Clonal Hematopoiesis and Inflammation in the VasculaturE (CHIVE): a prospective, longitudinal cohort and biorepository.

Clonal hematopoiesis (CH) is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. Increasingly available genetic testing has made incidental discovery of CH clinically common, yet evidence-based guidelines and effective management strategies to prevent adverse CH health outcomes are lacking. To address this gap, the prospective CHIVE registry and biorepository was created to identify and monitor individuals at risk, support multidisciplinary CH clinics, and to refine standards of practice for CH risk mitigation. Data from the first 181 patients enrolled in this registry recapitulate the molecular epidemiology of CH from biobank scale retrospective studies, with DNMT3A, TET2, ASXL1, and TP53 as the most commonly mutated genes. CH patients had higher rates of end organ dysfunction, in particular chronic kidney disease (p=0.001). Among patients with CH, variant allele frequency was independently associated with presence of cytopenias (p=0.008) and progression to hematologic malignancy (p=0.010), while other common high-risk CH clone features were not clear. Notably, accumulation of multiple distinct high-risk clone features was also associated with cytopenias (p=0.013) and hematologic malignancy progression (p=0.004), supporting a recently published CH risk score. Surprisingly, ~30% of patients enrolled in CHIVE from CH clinics were adjudicated as not having CHIP, highlighting the need for molecular standards and purpose-built assays in this field. Maintenance of this well-annotated cohort and continued expansion of CHIVE to multiple institutions is underway and will be critical to understand how to thoughtfully care for this patient population.

Carcinoid Heart Disease Management: A Multi-Disciplinary Collaboration.

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate.

Patient-specific comorbidities as prognostic variables for survival in myelofibrosis.

Treatment decisions in primary myelofibrosis (PMF) are guided by numerous prognostic systems. Patient-specific comorbidities have influence on treatment-related survival and are considered in clinical contexts but have not been routinely incorporated into current prognostic models. We hypothesized that patient-specific comorbidities would inform prognosis and could be incorporated into a quantitative score. All patients with PMF or secondary myelofibrosis with available DNA and comprehensive electronic health record (EHR) data treated at Vanderbilt University Medical Center between 1995 and 2016 were identified within Vanderbilt's Synthetic Derivative and BioVU Biobank. We recapitulated established PMF risk scores (eg, Dynamic International Prognostic Scoring System [DIPSS], DIPSS plus, Genetics-Based Prognostic Scoring System, Mutation-Enhanced International Prognostic Scoring System 70+) and comorbidities through EHR chart extraction and next-generation sequencing on biobanked peripheral blood DNA. The impact of comorbidities was assessed via DIPSS-adjusted overall survival using Bonferroni correction. Comorbidities associated with inferior survival include renal failure/dysfunction (hazard ratio [HR], 4.3; 95% confidence interval [95% CI], 2.1-8.9; P = .0001), intracranial hemorrhage (HR, 28.7; 95% CI, 7.0-116.8; P = 2.83e-06), invasive fungal infection (HR, 41.2; 95% CI, 7.2-235.2; P = 2.90e-05), and chronic encephalopathy (HR, 15.1; 95% CI, 3.8-59.4; P = .0001). The extended DIPSS model including all 4 significant comorbidities showed a significantly higher discriminating power (C-index 0.81; 95% CI, 0.78-0.84) than the original DIPSS model (C-index 0.73; 95% CI, 0.70-0.77). In summary, we repurposed an institutional biobank to identify and risk-classify an uncommon hematologic malignancy by established (eg, DIPSS) and other clinical and pathologic factors (eg, comorbidities) in an unbiased fashion. The inclusion of comorbidities into risk evaluation may augment prognostic capability of future genetics-based scoring systems.

High burden of clonal hematopoiesis in first responders exposed to the World Trade Center disaster.

The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to aerosolized dust, gases and potential carcinogens. Clonal hematopoiesis (CH) is defined as the acquisition of somatic mutations in blood cells and is associated with smoking and exposure to genotoxic stimuli. Here we show that deep targeted sequencing of blood samples identified a significantly higher proportion of WTC-exposed first responders with CH (10%; 48 out of 481) when compared with non-WTC-exposed firefighters (6.7%; 17 out of 255; odds ratio, 3.14; 95% confidence interval, 1.64-6.03; P = 0.0006) after controlling for age, sex and race/ethnicity. The frequency of somatic mutations in WTC-exposed first responders showed an age-related increase and predominantly affected DNMT3A, TET2 and other CH-associated genes. Exposure of lymphoblastoid cells to WTC particulate matter led to dysregulation of DNA replication at common fragile sites in vitro. Moreover, mice treated with WTC particulate matter developed an increased burden of mutations in hematopoietic stem and progenitor cell compartments. In summary, the high burden of CH in WTC-exposed first responders provides a rationale for enhanced screening and preventative efforts in this population.

The evolving role of next generation sequencing in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are clonal haematological disorders characterized by haematopoietic cell dysplasia, peripheral blood cytopenias, and a predisposition for developing acute myeloid leukaemia (AML). Cytogenetics have historically been important in diagnosis and prognosis in MDS, but the growing accessibility of next generation sequencing (NGS) has led to growing research in the roles of molecular genetic variation on clinical decision-making in these disorders. Multiple genes have been previously studied and found to be associated with specific outcomes or disease types within MDS and knowledge of mutations in these genes provides insight into previously defined MDS subtypes. Knowledge of these mutations also informs development of novel therapies in the treatment of MDS. The precise role of NGS in the diagnosis, prognosis and monitoring of MDS remains unclear but the improvements in NGS technology and accessibility affords clinicians an additional practice tool to provide the best care for patients.

Refractory macrocytic anemias in patients with clonal hematopoietic disorders and isolated mutations of the spliceosome gene ZRSR2.

Although mutations in RNA splicing genes occur frequently in patients with clonal cytopenias of unknown significance (CCUS) and myelodysplastic syndromes (MDS), very often additional common myeloid gene driver mutations are present at diagnosis. Thus, the clinical significance of isolated mutations in the most commonly mutated RNA splicing genes remains unknown. Here we report five unusual patients with an isolated mutation causing a loss of function of ZRSR2, a protein required for recognition of a functional 3' splice site. Two of the patients had a diagnosis of CCUS and three patients had an MDS disorder characterized by low risk features and absence of complex cytogenetic abnor-malities. Notably, all five cases were characterized predominantly by macrocytic anemia. In addition, one CCUS patient followed for more than 15 years with a transfusion dependent macrocytic anemia was found to have an inactivating ZRSR2 mutation with an allele frequency of >60%. We conclude that the common clinical features of patients with an isolated mutation of ZRSR2 are a macrocytic anemia without leukopenia, thrombocytopenia or an increase in marrow blast percentage. At least in some cases, the presence of an isolated ZRSR2 mutation can accompany a dominant hematopoietic clone with a low risk for transformation to frank dysplasia or acute leukemia.