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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)

Growing evidence supports the efficacy of cord blood transplantation (CBT), and the number of CBTs is increasing. Numerous studies confirm the presence of a graft-versus-leukemia (GVL) effect following CBT, and preliminary data suggests that double-unit CBT may be associated with a decreased risk of relapse. We have observed a low relapse rate following CBT among patients with acute leukemias in morphologic complete remission (CR) at the time of myeloablative (MA) transplant. To further assess this observation, we conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving CBTs versus patients receiving matched unrelated donor (MURD) and mismatched unrelated donor (MMURD) transplants at our center. Thirty-one consecutive CBT patients (aged 0.6-42 years, median 22 years), transplanted between April 2006 and June 2008, were compared to matched subjects selected on the basis of disease type and remission number, cytogenetic risk status, minimal residual disease status (MRD), time from diagnosis to first relapse (for patients beyond CR1), use of imatinib for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) patients, age, and date of transplant. With a median follow-up among surviving CBT patients of 21.1 months (range: 6.6-32.6 months), there has been 1 relapse among cord patients versus 8 relapses among MURD patients (P=.018) and 7 relapses among MMURD patients (P=.019). Treatment-related mortality (TRM) between cohorts is comparable. Although we have observed a high incidence of acute graft-versus-host disease (aGVHD) following CBT, the incidence of National Institutes of Health (NIH) consensus criteria chronic GVHD (cGVHD) has been low. These data support increased investigation of the use of CBT.
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PMID:Low relapse without excessive transplant-related mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis. 1966 Jul 26

Allogeneic haematological stem cell transplantation (HSCT) has developed into immunotherapy. Donor CD4+, CD8+ and natural killer (NK) cells have been reported to mediate graft-versus-leukaemia (GVL) effects, using Fas-dependent killing and perforin degranulation to eradicate malignant cells. Cytokines, such as interleukin-2, interferon-gamma and tumour necrosis factor-alpha potentiate the GVL effect. Post-transplant adoptive therapy of cytotoxic T-cells (CTL) against leukaemia-specific antigens, minor histocompatibility antigens, or T-cell receptor genes may constitute successful approaches to induce anti-tumour effects. Clinically, a significant GVL effect is induced by chronic rather than acute graft-versus-host disease (GVHD). An anti-tumour effect has also been reported for myeloma, lymphoma and solid tumours. Reduced intensity conditioning enables HSCT in older and disabled patients and relies on the graft-versus-tumour effect. Donor lymphocyte infusions promote the GVL effect and can be given as escalating doses with response monitored by minimal residual disease. A high CD34+ cell dose of peripheral blood stem cells increases GVL. There is a balance between effective immunosuppression, low incidence of GVHD and relapse. For instance, T-cell depletion of the graft increases the risk of relapse. This paper reviews the current knowledge in graft-versus-cancer effects. Future directions, such as immunotherapy using leukaemia-specific CTLs, allo-depleted T-cells and suicide gene manipulated T-cells, are presented.
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PMID:The allogeneic graft-versus-cancer effect. 1973 62

Efforts to develop curative treatment strategies for chronic lymphocytic leukemia (CLL) in recent years have focused on allogeneic stem cell transplantation (alloSCT). The crucial anti-leukemic principle of alloSCT in CLL appears to be the immune-mediated anti-host activities conferred with the graft (graft-versus-leukemia effects, GVL). Evidence for GVL in CLL is provided by studies analyzing the kinetics of minimal residual disease on response to immune modulation after transplantation, suggesting that GVL can result in complete and durable suppression of the leukemic clone. AlloSCT from matched related or unrelated donors can overcome the treatment resistance of poor-risk CLL, ie, purine analogue refractory disease and CLL with del 17p-. Even with reduced-intensity conditioning, alloSCT in CLL is associated with significant mortality and morbidity due to graft-versus-host disease, which has to be weighed against the risk of the disease when defining the indication for transplantation. Therefore, it can be regarded as a reasonable treatment option only for eligible patients who fulfill accepted criteria for poor-risk disease. If alloSCT is considered, it should be performed before CLL has advanced to a status of complete refractoriness to assure an optimum chance for a successful outcome. Prospective trials are underway to prove whether allo-SCT can indeed change the natural history of poor-risk CLL.
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PMID:Allotransplantation for chronic lymphocytic leukemia. 2000 45

A total of 50 consecutive patients (median age, 57.5 years) with AML (n=30) or myelodysplasia (MDS, n=20) underwent HLA matched related donor (MRD, n=27) or unrelated donor (MUD, n=23) peripheral blood hematopoietic cell transplantation after nonmyeloablative CY/fludarabine (Flu) conditioning. GVHD prophylaxis included CsA (n=19)+/-mycophenolate mofetil (n=31). At a median follow-up of 59 months, 21 patients (42%) were alive without evidence of disease. By Kaplan-Meier analysis, year 1-4 disease-free survival (DFS) and OS estimates were 0.50/0.58, 0.40/0.46, 0.37/0.43 and 0.37/0.41. MUD recipients were engrafted quickly (13.5 days) compared to MRD recipients (16 days) and relapsed/progressed less frequently (P=0.005). Overall grade 3/4 acute GVHD (aGVHD) occurred in 26% in the absence of antecedent mucositis and was associated with chronic GVHD (cGVHD) and poor OS. Extensive cGVHD developed in 51.2% of 100 day survivors. Rates of aGVHD, cGVHD and survival were similar between MRD and MUD recipients. Of 14 survivors with cGVHD, 5 (35.7%) experienced resolution off immunosuppression, suggesting that tolerance with HLA matched grafts is possible at an advanced age by this method. This study provides further evidence for prolonged DFS after CY/Flu MRD allotransplantation for AML/MDS, and extends the findings to older patients and those with unrelated donors.
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PMID:Long-term disease-free survival after nonmyeloablative cyclophosphamide/fludarabine conditioning and related/unrelated allotransplantation for acute myeloid leukemia/myelodysplasia. 2006 92

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is increasingly being used for treatment of hematologic malignancies, and the immunologic graft-versus-tumor effect (GVT) provides its therapeutic effectiveness. Disease relapse remains a cause of treatment failure in a significant proportion of patients undergoing alloHSCT without improvements over the last 2-3 decades. We summarize here current data and outline future research regarding the epidemiology, risk factors, and outcomes of relapse after alloHSCT. Although some factors (eg, disease status at alloHSCT or graft-versus-host disease [GVHD] effects) are common, other disease-specific factors may be unique. The impact of reduced-intensity regimens on relapse and survival still need to be assessed using contemporary supportive care and comparable patient populations. The outcome of patients relapsing after an alloHSCT generally remains poor even though interventions including donor leukocyte infusions can benefit some patients. Trials examining targeted therapies along with improved safety of alloHSCT may result in improved outcomes, yet selection bias necessitates prospective assessment to gauge the real contribution of any new therapies. Ongoing chronic GVHD (cGVHD) or other residual post-alloHSCT morbidities may limit the applicability of new therapies. Developing strategies to promptly identify patients as alloHSCT candidates, while malignancy is in a more treatable stage, could decrease relapses rates after alloHSCT. Better understanding and monitoring of minimal residual disease posttransplant could lead to novel preemptive treatments of relapse. Analyses of larger cohorts through multicenter collaborations or registries remain essential to probe questions not amenable to single center or prospective studies. Studies need to provide data with detail on disease status, prior treatments, biologic markers, and posttransplant events. Stringent statistical methods to study relapse remain an important area of research. The opportunities for improvement in prevention and management of post-alloHSCT relapse are apparent, but clinical discipline in their careful study remains important.
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PMID:NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. 2039 76

Relapse of pediatric acute lymphoblastic leukemia (ALL) remains the main cause of treatment failure after allogeneic stem cell transplantation (alloSCT). A high level of minimal residual disease (MRD) before alloSCT has been shown to predict these relapses. Patients at risk might benefit from a preemptive alloimmune intervention. In this first prospective, MRD-guided intervention study, 48 patients were stratified according to pre-SCT MRD level. Eighteen children with MRD level >or=1 x 10(-4) were eligible for intervention, consisting of early cyclosporine A tapering followed by consecutive, incremental donor lymphocyte infusions (n=1-4). The intervention was associated with graft versus host disease >or=grade II in only 23% of patients. Event-free survival in the intervention group was 19%. However, in contrast with the usual early recurrence of leukemia, relapses were delayed up to 3 years after SCT. In addition, several relapses presented at unusual extramedullary sites suggesting that the immune intervention may have altered the pattern of leukemia recurrence. In 8 out of 11 evaluable patients, relapse was preceded by MRD recurrence (median 9 weeks, range 0-30). We conclude that in children with high-risk ALL, immunotherapy-based regimens after SCT are feasible and may need to be further intensified to achieve total eradication of residual leukemic cells.
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PMID:Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation. 2053 48

The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK) with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes; amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine 25 mg/m(2) or a single dose of cyclophosphamide 1,000 mg/m(2), 2 subcutaneous injections of alpha interferon (IFN) 3 x 10(6) and COX2 inhibitors, followed by administration of IMAK (65 +/- 5 CD3(+)CD56(-); 17 +/- 5 CD3(-)CD56(+)) in conjunction with low dose subcutaneous rIL-2 (6 x 10(6) IU/m(2)/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of 21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors, preferably at a stage of minimal residual disease with the goal in mind to eradicate all malignant cells at an early stage of the disease.
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PMID:Immunotherapy in high-risk chemotherapy-resistant patients with metastatic solid tumors and hematological malignancies using intentionally mismatched donor lymphocytes activated with rIL-2: a phase I study. 2056 4

Haematopoietic stem cells transplantation, widely used these last decades, represent the ultimate treatment resource for patients with haematological malignancies. Long range success of this treatment is particularly affected by relapse of the initial disease, graft rejection or graft versus host disease. Chimerism analysis after transplantation had been used since several years to document engraftment, to determine the risk of relapse and to adapt therapy promptly when necessary. Usefulness of this analysis for the outcome of transplanted patients, as well as the impact of using high sensitive techniques coupled with specific cell populations sorted have been demonstrated by retrospective studies. Follow-up of chimerism would allow to operate efficiently before the onset of clinical signs in leukaemic patients with high risk of relapse and to control the expression of minimal residual disease when specific molecular markers could not be monitored.
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PMID:[Chimerism analysis after allogeneic haematopoietic stem cell transplantation. Interest of cell sorting: general review]. 2112 7

A retrospective analysis identified 161 consecutive adults with acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) with full-intensity (myeloablative) conditioning between 1998 and 2006. Median patient age was 36.1 years. Seventy-six patients were in first complete remission (CR1), and 85 were in second or greater CR or in relapse. Fifty-nine patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. A total of 159 patients received chemotherapy plus total body irradiation for conditioning. Graft-versus-host disease prophylaxis included a calcineurin inhibitor plus methotrexate or mycophenolate mofetil. Sixty of the donors were related, and 101 were unrelated. A total of 110 patients received granulocyte-colony stimulating factor-stimulated peripheral blood, 47 received bone marrow, and 4 received cord blood as the stem cell source. Fifty-five patients relapsed at a median of 231 days after transplantation. The estimated 5-year probabilities of relapse-free survival, relapse, and nonrelapse mortality were 47%, 30%, and 29%, respectively. By multivariate analyses, transplantation while in CR1 was the most important predictor of successful transplantation. Pretransplantation evidence of minimal residual disease, especially as detected by flow cytometric analysis, was associated with both lower overall survival and lower relapse-free survival. Compared with a similar cohort of patients undergoing transplantation between 1990 and 1997, overall survival was similar for patients undergoing transplantation in CR1, with lower nonrelapse mortality being offset by higher rates of relapse in patients who underwent transplantation more recently.
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PMID:Allogeneic hematopoietic cell transplantation with full-intensity conditioning for adult acute lymphoblastic leukemia: results from a single center, 1998-2006. 2118 75

Dendritic cells (DCs) are a heterogeneous population of antigen-presenting cells derived from hematopoietic progenitors that bridge the transition between the innate and adaptive immune responses, while maintaining self-tolerance and Th1/Th2 homeostasis, by priming other cells in either an immunogenic or tolerogenic direction. Through their role in both innate and adaptive immunity, DCs play a major part in transplant engraftment and rejection and in graft-versus-host disease (GvHD). Preferentially tolerogenic or immunogenic DC subtypes offer targets for immunotherapy, to optimize transplant success rates and prolong disease-free and overall survival. Cord blood DCs are immature and preferentially tolerogenic, due to maternal-fetal tolerance, leading to better graft acceptance and immune reconstitution and explaining the lower incidence and severity of GvHD in CB transplantation, despite donor-host mismatching. Manipulation of DC maturation and cell loading with tumor-antigens can direct antitumor immunity and target minimal residual disease, as demonstrated for acute myeloid leukemia, optimizing the graft-versus-leukemia effect.
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PMID:Dendritic cells in cord blood transplantation: a review. 2177 81


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