- Allogeneic stem cell transplantation for non-malignant diseases
- Login using
- Department of Oncology & Metabolism
- 1. Introduction
The data were first confirmed by the reporting team, which received a computer printout of the entered data. Selective comparison also was used with Med-A data sets in the European Group for Blood and Marrow Transplantation Promise data system or by cross-checking with national registries.
Onsite visits of selected teams were part of the quality-control program within the Center for International Blood and Marrow Transplantation and the European Group for Blood and Marrow Transplantation. No formal response rate can be evaluated for the other participating countries; there is no formal regulatory framework for cross-confirmation. For autologous HSCT, no formal framework exists to capture nonreporting teams and to validate response rates with accuracy.
Information on additional transplants eg, retransplants or multiple HSCTs 21 was not included. Transplant rates were computed as the number of HSCTs per 10 million inhabitants. Population data were obtained from the US census office.
Allogeneic stem cell transplantation for non-malignant diseases
Team density refers to the number of transplant teams per 1 million inhabitants. Transplant rates within the reporting participating countries were compared with a range of macroeconomic health care indicators: gross national income per capita; total health care expenditures; governmental health care expenditures; adult, infant and maternal mortality rate; number of hospital beds per capita; cesarean delivery rates; human developmental index, which is a composite index reflecting the developmental status of all countries in the world in a scale from 0 to 1.
Data from were used for all comparisons whenever possible. The association of the macroeconomic factors with HSCT rates was estimated by single linear and multiple linear regression analysis, using the least squares method. The goodness of fit was measured using the coefficient of determination r 2. For the single and multiple linear regression analyses, the dependent variables were transformed to point out the linear associations.
In the multiple regression analyses, all factors were assessed for their multicollinearity. Taiwan and Hong Kong were excluded from the multiple economic comparisons because of missing information on governmental health care expenditures. Cesarean delivery rates were included in the single linear analyses but not the multiple regression analyses, because data from too many countries were missing. All statistical analyses were performed with EViews version 5.
The median HSCT rates varied between the continental regions and between participating countries from Transplant rates for allogeneic HSCT ranged from The first factor in the multiple linear regression analysis, government health care expenditure GOV , explained The second factor, team density TD , increased R 2 to All other factors, including the human development index, became insignificant, mainly due to multicollinearity with gross national income per capita, meaning that several factors did correlate highly with each other.
Therefore, the equation of the multiple regressions was. It describes the achievements, illustrates the major differences, and points to the key needs. Transplant activity is concentrated in countries with higher governmental health care expenditures, higher gross national income per capita, and higher team density. Hence, availability of resources, governmental support, and access to a transplant center are the key factors related to regional HSCT activity.
However, disease prevalence can differ between regions and could contribute to differences in HSCT rates; those data were not included in this report. The close link of HSCT rates with gross national income per capita was recognized many years ago; HSCT is an expensive procedure with a substantial investment for a single patient. However, gross national income per capita explained only parts of the variations. Therefore, we were specifically interested in other macroeconomic factors associated with HSCT rates.
These factors were chosen with intention. They were either directly linked to availability of resources gross national income per capita, health care expenditures , to governmental support governmental health care expenditures , or to the overall infrastructure in a country human development index. Others reflect quality measures of the health care system mortality rates or indicate potential overuse of the health care system hospital beds, cesarean delivery.
Of all macroeconomic factors, this study identified governmental health care expenditures as the most closely associated factor with HSCT rates. Our study could not assess the role of the health care system in the participating countries because there is no globally accepted definition available. Definitive explanations cannot be given, but some assumptions can be made. The cost-effectiveness of HSCT compared with conventional treatment has at least recently been discussed for patients with chronic myeloid leukemia in middle-income countries.
There was no indication for saturation in this association. Hence, a minimum number of transplant teams per inhabitants must be available so that patients have sufficient access. It does not appear that transplant teams overuse their infrastructure. There were significant differences between the regions concerning indications and donor type, with fewer autologous HSCTs in Asia and the Eastern Mediterranean and Africa than in the Americas and Europe.
There also were more HLA identical sibling donor HSCTs for congenital disorders or for aplastic anemia in countries with limited resources.
A matched sibling donor HSCT might represent the most efficient way of therapy for a patient with aplastic anemia, thalassemia, or severe combined immunodeficiency in a country with some but still limited resources. No induction, consolidation chemotherapy is needed as would be the case for patients with acute leukemia. There are some limitations of this study that warrant caution in interpretation.
The organizations collecting the data had neither legal enforcement to obtain nor the possibility to control all data locally for accuracy and completeness. A few countries choose not to report any data. Most missing information relates to numbers of autologous HSCTs because they are performed in some countries outside of the realm of national transplant organizations and in nonuniversity institutions. Despite these limitations, the main observations of this study regarding the main indications, donor type, transplant rates, and associations with macroeconomic factors should remain valid.
Finally, we had neither information on outcome of the transplant procedures nor on correctness of the indication; this is beyond the scope of this study and would require a much longer follow-up time. This study was in part triggered by the increasing awareness by scientific and health care organizations, including the World Health Organization, to address key aspects of cell, tissue, and organ transplantation on a global level. In contrast to solid organ transplantation, HSCT faces limitations other than donor organ shortage.
In addition to traditional HSCT, novel treatment forms with hematopoietic stem cells for nonhematopoietic use or transplantation of nonhematopoietic stem cells for organ and tissue repair are under investigation. In conclusion, this global overview on HSCT activity demonstrates that it is an accepted therapy worldwide, with different needs and priorities in different regions.
Department of Oncology & Metabolism
Transplant activity is concentrated in countries with higher health care expenditures, higher gross national income per capita, and higher team density; hence, the availability of resources, governmental support, and access to a transplant center determine regional HSCT activity. If signs of extravascular hemolysis occur in the post-transplant course after D-mismatched HSCT, one should consider de novo D immunization and apply supportive care accordingly. It is more frequently observed in the constellation of group A donors in group O recipients and results from the presence of recipient-derived residual B lymphocytes or plasma cells which produce isohemagglutinins directed against donor RBCs.
Pre-transplant reduction of host anti-donor isohemagglutinins either by plasma exchange or immunoadsorption, or application of donor type packed RBCs, is reported to reduce the risk of PRCA [ 16 , 26 ]. Since the incidence of PRCA is relatively low and spontaneous remissions are observed in a number of patients, a post-transplant prophylactic treatment of all major ABO-mismatched allogeneic HSCT recipients is not recommended [ 27 ].
If anti-donor isohemagglutinins persist for more than 60 days after HSCT, the probability of spontaneous clearance is low.
- ABO-Mismatched Allogeneic Hematopoietic Stem Cell Transplantation.
- Subscribe to our Newsletter!
- The Depths of Courage: American Submariners at War with Japan, 1941-1945.
In such cases various treatment modalities to remove persisting isohemagglutinins have been described [ 28 ]. Those may include erythropoietin [ 29 ], plasma exchange or immunoadsorption [ 21 ], taper of immunosuppressive drugs, or administration of donor leukocyte infusions DLI [ 22 , 30 ].
In addition, the use of rituximab, a monoclonal antibody directed against CDpositive B cells, has been shown to be effective in some case reports [ 31 ]. Several registry and cohort studies demonstrate that the presence of anti-donor isohemagglutinins e. Despite it is known that ABO blood group antigens are also expressed on lymphocytes and platelets, no clear influence of ABO mismatch with regard to leukocyte and platelet recovery has been found [ 33 , 34 ].
In terms of platelet engraftment a meta-analysis of 7 cohort studies, the report for the JMDP, and other studies showed a delay in recovery for recipients of major ABO-incompatible grafts [ 6 , 37 , 38 ].
This phenomenon has previously been reported by other authors to be limited to major ABO-incompatible transplantation, who speculated that anti-donor isohemagglutinins bind to A or B antigens absorbed on the surface of neutrophils, platelets, or their precursors [ 32 ]. Remberger et al. In this study, 6 patients with graft failure were detected, including 4 of 67 major ABO mismatch and 2 of 16 bi-directional ABO mismatch cases. Five of 6 patients with graft failure had at least one HLA allele-mismatched donor, making it difficult to precisely ascribe the definitive role of ABO mismatch in this setting.
In the report of the JMDP an increased risk for secondary graft failure was observed in univariate analysis for patients receiving any kind of ABO-mismatched graft but these findings could not be confirmed in multivariate analysis [ 6 ]. In contrast to the results above, other studies have not found a higher risk of secondary graft failure in combination with ABO-mismatched transplantation, leading to the assumption that additional factors may have an influence on sustained engraftment [ 40 , 41 , 42 ].
As ABO antigens are not only expressed on blood cells but also on non-hematopoietic structures and tissue e.
However, results of published studies are conflicting table 2. Kimura et al. Their hypothesis is that epithelial cells of the large bile tract expressing ABO blood group antigens may be injured by donor-derived isohemagglutinins, thereby possibly increasing the incidence and severity of liver GVHD. On the contrary Seebach et al. In a study of Bacigalupo et al.
Keever-Taylor et al. Ludajic et al. Other publications did not observe any influence of ABO mismatch on the incidence of clinically significant acute GVHD [ 8 , 23 , 37 ]. None of the four large register studies which included RIC cases reported an effect of ABO mismatch on risk of malignant disease relapse [ 6 , 32 , 35 , 36 ]. In two of these studies data regarding relapse were even not reported as did most of the cohort studies table 2. Three studies showed an influence but with conflicting results.
Mehta et al.
The latter study included only RIC cases. In contrast Erker et al. Some authors assume that by using RIC regimens, any graft-versus-tumor effect may be more evident, resulting in different findings compared to myeloablative treatment protocols [ 11 , 42 ] table 2. As already discussed, the transplantation of ABO-mismatched grafts can cause severe immediate or delayed immune hemolytic reactions, leading to the death of the patient in the worst case.
Besides this complication which can be avoided by prophylactic actions in nearly all cases, no other consistent effect on transplant-related mortality has been found table 2. After the introduction of RIC regimens, some authors found an increased mortality for patients receiving ABO-mismatched grafts [ 6 , 36 , 42 , 49 ]. One possible reason is that myeloablative conditioning could obscure such an effect due to the higher toxicity [ 11 ]. However, results of cohort and registry studies are conflicting. Two registry studies found a higher risk for NRM in the RIC cohort, one of those also for major ABO-mismatched cases if myeloablative conditioning was applied [ 6 , 36 ], whereas some cohort studies observed an increased risk for patients after minor, major or bi-directional ABO-mismatched transplants [ 4 , 8 , 46 ] table 2.
Overall, 5, allogeneic transplants were performed using stem cells collected from the bone marrow 2, family; 2, unrelated , 16, with peripheral blood stem cells family; 10, unrelated and with cord blood stem cells 84 family; 1, unrelated.