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Antineoplásicos Inmunológicos , Hematopoyesis Clonal , Inmunoterapia Adoptiva , Linfoma de Células B , Linfoma de Células T , Neoplasias Primarias Secundarias , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/inmunología , Receptores Quiméricos de Antígenos/inmunología , Riesgo , Hematopoyesis Clonal/genética , Hematopoyesis Clonal/inmunología , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/virología , Herpesvirus Humano 4/aislamiento & purificación , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunologíaRESUMEN
There is no general consensus on the set of mutations capable of driving the age-related clonal expansions in hematopoietic stem cells known as clonal hematopoiesis, and current variant classifications typically rely on rules derived from expert knowledge. In this issue of Cancer Discovery, Damajo and colleagues trained and validated machine learning models without prior knowledge of clonal hematopoiesis driver mutations to classify somatic mutations in blood for 12 genes in a purely data-driven way. See related article by Demajo et al., p. 1717 (9).
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Hematopoyesis Clonal , Aprendizaje Automático , Mutación , Humanos , Hematopoyesis Clonal/genéticaRESUMEN
Recent advances in imaging suggested that spatial organization of hematopoietic cells in their bone marrow microenvironment (niche) regulates cell expansion, governing progression, and leukemic transformation of hematological clonal disorders. However, our ability to interrogate the niche in pre-malignant conditions has been limited, as standard murine models of these diseases rely largely on transplantation of the mutant clones into conditioned mice where the marrow microenvironment is compromised. Here, we leveraged live-animal microscopy and ultralow dose whole body or focal irradiation to capture single cells and early expansion of benign/pre-malignant clones in the functionally preserved microenvironment. 0.5 Gy whole body irradiation (WBI) allowed steady engraftment of cells beyond 30 weeks compared to non-conditioned controls. In-vivo tracking and functional analyses of the microenvironment showed no change in vessel integrity, cell viability, and HSC-supportive functions of the stromal cells, suggesting minimal inflammation after the radiation insult. The approach enabled in vivo imaging of Tet2+/- and its healthy counterpart, showing preferential localization within a shared microenvironment while forming discrete micro-niches. Notably, stationary association with the niche only occurred in a subset of cells and would not be identified without live imaging. This strategy may be broadly applied to study clonal disorders in a spatial context.
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Hematopoyesis Clonal , Nicho de Células Madre , Animales , Ratones , Nicho de Células Madre/efectos de la radiación , Células Madre Hematopoyéticas/efectos de la radiación , Células Madre Hematopoyéticas/metabolismo , Irradiación Corporal Total , Ratones Endogámicos C57BL , Rastreo Celular/métodos , Microscopía Intravital/métodosRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.
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Hematopoyesis Clonal , Dioxigenasas , Humanos , Hematopoyesis Clonal/genética , Masculino , Femenino , Anciano , Estudios Longitudinales , Persona de Mediana Edad , Dioxigenasas/genética , ADN Metiltransferasa 3A , Factores de Empalme de ARN/genética , Factores de Empalme de ARN/metabolismo , Aterosclerosis/genética , Factores de Riesgo , Secuenciación del Exoma , Proteínas de Unión al ADN/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Envejecimiento/genética , Incidencia , MutaciónRESUMEN
Clonal hematopoiesis (CH) is an age-related process whereby hematopoietic stem and progenitor cells (HSPCs) acquire mutations that lead to a proliferative advantage and clonal expansion. The most commonly mutated genes are epigenetic regulators, DNA damage response genes, and splicing factors, which are essential to maintain functional HSPCs and are frequently involved in the development of hematologic malignancies. Established risk factors for CH, including age, prior cytotoxic therapy, and smoking, increase the risk of acquiring CH and/or may increase CH fitness. CH has emerged as a novel risk factor in many age-related diseases, such as hematologic malignancies, cardiovascular disease, diabetes, and autoimmune disorders, among others. Future characterization of the mechanisms driving CH evolution will be critical to develop preventative and therapeutic approaches.
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Hematopoyesis Clonal , Neoplasias Hematológicas , Humanos , Hematopoyesis Clonal/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/metabolismo , Mutación , Células Madre Hematopoyéticas/metabolismo , Epigénesis Genética , Factores de Riesgo , AnimalesRESUMEN
As individuals age, their hematopoietic stem cells can sporadically acquire genetic mutations, known as clonal hematopoiesis. Although most of these genomic aberrations are of little consequence, particular changes in certain contexts can lead to the development of hematologic malignancies, such as myelodysplastic syndromes and acute myeloid leukemia. Owing to its pervasive extrahematologic interactions, clonal hematopoiesis is a recognized risk factor for and is causally implicated in the development of several chronic diseases of aging and/or inflammation, such as atherosclerotic cardiovascular disease. Here, we provide a review of the diagnosis and clinical implications of clonal hematopoiesis, as well as evolving management strategies in the absence of formal consensus guidelines.
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Hematopoyesis Clonal , Humanos , Síndromes Mielodisplásicos/terapia , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Mutación , Manejo de la Enfermedad , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/diagnóstico , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patologíaRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations. While CHIP is typically asymptomatic, it has garnered substantial attention due to its association with the pathogenesis of multiple disease conditions, including cardiovascular disease (CVD) and hematological malignancies. In this Review, we will discuss seminal and recent studies that have advanced our understanding of mechanisms that drive selection for mutant HSPCs in the BM niche. Next, we will address recent studies evaluating potential relationships between the clonal dynamics of CHIP and hematopoietic development across the lifespan. Next, we will examine the roles of systemic factors that can influence hematopoietic stem cell (HSC) fitness, including inflammation, and exposures to cytotoxic agents in driving selection for CHIP clones. Furthermore, we will consider how - through their impact on the BM niche - lifestyle factors, including diet, exercise, and psychosocial stressors, might contribute to the process of somatic evolution in the BM that culminates in CHIP. Finally, we will review the role of old age as a major driver of selection in CHIP.
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Hematopoyesis Clonal , Células Madre Hematopoyéticas , Nicho de Células Madre , Humanos , Células Madre Hematopoyéticas/metabolismo , Hematopoyesis Clonal/genética , Animales , Médula Ósea/metabolismo , MutaciónRESUMEN
The cardiovascular complications of atherosclerosis are thought to arise from an inflammatory response to the accumulation of cholesterol-rich lipoproteins in the arterial wall. The positive outcome of CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) provided key evidence to support this concept and suggested that inflammasomes and IL-1ß are important inflammatory mediators in human atherosclerotic cardiovascular diseases (ACVD). In specific settings NLRP3 or AIM2 inflammasomes can induce inflammatory responses in the arterial wall and promote the formation of unstable atherosclerotic plaques. Clonal hematopoiesis (CH) has recently emerged as a major independent risk factor for ACVD. CH mutations arise during ageing and commonly involves variants in genes mediating epigenetic modifications (TET2, DNMT3A, ASXL1) or cytokine signaling (JAK2). Accumulating evidence points to the role of inflammasomes in the progression of CH-induced ACVD events and has shed light on the regulatory pathways and possible therapeutic approaches that specifically target inflammasomes in atherosclerosis. Epigenetic dynamics play a vital role in regulating the generation and activation of inflammasome components by causing changes in DNA methylation patterns and chromatin assembly. This review examines the genetic and epigenetic regulation of inflammasomes, the intersection of macrophage cholesterol accumulation with inflammasome activation and their roles in atherosclerosis. Understanding the involvement of inflammasomes in atherosclerosis pathogenesis may lead to customized treatments that reduce the burden of ACVD.
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Aterosclerosis , Epigénesis Genética , Inflamasomas , Humanos , Inflamasomas/metabolismo , Aterosclerosis/genética , Aterosclerosis/metabolismo , Aterosclerosis/inmunología , Animales , Hematopoyesis Clonal/genética , Metilación de ADN , Macrófagos/metabolismo , Macrófagos/inmunología , Colesterol/metabolismo , Transducción de Señal , Predisposición Genética a la EnfermedadRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular (CV) disease in the general population. Currently, it is unclear whether this association is observed in large clinical trial cohorts with a high burden of existing CV disease or whether CV therapies can mitigate CHIP-associated CV risk. To address these questions, we studied 63,700 patients from five randomized trials that tested established therapies for CV disease, including treatments targeting the proteins PCSK9, SGLT2, P2Y12 and FXa. During a median follow-up of 2.5 years, 7,453 patients had at least one CV event (CV death, myocardial infarction (MI), ischemic stroke or coronary revascularization). The adjusted hazard ratio (aHR) for CV events for CHIP+ patients was 1.07 (95% CI: 0.99-1.16, P = 0.08), with consistent risk estimates across each component of CV risk. Significant heterogeneity in the risk of MI was observed, such that CHIP+ patients had a 30% increased risk of first MI (aHR = 1.31 (1.05-1.64), P = 0.02) but no increased risk of recurrent MI (aHR = 0.94 (0.79-1.13), Pint = 0.008), as compared to CHIP- patients. Moreover, no significant heterogeneity in treatment effect between individuals with and without CHIP was observed for any of the therapies studied in the five trials. These results indicate that in clinical trial populations, CHIP is associated with incident but not recurrent coronary events and that the presence of CHIP does not appear to identify patients who will derive greater benefit from commonly used CV therapies.
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Enfermedades Cardiovasculares , Hematopoyesis Clonal , Humanos , Hematopoyesis Clonal/genética , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Infarto del Miocardio/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Factores de RiesgoRESUMEN
The rising prevalence of obesity-related illnesses, such as metabolic steatotic liver disease (MASLD), represents a significant global public health concern. This disease affects approximately 30 % of the adult population and is the result of metabolic abnormalities rather than alcohol consumption. Additionally, MASLD is associated with an increased risk of cardiovascular disease (CVD), chronic liver disease, and a variety of cancers, particularly gastrointestinal cancers. Clonal hematopoiesis (CH) is a biological state characterized by the expansion of a population of blood cells derived from a single mutated hematopoietic stem cell. The presence of CH in the absence of a diagnosed blood disorder or cytopenia is known as clonal hematopoiesis of indeterminate potential (CHIP), which itself increases the risk of hematological malignancies and CVD. Steatotic liver disease may also complicate the clinical course of cancer patients receiving antineoplastic agents, a condition referred to as chemotherapy induced steatohepatitis (CASH). This review will present an outline of the various aspects of MASLD, including complications. Furthermore, it will summarize the existing knowledge on the emerging association between CHIP and MASLD and present the available data on patient cases with concurrent MASLD and hematological neoplasms. Finally, it will provide a brief overview of the chemotherapeutic drugs associated with CASH, the underlying pathophysiologic mechanisms and their clinical implications.
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Antineoplásicos , Hígado Graso , Neoplasias Hematológicas , Humanos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Hígado Graso/inducido químicamente , Hígado Graso/patología , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Hematopoyesis ClonalRESUMEN
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
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Bancos de Muestras Biológicas , Polimorfismo de Nucleótido Simple , Telómero , Secuenciación Completa del Genoma , Humanos , Telómero/genética , Reino Unido , Secuenciación Completa del Genoma/métodos , Homeostasis del Telómero/genética , Masculino , Femenino , Hematopoyesis Clonal/genética , Estudio de Asociación del Genoma Completo/métodos , Anciano , ADN Helicasas/genética , Persona de Mediana Edad , Biobanco del Reino UnidoRESUMEN
BACKGROUND: Cardiac surgery triggers sterile innate immune responses leading to postoperative complications. Clonal hematopoiesis (CH) is associated with short-term inflammation-mediated outcomes after cardiac surgery. The impact of CH on long-term postoperative outcomes remains unknown. METHODS AND RESULTS: In this cohort study, patients undergoing elective cardiac surgery were included from January 2017 to September 2019. Patients were screened for CH using a predefined gene panel of 19 genes. Recorded clinical events were all-cause death, major adverse cardiac and cerebral events including cardiovascular death, myocardial infarction or nonscheduled coronary revascularization, stroke, and hospitalization for acute heart failure. The primary study outcome was time to a composite criterion including all-cause mortality and major adverse cardiac and cerebral events. Among 314 genotyped patients (median age: 67 years; interquartile range 59-74 years), 139 (44%) presented with CH, based on a variant allelic frequency ≥1%. Carriers of CH had a higher proportion of patients with a history of atrial fibrillation (26% for CH versus 17% for non-CH carriers, P=0.022). The most frequently mutated genes were DNMT3A, TET2, and ASXL1. After a median follow-up of 1203 [813-1435] days, the primary outcome occurred in 50 patients. After multivariable adjustment, CH was independently associated with a higher risk for the primary outcome (hazard ratio, 1.88 [95% CI, 1.05-3.41], P=0.035). Most adverse events occurred in patients carrying TET2 variants. CONCLUSIONS: In patients undergoing cardiac surgery, CH is frequent and associated with a 2-fold increased long-term risk for major adverse clinical outcomes. CH is a novel risk factor for long-term postcardiac surgery complications and might be useful to personalize management decisions. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03376165.
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Procedimientos Quirúrgicos Cardíacos , Hematopoyesis Clonal , Complicaciones Posoperatorias , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Hematopoyesis Clonal/genética , Dioxigenasas/genética , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Proteínas de Unión al ADN/genética , Mutación , Complicaciones Posoperatorias/genética , Complicaciones Posoperatorias/epidemiología , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Medición de Riesgo/métodos , Factores de Riesgo , Factores de TiempoRESUMEN
The number of somatic mutations among all tissues increases along with age. This process was well-studied in hematopoietic stem cells (HSCs). Some mutations lead to a proliferative advantage and expansion of HSCs to form a dominant clone. Clonal hematopoiesis is general in the elderly population. Clonal hematopoiesis of indeterminate potential (CHIP) is a more common phenomenon in the elderly and is defined as somatic mutations in clonal blood cells without any other hematological malignancies. The development of CHIP is an independent risk factor for hematological malignancies, cardiovascular diseases, and reduced overall survival. CHIP is frequently associated with mutations in DNMT3A and TET2 genes involved in DNA methylation. The epigenetic human body clocks have been developed based on the age-related changes in methylation, making it possible to detect epigenetic aging. The combination of epigenetic aging and CHUP is associated with adverse health outcomes. Further research will reveal the significance of clonal hematopoiesis and CHIP in aging, acquiring various diseases, and determining the feasibility of influencing the mutagenic potential of clones.
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Envejecimiento , Hematopoyesis Clonal , Epigénesis Genética , Humanos , Envejecimiento/fisiología , Envejecimiento/genética , Hematopoyesis Clonal/genética , Mutación , Metilación de ADN , Células Madre Hematopoyéticas/metabolismo , ADN Metiltransferasa 3A , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/diagnóstico , Dioxigenasas , Hematopoyesis/genética , Hematopoyesis/fisiología , ADN (Citosina-5-)-Metiltransferasas/genéticaRESUMEN
Clonal haematopoiesis of indeterminate potential (CHIP) has been associated with many adverse health outcomes. However, further research is required to understand the critical genes and pathways relevant to CHIP subtypes, evaluate how CHIP clones evolve with time, and further advance functional characterisation and therapeutic studies. Large epidemiological studies are well placed to address these questions but often collect saliva rather than blood from participants. Paired saliva- and blood-derived DNA samples from 94 study participants were sequenced using a targeted CHIP-gene panel. The ten genes most frequently identified to carry CHIP-associated variants were analysed. Fourteen unique variants associated with CHIP, ten in DNMT3A, two in TP53 and two in TET2, were identified with a variant allele fraction (VAF) between 0.02 and 0.2 and variant depth ≥ 5 reads. Eleven of these CHIP-associated variants were detected in both the blood- and saliva-derived DNA sample. Three variants were detected in blood with a VAF > 0.02 but fell below this threshold in the paired saliva sample (VAF 0.008-0.013). Saliva-derived DNA is suitable for detecting CHIP-associated variants. Saliva can offer a cost-effective biospecimen that could both advance CHIP research and facilitate clinical translation into settings such as risk prediction, precision prevention, and treatment monitoring.
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Hematopoyesis Clonal , ADN Metiltransferasa 3A , Proteínas de Unión al ADN , Saliva , Humanos , Saliva/metabolismo , Hematopoyesis Clonal/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Femenino , Masculino , ADN/genética , Dioxigenasas/genética , Proteínas Proto-Oncogénicas/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Adulto , Persona de Mediana Edad , Anciano , AlelosRESUMEN
Therapy-related myeloid neoplasms (t-MN) are characterized by aggressive features and a dismal prognosis. Recent evidence suggests a higher incidence of t-MN in individuals harboring clonal hematopoiesis of indeterminate potential (CHIP). In order to gain insight into CHIP-driven malignant progression, we gathered data from ten published reports with available detailed patient characteristics at the time of primary malignancy and t-MN development. Detailed clinical and molecular information on primary malignancy and t-MN were available for 109 patients: 43% harbored at least one somatic mutation at the time of the primary malignancy. TET2 and TP53 mutations showed an increasing variant allele frequency from CHIP to t-MN. ASXL1-associated CHIP significantly correlated with the emergence of TET2 and CEBPA mutations at t-MN, as well as U2AF1-driven CHIP with EZH2 mutation and both IDH2 and SRSF2-driven CHIP with FLT3 mutation. DNMT3A-driven CHIP correlated with a lower incidence of TP53 mutation at t-MN. In contrast, TP53-driven CHIP correlated with a complex karyotype and a lower tendency to acquire new mutations at t-MN. Patients with multiple myeloma as their first malignancy presented a significantly higher rate of TP53 mutations at t-MN. The progression from CHIP to t-MN shows different scenarios depending on the genes involved. A deeper knowledge of CHIP progression mechanisms will allow a more reliable definition of t-MN risk.
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Mutación , Neoplasias Primarias Secundarias , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hematopoyesis Clonal/genética , Progresión de la Enfermedad , Trastornos Mieloproliferativos/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiologíaRESUMEN
Clonal hematopoiesis of indeterminate potential (CHIP) is a common risk factor for hematologic malignancies and cardiovascular diseases. This study aimed to investigate the association between CHIP-related mutations and symptomatic heart failure (HF) in patients diagnosed with acute myeloid leukemia (AML). A total of 563 patients with newly diagnosed AML who underwent DNA sequencing of bone marrow before treatment were retrospectively investigated. Cox proportional hazard regression models and Fine and Gray's subdistribution hazard regression models were used to assess the association between CHIP-related mutations and symptomatic HF. A total of 79.0% patients had at least 1 CHIP-related mutation; the most frequent mutations were DNMT3A, ASXL1, and TET2. A total of 51 patients (9.1%) developed symptomatic HF. The incidence of symptomatic HF was more frequent in patients with DNMT3A mutations (p <0.01), with a 1-year cumulative incidence of symptomatic HF in patients with DNMT3A mutations of 11.4%, compared with 3.9% in patients with wild-type DNMT3A (p <0.01). After adjustment for age and anthracyclines dose, DNMT3A mutations remained independently correlated with HF (hazard ratio 2.32, 95% confidence interval 1.26 to 4.29, p = 0.01). In conclusion, in patients with AML, the presence of DNMT3A mutations was associated with a twofold increased risk for symptomatic HF, irrespective of age and anthracyclines use.
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Hematopoyesis Clonal , ADN (Citosina-5-)-Metiltransferasas , ADN Metiltransferasa 3A , Insuficiencia Cardíaca , Leucemia Mieloide Aguda , Mutación , Humanos , Masculino , Femenino , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/epidemiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/epidemiología , Persona de Mediana Edad , Hematopoyesis Clonal/genética , Estudios Retrospectivos , ADN (Citosina-5-)-Metiltransferasas/genética , Anciano , Adulto , Incidencia , Dioxigenasas , Proteínas de Unión al ADN/genética , Factores de Riesgo , Proteínas Represoras/genética , Proteínas Proto-Oncogénicas/genéticaRESUMEN
PURPOSE: Thrombocytopenia is a relatively common dose-limiting toxicity during peptide receptor radionuclide therapy (PRRT) in patients with NET. Although uncommon, some patients develop persistent cytopenia and eventually therapy-related myeloid neoplasm (t-MN), which has a dismal prognosis. As the indications for PRRT are expanding, it is important to investigate factors that may predict cytopenias during/after PRRT. We prospectively evaluated the prevalence of clonal hematopoiesis (CH) and cytopenia in patients with NET undergoing PRRT. MATERIALS AND METHODS: Patients with metastatic NET with plan to receive four cycles of lutetium-177 were enrolled. CH was evaluated before PRRT using a panel of 220 genes with a targeted depth of ≥1,000×. Patients were followed during PRRT and every 3 months thereafter. RESULTS: Of 37 patients enrolled, the median age was 68 years and 51.4% were male. Previous treatment exposures included alkylating agents in 30%, platinum agents in 8%, and external radiation in 13%. CH was detected in 35.1% using a variant allele frequency (VAF) cutoff of ≥2% and 45.9% with a VAF of ≥1%. The most common mutations were in age-related genes (DNMT3A, TET2). CH was not associated with anemia or neutropenia; however, it was associated with lower platelet count at baseline and more time spent in a thrombocytopenic state during/after PRRT. Five patients had bone marrow biopsies (BMBs) because of sustained hematologic dysfunction post-PRRT, and of those, diagnoses included clonal cytopenia of undetermined significance (CCUS) in three and idiopathic cytopenia of undetermined significance (ICUS) in two. CONCLUSION: CH is present in 35.1% of patients with NET and is associated with thrombocytopenia risk during PRRT. Future studies with long-term follow-up will delineate whether CH might be a predictor for higher risk of t-MN after PRRT.