Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

Weeks, Lachelle D.; Niroula, Abhishek; Neuberg, Donna; Wong, Waihay J.; Lindsley, R. Coleman; Luskin, Marlise R.; Berliner, Nancy; Stone, Richard; DeAngelo, Daniel J.; Soiffer, Robert J.; Uddin, Md Mesbah; Griffin, Gabriel K.; Vlasschaert, Caitlyn; Gibson, Christopher J.; Jaiswal, Siddhartha; Bick, Alexander; Malcovati, Luca; Natarajan, Pradeep; Ebert, Benjamin L.

doi:10.1056/evidoa2200310

Cited by 139 publications

(51 citation statements)

References 54 publications

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“…A recent study revealed that 10-year probability rates of progression to neoplasms in the CHIP population range from 0.01% to 0.7%, with age > 65 as one of the risk factors. 47 In line, neither patients in the CHIP nor in the non-CHIP groups were observed to develop hematopoietic malignancy in our cohort. Evidence suggested that the prognostic effects of CHIP were primarily attributed to cardiovascular diseases.…”

Section: Discussionsupporting

confidence: 54%

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study

Liu,

Zhou,

Lian

et al. 2024

Hypertension

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BACKGROUND: The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear. METHODS: Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined. RESULTS: In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A , TET2 , RUNX1 , and ASXL1 . During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively ( P <0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257–3.816]; P =0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1β and interleukin-6 and lower interleukin-4 and IgG galactosylation levels. CONCLUSIONS: This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

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Section: Discussionsupporting

confidence: 54%

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study

Liu,

Zhou,

Lian

et al. 2024

Hypertension

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“…In summary, our findings support a key role for telomere maintenance in the development of CH, via mechanisms specific to the mutant gene driving clonal expansion. Since CH is a causal risk factor for progression to myeloid cancers and for a range of non-haematologic diseases, with larger CH clones conferring higher risks (Weeks et al 2023; Jaiswal 2020), therapeutic modulation of telomere biology might be an important focus as strategies for prevention and treatment of CH and its sequelae.…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of telomere length in 462,675 UK Biobank whole-genome sequences

Burren,

Dhindsa,

Deevi

et al. 2023

Preprint

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Telomeres protect the ends of chromosomes from damage, and genetic regulation of their length is associated with human disease and ageing. We developed a joint telomere length (TL) metric, combining both qPCR and whole genome sequencing (WGS) measurements across 462,675 UK Biobank participants that increased our ability to capture TL heritability by 36% (h2mean=0.058 to h2combined=0.079) and improved predictions of age. Exome-wide rare variant (minor allele frequency<0.001) and gene-level collapsing association studies identified 53 variants and 22 genes significantly associated with TL that included allelic series inACDandRTEL1. Five of the 31 rare-variant TL associated genes (16%) were also known drivers of clonal haematopoiesis (CH), prompting somatic variant analyses. Stratifying by CH clone size, we uncovered novel gene-specific associations with TL, including lengthened telomeres in individuals with largeSRSF2-mutant clones, in contrast to the progressive telomere shortening observed with increasing clonal expansions driven by other CH genes. Our findings demonstrate the impact of rare variants on TL with larger effects in genes associated with CH, a precursor of myeloid cancers and several other non-malignant human diseases. Telomere biology is likely to be an important focus for the prevention and treatment of these conditions.

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“…CCUS has been formally introduced in the 2022 revision of the WHO classification as a precursor myeloid disease state, alongside clonal hematopoiesis of indeterminate potential (CHIP) [7]. Formal prognostic models to assess the risk of individuals with CHIP or CCUS to progress to myeloid neoplasms are emerging [27,31].…”

Section: Enhanced Mds Diagnosis With Molecular Profilingmentioning

confidence: 99%

Novel precision medicine approaches and treatment strategies in hematological malignancies

et al. 2023

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Genetic testing has been applied for decades in clinical routine diagnostics of hematological malignancies to improve disease (sub)classification, prognostication, patient management, and survival. In recent classifications of hematological malignancies, disease subtypes are defined by key recurrent genetic alterations detected by conventional methods (i.e., cytogenetics, fluorescence in situ hybridization, and targeted sequencing). Hematological malignancies were also one of the first disease areas in which targeted therapies were introduced, the prime example being BCR::ABL1 inhibitors, followed by an increasing number of targeted inhibitors hitting the Achilles’ heel of each disease, resulting in a clear patient benefit. Owing to the technical advances in high‐throughput sequencing, we can now apply broad genomic tests, including comprehensive gene panels or whole‐genome and whole‐transcriptome sequencing, to identify clinically important diagnostic, prognostic, and predictive markers. In this review, we give examples of how precision diagnostics has been implemented to guide treatment selection and improve survival in myeloid (myelodysplastic syndromes and acute myeloid leukemia) and lymphoid malignancies (acute lymphoblastic leukemia, diffuse large B‐cell lymphoma, and chronic lymphocytic leukemia). We discuss the relevance and potential of monitoring measurable residual disease using ultra‐sensitive techniques to assess therapy response and detect early relapses. Finally, we bring up the promising avenue of functional precision medicine, combining ex vivo drug screening with various omics technologies, to provide novel treatment options for patients with advanced disease. Although we are only in the beginning of the field of precision hematology, we foresee rapid development with new types of diagnostics and treatment strategies becoming available to the benefit of our patients.

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Prediction of Risk for Myeloid Malignancy in Clonal Hematopoiesis

Cited by 139 publications

References 54 publications

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study

Genetic architecture of telomere length in 462,675 UK Biobank whole-genome sequences

Novel precision medicine approaches and treatment strategies in hematological malignancies

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