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)

The goal of this study was to investigate the association of natural killer (NK) cell recovery with clinical outcomes after unmanipulated haploidentical blood and marrow transplantation. We sequentially monitored the reconstitution kinetics of circulating NK cells, CD56(bright) and CD56(dim), in 43 patients by flow cytometry, and the functionality recovery of cytokine or cytotoxicity of NK cells by flow cytometry or lactate dehydrogenase release assay after transplantation. Reconstitution of NK cells was rapid but accompanied by skewing of cell subsets mainly in CD56(bright), which recovered earlier. Linear regression analysis demonstrated that dose of CD34(+) cells in the allografts was inversely correlated with the ratio of T/NK cells (beta = -0.506, P = .003) and CD56(dim)/CD56(bright) cell (beta = -.403, P = .018) by day 14 after hematopoietic stem cell transplantation (HSCT), and the dose of CD3(+) T cells in the allografts was also inversely correlated with the ratio CD56(dim)/CD56(bright) cells by day 14 after HSCT (beta = -0.474, P = .005). Moreover, the dose of CD56(dim) NK cells in the allograft was positively associated with the day 14 CD56(brigh) NK cells (beta = 0.494, P = .032) and inversely correlated with the day 14 ratio of CD56(dim)/CD56(bright) cells (beta = -0.617, P = .005). Compared with nonacute graft-versus-host disease (GVHD) patients, patients with acute GVHD (aGVHD) had a higher level of NK subsets during week 2 posttransplantation. Cox regression analysis revealed that the patients with more CD56(bright) NK cells in the recovery stage had a higher survival rate (hazard risk [HR], 0.406; P = .017) and the patients with a higher ratio of T/NK (>1.0) had a higher chance of getting aGVHD (HR, 3.436; P = .059) and chronic GVHD (HR, 3.925; P = .028). Our results suggest that the recovery of NK cells is and can be used as an indicator to predicate the clinical outcomes after unmanipulated haploidentical transplantation.
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PMID:Effects of the NK cell recovery on outcomes of unmanipulated haploidentical blood and marrow transplantation for patients with hematologic malignancies. 1827 99

Allogeneic stem cell transplantation (SCT) with reduced-intensity conditioning (RIC) has the potential to lead to long-term remissions for patients with lymphoma. However, the role of RIC SCT in the treatment of lymphoma is still unclear. Specifically, the relative benefit of RIC SCT across lymphoma histologies and the prognostic factors in this population are incompletely defined. We retrospectively analyzed the outcomes of 87 patients with advanced lymphoma who underwent RIC SCT at the Dana-Farber Cancer Institute over a 6-year period with a homogeneous conditioning regimen consisting of fludarabine and low-dose busulfan. Thirty-six patients had Hodgkin disease (HD) and 51 had non-Hodgkin lymphoma (NHL). Sixty-eight percent had undergone prior autologous transplantation. The 1-year cumulative incidence of nonrelapse mortality was 13%, and the 3-year cumulative incidence of progression was 49%. The incidence of grade 3-4 acute GVHD was 11%. The 2-year cumulative incidence of chronic GVHD was 68%, and its development was associated with a decreased risk of progression and an improved progression-free survival (PFS). Three-year overall survival (OS) was 56% for patients with HD, 81% for indolent NHL, 42% for aggressive NHL, and 40% for mantle cell lymphoma. The corresponding figures for 3-year PFS were 22%, 59%, 22%, and 30%, respectively. Multivariate analysis identified elevated pretransplantation lactate dehydrogenase (LDH) as an adverse factor for PFS, while indolent NHL histology was favorable. For OS, advanced age and elevated pretransplantation LDH were adverse factors, whereas indolent NHL histology was favorable. Low early donor chimerism was not predictive of poor outcome in univariate or multivariate analyses. Moreover, progression was not associated with loss of chimerism. These results emphasize the importance of lymphoma histology for patients undergoing RIC SCT, as well as the lack of relevance of donor chimerism for outcome in this patient population.
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PMID:Allogeneic transplantation with reduced-intensity conditioning for Hodgkin and non-Hodgkin lymphoma: importance of histology for outcome. 1834 84

Each year in the US, more than 10 000 patients benefit from allogeneic haematopoietic stem cell transplantation (HSCT), a modality that offers an excellent chance of eradicating malignancy but confers a higher risk of treatment-related mortality. An uncommon but devastating consequence of HSCT is transplantation-associated thrombotic microangiopathy (TA-TMA). The incidence of TA-TMA ranges from 0.5% to 76%, with a mortality rate of 60-90% despite treatment. Although there appears to be a consistent treatment approach to idiopathic thrombotic thrombocytopenic purpura (TTP) using plasma exchange, corticosteroids and rituximab, the treatment strategies for TA-TMA are perplexing, in part, because the literature regarding this complex condition does not provide true consensus for incidence, aetiology, diagnostic criteria, classification and optimal therapy. The classic definition of idiopathic TTP includes schistocytes on the peripheral blood smear, thrombocytopenia and increased serum lactate dehydrogenase. Classic idiopathic TTP has been attributed to deficient activity of the metalloproteinase responsible for cleaving ultra-large von Willebrand factor multimers. This protease is a member of the 'a disintegrin and metalloprotease with thrombospondin type 1 motif' family and is subsequently named ADAMTS-13. Severely deficient ADAMTS-13 activity (<5% of normal) is associated with idiopathic TTP in 33-100% of patients. In constrast to the pathophysiology of idiopathic TTP, patients with TA-TMA have >5% ADAMTS-13 serum activity. These data may explain why plasma exchange, a standard treatment modality for idiopathic TTP that restores ADAMTS-13 activity, is not effective in TA-TMA. TA-TMA has a multifactorial aetiology of endothelial damage induced by intensive conditioning therapy, irradiation, immunosuppressants, infection and graft-versus-host disease. Treatment consists of substituting calcineurin inhibitors with an alternative immunosuppressive agent that possesses another mode of action. One candidate may be daclizumab, especially in those with mild to moderate TMA. Rituximab therapy or the addition of defibrotide may also be beneficial. In general, plasma exchange is not recommended.
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PMID:Thrombotic microangiopathy in haematopoietic stem cell transplantation: diagnosis and treatment. 1922 75

Low CD34 + cell doses increase allograft-related mortality and very high doses increase the risk of graft-versus-host disease. The optimum CD34 + cell dose remains undefined. The effect of the CD34 + cell dose based on ideal weight was analyzed in 130 patients with hematologic malignancies undergoing reduced-intensity allogeneic blood cell transplantation in the context of factors known to affect the outcome: chemosensitivity, donor age, lactate dehydrogenase (LDH), human leukocyte antigen (HLA) match, performance status, and platelet count. The survival of patients receiving >8 x 10(6)/kg CD34 + cells was not significantly different from those receiving <6. The outcome of those receiving 6-8 x 10(6)/kg CD34 + cells was significantly better than the rest. This superiority was confirmed in multivariable analysis. Among patients receiving <or=8 x 10(6)/kg CD34 + cells, an increasing number of infused cells was associated with higher overall survival in a continuous fashion (Risk ratio (RR) 0.8759; p = 0.045). Cell dose based on actual weight did not correlate with survival. The number of CD34 + cells infused, a potentially modifiable factor, affects survival after reduced-intensity allogeneic transplantation. We recommend a CD34 + cell dose of 6-8 x 10(6) per kg ideal body weight to optimize outcome. The possible adverse effect of higher cell doses (>8) needs further confirmation.
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PMID:Optimizing the CD34 + cell dose for reduced-intensity allogeneic hematopoietic stem cell transplantation. 1967 77

Previous reports have suggested that a high serum cyclosporine A (CsA) level could result in a lower incidence of acute-graft-versus-host disease (aGVHD). An elevated serum lactate dehydrogenase (LDH) level has been reported to be an adverse predictor of outcome in stem cell transplantation (SCT) for acute myeloid leukemia. In this study, we retrospectively analyzed the records of 24 patients who received allogeneic SCT from an HLA-matched sibling donor for acute and chronic myelogenous leukemia. Univariate analysis showed that two factors (the serum CsA level at the third week after SCT and the LDH level at the third week after SCT) were significantly associated with the incidence of aGVHD among several variables (age, sex, stem cell source, cell dose, C-reactive protein, absolute lymphocyte count, conditioning regimens, and time to engraftment). A higher serum level of CsA and lower serum LDH level at the third week after SCT were associated with a lower incidence of aGVHD (P=0.015, 0.030). In multivariate analysis, the serum CsA level (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.022-0.652, P=0.0014) and serum LDH level (HR, 6.59; 95% CI, 1.197-36.316, P=0.030) at the third week after SCT were found to be independent factors that were significantly associated with the development of aGVHD. We conclude that a high CsA level and low LDH level might predict a low cumulative incidence of aGVHD after allogeneic transplantation from a matched sibling donor.
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PMID:Influence of lactate dehydrogenase and cyclosporine A level on the incidence of acute graft-versus-host disease after allogeneic stem cell transplantation. 1965 32

Factors predictive of response to plasma exchange (PE) in treatment of transplantation-associated thrombotic microangiopathy (TA-TMA) are generally poorly understood. To determine any clinical or laboratory factors predictive of response to PE in treatment of TA-TMA, we retrospectively reviewed all 11 cases of TA-TMA treated with PE at out institution between December 2001 and March 2008. Response to PE was correlated with associated clinical conditions, grade of TA-TMA, TA-TMA index and lactate dehydrogenase (LDH) level at diagnosis. Overall response to PE was 27%, with three complete responses (CRs) and eight non-responses (NRs) seen. Response to PE was significantly associated with the absence of acute GVHD at TA-TMA diagnosis, with three CR in four patients without active acute GVHD, and NR in seven patients with acute GVHD (P=0.024). There was no significant association seen between response to PE grade of TA-TMA (P=0.179), TA-TMA index (P=0.25) or LDH measurements (P=0.31). Our experience in use of therapeutic PE for management of TA-TMA suggests that PE may indeed be effective in the treatment of this disorder, depending on the clinical circumstance in which it develops. PE is potentially efficacious in the absence of active acute GVHD, and ineffective when acute GVHD is manifest.
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PMID:Transplantation-associated thrombotic microangiopathy: effect of concomitant GVHD on efficacy of therapeutic plasma exchange. 1976 87

For patients with acute myelogenous leukemia (AML) who are unable to secure an acceptable HLA donor, the role of autologous stem cell transplantation (auto-SCT) has remained controversial. Its effectiveness remains unclear as, when analyzed on intention-to-treat strategies, a significant number do not undergo the procedure, whereas others seem to fail therapy from pretransplant recurrences. To improve our counseling to our patients on these 2 therapeutic options, we compared the outcome of patients in first remission of AML who actually underwent autologous or allogeneic transplantation. The choice for the type of graft was based on availability of HLA identical siblings. Patients received myeloablative conditioning followed by allogeneic or autologous cytokine mobilized peripheral blood stem cell transplantation. For prophylaxis of graft-versus-host disease (GVHD), grafts were incubated ex vivo with anti-CD52 antibodies and patients were prescribed cyclosporin until day 90. Patients were stratified by clinical and laboratory factors as well as cytogenetic risk. The endpoints were treatment-related mortality (TRM), disease-free survival (DFS), and overall survival (OS). The median presentation age for both transplant groups was 35 (14-60) years. Of the 112 consecutive patients achieving remission, autologous or allogeneic grafts were transplanted to 43 and 32 patients, respectively. There was no significant difference in the presentation clinical features, laboratory parameters, marrow morphology, or proportion of low and intermediate cytogenetic risk for both transplant options. Treatment mortality as well as relapse rate was similar (14% and 15%; 39% and 27%, respectively). At a median of 1609 and 1819 posttransplant days, 56% and 63% in each group survived. In univariate analysis performance status, cytogenetic risk, morphologic features of dysplasia, blast count, and lactate dehydrogenase (LDH) were significant factors for survival. Although for the entire group there was no difference in survival between both modalities, all patients with unfavorable cytogenetics receiving an autologous graft died of disease recurrence (3-year survival 35% versus 0%; P = .05). We conclude that patients with AML who have low or intermediate cytogenetic risk undergoing myeloablative conditioning followed by autologous or allogeneic T cell-depleted stem cell transplantation appeared to have similar outcome. However, those with unfavorable karyotype are unlikely to be cured with autologous grafts and are candidates for experimental modalities.
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PMID:Is there a role for autologous stem cell transplantation for patients with acute myelogenous leukemia? A retrospective analysis. 2087 30

Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication caused by the aggregation of platelets exposed to the thrombogenic subendothelial matrix of injured endothelial cells. Here, we present a case of a patient transplanted for idiopathic aplastic anemia with a T-cell depleted hematopoietic stem cell graft from an HLA-C mismatched unrelated donor. At day 7 posttransplant, she suffered from acute renal failure with hematuria. The presence of numerous schistocytes, an increased level of lactate dehydrogenase and a renal biopsy with multiple vascular injuries confirmed the diagnosis of severe TA-TMA. At day 14, she developed graft versus host disease and died 7 months posttransplantation of multiorgan failure. At day 15, we observed a sizable population of natural killer (NK) cells in the peripheral blood, the number of which reached 0.8 G/L at 4 months posttransplant. Most NK cells lacked inhibitory killer immunoglobulin-like receptors (KIR) specific for the KIR-ligands expressed in the patient. NK cells were also abundantly present in pericardial and pleural fluids and had invaded the kidney, where they colocalized with the renal vasculopathy. Because there are several mechanisms through which NK cells and platelets can activate each other reciprocally, it is conceivable that NK cells contribute to TA-TMA and its progression.
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PMID:Do NK cells contribute to the pathophysiology of transplant-associated thrombotic microangiopathy? 2171 46

Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplant (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight patients with advanced lymphoma underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporine-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years was 25% (95% confidence interval [CI]: 13-40%) and 44% (95% CI: 28-59%), respectively. Previous high-dose therapy and autologous stem cell transplant (HDT-ASCT) and elevated lactate dehydrogenase (LDH) at the time of allo-SCT resulted in inferior OS. Within this cohort of patients with high-risk lymphoma, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of progression of disease, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT.
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PMID:A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies. 2452 16

The role of allogeneic stem cell transplantation (SCT) in the management of aggressive non-Hodgkin lymphoma (NHL) remains to be defined, but the number of procedures performed continues to increase. We report here the outcomes of allogeneic SCT using carmustine, etoposide, cytarabine, and melphalan (BEAM)-Campath (Genzyme Corporation, Cambridge, MA) conditioning for aggressive NHL as reported to the British Society of Blood and Marrow Transplantation (BSBMT). This retrospective study identified 46 patients who reported to the BSBMT registry as having undergone BEAM-Campath conditioned allogeneic SCT for aggressive NHL between 1999 and 2010. Disease histology was diffuse large B cell lymphoma (DLBCL, n = 25), DLBCL/Burkitt lymphoma (n = 5), and T cell lymphoma (n = 16). At diagnosis, the median age was 42.5 (range, 17 to 59), 37 had advanced stage disease (Ann Arbor III/IV), 28 had 2 or more extra-nodal sites of disease, and 23 had elevated lactate dehydrogenase. International prognostic index was high or high/intermediate in 58%. The median number of prior therapies was 3 (range, 1 to 5) and 5 patients had previously undergone transplantation (4 autologous, 1 allogeneic). The median age at transplantation was 44.8 (range, 18 to 59), with 34 patients demonstrating chemo-sensitive disease and 22 undergoing transplantation in first response. Performance score was good in 40 patients and all engrafted with a median of 14 days (range, 11 to 27) to neutrophil recovery. At latest follow-up, 20 patients were alive with 17 in complete remission. Acute graft-versus-host disease (GVHD) developed in 7 patients and chronic GVHD developed in 13 (7 limited, 6 extensive). Five patients died from nonrelapse causes, with a cumulative incidence of nonrelapse mortality of 7% at 100 days and 11% at 3 and 5 years. Twenty-one patients died after lymphoma relapse, with a cumulative incidence of relapse/progression of 51% at 1 year and 53% at 5 years. Disease status at transplantation had no impact on relapse rate. Progression-free survival was 41% at 1 year and 36% at 5 years. Overall survival was 54% at 1 year and 42% at 5 years. Overall, BEAM-Campath-conditioned allogeneic SCT is well tolerated and able to deliver durable disease-free survival to a subset of patients with aggressive NHL. However, the high relapse rates indicate further investigation is needed to identify those patients most likely to benefit.
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PMID:Carmustine, etoposide, cytarabine, and melphalan (BEAM)-campath allogeneic stem cell transplantation for aggressive non-hodgkin lymphoma: an analysis of outcomes from the British Society of Blood and Marrow Transplantation. 2549 Jan 80


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