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)

We report a 39-year-old female patient who underwent HLA-identical sibling allogeneic BMT for CML in accelerated phase. Severe pancytopenia refractory to G-CSF associated with progressive splenomegaly and RBC/platelet transfusion dependency were present from day +60 after BMT. MRD assessed by FISH and RT-PCR multiplex for BCR-ABL rearrangement was negative, and complete chimerism was documented by VNTR on days +100, +180, +360 and 2 years after BMT. Splenectomy was performed on day +225 and pancytopenia resolved but chronic extensive graft-versus-host disease developed, with hepatic cholestasis, diffuse scleroderma and sicca-like syndrome. She was sequentially and progressively treated with different immunosuppressive therapy combinations with no clear benefit. On day +940, she presented with infection over the previously present ulcers on both limbs, which culminated in septic shock and death on day +1041. We conclude that, although splenectomy may reverse poor graft function after allogeneic BMT, hyposplenism may trigger or worsen chronic extensive GVHD leading to increased morbidity and mortality.
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PMID:Refractory chronic GVHD emerging after splenectomy in a marrow transplant recipient with accelerated phase CML. 1285 7

The Third Workshop on reduced intensity conditioning allogeneic stem cell transplants (RIC-HSCT) was convened by EBMT/AMGEN in Zurich in February 2003. Three general issues were addressed: the age effect, graft-versus-host disease (GvHD) and donor lymphocyte infusions (DLI). An age effect is seen and has a negative impact on survival; GvHD remains an issue that needs to be addressed, and DLI were shown to be a powerful tool against minimal residual disease, but not with rapidly progressing leukemia. The role of host antigen-presenting cells in the development of acute GvHD was outlined and discussed in the animal model. The emerging importance of Epstein Barr Virus infections was also discussed. Retrospective and prospective studies from the EBMT, national groups and single institutions included over 1800 patients: the incidence of acute GvHD grade III-IV was 11% extensive chronic GvHD 22% and TRM 20%. Most conditioning regimens include fludarabine in association with a reduced dose of a myeloablative agent (busulfan, TBI, thiotepa or melphalan). Most transplants were from HLA-identical siblings (77%), and used peripheral blood (90%) as a stem cell source. A consensus discussion on current evidence in RIC transplants is reported in this paper.
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PMID:Third EBMT/AMGEN Workshop on reduced-intensity conditioning allogeneic haemopoietic stem cell transplants (RIC-HSCT), and panel consensus. 1475 22

Despite major progress in treating hematologic malignancies and, to a lesser extent, metastatic solid tumors, much work remains ahead. With the anticancer potential of immunotherapy not yet fully exploited, patients with leukemia, malignant lymphoma, and other hematologic malignancies for which high-dose chemoradiotherapy is frequently recommended in conjunction with stem cell transplantation (SCT) can now benefit from the advantages of immunotherapy mediated by cytokines or alloreactive donor lymphocytes, while minimizing procedure-related toxicity and mortality. The feasibility of applying allogeneic cell-mediated immunotherapy in conjunction with allogeneic SCT following reduced-intensity conditioning, with minimal toxicity and no serious transplant-related complications, makes it possible to undertake such procedures on an outpatient basis as well as to offer an option for cure to elderly individuals and patients with less than optimal performance status. Being well tolerated, reduced-intensity transplants also offer a chance for cure to patients with otherwise resistant leukemia and malignant lymphoma who have relapsed after autologous SCT. Thus, the traditional obstacle of very high transplant-related toxicity and mortality due to multiorgan failure from cumulative toxicity of multiple anticancer agents and radiation therapy is overcome. Although immunotherapy mediated by allogeneic lymphocytes can be most effective, the immune potential of donor lymphocytes should be maximized by nonspecific or specific activation in vitro or in vivo, or both, for more effective eradication of resistant tumor cells, including in patients with bulky disease. More important is the challenge to target donor lymphocytes to the tumor and minimize their capacity to induce responses against normal host tissues, which frequently results in severe acute and chronic graft-versus-host disease (GVHD). Alternatively, donor lymphocytes should be eliminated as soon as tumor eradication is completed, or as soon as severe GVHD becomes prohibitive. Based on available experience, clinical application of innovative therapy, especially at the stage of minimal residual disease (MRD), may open new horizons for the treatment of malignancies considered until recently to be incurable. The feasibility of controlling cancer by targeted chemotherapy, best illustrated by the phenomenal activity of imatinib in patients with chronic myelogenous leukemia and, more recently, in gastrointestinal stromal tumors (including in patients fully resistant to all known anticancer agents) suggests that in the future, tumor-specific chemotherapy may represent the ultimate goal for achieving a stage of MRD with minimal multiorgan toxicity. Together, the combination of immunotherapy and targeted chemotherapy may provide the most logical approach for making real progress in controlling resistant hematologic malignancies and metastatic solid tumors.
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PMID:Nonmyeloablative stem cell transplantation: reduced-intensity conditioning for cancer immunotherapy--from bench to patient bedside. 1497 Sep 32

Graft rejection is a major cause of treatment failure after T-cell-depleted stem cell transplantation (TCD-SCT) and remains a therapeutic challenge. Donor leukocyte infusions (DLIs) have an efficient graft versus host effect, which has been successfully used to treat recipient relapses. We hypothesized that this effect could be exploited to counteract the host versus graft reactions responsible for graft rejection. We report two adult patients with haematological malignancies who underwent sex-mismatched TCD-SCT from HLA-identical sibling donors. Peripheral blood (PB) counts and bone marrow (BM) cellularity were studied on a serial basis. Sequential chimaerism and minimal residual disease analysis were performed by FISH on PB and BM samples as well as on leukocyte lineages (T and B lymphocytes and myeloid cells) purified from PB using immunomagnetic technology. Both patients were diagnosed with incipient graft rejection 2-3 months after engraftment, based on persistently decreasing PB counts and BM cellularity together with the observation of decreasing mixed chimaerism (increasing percentage of recipient cells), mostly in whole PB and T lymphocytes. Both patients were successfully treated with a single DLI (1 x 10(7) CD3+ cells/kg), thereafter achieving normal PB counts and BM cellularity as well as complete chimaerism. Interestingly, the only side effect observed was mild graft versus host disease that did not require treatment. In conclusion, provided that an early diagnosis is made, the graft versus host lymphohaemopoietic effect harboured by immunocompetent donor cells can be successfully used for the treatment of incipient graft rejection.
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PMID:Successful treatment of incipient graft rejection with donor leukocyte infusions, further proof of a graft versus host lymphohaemopoietic effect. 1506 92

The main goal of post-transplantation monitoring in hematopoietic stem cell transplantation (HSCT) is to predict negative events, such as disease relapse, graft rejection and graft-versus-host disease, in order to intervene with appropriate therapy. In this context, chimerism analysis is an important method in monitoring post HSCT outcome. Mixed chimerism (MC) is mainly evaluated to define engraftment and relapse. Detection of MC is a prerequisite in both myeloablative and nonmyeloablative HSCT, in order to assess the graft status and decide later therapeutic strategies such as donor lymphocyte infusion. In this review, we discuss various techniques including erythrocyte phenotyping, cytogenetic analysis, fluorescent in situ hybridization, restriction fragment length polymorphism, STR/VNTR analysis and real-time quantitative PCR, along with the various methods used to detect minimal residual disease (MRD) in different diseases such as chronic myeloid leukemia, acute myelomonocytic leukemia or acute lymphoblastic leukemia. The review mainly highlights the optimal methodological approach, which needs to be informative, sensitive and quantitatively accurate for MC detection. Future of post HSCT graft monitoring lies in the selection of the most accurate and sensitive technique to determine both MC and MRD. Such an approach would be helpful in not only determining relapse or rejection, but also in ascertaining various responses to different treatment modalities.
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PMID:Significance of chimerism in hematopoietic stem cell transplantation: new variations on an old theme. 1515 63

The aim of this study was to investigate if graft-versus-leukemia (GVL) activity conferred by allogeneic stem cell transplantation (allo-SCT) is effective in chronic lymphocytic leukemia (CLL) with unmutated V(H) gene status. The kinetics of residual disease (MRD) were measured by quantitative allele-specific immunoglobulin heavy chain (IgH) polymerase chain reaction (PCR) in 9 patients after nonmyeloablative allo-SCT for unmutated CLL. Despite an only modest decrease in the early posttransplantation phase, MRD became undetectable in 7 of 9 patients (78%) from day +100 onwards subsequent to chronic graft-versus-host disease or donor lymphocyte infusions. With a median follow-up of 25 months (range, 14-37 months), these 7 patients remain in continuous clinical and molecular remission. In contrast, PCR negativity was achieved in only 6 of 26 control patients (23%) after autologous SCT for unmutated CLL and it was not durable. Taken together, this study shows for the first time that GVL-mediated immunotherapy might be effective in CLL with unmutated V(H).
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PMID:Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. 1520 68

In an attempt to induce a graft-versus-myeloma effect, we administered donor lymphocyte infusions (DLI) after high-dose therapy with autologous stem cell transplant rescue to seven patients with refractory or relapsed multiple myeloma. High-dose therapy consisted of melphalan, idarubicin and etoposide (days -9 to -6) followed by autologous stem cell infusion on day 0. DLI (five of seven donors with two or three HLA antigens mismatched) were administered on days +1, +5 and +10 along with IL-2 (from day +1 through +12). Six of the seven patients developed acute graft-versus-host disease (GVHD), which resolved spontaneously, coincidentally with autologous hematopoietic reconstitution. One patient failed to engraft and received a second autologous graft. One patient died from complications of a pulmonary hemorrhage after experiencing GVHD. With a minimum follow-up of 38 months, five patients remain without disease progression in complete remission or with minimal residual disease. In this setting, DLI/IL-2 is biologically active resulting in GVHD. A graft-versus-myeloma effect is suggested by the improved outcome of our small cohort of high-risk patients. The use of partially mismatched related donors makes this approach potentially available to nearly all patients.
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PMID:Adoptive immunotherapy with donor lymphocyte infusions and interleukin-2 after high-dose therapy and autologous stem cell rescue for multiple myeloma. 1528 96

Prior studies suggest that depletion of CD8+ T cells from donor bone marrow or donor lymphocyte infusions can reduce graft-versus-host disease (GVHD) without compromising graft-versus-leukemia. We explored CD8 depletion in patients undergoing matched related donor (MRD, n=25) and unrelated donor (URD, n=16) peripheral blood stem cell transplantation following myeloablative conditioning with cyclophosphamide (60 mg/kg/day i.v. x 2) and total body irradiation (200 cGy x 7 fractions). Ex vivo incubation of mobilized donor peripheral blood cells with anti-CD8 antibody coated high-density microparticles removed 99% of CD8+ cells. The median number of CD8+ cells infused was 3.9 x 10(5) cells/kg (2.2 x 10(5) in MRD, and 8.1 x 10(5) in URD patients). Post transplant immune suppression included tacrolimus in the MRD cohort, and tacrolimus plus mini-methotrexate (5 mg/m2 days +1, 3, 6, 11) in the URD cohort. All 41 patients engrafted. Grade 2-4 acute GVHD incidence was 61% (44% MRD, 88% URD). Chronic GVHD incidence was 50% (48% MRD, 55% URD). Relapse incidence was 4.9%. Estimated event-free and overall survival rates were 65 and 63%, respectively, at 1 year and 56 and 57%, respectively, at 2 years. There was no correlation between CD8+ number and GVHD or survival. A 2-log depletion of CD8+ cells from PBSC is insufficient to prevent GVHD.
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PMID:Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease. 1548 73

Evaluation of minimal residual disease (MRD) provides prognostic information on various hematological malignancies. We describe here the prognostic efficacy of real-time quantitative polymerase chain reaction (RQ-PCR)-based analysis of major bcr/abl mRNA in cases of Philadelphia chromosome-positive leukemia (Ph-leukemia). Twenty-one patients with Ph-leukemia were enrolled as subjects to determine the usefulness of RQ-PCR-based measurement of bcr-abl/abl ratios. Imatinib mesylate (imatinib) was administered to seven of the 21 patients before allogeneic stem cell transplantation (SCT). Hematological relapse or failure of treatment with SCT was observed in 2 of those patients who showed bcr-abl/abl ratios of more than 0.002%, and 5 of the 7 patients showed both RQ-PCR and RT-PCR negativity immediately after SCT. All of the 5 patients who did not receive imatinib before allogeneic SCT showed RQ-PCR negativity immediately after SCT, but the results of RT-PCR were positive in 3 patients at the same time points, and those became negative after donor lymphocyte infusion or the appearance of graft-versus-host disease. Administration of imatinib before SCT was thought to induce an early remission. On the other hand, 8 patients who received imatinib without SCT showed a remarkable decrease in bcr-abl/abl ratios. The ratio gradually rose in one patient with Ph+ALL, enabling prediction of the hematological relapse preceding detection by fluorescence in situ hybridization (FISH) analysis. Standardization of RQ-PCR analysis of bcr-abl mRNA will help to predict early hematological relapse in patients with MRD. In conclusion, it is thought that measurement of RQ-PCR-based major bcr/abl mRNA in patients who were given imatinib and were treated with SCT is useful for the evaluation of MRD and in deciding additional treatment.
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PMID:[Prognostic efficacy for measurement of real-time quantitative PCR-based major bcr/abl mRNA in patients with Philadelphia chromosome-positive leukemia]. 1567 15

We report the outcome following RIT for NHL in 88 patients (LG-NHL n = 41, HG-NHL n = 37, MCL n = 10). Thirty-seven had received prior autografts and 21 were in CR at transplant. Conditioning was with alemtuzumab, fludarabine and melphalan. Sixty-five patients received PBSC from HLA-identical siblings and 23 received BM from matched unrelated donors. GVHD prophylaxis was with cyclosporin A. Grade III-IV acute GVHD developed in 4 patients and chronic GVHD in 6 patients. With a median follow-up of 36 months (range 18-60), the actuarial overall survival (OS) at 3 years was 34% for HG-NHL, 60% for MCL and 73% for LG-NHL (p < or = 0.001). The 100-day and 3-year TRM for patients with LG-NHL were 2% and 11%, respectively, and were better (p = 0.01) than for patients with HG-NHL (27% and 38%, respectively). The actuarial current progression free survival (PFS) at 3 years, including those who achieved remission following DLI for progression, was 65% for LG-NHL 50% for MCL and 34% for HG-NHL (p = 0.002). Twenty-one patients received DLI for MRD, persistent disease or relapse and 15 received DLI for mixed hematopoietic chimerism. Patients with relapsed LG-NHL and CLL achieve excellent PFS with extremely low TRM and GVHD, even when matched family donors are unavailable.
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PMID:Outcome following alemtuzumab (CAMPATH-1H)-containing reduced intensity allogeneic transplant regimen for relapsed and refractory non-Hodgkin's lymphoma (NHL). 1573 76


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