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; Gibson, Christopher J.; Bick, Alexander; Griffin, Gabriel K.; Jaiswal, Siddhartha; Malcovati, Luca; Natarajan, Pradeep; Ebert, Benjamin L.

doi:10.1182/blood-2022-158960

Cited by 30 publications

(78 citation statements)

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“…In addition, data presented at ASH 2022 indicated that the most frequent mutation in CHIP/CCUS is DNMT3A . This is associated with a relative low frequency of progression to MN 35 . This data may allow proper selection of individuals with CHIP/CCUS for therapy or more intensive interventions.…”

Section: Diagnosismentioning

confidence: 92%

Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management

Garcia‐Manero

2023

American J Hematol

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Disease overview: The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older males and in individuals with prior exposure to cytotoxic therapy. Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry, and molecular genetics is usually complementary and may help refine diagnosis. A new WHO classification of MDS was proposed in 2022. Under this classification, MDS is now termed myelodysplastic neoplasms. Risk-stratification: Prognosis of patients with MDS can be calculated using a number of scoring systems. All these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. The most commonly accepted system is the Revised International Prognostic Scoring System (IPSS-R). Recently, genomic data has been incorporated resulting in the new IPSS-M classification.Risk-adapted therapy: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts, cytogenetic and mutational profiles, comorbidities, potential for allogeneic stem cell transplantation (alloSCT), and prior exposure to hypomethylating agents (HMA). Goals of therapy are different in lower risk patients than in higher risk and in those with HMA failure. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. In 2020, two agents were approved in the US for patients with MDS: luspatercept and oral decitabine/cedazuridine. In addition, currently other available therapies include growth factors, lenalidomide, HMAs, intensive chemotherapy, and alloSCT. A number of phase 3 combinations studies have been completed or are ongoing at the time of this report.At the present time there are no approved interventions for patients with progressive or refractory disease particularly after HMA based therapy. In 2021, several reports indicated improved outcomes with alloSCT in MDS as well as early results from clinical trials using targeted intervention.

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Section: Diagnosismentioning

confidence: 92%

Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management

Garcia‐Manero

2023

American J Hematol

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“…Studies have also assessed risk for AML progression and found the highest effect size with TP53 91 (HR 12.5, 95% CI 5–160.5), U2AF1 91 (HR 7.9, 95% CI 4.1–192.2), IDH 92 (both IDH1 and IDH2 , HR 28.5, 95% CI 2.5–879.1), and splicing genes 92 ( SF3B1, SRSF2 and U2AF1 , HR 7.4, 95% CI 1.7–32.2) CH. Individualized models for clone‐specific expansion in the context of extrinsic factors can provide valuable clinical information for decisions such as pursuing adjuvant chemotherapy and hematopoietic stem cell transplantation among others 93 . Weeks et al have recently presented a clonal hematopoiesis risk score (CHRS) which uses clinical/hematopoietic (red cell distribution width, mean corpuscular volume, cytopenias, and age) and genetic variables (single DNMT3A , high risk mutations, mutation number, and variant allele fraction) to divide CH patients into low, intermediate, and high risk groups for progression to myeloid neoplasms 93 .…”

Section: Clonal Fitness and Selection Pressuresmentioning

confidence: 99%

“…Individualized models for clone‐specific expansion in the context of extrinsic factors can provide valuable clinical information for decisions such as pursuing adjuvant chemotherapy and hematopoietic stem cell transplantation among others 93 . Weeks et al have recently presented a clonal hematopoiesis risk score (CHRS) which uses clinical/hematopoietic (red cell distribution width, mean corpuscular volume, cytopenias, and age) and genetic variables (single DNMT3A , high risk mutations, mutation number, and variant allele fraction) to divide CH patients into low, intermediate, and high risk groups for progression to myeloid neoplasms 93 . Such models can be further refined by incorporating extrinsic factors such as type of chemotherapy and/or radiation exposure and smoking among others.…”

Section: Clonal Fitness and Selection Pressuresmentioning

confidence: 99%

“…IDH92 (both IDH1 and IDH2, HR 28.5, 95% CI 2.5-879.1), and splicing genes92 (SF3B1, SRSF2 and U2AF1, HR 7.4, 95% CI 1.7-32.2) CH. Individualized models for clone-specific expansion in the context of extrinsic factors can provide valuable clinical information for decisions such as pursuing adjuvant chemotherapy and hematopoietic stem cell transplantation among others 93. …”

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confidence: 99%

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Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

Mangaonkar

Patnaik

2023

American J Hematol

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Condition Overview: Clonal hematopoiesis (CH) refers to age-associated expansion of somatic variants in hematopoietic stem and progenitor cells (HSPC).Diagnosis: CH of indeterminate potential (CHIP) is operationally defined as pathogenic variants in HSPCs at a variant allele frequency ≥2%.Clinical Associations: CH is associated with increased occurrence of several hematological conditions such as cytopenias (also called clonal cytopenia of undetermined significance), hematological (predominantly myeloid but also lymphoid) neoplasms, cytosis (including monocytosis), and non-hematological conditions such as atherosclerotic cardiovascular and cerebrovascular disease, ischemic congestive heart failure, venous thromboembolism, type 2 diabetes mellitus, chronic obstructive pulmonary disease, osteoporosis, gout, with a potential protective effect in Alzheimer's disease (AD).Management Recommendations: As of now, there is limited prospective data for CH testing; however, CH detection is becoming increasingly prevalent due to ubiquitous use of somatic and germline NGS testing. This in addition to data suggesting that therapy related myeloid neoplasm (tMN) in many cases is preceded by the detection of CH clones, has led to the establishment of CH clinics at several institutions. At our institution, on a research basis, we currently recommend testing for CH for individuals with persistent (≥4 months) unexplained cytopenias, in patients with malignancies prior to adjuvant cytotoxic chemotherapy and/or radiation or radionuclide therapy, screening prior to autologous hematopoietic stem cell transplantation and chimeric antigen receptor T cell (CAR-T) therapy and to assess as to whether or not, potential germline mosaic variants actually represent CH. | INTRODUCTIONClonal hematopoiesis (CH) is defined by the detection of somatic variants in hematopoietic stem and progenitor cells, with the potential to expand over time, based on clonal selection pressures. CH was first identified by observing non-random chromosome X-inactivation patterns in the myeloid compartment of healthy women increasing with age, suggesting age-related clonal expansions, 1,2 and confirmed subsequently to be secondary to somatic TET2 mutations, laying the groundwork for future studies in CH involving large numbers of biobanked samples. 3 Interestingly, CH mutations predominantly affect the epigenetic regulator genes (most commonly; DNMT3A, TET2 and ASXL1) and also occur in myeloid neoplasms, suggesting that CH is a neoplastic precursor event, akin to monoclonal gammopathy in plasma

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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 30 publications

References 0 publications

Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management

Myelodysplastic syndromes: 2023 update on diagnosis, risk‐stratification, and management

Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

Novel precision medicine approaches and treatment strategies in hematological malignancies

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