CHIP, CCUS, and Other Acronyms: Definition, Implications, and Impact on Practice

2019 ◽  
pp. 400-410 ◽  
Author(s):  
Amy E. DeZern ◽  
Luca Malcovati ◽  
Benjamin L. Ebert
Keyword(s):  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Clonal Hematopoiesis ◽  
Clinical Challenge ◽  
Myeloid Neoplasms ◽  
Active Research ◽  
The Relationship ◽  
Precursor States ◽  
Undetermined Significance

Unexplained blood cytopenias can be a clinical challenge for patients and clinicians alike. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes (MDS) is currently an area of active research. There have been marked developments in our understanding of clonal hematopoiesis based on findings of somatic mutations in genes known to be associated with MDS. This has led to newer terms to describe precursor states to MDS, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). These conditions may allow earlier diagnosis, modify surveillance for MDS, and guide additional therapies. This review summarizes recent updates in the field for affected patients.

scholarly journals Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes

Blood ◽  
2015 ◽  
Vol 126 (1) ◽  
pp. 9-16 ◽  
Author(s):  
David P. Steensma ◽  
Rafael Bejar ◽  
Siddhartha Jaiswal ◽  
R. Coleman Lindsley ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Clonal Expansion ◽  
Diagnostic Uncertainty ◽  
Clonal Hematopoiesis ◽  
Lymphoid Neoplasia ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Large Populations ◽  
Precursor States

Abstract Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

scholarly journals Current State and Challenges in Development of Targeted Therapies in Myelodysplastic Syndromes (MDS)

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 217-236
Author(s):  
Michele Stanchina ◽  
Sana Chaudhry ◽  
Matthew Karr ◽  
Justin Taylor
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Somatic Mutations ◽  
Clonal Hematopoiesis ◽  
Current State ◽  
Myeloid Neoplasms ◽  
Symptomatic Management ◽  
Progression Of Disease ◽  
Clinical Models ◽  
Generation Sequencing

Myelodysplastic syndromes (MDS) encompass a variety of myeloid neoplasms characterized by ineffective hematopoiesis. The interaction of abnormal clonal hematopoiesis and changes in the bone marrow microenvironment propagate abnormal clones. Advances in next generation sequencing has identified over 100 somatic mutations, but despite deepened understanding of the genetics of MDS, therapeutic discoveries have remained limited. To date, only five drugs have been approved for MDS: Azacitidine, Decitabine, Lenalidomide, Luspatercept, and oral Decitabine with Cedazuridine. Current strategies for low-risk MDS continue to focus on symptomatic management and correction of cytopenias, while treatment for high-risk MDS focuses on delaying progression of disease and improving survival. In this review we discuss some of the challenges in developing pre-clinical models of MDS in which to test therapeutics, the advances that have been made, and promising novel therapeutics in the pipeline.

scholarly journals Aging, hematopoiesis, and the myelodysplastic syndromes

2017 ◽  
Vol 1 (26) ◽  
pp. 2572-2578 ◽  
Author(s):  
Stephen S. Chung ◽  
Christopher Y. Park
Keyword(s):  
Myelodysplastic Syndromes ◽  
Bone Marrow Failure ◽  
Hematologic Malignancies ◽  
Relative Increase ◽  
Extrinsic Factors ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
The Many ◽  
The Relationship

Abstract The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.

scholarly journals Treatments targeting MDS genetics: a fool’s errand?

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 277-285 ◽  
Author(s):  
Amy E. DeZern
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Patient Outcomes ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Failure ◽  
Targeted Agents ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Improve Patient

Abstract The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure characteristically seen in patients. The heterogeneity of myelodysplastic syndrome pathobiology has historically posed a challenge to the development of newer therapies. Recent advances in molecular characterization of myelodysplastic syndromes are improving diagnostic accuracy, providing insights into pathogenesis, and refining therapeutic options for patients. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.

scholarly journals Novel and Significant Impact of Germline Variants Predisposed to Pathogenic Somatic Mutations and Loss of Heterozygosity (LOH) in Myelodysplastic Syndromes (MDS) and Clonal Hematopoiesis of Indeterminate Potential (CHIP)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 108-108
Author(s):  
Hideki Makishima ◽  
Tetsuichi Yoshizato ◽  
Yasuhito Nannya ◽  
Yasuhide Momozawa ◽  
Yoshiko Atsuta ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Loss Of Heterozygosity ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Somatic Mutations ◽  
Risk Haplotype ◽  
Germline Variants ◽  
Clonal Hematopoiesis ◽  
Risk Alleles ◽  
Significant Enrichment

Abstract While germline predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) has long been recognized mainly through rare familial and pediatric cases, it has been drawing an increasing attention, on the basis of the recent discovery of novel risk alleles for MDS/AML through studies relying on revolutionized sequencing technologies; according to these studies, it suggest that more numbers of MDS/AML cases than expected might have germline predisposition. Moreover, it is suggested that germline variations may also confer predisposition to age-related clonal hematopoiesis or "CHIP", which has been implicated in the development of MDS/AML. In this study, we explored germline predisposition to MDS and CHIP through intensive sequencing of blood samples from large cohorts of AML/MDS patients and 'hematologically' healthy individuals (HHIs), in which germline variants in 21 genes implicated in sporadic or familial MDS/AML or CHIP were interrogated among patients with MDS/AML from the Japan Marrow Donor Program (n=797) and HHIs aged >60 years from Biobank Japan (n=10,852). Germline variants were referred to NCBI dbSNP Build 151 database, excluding the entries in COSMIC ver.7 and in-house database, followed by manual curations. Somatic mutations and CHIP in the 21 genes were also analyzed for MDS/AML and HHIs, respectively. In total, 30,286 germline variants, including both synonymous and non-synonymous changes, were detected in 21 genes in the entire cohort. By comparing their frequencies between in MDS/AML and HHIs, we identified 6 germline variants in showing a significant enrichment in MDS/AML. Among these most frequently observed was variants in DDX41, for which a total of 3,721 variants were detected in 3,688 HHIs. Among these, 3 variants were significantly enriched in MDS/AML, including p.A500fs (OR=13.1 [6.6-25.9] (95%CI) (n=15), p.S363del (OR=41.0, [4.3-349.5]) (n=3), and p.Y259C (OR=34.2, [6.6-176.8]) (n=5). Of interest, 14 of 23 MDS patients with one of these alleles carried somatic DDX41 mutations, typically p.R525H, which were not found in any of HHIs, further supporting the relevance of these DDX41 risk alleles. Also including an additional 2 nonsense/splicing variants, 5 DDX41 alleles found in 25 MDS/AML patients were thought to represent germline predisposition to MDS/AML. Similarly, RUNX1 p.H85N (OR=9.10, [1.52-54.52]) (n=2), CBL p.P782L (OR=4.27, [1.56-11.70]) (n=5), and GNAS p.H69N (OR = 2.90, [1.28-6.59]) (n=7) showed a significant enrichment in MDS/AML. Combined, these putative risk alleles accounted for 4.6% (37/797) of sporadic MDS and sAML. None of these alleles were observed in the Caucasian population of Exome Aggregation Consortium dataset, suggesting Asian origins of these variants. We next evaluated the effects of germline variants on CHIP. CHIP mutations were detected in 929 HHIs, where DNMT3A mutations (n=290) were most prevalent, followed by TET2 (n=124) and ASXL1 (n=68) mutations. By comparing allele frequency of each of 1,276 germline variants between healthy donors with and without CHIP, we identified two haplotypes at the JAK2 and TET2 loci, defined by T/A at c.C489T/c.G2490A (JAK2) and G/G/T at c.G652A/c.G3117A/c.T4140C (TET2), which were significantly enriched in the cases carrying CHIP with the JAK2 (p.V617F) and TET2 mutations, respectively (T/A vs. C/G; OR=3.36, [1.41-8.01] for JAK2 and G/G/T vs. A/A/C; OR=1.85, [1.19-2.86] for TET2). Intriguingly, the JAK2 risk haplotype (C/G) were also enriched in MDS cases with JAK2 p.V617F mutations (T/A vs. C/G; OR=3.06, [1.26-7.60]). Similarly, the TET2 risk haplotype (G/G/T) tended to be enriched in MDS cases with TET2 mutations, although not statistically significant. Finally, variant allele frequency of JAK2 p.V617F mutations in CHIP exceeded 0.5 in 4 out of 26 JAK2 CHIP-positive patients (15%), suggesting the presence of loss of heterozygosity (LOH) in chromosome 9p. In conclusion, through a large-scale detection of germline variants in 21 common drivers of MDS/AML as well as CHIP, we identified multiple novel germline variants or haplotypes that showed a significant predisposition to the development of adult-onset MDS or CHIP, respectively. Our findings provide novel insights into the genetic basis of myeloid leukemogenesis and the development of CHIP. Disclosures Nakagawa: Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Kanda:Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Taisho-Toyama: Research Funding; CSL Behring: Research Funding; Tanabe-Mitsubishi: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria.

scholarly journals Clinical Relevance of Clonal Hematopoiesis in the Oldest-Old Population: Analysis of the "Health and Anemia" Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 750-750
Author(s):  
Marianna Rossi ◽  
Manja Meggendorfer ◽  
Matteo Zampini ◽  
Mauro Tettamanti ◽  
Emma Riva ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Clonal Evolution ◽  
Oldest Old ◽  
Vascular Diseases ◽  
Employment Equity ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
Equity Ownership ◽  
The Relationship

Abstract 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.

Mutational Status of TET2, JAK2, and MPL in Refractory Anemia with Ringed Sideroblasts Associated with Marked Thrombocytosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 418-418
Author(s):  
Luca Malcovati ◽  
Angela Brisci ◽  
Daniela Pietra ◽  
Matteo G Della Porta ◽  
Anna Gallífi ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Refractory Anemia ◽  
Ringed Sideroblasts ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Mutational Status ◽  
Mutant Genes ◽  
Myelomonocytic Leukemia

Abstract Abstract 418 According to the WHO classification, myelodysplastic/myeloproliferative neoplasms include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U). The best characterized of these latter conditions is the provisional entity defined as refractory anemia with ringed sideroblasts (RARS) associated with marked thrombocytosis (RARS-T); up to 60% of RARS-T patients harbor the JAK2 (V617F) mutation. Somatic mutations of TET2 have been recently described in myeloid neoplasms, where they appear to be associated with the amplification of the mutated clone at the early stages of hematopoietic differentiation [N Engl J Med. 2009 May 28;360(22):2355-7]. In order to gain a deeper insight into the pathophysiology of RARS-T, we studied a cohort of 187 patients with myeloid neoplasms and investigated the relationship between ringed sideroblasts, thrombocytosis, and mutational status of TET2, JAK2 and MPL. RARS-T was defined according to the following WHO criteria: i) refractory anemia associated with erythroid dysplasia and ringed sideroblasts ≥ 15%; ii) < 5% blasts in the bone marrow; iii) platelet count ≥ 450 × 109/L; iv) presence of large atypical megakaryocytes similar to those observed in BCR/ABL1-negative myeloproliferative neoplasms; v) absence of del(5q), t(3;3)(q21;q26) or inv(3)(q21q26). The combination of ringed sideroblasts ≥ 15% and platelet count ≥ 450 × 109/L was found in 19 subjects fulfilling the diagnostic criteria for RARS-T, while 24 patients had RARS without thrombocytosis. JAK2 and MPL mutations were detected in circulating granulocytes and bone marrow CD34+ cells - but not in T-lymphocytes - from 11 out of 19 (58%) RARS-T patients. Three RARS patients, who initially had low to normal platelet counts, progressed to RARS-T, and two of them acquired JAK2 (V617F) at this time. Somatic mutations of TET2 were found in three of the 15 RARS-T patients studied, and the presence of multiple mutant genes allowed analysis of subclones in two of them. One of these patients carried the following three somatic mutations: TET2 (C1271Y), JAK2 (V617F) and MPL (W515L). Analysis of genomic DNA from circulating granulocytes showed 50% TET2 (C1271Y) mutant alleles but smaller proportions of JAK2 (V617F) and MPL (W515L) mutant alleles (5.8% and 20% respectively). We then analyzed five BFU-E grown from peripheral blood mononuclear cells obtained from this patient. All these five colonies were heterozygous for TET2 (C1271Y), while three of them were heterozygous also for MPL (W515L) and the remaining two were heterozygous also for JAK2 (V617F), clearly indicating that erythroid progenitors carrying JAK2 or MPL mutants belonged to subclones of the dominant TET2 (C1271Y) clone. A woman with the TET2 (S1612LfsX4) mutation (50% granulocyte mutant alleles) and fully clonal hematopoiesis as indicated by X-chromosome inactivation patterns, carried 28% JAK2 (V617F) mutant alleles in circulating granulocytes, indicating that granulocytes harboring JAK2 mutant alleles belonged to a subclone of the initial TET2 (S1612LfsX4) mutant clone. Over a 5-year period, in fact, the initial TET2 mutant clone was completely replaced by the TET2/JAK2 mutant subclone. In other two female patients with RARS-T and no somatic mutation of TET2, granulocytes carrying JAK2 (V617F) represented only a fraction (11 to 22%) of clonal granulocytes as determined by X-chromosome inactivation patterns (96 to 100%). Somatic mutations of TET2 were detected also in a significant proportion of patients with RARS without thrombocytosis, while no JAK2 or MPL mutation was identified in these individuals. These observations suggest that the occurrence of a TET2 mutation may represent the initial event determining clonal dominance of hematopoietic cells both in RARS and RARS-T patients, while the subsequent occurrence of JAK2 and/or MPL mutations likely generates myelodysplastic/myeloproliferative subclones in RARS-T patients. In conclusion, RARS-T is indeed a myeloid neoplasm with both myelodysplastic and myeloproliferative features at the molecular and clinical level, and it may develop from RARS through the acquisition of somatic mutations of JAK2, MPL or other as-yet-unknown genes on the background of clonal hematopoiesis caused by somatic mutations of TET2 or other similar (as-yet-unknown) mutant genes. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Aging, hematopoiesis, and the myelodysplastic syndromes

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 73-78 ◽  
Author(s):  
Stephen S. Chung ◽  
Christopher Y. Park
Keyword(s):  
Myelodysplastic Syndromes ◽  
Bone Marrow Failure ◽  
Hematologic Malignancies ◽  
Relative Increase ◽  
Extrinsic Factors ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis ◽  
Increased Risk ◽  
The Many ◽  
The Relationship

Abstract The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.

scholarly journals Clinical, Molecular, and Prognostic Comparisons between Clonal Cytopenias of Undetermined Significance and Lower-Risk Myelodysplastic Syndromes - a Study of 184 Molecularly Annotated Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Marissa Li ◽  
Terra Lasho ◽  
Alejandro Ferrer ◽  
Naseema Gangat ◽  
Aref Al-Kali ◽  
...  
Keyword(s):  
Clinical Trial ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Lower Risk ◽  
Morphological Evidence ◽  
Red Cell ◽  
Cell Counts ◽  
Myeloid Neoplasms ◽  
Undetermined Significance

Introduction Clonal cytopenias of undetermined significance (CCUS) is defined by the presence of somatic driver mutations/copy number variations in hematopoietic cells in patients with low blood counts, in the absence of morphological evidence for myeloid neoplasms. Patients with CCUS are often symptomatic and can be transfusion dependent (TD), with high rates of progression to myeloid neoplasms, especially myelodysplastic syndromes (MDS). In addition, similar to MDS, there are reports of CCUS patients responding to hypomethylating agents. Due to the lack of a formal diagnosis/morphological dysplasia, CCUS patients are often denied therapies or clinical trial enrollment. We carried out this study to validate our hypothesis that CCUS shares similar clinical and survival characteristics with lower risk MDS (LR-MDS). Methods CCUS patients were prospectively identified from the clonal hematopoiesis clinic, whereas LR-MDS patients were retrospectively identified from our institutional database. LR-MDS was defined as very low, low and intermediate risk MDS based on the R-IPSS categorization. Baseline demographics, blood counts, bone marrow (BM) morphology, cytogenetics, and NGS results were abstracted. Transfusion dependency was defined as requiring at least one unit of red cell or platelets every 4 weeks. The Mann-Whitney-U and Fischer's exact test were used to compare quantitative and qualitative data in subgroups. Kaplan-Meier overall survival (OS) estimates were used for survival analysis and compared using the log-rank test. Results 186 patients were included in the study; 74 (40%) with CCUS and 112 (60%) with LR-MDS, median age 66 years, with 63% being male (Table 1). In the CCUS group, 93% had one or more mutations (67% &gt;1 mutation) detected by NGS, while 7% had clonal cytogenetic abnormalities. Common mutations in CCUS included TET2 (30%), SRSF2 (20%), DNMT3A (13%) and ASXL1 (11%); with 28% of patients being red cell TD and 15% being platelet TD. On application of the R-IPSS stratification, 40%, 45%, 12% and 3% were in the very low, low, intermediate and high risk categories, respectively. LR-MDS subtypes included MDS-RS (50%), MDS-MLD (21%), MDS-EB (10%), MDS del5q (7%), and MDS-U (12%). SF3B1 mutations were seen in 67% (95% of MDS-RS), while TET2 and DNMT3A mutations were seen in 29% and 21%, respectively. 60% of LR-MDS patients had &gt;1 mutation. 44% were red cell TD, while 10% were platelet TD. In comparison to patients with CCUS, LR-MDS patients were more likely to have higher white blood cell counts (p=0.002), higher neutrophil counts (p=0.009), higher platelet counts (p&lt;0.001), be red cell TD (p=0.031), have BM ring sideroblasts (p&lt;0.001), have higher BM blast% (p=0.004) and carry SF3B1 mutations (p&lt;0.001); whereas CCUS patients were more likely to have higher monocyte counts (p=0.009) and more likely to carry IDH1 (p=0.005), ZRSR2 (p=0.005) and ATM (p=0.012) mutations. Importantly there were no differences with regards to R-IPSS cytogenetic risk groups, R-IPSS prognostic categories, platelet TD, and mutations involving TET2, DNMT3A, SRSF2 and ASXL1 and TP53. Notably signal pathway mutations and mutations involving tumor suppressor genes were infrequent (&lt;5%) in both groups. The LR-MDS patients had a longer median follow up (53 vs 15 months) and at last follow up 72 (64%) and 11 (15%) deaths had been documented in the LR-MDS and CCUS groups respectively. 13 (18%) CCUS patients progressed to MDS (10) and AML (3) over a median of 15 months, while 9 (8%) LR-MDS patients progressed to higher grade MDS (1) and AML (8), respectively (median follow up 53 months). There was no difference in the median survival between CCUS (median OS not reached) versus LR-MDS (median OS 8.3 years) (p=0.372, Figure 1). Conclusion In spite of subtle phenotypic/molecular differences between LR-MDS and CCUS, both entities had similar prognostication, distribution of high risk mutations and survival outcomes. Within a short follow-up, 18% of CCUS patients progressed to MDS/AML, indicating that regardless of the absence of dysplasia these entities are a continuum of myeloid neoplasms. In order to improve access to treatments and clinical trial opportunities, we recommend that close consideration be given to consider CCUS as a MDS subtype. Disclosures Shah: Dren Bio: Consultancy.

scholarly journals Cardiovascular Disease, Aging, and Clonal Hematopoiesis

2020 ◽  
Vol 15 (1) ◽  
pp. 419-438 ◽  
Author(s):  
Megan A. Evans ◽  
Soichi Sano ◽  
Kenneth Walsh
Keyword(s):  
Cardiovascular Disease ◽  
Somatic Mutations ◽  
Mutant Cell ◽  
Experimental Studies ◽  
The Elderly ◽  
Epidemiological Studies ◽  
Clonal Hematopoiesis ◽  
Traditional Risk Factors ◽  
The Relationship ◽  
Shed Light

Traditional risk factors are incompletely predictive of cardiovascular disease development, a leading cause of death in the elderly. Recent epidemiological studies have shown that human aging is associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive advantage to a mutant cell, thus allowing for its clonal expansion, a phenomenon known as clonal hematopoiesis. Unexpectedly, these mutations have been associated with a higher incidence of cardiovascular disease, suggesting a previously unrecognized connection between somatic mutations in hematopoietic cells and cardiovascular disease. Here, we provide an up-to-date review of clonal hematopoiesis and its association with aging and cardiovascular disease. We also give a detailed report of the experimental studies that have been instrumental in understanding the relationship between clonal hematopoiesis and cardiovascular disease and have shed light on the mechanisms by which hematopoietic somatic mutations contribute to disease pathology.

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