Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly

April 19, 2019 updated by: Istituto Clinico Humanitas

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 myelodysplasia(MDS). 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 (i.e., 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) technologies,the 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 clinical/hematological features and progression into MDS and/or 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 patient's risk of disease associated morbidity/mortality. 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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Actual)

5000

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
    • Milano
      • Rozzano, Milano, Italy, 20089
        • Istituto Clinico Humanitas

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

65 years and older (OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

4280 subjects with a biobanked blood sample available for genetic analysys out of the 8740 subjects enrolled in the Health & Anemia Trial.

Description

Health & Anemia Trial population

Inclusion Criteria:

  • 65 years or older
  • residence in the town of Biella, Italy
  • consence fo biobanking

Exclusion Criteria:

No exclusion criteria other than age, residence and lack of a biobanked sample

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Health and Anemia
individuals belonging to the "Health and Anemia'' prospective population-based observational study (2003-2013) of all elderly residents (>65 years) in the municipality of Biella
Diagnostic test: targeted genome sequencing
Monzino
individuals belonging to the "Monzino Over 80 trial"
Diagnostic test: targeted genome sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
genotype-phenotype correlation
Time Frame: 2016-2019
genes associated with the induction of clonal hematopoiesis in elderly people, and then to correlate somatic mutations with clinical/hematological features and progression into MDS and/or overt leukemia
2016-2019

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Istituto Clinico Humanitas

Collaborators

Istituto Di Ricerche Farmacologiche Mario Negri

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2003

Primary Completion (Actual)

June 1, 2018

Study Registration Dates

First Submitted

April 5, 2019

First Submitted That Met QC Criteria

April 8, 2019

First Posted (Actual)

April 9, 2019

Study Record Updates

Last Update Posted (Actual)

April 22, 2019

Last Update Submitted That Met QC Criteria

April 19, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CARIPLO 2016

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Anemia

Clinical Trials on targeted genome sequencing

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Netherlands

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe