| 1. |
- Remberger, Mats, et al.
(författare)
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Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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| 2. |
- Sairafi, Darius
(författare)
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Methods and biomarkers for outcome prediction after allogeneic hematopoietic stem cell transplantation
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Allogeneic hematopoietic stem cell transplantation (HSCT) is a potent immunotherapeutic procedure but its usability is limited by a high risk of serious complications. A prerequisite for timely initiation of preventive measures is the availability of predictive methods. This thesis aims to evaluate techniques that may potentially be used to assess the risk of some of these complications on the individual level. Defective function of the pattern recognition receptor NOD2, due to naturally occurring gene polymorphism, has been indicated as a risk factor for graft--‐versus--‐host disease (GVHD). We investigated the potential influence of NOD2 on clinical outcome after HSCT in a retrospective study of 198 patients. Contrary to previous reports, we found no association between NOD2 mutations and acute GVHD, transplant--‐related mortality (TRM) or overall survival. We conclude that NOD2 genotyping is not a pertinent analysis before HSCT. Leukemic relapse is a major cause of death after HSCT. Donor lymphocyte infusion (DLI) is one of the few therapeutic options remaining in these situations. Previous studies have shown varying results regarding treatment efficacy against acute leukemia. We aimed to investigate if the use of molecular techniques for relapse monitoring could improve the clinical outcome after DLI. Through retrospective analysis of 118 patients treated with DLI we showed that those with acute leukemia or myelodysplastic syndrome, who had received DLI based on the result of molecular methods, had a better survival rate than those treated during hematologic relapse (16% vs. 43%, p<0.006). Non--‐ hematological relapse and chronic GVHD were identified as independent predictors for response to DLI in multivariate analysis. The overall incidence of severe acute GVHD was only 8.5% and was acceptable (14%) in the cohort treated before 100 days post--‐HSCT. Our conclusion is that early administration of DLI to patients with acute leukemia, based on changes in cell lineage--‐specific chimerism and MRD analysis can significantly improve relapse--‐free survival after HSCT. Adaptive immunity is compromised after HSCT, mainly due to defective T--‐cell function. Reconstitution of the T--‐cell population is dependent on thymic function. We quantitatively assessed thymic function in 260 patients during a two--‐year period following HSCT. Levels of T--‐cell receptor excision circles (TRECs) in separated T--‐cells were measured with real--‐time quantitative PCR and used as a surrogate marker for thymic function. We found that low TREC levels 3--‐6 months after HSCT was correlated to inferior survival, increased TRM, and higher incidence of cytomegalovirus reactivation. We could also for the first time show that the use of bone marrow grafts and anti--‐thymocyte globulin had a negative effect on TREC levels, as did mesenchymal stromal cells when co--‐infused with umbilical cord blood grafts. We conclude that TREC analysis appears to have a high predictive value concerning outcome parameters after HSCT, and that factors related to the transplant procedure may significantly affect thymic function. Finally, we present the results of a prospective pilot study in which we sought to design a functional, individualized strategy for assessing the risk of acute GVHD. Peripheral blood mononuclear cells were collected from patients and donors before HSCT and co--‐cultured in a mixed lymphocyte reaction (MLR) in the GVHD direction. Cells were phenotypically characterized by flow cytometry before and after MLR. We found that donors corresponding to patients who later developed acute GVHD grades II–IV had significantly higher levels of γδ T--‐cells and NKT--‐cells in peripheral circulation. We could also demonstrate a possible correlation between a high proportion of naive CD4+ T--‐cells in the allogeneic MLRs and occurrence of acute GVHD in vivo. We conclude that flow cytometric analysis of donor cells for phenotype and allogeneic reactivity may be used to predict acute GVHD before HSCT.
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| 3. |
- Uhlin, Michael, et al.
(författare)
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Mesenchymal Stem Cells Inhibit Thymic Reconstitution After Allogeneic Cord Blood Transplantation
- 2012
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 21:9, s. 1409-1417
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Tidskriftsartikel (refereegranskat)abstract
- Cord blood (CB) as a source of stem cells has been a successful addition to the field of allogeneic stem cell transplantation (ASCT). The increased human leukocyte antigen (HLA) permissiveness of CB grafts has made it possible for more patients to undergo treatment. The drawback is that patients suffer from a longer period of compromised immunity. We analyzed T-cell receptor excision circles (TRECs), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels after cord blood transplantation (CBT) in 50 patients transplanted at our center. These immunological parameters were compared retrospectively with clinical factors and complications. We found that TREC levels after CBT were lower in adults, patients with myeloablative conditioning, and in patients with a lower nucleated cell dose in the graft. In addition mesenchymal stem cells (MSC) as co-infusion at the time of CBT had a negative effect on TREC reconstitution. This was found to be associated with decreased overall survival for this patient category. Reduced IgM and IgG levels post-CBT were associated with a major ABO mismatch, and infusion of MSCs. Our results highlight the importance of close monitoring of the immune reconstitution after CBT. In addition it shows a potentially new suppressive effect of MSCs on the immune system.
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