CLONAL HEMATOPOIESIS IS COMMON IN HIP ARTHROPLASTY PATIENTS AND ASSOCIATES WITH AUTOIMMUNE DISEASE AND LOWER HEMOGLOBIN LEVELS
Author(s): ,
Judith S. Hecker
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Luise Hartmann
Affiliations:
Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany
,
Jennifer Rivière
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany
,
Michèle C. Buck
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany
,
Mark van der Garde
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Maja Rothenberg-Thurley
Affiliations:
Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany
,
Luise Fischer
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Department of Medicine I,Technical University of Dresden,Germany
,
Susann Winter
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Department of Medicine I,Technical University of Dresden,Germany
,
Bianka Ksienzyk
Affiliations:
Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany
,
Frank Ziemann
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany;Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany
,
Maria Solovey
Affiliations:
Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany
,
Martina Rauner
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany;Center for Healthy Aging,Technical University of Dresden,Germany
,
Elena Tsourdi
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Center for Healthy Aging,Technical University of Dresden,Germany
,
Katja Sockel
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Department of Medicine I,Technical University of Dresden,Germany
,
Marie Schneider
Affiliations:
German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Dept. of Hematology and Cell Therapy,University Hospital Leipzig,Germany
,
Anne S. Kubasch
Affiliations:
Dept. of Hematology and Cell Therapy,University Hospital Leipzig,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany
,
Martin Nolde
Affiliations:
Orthopedic Center Bogenhausen,Munich,Germany
,
Dominikus Hausmann
Affiliations:
Orthopedic Center Bogenhausen,Munich,Germany
,
Alexander C. Paulus
Affiliations:
Department of Orthopedic Surgery,University Hospital LMU,Munich,Germany
,
Jörg Lützner
Affiliations:
Department of Orthopedic Surgery,Technical University of Dresden,Germany
,
Andreas Roth
Affiliations:
Department of Orthopedic Surgery,University Hospital Leipzig,Germany
,
Florian Bassermann
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany
,
Karsten Spiekermann
Affiliations:
Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany
,
Carsten Marr
Affiliations:
Institute of Computational Biology, Helmholtz Zentrum München,German Research Center for Environmental Health,Neuherberg,Germany
,
Lorenz C. Hofbauer
Affiliations:
German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Center for Healthy Aging,Technical University of Dresden,Germany
,
Uwe Platzbecker
Affiliations:
German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Dept. of Hematology and Cell Therapy,University Hospital Leipzig,Germany
,
Klaus H. Metzeler
Affiliations:
German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany;Laboratory for Leukemia Diagnostics, Department of Medicine III,University Hospital LMU,Munich,Germany;Dept. of Hematology and Cell Therapy,University Hospital Leipzig,Germany
Katharina S. Götze
Affiliations:
III. Medical Department,Klinikum rechts der Isar,Munich,Germany;German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Consortium (DKTK), CHOICE consortium,Munich/Dresden,Germany
EHA Library. S. Hecker J. 06/09/21; 325654; EP896
Dr. Judith S. Hecker
Dr. Judith S. Hecker
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP896

Type: E-Poster Presentation

Session title: Myelodysplastic syndromes - Biology & Translational Research

Background
Clonal hematopoiesis (CH) is a common age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of ‘healthy’ hematopoietic cells in experimental hematology.

Aims
We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA for OA.

Methods

BM samples were collected from 200 patients without known hematologic disease undergoing THA for OA between 07/2017 and 08/2020 after written informed consent. The study was approved by the respective ethics committees in accordance with the Declaration of Helsinki. Targeted sequencing of 68 genes recurrently mutated in hematologic malignancies identified variants with a VAF threshold of ≥1%. For correlative analyses of clinical parameters, only variants fulfilling the current CHIP definition (clonal hematopoiesis of indeterminate potential, defined as somatic variants with allele frequencies [VAF] 2%) were included. Statistical analysis was performed with GraphPad Prism v6.0 and R v3.6.3.

Results
Prevalence of CH was 50.0%, including 77 patients with CHIP, and 23 patients harboring CH with lower mutation burden (VAF 1-2%). CH became progressively more frequent with age (Figure 1A). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). Most patients (n=56) had 1 mutation, 32 harbored 2 variants, and 10 carried 3 mutations, while two patients harbored 4 or 5 mutations, respectively. Number of variants per individual correlated with age (p=0.031), whereas VAF (median 2.7%, range 1.0-32.7%) did not (p=0.73). CHIP significantly correlated with older age (median, 74.0 years [y] with CHIP vs. 68.5 y without, respectively; p<0.00010), lower hemoglobin levels (median, 12.7 g/dL vs. 13.7 g/dL; p=0.0020) and higher MCV (median, 91.8 fl vs. 89.0 fl; p=0.0076). Of note, 66.7% of the patients with anemia had detectable mutations with VAF≥2% (who would thus be classified as clonal cytopenia of uncertain significance [CCUS]), whereas prevalence of CHIP was lower in patients with normal hemoglobin levels (32.7%, p=0.0014). Furthermore, we observed an enrichment of SF3B1 and TP53 mutations in anemic patients compared to those with normal blood counts (p=0.020). CHIP carriers were more likely to have CVD (p=0.0080), as previously reported, and present/prior malignancy (p=0.029). Strikingly, CHIP also associated with presence of autoimmune disease (AID, p=0.034), comprising diverse autoimmune disorders. Multivariate analysis with adjustment for age and sex confirmed significant associations between CHIP and older age (p=0.025), lower hemoglobin levels (p=0.0078), and AID (p=0.0081), but not with CVD or malignancy (Figure 1B).

Conclusion
Prevalence of CH in our prospectively enrolled cohort of older adults undergoing THA for OA is considerably higher than previously reported in healthy individuals or specific patient groups, such as those with ischemic heart failure or CVD. Together, these findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA, AID and anemia, and question the use of hip bone-derived cells as ‘healthy’ experimental controls.

Keyword(s): Autoimmune disease, Clonality, Hematopoiesis, Hematopoietic cell

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP896

Type: E-Poster Presentation

Session title: Myelodysplastic syndromes - Biology & Translational Research

Background
Clonal hematopoiesis (CH) is a common age-related condition predisposing to blood cancer and cardiovascular disease (CVD). Murine models demonstrate CH-mediated altered immune function and proinflammation. Low-grade inflammation has been implicated in the pathogenesis of osteoarthritis (OA), the main indication for total hip arthroplasty (THA). THA-derived hip bones serve as a major source of ‘healthy’ hematopoietic cells in experimental hematology.

Aims
We prospectively investigated frequency and clinical associations of CH in 200 patients without known hematologic disease undergoing THA for OA.

Methods

BM samples were collected from 200 patients without known hematologic disease undergoing THA for OA between 07/2017 and 08/2020 after written informed consent. The study was approved by the respective ethics committees in accordance with the Declaration of Helsinki. Targeted sequencing of 68 genes recurrently mutated in hematologic malignancies identified variants with a VAF threshold of ≥1%. For correlative analyses of clinical parameters, only variants fulfilling the current CHIP definition (clonal hematopoiesis of indeterminate potential, defined as somatic variants with allele frequencies [VAF] 2%) were included. Statistical analysis was performed with GraphPad Prism v6.0 and R v3.6.3.

Results
Prevalence of CH was 50.0%, including 77 patients with CHIP, and 23 patients harboring CH with lower mutation burden (VAF 1-2%). CH became progressively more frequent with age (Figure 1A). Most commonly mutated genes were DNMT3A (29.5%), TET2 (15.0%) and ASXL1 (3.5%). Most patients (n=56) had 1 mutation, 32 harbored 2 variants, and 10 carried 3 mutations, while two patients harbored 4 or 5 mutations, respectively. Number of variants per individual correlated with age (p=0.031), whereas VAF (median 2.7%, range 1.0-32.7%) did not (p=0.73). CHIP significantly correlated with older age (median, 74.0 years [y] with CHIP vs. 68.5 y without, respectively; p<0.00010), lower hemoglobin levels (median, 12.7 g/dL vs. 13.7 g/dL; p=0.0020) and higher MCV (median, 91.8 fl vs. 89.0 fl; p=0.0076). Of note, 66.7% of the patients with anemia had detectable mutations with VAF≥2% (who would thus be classified as clonal cytopenia of uncertain significance [CCUS]), whereas prevalence of CHIP was lower in patients with normal hemoglobin levels (32.7%, p=0.0014). Furthermore, we observed an enrichment of SF3B1 and TP53 mutations in anemic patients compared to those with normal blood counts (p=0.020). CHIP carriers were more likely to have CVD (p=0.0080), as previously reported, and present/prior malignancy (p=0.029). Strikingly, CHIP also associated with presence of autoimmune disease (AID, p=0.034), comprising diverse autoimmune disorders. Multivariate analysis with adjustment for age and sex confirmed significant associations between CHIP and older age (p=0.025), lower hemoglobin levels (p=0.0078), and AID (p=0.0081), but not with CVD or malignancy (Figure 1B).

Conclusion
Prevalence of CH in our prospectively enrolled cohort of older adults undergoing THA for OA is considerably higher than previously reported in healthy individuals or specific patient groups, such as those with ischemic heart failure or CVD. Together, these findings underscore the association between CH and inflammatory diseases. Our results have considerable relevance for management of patients with OA, AID and anemia, and question the use of hip bone-derived cells as ‘healthy’ experimental controls.

Keyword(s): Autoimmune disease, Clonality, Hematopoiesis, Hematopoietic cell

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