Ignite Creation Date:
2024-05-06 @ 12:53 PM
Last Modification Date:
2024-10-26 @ 1:05 PM
Study NCT ID:
NCT03871296
Status:
RECRUITING
Last Update Posted:
2023-05-30
First Post:
2019-02-04
Brief Title:
DNA Methylation in Allogeneic Hematopoietic Stem Cell Transplantation
Sponsor:
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Organization:
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Study Overview
Official Title:
DNA Methylation in Allogeneic Hematopoietic Stem Cell Transplantation MET_SCT_2018
Status:
RECRUITING
Status Verified Date:
2023-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MET_SCT_2018
Brief Summary:
As a consequence of the impending increase in life expectancy there is urgent need to adopt life-saving interventions such as hematopoietic stem cell transplantation SCT in groups of patients that have been regarded as unsuitable for such medical procedures owing to their advanced age However a growing body of evidence shows that age per se does not account for a reliable estimation of the capability of an individual to cope with the stressful procedure of SCT and to deal with the cognate adverse effects Recent literature shows that changes in epigenetic markers ie the extent of methylation at specific loci of genomic DNA marks the rate of aging and allows for the estimation of the so called biologic aging In other words individuals of the same chronologic age may turn out to be older or younger respect when their biologic age is assessed This latter is expected to be tightly linked to changes in major homeostatic mechanisms and consequently to be in relationship the chance of successful SCT The primary objective of the study is the study of DNA in patients undergoing allogeneic haematopoietic stem cell transplantation DNA will be assessed for the extent of methylation which will be also in relationship with circulating exogenous DNA ie the microbiome
Detailed Description:
The use of hematopoietic stem cell transplantation SCT in groups of patients previously unsuitable because of age is progressively increasing Nowadays allogeneic SCT in patients aged over 60 years represents approximately 18 In the European SCT database the number of patients aged 65 years was 1 up to 2000 and 67 after 2000 This trend is the consequent to a growing clinical need caused to the progressive global aging of general population and to the increasing proportion of subjects with good performance status among elderly patients
Fitness to transplantation is currently measured by the absence of the major comorbidities assessed by Sorrors Comorbidity Index score HCT-CI The score correlates with the outcome after transplant and provides clear indications on the intensity of the chemotherapy to be administered in pre-transplant phase in order to reduce Non Relapse Mortality NRMNRM is the mortality not due to the recovery of the disease it can arise from three orders of complications immunological Graft versus Host Disease -GVHD- infectious opportunistic infections and toxic organ toxicity related to chemotherapy The intensity of conditioning regimen is reduced consequently in presence of comorbidity and in the elderly patient more frequently affected by comorbidities But reducing the intensity of conditioning regimen also means significantly increasing the probability of relapse of haematological disease and therefore this reduction must be made on the basis of indexes of aging and comorbidity as mentioned above HCT-CI in order to not overly reduce the curative potential of the transplantThis study aims to apply innovative markers of biological age for the evaluation of SCT patients Biological age assessment is a rapidly expanding research area that has produced very promising results Biological age is an index composed of molecular markers such as DNA methylation of nucleated blood cells or the level of glycans associated with circulating proteins it is strongly related to chronological age but is capable of expressing the speed of aging of the single subject and consequently is able to highlight the risks for health associated with aging with more emphasis than chronological age The recent literature clearly indicates that DNA is also present in the non-cellular fraction in the form of free DNA that it is largely contained in the compartment of nanovesicles In particular it is interesting to study if nanovesicles DNA can provide useful data regarding the epigenome and to verify how the epigenome is linked with the presence of exogenous DNA that is the microbiomeThis entity includes all the bacterial and viral species that coexist with every human mostly located in the gastrointestinal tract and which are increasingly determining to understand the pathogenesis of inflammatory andor metabolic diseases as well as the biological bases of aging In this regard the recent literature shows a close relationship between GVHD viroma and intestinal microbiomeEpigenetics does not specifically deal with the modification of the sequence of the subjects DNA but with all the regulatory processes that influence gene expression In particular methylation is an epigenetic modification of DNA Therefore epigenetic studies differ from classical genetic studies in which the analysis of the exact DNA sequence of the subjects is carried out In this protocol the investigators will refer to the study of DNA as the study of its modifications in the methylation status and not in its sequence
Primary objective of the study
- Study of DNA in samples of patients undergoing allogeneic haematopoietic stem cell transplantation In particular DNA will be extracted from leukocytes and plasma extracellular nanovesicles DNA will be assessed for the extent of methylation which will be also in relationship with circulating exogenous DNA ie the microbiome
Secondary objectives
Study of DNA in urine and faeces samples of the same subjects to describe further elements of the systemic microbiome - namely the urinary virome and the intestinal microbiome-
Correlation of circulating epigenome and systemic microbiome with clinical outcomes overall survival GVHD incidence of infections and comorbidity index HCT-CI
Exclusion criteria
- Absence of signed informed consent
No treatment is provided patients will be treated and followed according to normal clinical practice and according to international guidelines
The visits and evaluations are those of routine practice will not be modified Samples of different biological materials will be taken at the start of recovery at day -1 1 and after 1 3 6 9 12 months after transplantation After discharge all patients will be followed as usual by the Day Hospital of the Transplant Unit of the Hematology Institute where the prospective collection of samples at defined times will continue
The primary objective of the study is descriptive The evaluation of the main clinical variables is done with descriptive analysis mean median range etc Survival analysis will be performed according to Kaplan-Meier methodology for censored data Regression analysis for censored data will be performed using Cox proportional risk models
The DNA methylation is expressed in terms of continuous variables as a percentage of methylation of the different analyzed gene loci The analysis of methylation data will be performed through a pipeline of algorithms developed by the proponents The viromic data are nominal variables presenceabsence of viral species
The study is of exploratory nature and it is expected to enroll 50 patients
Fitness to transplantation is currently measured by the absence of the major comorbidities assessed by Sorrors Comorbidity Index score HCT-CI The score correlates with the outcome after transplant and provides clear indications on the intensity of the chemotherapy to be administered in pre-transplant phase in order to reduce Non Relapse Mortality NRMNRM is the mortality not due to the recovery of the disease it can arise from three orders of complications immunological Graft versus Host Disease -GVHD- infectious opportunistic infections and toxic organ toxicity related to chemotherapy The intensity of conditioning regimen is reduced consequently in presence of comorbidity and in the elderly patient more frequently affected by comorbidities But reducing the intensity of conditioning regimen also means significantly increasing the probability of relapse of haematological disease and therefore this reduction must be made on the basis of indexes of aging and comorbidity as mentioned above HCT-CI in order to not overly reduce the curative potential of the transplantThis study aims to apply innovative markers of biological age for the evaluation of SCT patients Biological age assessment is a rapidly expanding research area that has produced very promising results Biological age is an index composed of molecular markers such as DNA methylation of nucleated blood cells or the level of glycans associated with circulating proteins it is strongly related to chronological age but is capable of expressing the speed of aging of the single subject and consequently is able to highlight the risks for health associated with aging with more emphasis than chronological age The recent literature clearly indicates that DNA is also present in the non-cellular fraction in the form of free DNA that it is largely contained in the compartment of nanovesicles In particular it is interesting to study if nanovesicles DNA can provide useful data regarding the epigenome and to verify how the epigenome is linked with the presence of exogenous DNA that is the microbiomeThis entity includes all the bacterial and viral species that coexist with every human mostly located in the gastrointestinal tract and which are increasingly determining to understand the pathogenesis of inflammatory andor metabolic diseases as well as the biological bases of aging In this regard the recent literature shows a close relationship between GVHD viroma and intestinal microbiomeEpigenetics does not specifically deal with the modification of the sequence of the subjects DNA but with all the regulatory processes that influence gene expression In particular methylation is an epigenetic modification of DNA Therefore epigenetic studies differ from classical genetic studies in which the analysis of the exact DNA sequence of the subjects is carried out In this protocol the investigators will refer to the study of DNA as the study of its modifications in the methylation status and not in its sequence
Primary objective of the study
- Study of DNA in samples of patients undergoing allogeneic haematopoietic stem cell transplantation In particular DNA will be extracted from leukocytes and plasma extracellular nanovesicles DNA will be assessed for the extent of methylation which will be also in relationship with circulating exogenous DNA ie the microbiome
Secondary objectives
Study of DNA in urine and faeces samples of the same subjects to describe further elements of the systemic microbiome - namely the urinary virome and the intestinal microbiome-
Correlation of circulating epigenome and systemic microbiome with clinical outcomes overall survival GVHD incidence of infections and comorbidity index HCT-CI
Exclusion criteria
- Absence of signed informed consent
No treatment is provided patients will be treated and followed according to normal clinical practice and according to international guidelines
The visits and evaluations are those of routine practice will not be modified Samples of different biological materials will be taken at the start of recovery at day -1 1 and after 1 3 6 9 12 months after transplantation After discharge all patients will be followed as usual by the Day Hospital of the Transplant Unit of the Hematology Institute where the prospective collection of samples at defined times will continue
The primary objective of the study is descriptive The evaluation of the main clinical variables is done with descriptive analysis mean median range etc Survival analysis will be performed according to Kaplan-Meier methodology for censored data Regression analysis for censored data will be performed using Cox proportional risk models
The DNA methylation is expressed in terms of continuous variables as a percentage of methylation of the different analyzed gene loci The analysis of methylation data will be performed through a pipeline of algorithms developed by the proponents The viromic data are nominal variables presenceabsence of viral species
The study is of exploratory nature and it is expected to enroll 50 patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None