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

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ClinicalTrials.gov Identifier: NCT03907553
Recruitment Status : Completed
First Posted : April 9, 2019
Last Update Posted : April 22, 2019
Sponsor:
Collaborator:
Istituto Di Ricerche Farmacologiche Mario Negri
Information provided by (Responsible Party):
Istituto Clinico Humanitas

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 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.


Condition or disease Intervention/treatment
Anemia Clonal Hematopoiesis Diagnostic Test: targeted genome sequencing

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Study Type : Observational
Actual Enrollment : 5000 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Aging of Hematopoietic Stem Cells - Molecular Architecture of Marrow Dysplasia and Clinical Contribution of Ineffective Hematopoiesis to Frailty in the Elderly
Actual Study Start Date : July 2003
Actual Primary Completion Date : June 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Anemia

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



Primary Outcome Measures :
  1. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03907553


Locations
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Italy
Istituto Clinico Humanitas
Rozzano, Milano, Italy, 20089
Sponsors and Collaborators
Istituto Clinico Humanitas
Istituto Di Ricerche Farmacologiche Mario Negri
Publications of Results:
Other Publications:
Woll PS, Kjällquist U, Chowdhury O, Doolittle H, Wedge DC, Thongjuea S, Erlandsson R, Ngara M, Anderson K, Deng Q, Mead AJ, Stenson L, Giustacchini A, Duarte S, Giannoulatou E, Taylor S, Karimi M, Scharenberg C, Mortera-Blanco T, Macaulay IC, Clark SA, Dybedal I, Josefsen D, Fenaux P, Hokland P, Holm MS, Cazzola M, Malcovati L, Tauro S, Bowen D, Boultwood J, Pellagatti A, Pimanda JE, Unnikrishnan A, Vyas P, Göhring G, Schlegelberger B, Tobiasson M, Kvalheim G, Constantinescu SN, Nerlov C, Nilsson L, Campbell PJ, Sandberg R, Papaemmanuil E, Hellström-Lindberg E, Linnarsson S, Jacobsen SE. Myelodysplastic syndromes are propagated by rare and distinct human cancer stem cells in vivo. Cancer Cell. 2014 Jun 16;25(6):794-808. doi: 10.1016/j.ccr.2014.03.036. Epub 2014 May 15. Erratum in: Cancer Cell. 2014 Jun 16;25(6):861. Cancer Cell. 2015 Apr 13;27(4):603-5.
Papaemmanuil E, Cazzola M, Boultwood J, Malcovati L, Vyas P, Bowen D, Pellagatti A, Wainscoat JS, Hellstrom-Lindberg E, Gambacorti-Passerini C, Godfrey AL, Rapado I, Cvejic A, Rance R, McGee C, Ellis P, Mudie LJ, Stephens PJ, McLaren S, Massie CE, Tarpey PS, Varela I, Nik-Zainal S, Davies HR, Shlien A, Jones D, Raine K, Hinton J, Butler AP, Teague JW, Baxter EJ, Score J, Galli A, Della Porta MG, Travaglino E, Groves M, Tauro S, Munshi NC, Anderson KC, El-Naggar A, Fischer A, Mustonen V, Warren AJ, Cross NC, Green AR, Futreal PA, Stratton MR, Campbell PJ; Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium. Somatic SF3B1 mutation in myelodysplasia with ring sideroblasts. N Engl J Med. 2011 Oct 13;365(15):1384-95. doi: 10.1056/NEJMoa1103283. Epub 2011 Sep 26.

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Responsible Party: Istituto Clinico Humanitas
ClinicalTrials.gov Identifier: NCT03907553    
Other Study ID Numbers: CARIPLO 2016
First Posted: April 9, 2019    Key Record Dates
Last Update Posted: April 22, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Frailty
Pathologic Processes