeneic bone marrow transplantation. GVL effect is sometimes associated with the occurrence of graft-versus-host disease (GVHD). Analyses of GVL effect and GVHD showed that these two phenomena were separable in some conditions. Although we cannot yet completely control the development of the GVL effect without inducing GVHD in humans, basic analyses using animal models show potential benefits of the GVL effect for clinical applications. Autologous GVHD is another important phenomenon which can help to eradicate minimal residual disease. Interleukin 2 and/or cyclosporin A are extensively used in animal models and in humans to induce autologous GVHD, showing beneficial effects. In the future, cytokine usage and allogeneic stem cell transplantation or leukocyte infusion appear to be promising in the control of minimal residual disease. Further studies on the mechanisms of GVL effects and GVHD may well open a new era for cell transplantation.
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PMID:Graft-versus-leukemia effect and its clinical implications. 903 Oct 79

We observed a patient in whom graft-versus-host disease (GVHD) appeared to induce a positive effect. This 32-year-old male with Philadelphia chromosome-positive acute lymphoblastic leukemia received a bone marrow transplant (BMT) from an HLA-identical sibling donor. We analyzed the bone marrow with the reverse transcriptase-polymerase chain reaction to screen for the minor bcr/abl transcript, which indicates the presence of minimal residual disease (MRD). MRD was present in the pre- and post-transplant phases. There was no evidence of acute GVHD by post-transplant day 45. We abruptly discontinued the immunosuppressive therapy in an attempt to eliminate MRD by inducing an antileukemic reaction during GVHD. GVHD associated with diarrhea and liver dysfunction developed on day 64. On day 105, MRD disappeared and GVHD was treated with prednisolone and cyclosporin. The disappearance of MRD may have been due to the graft-versus-leukemia (GVL) effect mediated by the alloimmune response of donor T lymphocytes. These findings suggest that induction of the GVL effect may be useful for eliminating MRD after BMT in leukemia patients at high risk of recurrence of the disease.
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PMID:Eradication of minimal residual disease during graft-versus-host reaction induced by abrupt discontinuation of immunosuppression following bone marrow transplantation in a patient with Ph1-ALL. 924 45

Allogeneic bone marrow transplantation (BMT) is being increasingly used for the treatment of a variety of cancers ranging from leukemias to breast cancer. However, significant obstacles currently limit the efficacy of this treatment procedure. The predominant two are the occurrence of graft-versus-host disease (GVHD) and relapse from the cancer. While regimens exist that prevent the occurrence or severity of GVHD, these same regimens also increase the rate of relapse. Conversely, most attempts to reduce the relapse rate also result in increased GVHD. The use of NK cells as an adoptive immunotherapy after BMT is attractive for several reasons. NK cells exhibit antitumor effects both in vitro and in animal models and may, therefore, promote graft-versus-tumor (GVT) effects to remove minimal residual disease after allogeneic BMT. NK cells have also been shown to promote hematopoietic engraftment and donor cell reconstitution after allogeneic BMT in mice. The effects of NK cells on hematopoiesis are believed to be due to the hematopoietic growth factors they can produce after activation. Another advantage in using NK cells is that they can prevent the occurrence of GVHD after allogeneic BMT in mice. This effect is mediated at least in part by the immunosuppressive cytokine, transforming growth factor beta (TGF-beta). BMT studies in mice also indicate that the beneficial effects of NK cells are optimal if they are administered soon after the transplant. Thereafter, NK cells and, more importantly, IL-2, which is used to activate them, are detrimental and can exacerbate the subsequent GVHD. Thus, the use of activated NK cells after allogeneic BMT may provide GVT effects without inducing GVHD.
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PMID:The potential role of NK cells in the separation of graft-versus-tumor effects from graft-versus-host disease after allogeneic bone marrow transplantation. 925 29

Chronic myeloid leukaemia (CML) can be treated successfully with allogeneic bone marrow transplantation (BMT) leading to long-term disease-free survival. Leukemia relapse, however, remains a significant clinical problem. Relapse following BMT presumably results from the expansion of small numbers of recipient leukaemic cells which have survived the conditioning therapy. In order to define patients who are at a high risk of leukaemia relapse, a variety of techniques have been employed to detect persistence of host haemopoiesis (mixed chimaerism, MC) or residual leukaemia (minimal residual disease, MRD). However, the precise relationship between the detection of MC and MRD post-BMT is unknown. We have investigated chimaerism and MRD status in 22 patients who were in clinical and haematological remission post-allogeneic BMT for chronic phase CML. Chimaerism was assessed using short tandem repeat PCR (STR-PCR) while BCR-ABL mRNA detection using reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect the presence of MRD. Seventeen patients received unmanipulated marrow (non-TCD) while in five patients a T cell-depleted transplant (TCD) was performed as additional GVHD prophylaxis. Chimaerism was evaluated in 18 patients (14 non-TCD, four TCD). Mixed chimaerism was an uncommon finding in recipients of unmanipulated BMT (21%) when compared to TCD BMT (100%). No evidence of MRD, as identified using the BCR-ABL mRNA RT-PCR assay, was detected in those patients who were donor chimaeras. Early and transient MC and MRD was detected in four patients (two non-TCD, two TCD) who have subsequently converted to a donor profile. One patient has stable low-level MC but remains MRD negative 4 years post-BMT. Late MC and MRD was observed in two patients who relapsed >6 years after TCD BMT for CML. We conclude that mixed chimaerism is a rare event in recipients of unmanipulated BMT and that donor chimaerism as detected by STR-PCR assay is consistent with disease-free survival and identifies patients with a low risk of leukaemic relapse post-BMT for CML.
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PMID:Persistent donor chimaerism is consistent with disease-free survival following BMT for chronic myeloid leukaemia. 925 92

Conventional chemotherapy for multiple myeloma results in low complete response rates, and disease progression usually occurs within a couple of years. High-dose chemotherapy with autotransplantation, which has been shown to result in encouraging complete remission rates over several years in phase II studies, was recently shown in a randomized study to be superior to conventional therapy. Eventual tumor recurrence is a problem after autografting, and the development of novel maintenance chemotherapy or immunotherapy strategies is necessary to eliminate minimal residual disease. Although allogeneic transplantation cures a small proportion of patients, high transplant-related mortality and relapse rates hamper survival. Development of novel conditioning regimens and means to harness the graft-versus-myeloma effect without the associated morbidity of graft-versus-host disease are necessary to improve success rates. Supportive therapy, mainly bisphosphonates to delay progression of bone disease and improve bone density and erythropoietin to improve hemoglobin levels, also plays an important role in the overall management. This article reviews therapeutic advances in multiple myeloma from the 1996 literature.
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PMID:Advances in the treatment of multiple myeloma. 926 58

Cyclosporine A (CyA) was abruptly discontinued in an attempt to induce graft-versus-leukemia (GVL) effect following allogeneic bone marrow transplantation (BMT). It appeared that GVL effect was co-expressed with graft-versus-host disease (GVHD) in 2 of 4 patients and especially minimal residual disease was eliminated during GVHD in a patient with Philadelphia-positive acute lymphocytic leukemia. Subpopulation of cytotoxic T and natural killer cells increased significantly in patients with discontinuation of CyA. This finding suggests that GVL effect was increased following discontinuation of CyA. These results may provide a therapeutic strategy after BMT in patients with high-risk group for relapse of leukemia.
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PMID:[Graft-versus-leukemia effect induced by abrupt discontinuation of cyclosporine A following allogeneic bone marrow transplantation]. 931 Dec 69

Donor leukocyte therapy has resulted in a remission rate in excess of 70% in patients with relapse of chronic myeloid leukaemia (CML) following allogeneic bone marrow transplantation (BMT). Induction of remission with donor leukocyte infusions has been primarily successful for CML patients who have cytogenetic relapse or those with chronic-phase haematological relapse. Response rates appear to be lower in patients who have advanced-phase CML. The majority of patients with CML who enter remission have no detectable minimal residual disease when analysed for BCR-ABL mRNA transcripts by reverse-transcription polymerase chain reaction. The efficacy of donor leukocyte infusions and the ease of therapy are balanced by the potential for significant toxicity. The reported treatment-related mortality rate is almost 20%. The major toxicities of this treatment are secondary to marrow aplasia and graft-versus-host disease (GVHD) which may occur in up to 50% and 90% of responders respectively. Donor leukocytes with a T-cell content of only 1 x 10(7)/kg, approximately a factor of 10 fewer T cells than used in most early studies, are capable of inducing remissions in some patients. The use of lower doses of T cells or CD8+ depleted T cells may be associated with less GVHD. The optimal treatment schedule using donor leukocytes has yet to be determined. Factors which might influence outcome include phase of disease, use of interferon alpha, use of unrelated donors and human leukocyte antigen disparity, T-cell dose, CD8+ depletion of leukocytes and time from BMT to leukocyte infusion.
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PMID:Donor leukocyte infusions. 937 69

Today more than 80000 allogeneic bone marrow transplantations (BMT) have been performed worldwide. The major indications are hematological malignancies such as acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and myelodysplastic syndromes. Unrelated donors are increasingly used and there are around 4 million volunteer donors available in different registers, the largest being the National Marrow Donor Program. Molecular typing has improved the typing technique which has resulted in a decreased risk of graft-versus-host disease (GVHD), lower transplant-related mortality (TRM) and improved leukemia-free survival (LFS). Using HLA-identical siblings, patients with AML in first complete remission (1 CR) and high-risk ALL in 1 CR are clear indications for BMT. However, if an HLA-identical sibling is not available, it is not known today if an unrelated bone marrow or autografting is the best option for all patients with acute leukemia in 1 CR. Because BMT is the only curable treatment for CML, a search for an unrelated donor should start as soon as it is evident that an HLA-identical sibling is not available. BMT within a year from diagnosis is of major importance for outcome. Allogeneic peripheral blood progenitor cells (PBPC) have been used as an alternative to bone marrow. Preliminary studies indicate a faster engraftment, but prospective randomized trials are necessary to establish the role of allogeneic PBPC. Umbilical cord blood has also been used as a source of allogeneic hematopoietic stem cells. Using cord blood from HLA-identical siblings, engraftment seems to be delayed, but the probability of GVHD is low. Preliminary data using unrelated cord blood cells are encouraging. GVHD has an important antileukemic effect. Recently, a graft-versus-myeloma and a graft-versus-breast-cancer effect has been demonstrated. In patients who relapse after BMT, donor lymphocytes can induce remission, especially in patients with CML. With molecular techniques it is possible to detect relapse at an early stage, so called minimal residual disease. Liposomal amphotericin B has few side-effects and decreased the death rate by invasive fungal infection in BMT recipients. Early diagnosis and treatment of cytomegalovirus (CMV) infection with new antiviral drugs have dramatically reduced the incidence and mortality in CMV disease. Cyclosporine combined with methotrexate is today the most widely used immunosuppressive regimen and has decreased GVHD and improved survival. However, several new immunosuppressive drugs need to be explored in clinical BMT. Immune modulation by for instance cytokines and cytokine inhibititors is a new exciting development.
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PMID:Allogeneic bone marrow transplantation for hematological malignancies--controversies and recent advances. 940 43

We report here that a patient with relapsed AML after allogeneic bone marrow transplantation achieved and maintained complete remission (CR) after effective donor leukocyte transfusion (DLT), without the occurrence of GVHD and marrow aplasia, for more than 21 months. This continuous CR maintenance is mainly due to the application of DLT at molecular relapse that was diagnosed by monitoring minimal residual disease (MRD) by the quantitation of WT1 (Wilms tumor gene) expression levels (WT1 assay). The present case demonstrates that early application of DLT at molecular relapse is essential for the improvement of the efficacy of DLT for relapsed AML after BMT.
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PMID:Successful donor leukocyte transfusion at molecular relapse for a patient with acute myeloid leukemia who was treated with allogenic bone marrow transplantation: importance of the monitoring of minimal residual disease by WT1 assay. 953 47

Thirty-eight patients with hematological malignancies, received T cell-depleted marrow transplants (BMT) and cyclosporine to prevent acute graft-versus-host disease (aGVHD), followed by delayed add-back of donor lymphocytes to prevent leukemia relapse. In 26 patients scheduled for donor T cell add-back of 2 x 10(6) cells/kg on day 30 and 5 x 10(7) cells/kg on day 45 (schedule 1), the overall probability of grade > or = II aGVHD developing was 31.5%, with a 15.5% probability of aGVHD occurring after T cell add-back. In 12 patients receiving 10(7) donor T cells/kg on day 30 (schedule 2), the probability of grade > or = II aGVHD was 100%. The incidence of grade III-IV aGVHD was higher in schedule 2 than in schedule 1 (P=0.02). Of 24 evaluable patients, 10 (46%) developed chronic GVHD which was limited in eight and extensive in two. Current disease-free survival for 18 patients at standard risk for relapse (chronic myeloid leukemia (CML) in chronic or accelerated phase, acute myeloid leukemia in remission) vs 20 patients with more advanced leukemia or multiple myeloma were respectively 72% vs 12% (P < 0.01) with a 29% vs 69% probability of relapse (P=0.08). In 12 CML patients surviving more than 3 months, PCR analysis of the BCR/ABL transcript showed that minimal residual disease after T cell add-back was transient except in two patients who developed hematological relapse. Results indicate that the risk of acute GVHD is low following substantial T cell doses, transfused 45 days after transplant, using cyclosporine prophylaxis. Furthermore a graft-versus-leukemia effect was conserved.
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PMID:T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect. 954 57


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