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Corresponding author. Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands. Tel.: +31-0-43-387-2029; fax: +31-0-43-387-5006.
Department of Internal Medicine, Section Hematology, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, the NetherlandsSchool for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands
Department of Internal Medicine, Section Hematology, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, the NetherlandsSchool for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands
Department of Internal Medicine, Section Hematology, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, the NetherlandsSchool for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands
Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the NetherlandsSchool for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the NetherlandsAlzheimer Center Limburg, Maastricht University Medical Center, Maastricht, the Netherlands
School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, the NetherlandsDepartment of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
Department of Internal Medicine, Section Hematology, Maastricht University Medical Center+, P. Debyelaan 25, 6229 HX, Maastricht, the NetherlandsSchool for Oncology and Developmental Biology (GROW), Maastricht University, Maastricht, the Netherlands
A cohort study with a large reference group matched on age, gender, and education representing the general population to study long-term adverse effects in hematopoietic stem cell transplantation (HCT) survivors.
•
The first study conducting extensive in-depth phenotyping in HCT survivors including assessment of relevant outcomes of cardiovascular, neurological, respiratory, and musculoskeletal diseases.
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HCT survivors and the reference group undergo the same measurements. The reference group enables detection of somatic diseases, mental disorders, and functional limitations that occur earlier or more frequently than expected.
Abstract
Objectives
The MOSA study (Maastricht Observational study of late effects after Stem cell trAnsplantation) aims to study the prevalence of adverse health effects in hematopoietic stem cell transplantation (HCT) survivors compared to a matched cohort, representing the general population.
Study Design and Setting
The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Participants of The Maastricht Study serve as a reference group matched on age, gender, and education to compare MOSA participants to the general population. In both studies, the same study protocol and extensive phenotyping measurements are used.
Results
HCT Survivors: Five hundred and thirty nine survivors were invited of which, so far, 123 (23%) participants completed the study assessments. Data will be analyzed and published separately. Reference Group: For each MOSA participant, four reference cases were matched. After matching, both groups are comparable with respect to age, gender, and education.
Conclusion
To our knowledge, this is the first study conducting such detailed phenotyping in HCT survivors. Comparison with a large reference group provides essential information about late effects of HCT and associated risk factors. This may improve screening and prevention strategies, potentially leading to a positive impact on morbidity, mortality, and quality of life.
The prevalence of a wide range of long-term adverse effects in hematopoietic stem cell transplantation (HCT) survivors compared to a large reference group including assessment of relevant outcomes of cardiovascular, neurological-, respiratory- and musculoskeletal diseases.
What this adds to what was known?
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Most data about long-term effects of stem cell transplantation are derived from large registries with limited collection of detailed post-transplant data on health and well-being. Our study used extensive in-depth phenotyping in HCT survivors including assessment of relevant outcomes of cardiovascular, neurological-, respiratory- and musculoskeletal diseases.
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Previous studies lacked comparison data derived from the general population. Our study used a large reference group matched on age, sex and education representing the general population allowing direct comparison.
What is the implication and what should change now?
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It enables detection of somatic diseases, mental disorders and functional limitations that occur earlier or more frequently than expected. This could improve screening and prevention strategies to help HCT survivors achieving the best possible outcome potentially leading to a positive impact in morbidity, mortality and quality of life.
1. Introduction
Hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for a wide range of hematological and nonhematological diseases. The number of transplants continues to rise over time, as a result of a growing number of indications and the introduction of reduced intensity conditioning regimens, making stem cell transplantation available for an increasingly broader range of patients. Also, more graft sources for hematopoietic stem cells have become available, including peripheral blood stem cells as an alternative to bone marrow stem cells [
]. As a consequence of more advanced HCT procedures and better supportive care, the long-term survival after HCT has improved substantially. Nowadays, treatment-related mortality of allogeneic transplantation ranges between 7% and 27% and treatment-related mortality of autologous transplantation ranges between 0% and 5%. Patients surviving for more than 2 years without evidence of relapse of the disease have a high probability of long-term survival after allogeneic HCT (80%–92%) and after autologous HCT (66%–87%) [
Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.
One and half million hematopoietic stem cell transplants (HSCT). Dissemination, trends and potential to improve activity by telemedicine from the Worldwide Network for Blood and Marrow Transplantation (WBMT).
These HCT survivors are at a risk of significant long-term health consequences associated with previous treatments and transplant procedures even if the primary disease has been cured [
National institutes of health hematopoietic cell transplantation late effects initiative: developing recommendations to improve survivorship and long-term outcomes.
]. The reasons for this may be diverse. HCT survivors are also at an increased risk of developing a number of subsequent morbidities, which can occur months, years, or even decades after treatment [
Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study.
National institutes of health hematopoietic cell transplantation late effects initiative: the cardiovascular disease and associated risk factors working group report.
Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study.
Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT.
Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years.
National Institutes of health hematopoietic cell transplantation late effects initiative: the immune dysregulation and pathobiology working group report.
Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long-term follow-up of a prospective study.
Ocular graft-versus-host disease after hematopoietic cell transplantation: expert review from the late effects and quality of life working committee of the center for international blood and marrow transplant research and transplant complications working party of the European society of blood and marrow transplantation.
]. Comorbidities as a result of high-dose chemotherapy or radiotherapy can occur in both procedures. In addition, HCT survivors may experience considerable emotional burden leading to an increased prevalence of depressive disorders, specifically in the first 5 years after transplantion [
Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS).
A thorough understanding of long-term health effects of HCT is important to improve follow-up care in survivors through better screening and prevention strategies for above-mentioned long-term complications, potentially leading to a positive impact on morbidity, mortality, and quality of life [
]. However, most data about long-term consequences of stem cell transplantation are derived from large registries with limited collection of detailed post-transplant information on health and well-being [
National institutes of health hematopoietic cell transplantation late effects initiative: the research methodology and study design working group report.
]. A major methodological limitation of previous studies is the lack of comparison data derived from the general population. This is important to distinguish between transplant-related and age-related problems and to investigate whether HCT survivors encounter more health problems than expected based on their chronological age [
National institutes of health hematopoietic cell transplantation late effects initiative: developing recommendations to improve survivorship and long-term outcomes.
The Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA) aims to investigate late complications (occurring >2 years after transplant) in HCT survivors by comparing them to a matched reference group, representing the general population. The study provides comprehensive information about the prevalence of a wide range of late adverse health effects in HCT survivors. The reference group enables detection of any diseases that occur more frequently or earlier than expected in life. This will provide a better direction for outpatient clinic follow-up of HCT survivors.
2. Study design and setting
2.1 Study population
The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Both studies use the same study protocol, infrastructure, research personnel, and measurements.
2.1.1 HCT survivors: the Maastricht Observational study of late effects after stem cell trAnsplantation (MOSA)
A central database that contains all HCTs carried out since 1990 and onwards at the Maastricht University Medical Centre (MUMC) is used to identify HCT survivors. From this database, individuals that fit the inclusion criteria of the MOSA study are selected. The MOSA study includes patients aged 18 years or older at the time of transplantation who survived more than 2 years after an allogeneic or autologous stem cell transplant and had no evidence of an active disease. HCT survivors with more than one transplant and patients who are unable to read and understand the Dutch language are excluded. A minimum survival of 2 years after transplant is required to minimize the risk of short-term disease-related and treatment-related morbidity and mortality and to allow late effects to be evaluable [
]. The study inclusions started in 2015 and are ongoing. We aim to include a total number of 200 participants. Eligible patients are actively invited to participate in the MOSA study by letter or directly by their hematologist during a hospital visit. The MOSA study (protocol number NL-48599) follows the principles of the Declaration of Helsinki and was approved by the Medical Ethical Committee of the MUMC (MEC 10-2-023).
2.1.2 Reference group: participants of The Maastricht Study
Participants of The Maastricht Study serve as a matched reference group to compare MOSA participants with the general population. Detailed information about this observational population-based cohort study has been described in a previously published design paper [
]. In short, The Maastricht Study is a large (n > 9,000) extensive phenotyping study to determine the health status in the general population and in participants with type two diabetes mellitus (T2DM). All individuals aged between 40 and 75 years and living in the southern part of The Netherlands are eligible for participation. Mass media campaigns and targeted strategies are used to recruit participants. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and The Netherlands Health Council under the Dutch “Law for Population Studies” (Permit 131088-105234-PG). All participants gave a written informed consent.
The MOSA participants and the reference group are matched at group-level at a 1:4 ratio based on age, gender, and education. Inclusion of the Maastricht study started in 2010 and is still ongoing. Data acquired in 2010–2013 are used to select the reference group. The Maastricht Study is, by design, enriched for patients with T2DM. To take this into account, the matching procedure is stratified on T2DM status, allowing a prevalence of 7% T2DM in the reference group, which is comparable to the prevalence in the general Dutch adult population [
MOSA and The Maastricht Study share the same study protocol and therefore the exact same extensive phenotyping measurements are used for both HCT survivors and the reference group. All MOSA participants are assessed at the research center of The Maastricht Study. Participation for detailed phenotyping involves three site visits of 4 hours each, plus two additional shorter visits. The full examination is completed within a time window of 3 months. With this extensive phenotyping approach (Figure 1), a broad range of relevant outcomes within the cardiovascular, neurological, respiratory, and musculoskeletal domains can be studied. In short, four clusters of determinants are covered in relation to the chronic diseases of interest: biomarkers, lifestyle, public health parameters, and disease specific factors. An overview of all measurements performed is described elsewhere [
]. This includes laboratory assessments, physical examinations, function tests, general and disease specific questionnaires, cognitive tests, and psychiatric assessments.
Fig. 1An advanced phenotyping approach is applied. The bottom of the figure shows main categories of determinants that are measured. The top of the figure presents the main clinical outcomes that are studied.
Reprinted with permission from Schram, M.T et al., The Maastricht Study: an extensive phenotyping study on determinants of type 2 diabetes, its complications, and its comorbidities. The European Journal of Epidemiology, 2014 29 (6): p. 439-451 [
3.1 Descriptive characteristics of HCT survivors and the reference group representing the general population
Characteristics of the study population and the reference group are presented using descriptive statistics. Continuous variables are presented as the mean with standard deviation for normally distributed variables and as the median with interquartile range for non-normally distributed variables. Discrete variables are presented as n (%). These data are presented in the current design paper and were calculated using Statistical Package for Social Science (SPSS) 25.
3.2 Statistical approach for future analyses
All statistical analyses that are planned for the MOSA study will be performed using SPSS. A P value less than 0.05 will be set to indicate a statistically significant difference in two-sided tests.
Crude differences between HCT survivors and the reference group will be assessed. For between-group comparisons of continuous characteristics, the independent sample t-test is used for normally distributed data and the Mann-Whitney test for non-normally distributed data. Differences in the frequency of discrete characteristics between groups are evaluated using the Chi-squared test.
Multivariable regression analyses will be used to evaluate the association between determinants and end points. This statistical method allows adjustment for the association of confounding variables. Besides the matching variables (age, gender, and education), other potential confounders will be taken into account. These include general health factors and lifestyle factors that might distort differences between HCT survivors and the reference group. Differences between groups in continuous scores and dichotomous outcomes will be evaluated using multiple linear and logistic regressions, respectively. Effect modification by age and gender will be tested by adding relevant interaction terms to the regression models.
4. Results: descriptive characteristics of the currently included study participants
4.1 HCT survivors: MOSA cohort
Currently, a total of 539 survivors all fulfilling the inclusion criteria, were invited to participate in the MOSA study, of whom 136 (25%) signed an informed consent. Of these participants, 123 (23%) fully completed the study assessments till now.
Most patients were diagnosed with lymphoid malignancies (n = 42; 34%), followed by multiple myeloma (n = 29; 24%), acute leukemia (n = 29; 24%), solid tumors (n = 8; 7%), chronic leukemia (n = 7; 6%), myeloproliferative neoplasm/myelodysplastic syndrome (MDS) (n = 7; 6%), and aplastic anemia (n = 1; 1%).
Most HCT survivors were treated with autologous HCT (n = 77; 63%).
The median age at the time of transplant was 51 years (range 19–69).
The median number of years after transplant is 7 years (range 2–25); 35% of participants were transplanted 2 to 5 years ago, 37% 6 to 10 years ago, 17% 11 to 15 years ago, and 11% more than 15 years ago.
The median age at the time of participation in the MOSA study is 61 years (range 23–75) (Table 1).
Table 1General characteristics of currently included HCT survivors and reference group
The study participants and the reference group were matched on age, gender, and level of education. Differences between both groups are not significant (P > 0.5).
4.2 Reference group: matched participants of The Maastricht Study representing the general population
For each MOSA participant, four participants of The Maastricht Study are matched on age group, gender, and level of education. For two MOSA participants, direct matching was not possible because of missing data about education. For these participants matching was based on age and gender, although education was randomly chosen. Seven MOSA participants (6%) were aged ≤40 years at the time of study participation. Direct matching by age group was therefore not possible. For this subgroup, the adjacent age category (41–50 years) was used.
After matching, both groups are comparable with respect to gender, education, and mean age at study participation (Table 1). The prevalence of T2DM in the matched cohort is 7.3%, similar to the prevalence in the general Dutch adult population.
5. Discussion
The MOSA study is a cohort study with a general population comparison sample to assess late effects in HCT survivors. These late or long-term effects of HCT are defined as effects on health that occur >2 years after transplant. The major methodological strength of this study is the use of a large reference group from the general population that is matched on age, gender, and level of education. Another strength is the shared study infrastructure that is used to phenotype both the HCT survivors and the matched reference group. All participants were thus phenotyped using the exact same techniques and study protocol, allowing direct comparisons. Moreover, the phenotyping protocols carried out are extensive, which allows for in-depth analyses of a broad range of relevant outcomes. This includes the presence of a subclinical disease. This design will enable us to evaluate late effects of HCT on survivors, such as overexpression of somatic diseases, mental disorders, and functional limitations. This study additionally makes it possible to explore underlying risk factors.
Also, the time after transplant is on average quite long, with a median of 7 years after transplant and a follow-up of >15 years after transplant in 11% of cases. Because this study focuses on late effects of treatment, this long time after follow-up is considered an advantage.
Some methodological aspects of the MOSA study warrant further discussion.
The extensiveness of available data comes with an increased risk of spurious findings. This risk is mitigated by focusing our analyses on relevant domains, using prespecified hypotheses and research questions.
The residential area of the MOSA participants does not exactly match with that of The Maastricht Study, although there is a substantial overlap. All HCTs were carried out at MUMC+, an HCT referral center for the southeastern part of The Netherlands, an area with about 2,000,000 inhabitants. The reference group is recruited from an area with approximately 200,000 inhabitants, within the southern part of The Netherlands [
]. However, because The Netherlands is a relatively small and homogenous country, where culture and lifestyle do not differ much, this is not expected to bias our results. Moreover, the age restrictions for participation in The Maastricht Study were more stringent (40–75 years) than for the MOSA study (>18 years, with no upper limit). However, the final percentage of MOSA participants younger than 40 years is expected to be small and is only 6% in the current interim analysis. Therefore, we do not expect the difference in the age criteria to bias our results. To further mitigate potential bias, we will perform sensitivity analyses excluding MOSA participants younger than 40 years.
As is the case for all studies on late effects of treatments or diseases, some forms of bias may be inevitable [
]. In our study, selection bias is the main type of bias to be taken into account. The population able or willing to participate in follow-up studies is expected to be a relatively healthy population. This may be relevant in this study, where the extensiveness of investigations can be perceived a burden by the HCT survivors, in particular by those of lesser health. As a result, relatively unhealthy participants may have opted not to join the MOSA study. This may induce a ‘bias towards null’, because any negative health impact of stem cell transplantation on the MOSA study would likely be more pronounced in the population who did not participate. To assess selection bias and to get a more thorough understanding of the complete group of stem cell survivors, a survey to characterize the group of patients who declined to participate or who did not respond to the invitation for the MOSA study was conducted. Analyses of the results of the survey are in progress.
6. Conclusion
The MOSA study is a matched cohort study of late effects after HCT. To our knowledge, this is the first study conducting such detailed phenotyping in long-term HCT survivors including a matched cohort representing the general population allowing direct comparisons. This creates a unique set of data providing essential information about late effects of HCT and associated risk factors. This information may improve screening and prevention strategies in HCT survivors, potentially leading to a positive impact on morbidity, mortality, and quality of life.
Universitair hoofddocent Epidemiology GROW-School for Oncology and Developmental Biology Fac. Health, Medicine and Life Sciences, Maastricht University.
Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.
One and half million hematopoietic stem cell transplants (HSCT). Dissemination, trends and potential to improve activity by telemedicine from the Worldwide Network for Blood and Marrow Transplantation (WBMT).
National institutes of health hematopoietic cell transplantation late effects initiative: developing recommendations to improve survivorship and long-term outcomes.
Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study.
National institutes of health hematopoietic cell transplantation late effects initiative: the cardiovascular disease and associated risk factors working group report.
Diabetes, hypertension, and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study.
Neurocognitive dysfunction in hematopoietic cell transplant recipients: expert review from the late effects and Quality of Life Working Committee of the CIBMTR and complications and Quality of Life Working Party of the EBMT.
Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years.
National Institutes of health hematopoietic cell transplantation late effects initiative: the immune dysregulation and pathobiology working group report.
Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long-term follow-up of a prospective study.
Ocular graft-versus-host disease after hematopoietic cell transplantation: expert review from the late effects and quality of life working committee of the center for international blood and marrow transplant research and transplant complications working party of the European society of blood and marrow transplantation.
Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS).
National institutes of health hematopoietic cell transplantation late effects initiative: the research methodology and study design working group report.
Funding: This work was supported by the Foundation Bewellim. KVK-number: 41066464; RSIN 2979640.
Ethics and dissemination: Ethics approval was provided by the Medical Ethics Committee Maastricht University Medical Centre, the Netherlands (MEC 10-2-023). Results of the main trial and each of the secondary end points will be submitted for publication in a peer-reviewed journal.
Trial registration number: NL-48599.
Declarations of interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
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