Ignite Creation Date:
2024-05-06 @ 1:00 PM
Last Modification Date:
2024-10-26 @ 1:07 PM
Study NCT ID:
NCT03907553
Status:
COMPLETED
Last Update Posted:
2019-04-22
First Post:
2019-04-05
Brief Title:
Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly
Sponsor:
Istituto Clinico Humanitas
Organization:
Istituto Clinico Humanitas
Study Overview
Official Title:
Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly
Status:
COMPLETED
Status Verified Date:
2019-04
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:
None
Brief Summary:
The prevalence and incidence of anemia tend to increase with advancing age Relatively low hemoglobin concentrations are a common laboratory finding in the elderly for the most part judged by physicians as a sign without clinical relevance or as a marker of an underlying chronic disease having no independent influence on health
In recent years several studies have started to challenge the widespread and self-perpetuating perception of anemia as an innocent bystander reporting worse cognitive and quality of life outcomes and increased risk of hospitalization and mortality in the general population Focusing on elderly people anemia has a clear association with the phenotypic features of frailty syndrome affecting 3-5 of individuals of 65-70 years of age and more importantly 30 of those aged 85 years or older
Among frail older adults anemia is a powerful prognostic factor for the development of frailty-related problems such as muscle weakness reduced performance falls and mortality Nutrient deficiency chronic inflammation and renal insufficiency account for the large majority of cases of anemia in the elderly while underlying cause remained unexplained in 25 of the cases Preliminary evidence indicates that a significant proportion of unexplained anemia may account for myelodysplasiaMDS MDS is a condition typically occurring in elderly people characterized by clonal proliferation of hematopoietic stem cells HSC which partly retain their capacity to differentiate and maturate but do so in an inefficient manner ineffective hematopoiesis Anemia represents the most important prognostic factor in MDS With time a portion of patients evolve into overt myeloid malignancy ie acute leukemia
Somatic mutations occur in the genomes of healthy HSC at a low but detectable frequency during normal DNA replication Although most mutations are rapidly corrected by DNA repair mechanisms those that persist are propagated during HSC self-renewal Some evidence suggest that these early driver mutations dictate future trajectories of evolution with distinct clinical phenotypes There has been much excitement in the research community about the translational opportunities offered by genome sequencing possibly leading to the identification of specific types of mutational processes of how genome interact with environmental factors in determining clinical conditions associated with aging and to the implementation of a personalized molecular diagnosis and treatment for every patient In this translational research project using an integrated genomic analysis based on next generation sequencing NGS technologiesthe investigators plan to dissect the genomic architecture of MDS significantly contributing to many features of frailty and to individual vulnerability The investigators will perform mutation analysis of candidate genes in a large and well characterized cohort of individuals belonging to the Health and Anemia study Health and Anemia is a prospective population-based observational study 2003-2013 of all elderly residents in the municipality of Biella Piedmont a town in the north-west of Italy Hematological parameters together with data on cognition and functional status mood and quality of life fatigue hospitalization and mortality were collected for all patients Moreover complete information on the development of hematological malignancies was provided by local tumor registry up to 2018 The investigators aim to identify genes associated with the induction of clonal hematopoiesis in elderly people and then to correlate somatic mutations with clinicalhematological features and progression into MDS andor overt leukemia Moreover The investigators will genotype single-cell-derived hematopoietic colonies from CD34 compartments hematopoietic stem cells multipotent progenitors common myeloid progenitors and granulocyte progenitors in order to clarify the clonal architecture of marrow dysplasia in HSC the dynamics of clonal establishment and expansion during hematopoietic differentiation and their relationship with the disease phenotype and evolution Finally by analysing clinical data from Health and Anemia study the investigators will investigate the clinical contribution of myelodysplasia-related anemia to the development of frailty syndrome and its clinical sequela The definition of molecular architecture of marrow dysplasia would allow us to improve the current diagnosis and classification of anemia in the elderly and the assessment of individual patients risk of disease associated morbiditymortality Finally in patients with marrow dysplasia gene sequencing is expected to predict the vulnerability of a particular genotype to specific treatment thus providing a basis for optimizing at individual level timing and modality of therapeutic intervention The study population of the MOnzino 80-plus study will be used as validation cohort
In recent years several studies have started to challenge the widespread and self-perpetuating perception of anemia as an innocent bystander reporting worse cognitive and quality of life outcomes and increased risk of hospitalization and mortality in the general population Focusing on elderly people anemia has a clear association with the phenotypic features of frailty syndrome affecting 3-5 of individuals of 65-70 years of age and more importantly 30 of those aged 85 years or older
Among frail older adults anemia is a powerful prognostic factor for the development of frailty-related problems such as muscle weakness reduced performance falls and mortality Nutrient deficiency chronic inflammation and renal insufficiency account for the large majority of cases of anemia in the elderly while underlying cause remained unexplained in 25 of the cases Preliminary evidence indicates that a significant proportion of unexplained anemia may account for myelodysplasiaMDS MDS is a condition typically occurring in elderly people characterized by clonal proliferation of hematopoietic stem cells HSC which partly retain their capacity to differentiate and maturate but do so in an inefficient manner ineffective hematopoiesis Anemia represents the most important prognostic factor in MDS With time a portion of patients evolve into overt myeloid malignancy ie acute leukemia
Somatic mutations occur in the genomes of healthy HSC at a low but detectable frequency during normal DNA replication Although most mutations are rapidly corrected by DNA repair mechanisms those that persist are propagated during HSC self-renewal Some evidence suggest that these early driver mutations dictate future trajectories of evolution with distinct clinical phenotypes There has been much excitement in the research community about the translational opportunities offered by genome sequencing possibly leading to the identification of specific types of mutational processes of how genome interact with environmental factors in determining clinical conditions associated with aging and to the implementation of a personalized molecular diagnosis and treatment for every patient In this translational research project using an integrated genomic analysis based on next generation sequencing NGS technologiesthe investigators plan to dissect the genomic architecture of MDS significantly contributing to many features of frailty and to individual vulnerability The investigators will perform mutation analysis of candidate genes in a large and well characterized cohort of individuals belonging to the Health and Anemia study Health and Anemia is a prospective population-based observational study 2003-2013 of all elderly residents in the municipality of Biella Piedmont a town in the north-west of Italy Hematological parameters together with data on cognition and functional status mood and quality of life fatigue hospitalization and mortality were collected for all patients Moreover complete information on the development of hematological malignancies was provided by local tumor registry up to 2018 The investigators aim to identify genes associated with the induction of clonal hematopoiesis in elderly people and then to correlate somatic mutations with clinicalhematological features and progression into MDS andor overt leukemia Moreover The investigators will genotype single-cell-derived hematopoietic colonies from CD34 compartments hematopoietic stem cells multipotent progenitors common myeloid progenitors and granulocyte progenitors in order to clarify the clonal architecture of marrow dysplasia in HSC the dynamics of clonal establishment and expansion during hematopoietic differentiation and their relationship with the disease phenotype and evolution Finally by analysing clinical data from Health and Anemia study the investigators will investigate the clinical contribution of myelodysplasia-related anemia to the development of frailty syndrome and its clinical sequela The definition of molecular architecture of marrow dysplasia would allow us to improve the current diagnosis and classification of anemia in the elderly and the assessment of individual patients risk of disease associated morbiditymortality Finally in patients with marrow dysplasia gene sequencing is expected to predict the vulnerability of a particular genotype to specific treatment thus providing a basis for optimizing at individual level timing and modality of therapeutic intervention The study population of the MOnzino 80-plus study will be used as validation cohort
Detailed Description:
None
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