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)

Alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody that targets the human CD52 antigen. CD52 is expressed by a variety of lymphoid neoplasms and most human mononuclear cell subsets. In 2001, alemtuzumab was approved for marketing in the United States and Europe for use in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). In heavily pretreated patients with CLL, the overall response rate (ORR) is approximately 35%, and in previously untreated patients the ORR is greater than 80%, with a recent randomized study suggesting it is superior to alkylator-based therapy. Importantly, alemtuzumab is effective in patients with high-risk del(17p13.1) and del(11q22.3) CLL. Alemtuzumab combination studies with fludarabine and/or monoclonal antibodies such as rituximab have demonstrated promising results. Alemtuzumab is also being studied in CLL patients as consolidation therapy for treatment of minimal residual disease, in preparation for stem cell transplantation and to prevent acute and chronic graft versus host disease. Alemtuzumab is frequently associated with acute 'first-dose' reactions when administered intravenously, but is much better tolerated when administered subcutaneously without loss of therapeutic efficacy. Additional potential adverse events associated with alemtuzumab administration include myelosuppression as well as profound cellular immune dysfunction with the associated risk of viral reactivation and other opportunistic infections. Additional studies detailing the mechanism of action of alemtuzumab as well as new strategies for prevention of opportunistic infections will aid in the future therapeutic development of this agent.
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PMID:Alemtuzumab (Campath-1H) in the treatment of chronic lymphocytic leukemia. 1753 18

We have performed combined organ and hematopoietic cell transplantation using a similar conditioning regimen in mice and humans. In the mouse model of MHC-mismatched combined heart and marrow transplantation, we compared conditioning of BALB/c hosts with total lymphoid irradiation (TLI: 10 doses of 240 cGy each) targeted to the spleen, lymph nodes and thymus to conditioning with a single dose of sublethal total body irradiation (TBI; 450 cGy). Conditioning also included three injections of anti-thymocyte serum (ATS), in both groups. C57BL/6 heart grafts, marrow cells and blood mononuclear cells were transplanted 24 h after the completion of irradiation. Blood mononuclear cells were added to the marrow cells to engender severe graft versus host disease (GVHD) that is present after combined organ and hematopoietic cell transplantation in humans given non-myeloablative conditioning. Both TLI and TBI conditioned groups accepted the organ grafts and became stable chimeras. However, the TBI group all died of GVHD during the 100-day observation period. The TLI group survived during the same period without clinical signs of GVHD. These hosts were tolerized to the donor organ grafts, since third party grafts were rejected rapidly when transplanted after 100 days. When NK T-cell-deficient CD1d(-/-) BALB/c hosts were used instead of wild-type hosts in the TLI/ATS conditioned group, then all hosts survived but all rejected the organ grafts and almost all failed to develop stable chimerism. None developed GVHD. Since host NK T cells were required for graft acceptance and NK T cells are activated after recognition of CD1d on antigen presenting cells, we compared heart and marrow graft survival from wild-type versus CD1d(-/-) donors after transplantation to TLI and ATS conditioned wild-type hosts. Whereas marrow and heart grafts from wild-type donors were accepted, almost all grafts from CD1d donors were rejected. Grafts from control Jalpha18(-/-) donors that were NK T cell deficient but expressed CD1d were all accepted. The results indicate that host NK T cells facilitate graft acceptance by recognizing CD1d on donor cells. We applied the TLI conditioning regimen using 10 doses of 80 cGy each and 5 doses of rabbit ATG to human recipients of HLA-matched G-CSF "mobilized" blood mononuclear cell transplants for the treatment of leukemia and lymphoma [R. Lowsky, T. Takahashi, Y.P. Liu, et al., Protective conditioning for acute graft-versus-host disease. N. Engl. J. Med. 353 (2005) 1321-1331.]. Currently more than 100 transplants have been performed, and the incidence of acute GVHD has been about 4% when both MRD and MUD transplants are combined. Almost all recipients became complete chimeras after receiving grafts that contained 2-3x10(8) CD3(+) T cells/kg. In further studies, we applied the same TLI and ATG conditioning regimen to combined kidney and G-CSF "mobilized" blood stem cell transplantation from HLA-matched sibling donors. The hematopoietic grafts in the latter protocol were selected CD34(+) cells with 1x10(6) CD3(+) T cells/kg added back to the hematopoietic cells. Preliminary results indicate that stable mixed chimerism can be achieved using this protocol allowing for complete immunosuppressive drug withdrawal without GVHD or subsequent rejection episodes. Thus, conditioning with TLI based regimens can simultaneously protect against organ graft rejection and GVHD. Levels of chimerism are dependent upon the content of donor T cells in the hematopoietic graft.
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PMID:Protective conditioning against GVHD and graft rejection after combined organ and hematopoietic cell transplantation. 1782 36

Invasive aspergillosis (IA) is an important infectious complication in allogeneic stem cell transplant (SCT) recipients. Diagnosis of IA has been difficult and often delayed and treatment outcome has been poor, with mortality rates up to 80%. This review summarizes recent developments in this field. There are indications that the incidence of IA may be decreasing due to multiple factors including better understanding of pathogenesis of IA, earlier diagnosis, and various prophylactic and preventive strategies. Recently posaconazole has shown to be effective in reducing the risk of IA in patients treated for graft-versus-host disease (GVHD). Early use of high-resolution thoracic computed tomography assisted with complimentary methods including bronchoalveolar lavage and serum galactomannan determinations are useful in early diagnosis. Our treatment armamentarium against IA has broadened significantly during the last years and there are some indications of improved outcome more recently. On the other hand, increasing use of blood progenitor grafts instead of marrow with higher risk of chronic GVHD, increasing age of SCT recipients, and wide use of donor lymphocyte infusions for treatment of minimal residual disease or relapse may affect to the opposite direction. Despite some promises and improvements, IA will continue to remain a challenge in the upcoming years.
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PMID:Changing landscape of invasive aspergillosis in allogeneic stem cell transplant recipients. 1826 85

The purpose of this study was to prospectively analyze minimal residual disease(MRD) kinetics after reduced-intensity allogeneic stem cell transplantation (allo-SCT) in high-risk chronic lymphocytic leukemia (CLL). Subjects were the first 30 consecutive patients from a prospective clinical trial, and seven pilot patients treated identically. Using real-time quantitative-PCR (RQ-PCR) and/or flow-based MRD monitoring (sensitivity >or=10(-4)), five distinct patterns of MRD kinetics could be identified: patients who promptly achieved durable MRD negativity without direct evidence of graft-versus-leukemia (GVL) effects (Group 1) (n=4; no clinical relapse); patients with complete and sustained MRD response after GVL induced by immunosuppression tapering (Group 2) or donor lymphocyte infusions (Group 3) (n=18; one relapse); patients without MRD response due to lack of GVL (Group 4) (n=2; two relapses); patients with incomplete and transient MRD response to GVL (Group 5) (n=4; three relapses). In summary, this study provides a comprehensive map of possible MRD courses and their prognostic implications after T-replete allo-SCT in high-risk CLL, indicating that effective GVL activity is induced virtually in all patients who develop chronic GVHD. However, in a significant proportion of cases, this does not translate into sustained disease control due to development of secondary GVL resistance.
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PMID:Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. 1841 4

We assessed the combination of sirolimus, tacrolimus, and low-dose methotrexate as acute graft-versus-host disease (aGVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation from matched related (MRD, n = 46) and unrelated (URD, n = 45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized PBSC. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II-IV and III-IV aGVHD were 16% and 7%, respectively. There was no difference in the incidence of aGVHD between MRD and URD cohorts. Two-year cumulative incidence of extensive chronic GVHD (cGVHD) was 40%. Relapse-free survival (RFS) at 2 years was 34%: 21% in MRD and 45% in URD. Overall survival (OS) at 2 years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following RIC with fludarabine and low-dose intravenous busulfan is associated with rapid engraftment, low rates of aGVHD, and achievement of high levels of donor chimerism.
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PMID:Sirolimus, tacrolimus, and low-dose methotrexate as graft-versus-host disease prophylaxis in related and unrelated donor reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. 1864 May 76

This study was aimed to investigate the chimerism and fusion gene expression in patients with CML after allo-HSCT, to analyse engraftment and minimal residual disease by using STR-PCR combined with RT-PCR qualitative and quantitative assays, and to evaluate their clinical value for predicting disease relapse. 4 relapsed patients with CML after allo-HSCT were dynamically investigated. Qualitative analysis of donor chimerism was performed by multiplex PCR amplification of STR markers and capillary electrophoresis with fluorescence detection, qualitative detection of bcr/abl transcripts was performed by RT-PCR. The results showed that the 100% donor chimerism appeared in 4 patients on day 28 after transplantation and bcr/abl expression was negative, but the 4 patients were in status of unstable mixed chimerism (DC: 0% - 80.4%) at the different time points during the following up with bcr/abl gene positive. 2 patients of them were continuously mixed chimerism after relapse of CML, the other 2 changed from MC to CC by intervention of clinical treatment. Decreasing values of donor chimerism were detected prior to the occurrence of graft rejection and CML relapse, and bcr/abl gene expression was positive. It is concluded that the results of STR-PCR in the range of its sensitivity fully correspond with bcr/abl tests in patients. The combination of STR-PCR with RT-PCR will provide a highly sensitive and valuable tool for evaluating engraftment, graft rejection, and relapse and predicting GVHD. Furthermore, it can provide a basis for early intervention of clinical treatment, and can identify these high risk patients with molecular or cytogenetic relapse after allo-HSCT.
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PMID:[Dynamic detection of chimerism and fusion gene in chronic myeloid leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation]. 1871 71

This study evaluates the prognostic value of minimal residual disease (MRD) monitoring by multiparametric flow cytometry in 41 patients with acute myeloid leukemia or myelodysplastic syndrome undergoing allogeneic transplantation. MRD assessment after transplant (day +100) allowed to discriminate different risk populations, being the most significant cut-off value for outcome level of MRD < or > or = 10(-3). Outcome was significantly better among patients with low (<10(-3)) versus high (> or = 10(-3)) MRD at day +100 after transplant. Thus, overall survival was 73% versus 25% at 4 years among patients with low versus high MRD at day +100 after transplant (P = 0.002); 74% of patients with low MRD were event free at 4 years as compared to 17% among patients with high MRD (P = 0.01). In multivariate analysis, MRD value as well as chronic GVHD significantly influenced outcome. In conclusion, MRD monitoring early post-transplant is an important tool for outcome prediction and should be considered in decision making after allogeneic transplantation.
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PMID:Minimal residual disease monitoring after allogeneic transplantation may help to individualize post-transplant therapeutic strategies in acute myeloid malignancies. 1912 59

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) for multiple myeloma is associated with high transplantation-related mortality (TRM). Nonmyeloablative allogeneic transplantation (NST) uses the well-known graft-versus-myeloma (GVM) effect to eradicate minimal residual disease. The Eastern Cooperative Oncology Group conducted a Phase II trial of autologous HSCT followed by NST to provide maximal tumor cytoreduction to allow for a subsequent GVM effect. Patients received melphalan 200 mg/m(2) with autologous HSCT, followed by fludarabine 30 mg/m(2) in 5 daily doses and cyclophosphamide 1 g/m(2) in 2 daily doses with matched sibling donor NST. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and corticosteroids. The primary endpoints were TRM, graft failure, acute GVHD, progression-free survival (PFS), and overall survival (OS). Thirty-two patients were enrolled into the study; 23 patients completed both transplantations (72%). Best responses post-NST were 7 (30%) complete remission (CR), 11 (48%) partial remission (PR), 2 (9%) no response, and 3 (13%) not evaluable. Acute grade III-IV GVHD was observed in 4 patients (17%), and chronic GVHD was seen in 13 patients (57%; 7 limited, 6 extensive). Chronic GVHD resulted in the following responses: 3 (23%) CR, 1 continuing CR, and 6 (46%) PR. Two patients (8.7%) had early TRM. With a median follow up of 4.6 years, the median PFS was 3.6 years, and the 2-year OS was 78%. Our findings indicate that autologous HSCT followed by NST is feasible, with a low early TRM in a cooperative group setting. The overall response rate was 78%, including 30% CR, similar to other reports for autologous HSCT-NST. Because a plateau in PFS or OS was not observed with this treatment approach even in patients achieving CR, we suggest that future studies use posttransplantation maintenance therapy.
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PMID:A Phase II trial of autologous stem cell transplantation followed by mini-allogeneic stem cell transplantation for the treatment of multiple myeloma: an analysis of Eastern Cooperative Oncology Group ECOG E4A98 and E1A97. 1913 46

The humanized anti-CD52 monoclonal antibody alemtuzumab belongs to the family of Campath-1 antibodies, which were initially developed for their ability to prevent graft-versus-host disease (GVHD) and graft rejection in stem cell transplantation. Alemtuzumab is indicated for the treatment of chronic lymphocytic leukaemia (CLL) and has demonstrated considerable activity in relapsed/refractory disease and in previously untreated disease. It has been shown to induce minimal residual disease-negative responses as a single agent or as part of consolidation therapy in a meaningful proportion of patients with CLL and has shown promising activity in patients with high-risk cytogenetic markers. Alemtuzumab may also have significant activity in T-cell malignancies, such as mycosis fungoides and T-cell prolymphocytic leukaemia. Recent studies also have evaluated alemtuzumab as part of a conditioning regimen to prevent GVHD in stem cell transplantation. This article reviews our current understanding of alemtuzumab and discusses its emerging role in the treatment of CLL and other haematological malignancies.
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PMID:Rediscovering alemtuzumab: current and emerging therapeutic roles. 1918 94

The antineoplastic effect of allogeneic stem cell transplantation after reduced-intensity conditioning (RIC) relies on the graft-versus-tumour (GvT) reaction. GvT is closely linked to the development of graft-versus-host disease (GvHD). The incidence of acute GvHD after RIC seems lower than after myeloablative conditioning (MAC), whereas the incidence of chronic GvHD after RIC seems similar to after MAC. The results of RIC for acute myeloid leukaemia show a non-relapse mortality of approximately 15% at one year, a relapse incidence of approximately 40% after a median of 4-6 months, translating into overall and disease-free survival rates of 40-60%. The factors associated with improved outcome in most studies are the stage of the disease at transplantation, age and the development of chronic GvHD (and thus GvT). In a recent report, chronic GvHD was the most important factor associated with prolonged survival. Future efforts should be directed at aiming to decrease relapse rates. For this purpose, an adequate identification of high-risk patients, close monitoring of minimal residual disease after the procedure, and the use of antineoplastic drugs or immunotherapy may be of help.
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PMID:Allogeneic stem cell transplantation after reduced-intensity conditioning for acute myeloid leukaemia: impact of chronic graft-versus-host disease. 1956 12


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