Clonal Hematopoiesis and Inflammation in the Vasculature (CHIVE), a Prospective, Longitudinal Clonal Hematopoiesis Cohort and Biorepository

Abstract

Introduction Clonal hematopoiesis (CH), the expansion of a clonal population of hematopoietic cells, is an age-associated phenomenon leading to increased risk of both hematologic malignancy and non-malignant organ dysfunction. There have been significant advances in our understanding of the underlying pathophysiology of CH in recent years. However, additional studies are needed to better understand clinical trajectories and optimal care of patients with CH. To address this gap, the prospective, longitudinal CHIVE (Clonal Hematopoiesis and Inflammation in the VasculaturE) registry and biorepository was created to support multidisciplinary CH clinics. Methods Adults without active hematological malignancy who were clinically identified to have CH or who were at risk for CH were sequentially enrolled utilizing a multidisciplinary referral approach between October 2020 to April 2023 at Vanderbilt University Medical Center (VUMC). Research samples were procured at the time of routine clinical blood draws or bone marrow biopsies and stored in a newly established biorepository, equipped to store DNA, plasma, and viably cryopreserved cells to enable a spectrum of downstream applications. Specimens were sequenced on a highly cost efficient (~$6/sample) targeted next generation sequencing capture panel that identified mutations residing in the 24 most frequently mutated CHIP genes.The VUMC CH clinic, which serves as a referral pool, were included in Arm A of CHIVE (n=57). We also sought out a population at risk for CH which included patients over 18 years of age with a history of solid tumor, cardiovascular disease, renal disease, rheumatologic disease, or diabetes, who were included in Arm B (n=122). Patients from Arm A or B were included in the CH-positive (CH+) group if they met criteria for CH on the research assay at any time during their enrollment in the study. All other genotyped patients who were not found to have CH by the research assay, regardless of their clinical CH status at study enrollment, were included in the CH-negative (CH-) group.Anthropometric data and clinical assessments, including laboratories and cardiovascular studies obtained in the course of routine clinical care were extracted from the electronic health record, and recorded and maintained in the CHIVE database. Results 261 patients were approached for consent to enroll in CHIVE and 179 were ultimately enrolled. More than one half (54%) of all participants had a CH mutation (CH+) and of those, 49.5% were female. Median age of CH+ patients was 71.9 (IQR 64.0-77.5). DNMT3A (n=44) and TET2 (n=39) were the most commonly mutated genes, while variant allele fractions (VAF) ranged from 2.1 - 79.8% (Figure 1). 246 samples were serial samples collected from 89 patients at regular intervals. Significantly more CH+ patients had a diagnosis of coronary artery disease compared to CH- patients (55.7% vs 32.9%, p=0.004). CH+ patients also had increased rates of hypertension and heart failure compared to the CH- group (p<0.001, 0.035, respectively). Laboratory evaluation showed CH+ patients to have a lower median white blood cell count, hemoglobin, and platelets, and elevated blood urea nitrogen values compared to CH- patients, differences that did not meet statistical significance. 8.2% of the CH+ patients progressed to frank hematologic malignancy over the course of the 2.5-year study (Table 1). Eight of the 97 CH+ and 2 of the 82 CH- patients died over the course of the study period resulting in a trend toward decreased survival in CH+ patients (p=0.112). Conclusions We demonstrate the feasibility of a prospective, observational study of CH patients utilizing a robust referral network to support both clinical care and translational research. A well-genotyped and phenotyped cohort of CH patients will be critical to future translational research efforts and clinical trials - a key function of our study design. Early clinical findings from our cohort recapitulate large scale retrospective datasets where CH patients are at an increased risk of development of hematologic malignancy, end organ damage, and all-cause mortality. Scaling this resource in collaboration with other centers is underway and will ultimately enable the development of clinical guidelines and treatment strategies for this increasingly recognized patient population.