-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

750 Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population: Analysis of the "Health and Anemia" StudyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 503. Clonal Hematopoiesis: Aging and Inflammation: Cause and consequence of clonal hematopoiesis
Hematology Disease Topics & Pathways:
Adult, Diseases, Technology and Procedures, Study Population, Clinically relevant, NGS
Monday, December 3, 2018: 4:00 PM
Room 11B (San Diego Convention Center)

Marianna Rossi, MD1*, Manja Meggendorfer, PhD2, Matteo Zampini1*, Mauro Tettamanti3*, Emma Riva3*, Elena Saba4*, Nicla Manes1*, Chiara Milanesi1*, Ubezio Marta1*, Lucio Morabito4*, Erica Travaglino5*, Clelia Peano6,7*, Solda Giulia8*, Rosanna Asselta8*, Stefano Duga8*, Karolina Malik9*, Carlo Selmi10,11*, Efrem Civilini12*, Sara Mandelli3*, Niccolò Bolli13*, George S. Vassiliou14,15*, Wolfgang Kern, MD2, Armando Santoro, MD1*, Ugo Lucca3*, Torsten Haferlach, MD16 and Matteo Giovanni Della Porta1*

1Cancer Center - IRCCS Humanitas Research Hospital & Humanitas University, Rozzano - Milan, Italy
2MLL Munich Leukemia Laboratory, Munich, Germany
3Department of Neuroscience, Laboratory of Geriatric Neuropsychiatry, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy
4Cancer Center - IRCCS Humanitas Research Hospital & Humanitas University, Rozzano- Milan, Italy
5Cancer Center - IRCCS Humanitas Research Hospital & Humanitas University, Rozzano - Milna, Italy
6: Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, Milan, Italy
7Humanitas Clinical and Research Center, Rozzano - Milan, Italy
8Department of Biomedical Sciences, Humanitas University, Rozzano - Milan, Italy
9Humanitas University, Rozzano - Milan, Italy
10Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano - Milan, Italy
11BIOMETRA Department, University of Milan, Milan, Italy
12Humanitas Universisty, Rozzano - Milan, Italy
13Department of Oncology and Hemato-Oncology, University of Milan & Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
14Haematological Cancer Genetics, Wellcome Sanger Institute, Cambridge, United Kingdom
15Department of Haematology, University of Cambridge, Cambridge, United Kingdom
16MLL Munchner Leukamie Labor Gmbh, Munchen, Germany

Background. Age-dependent clonal expansion of somatic mutations in the hematopoietic system is associated with an increased risk of hematological cancers (including myelodysplastic syndromes, MDS) and other illnesses (coronary heart disease and stroke). However, the presence of clonal hematopoiesis per se in a given individual has only limited predictive power. We hypothesized that the study of oldest-old population can define more specifically the relationship between mutations in the hematopoietic system and risk for MDS, inflammation and vascular diseases.

Methods. We analyzed 1004 oldest-old subjects (median age 84.2y, range 80-105) included in the “Health and Anemia” population-based study [Haematologica 2010;95:1849]. Using peripheral blood DNA, we looked for somatic mutations in 47 genes recurrently mutated in hematologic cancers.

Results. Clonal mutations were observed in 32.8% of individuals (range 1-5). The majority of variants occurred in 3 genes: DNMT3A (36.4%), TET2 (24.3%) and ASXL1 (6.5%). Mutations in splicing genes, PPM1D and TP53 were found in 7.4%, 5% and 2% of cases, respectively. The mutation frequencies increased with age, up to 50% in individuals aged over 90 years (P=.011). Clonal hematopoiesis was associated with a lower 5-y probability of survival (P=.03), and prognosis was even poorer in patients carrying ≥2 mutations (P=.002)

We first focused on the relationship between clonal hematopoiesis and MDS phenotype. Carrying a somatic mutation with a variant allele frequency (VAF) ≥.10, carrying ≥2 mutations, spliceosome gene mutations and co-mutation patterns involving TET2, DNMT3A had a positive predictive value for MDS (from .85 to 1.0). The most frequent early phenotypic changes in patients who developed MDS included an increasing red blood cell distribution width (RDW) and mean corpuscular volume (MCV). Preliminary analyses suggested that the combination of mutations and non-mutational factors (RDW, MCV, after excluding iron/vitamin depletion and thalassemia) may improve the capability to capture individual risk of developing MDS with respect to molecular data alone (P=.01)

We studied clonal evolution in 72 patients with multiple samples available over a period of 5y. Clonal hematopoiesis was found at baseline in 22 cases: 2 individuals acquired additional mutations during follow-up, and 5 displayed significant increase in VAF. In 9 subjects without clonal hematopoiesis, mutations were acquired during follow-up. RDW and MCV changes, induction of unexplained cytopenia and overt MDS phenotype were significantly restricted to subjects displaying clonal evolution.

We hypothesized that in oldest-old populations MDS could be underdiagnosed (many patients are not considered for bone marrow aspiration because of age). Cytopenia was a common finding in our cohort (20%) the underlying cause remaining unexplained in 27% of cases. In patients with unexplained anemia, carrying a somatic mutation had a positive predictive value for persistent, progressive, multilineage cytopenia (findings consistent with a MDS phenotype) and shorter survival (from .8 to .94). On this basis, 8% of all cytopenias might be undiagnosed MDS.

Finally, we investigated the association between clonal hematopoiesis with inflammatory and vascular diseases. Mutations in DNMT3A, TET2, and ASXL1 were each individually associated with risk of coronary heart disease and death, and preliminary analyses suggest that clonal hematopoiesis is also associated with increased risk of rheumatological diseases (P from .03 to.009). We identified mutations in macrophages isolated from synovial fluid of 4/17 patients with rheumatoid arthritis and from atherosclerotic plaques of 3/25 patients with carotid stenosis. Functional studies of macrophages (expression of specific chemokine and cytokine gene patterns) are ongoing.

All these findings are under validation in an independent cohort of 800 subjects enrolled in the “Monzino 80-plus” study [Alzheimers Dement 2015;11:258]].

Conclusion. Clonal hematopoiesis was associated with reduced survival in an oldest-old population. Specific mutational profiles define different risks of developing MDS and inflammatory/vascular diseases. Non mutational factors, such as early changes in red blood cell indices, may improve the capability to identify patients at increased risk of developing myeloid cancers.

Disclosures: Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Bolli: Celgene: Honoraria. Vassiliou: KYMAB: Consultancy, Equity Ownership; Celgene: Research Funding. Kern: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

<< Previous Abstract | Next Abstract
*signifies non-member of ASH