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Clonal Hematopoiesis Registry Providing a Step Toward Evidence-Based Guidelines

June 6, 2024

July 2024

Katie Robinson

Katie Robinson is a medical writer based in New York.

Patients with clonal hematopoiesis (CH) have an increased risk of hematologic malignancy and nonmalignant organ dysfunction, but CH management strategies remain lacking. To help develop guidelines to prevent these adverse outcomes, researchers have developed the prospective CHIVE registry and biorepository, with initial data published in Blood Advances.

Linked to increasing age, CH presents as clonal hematopoiesis of indeterminate potential (CHIP), a state in which a patient is asymptomatic with a normal complete blood count. However, CH is often discovered incidentally through genetic testing, with more than two-thirds of CH mutations found in DNMT3A, TET2, or ASXL1 genes.

“Our hope with CHIVE is that as we follow people longitudinally with serial sampling, we are able to more accurately identify inflection points on disease evolution and intervention opportunities,” said corresponding author Michael R. Savona, MD, of Vanderbilt University School of Medicine in Tennessee. “It is early, but our pilot validates the findings from large database retrospective analyses. These large studies brought CHIP to light, and it is critical that we confirm findings from retrospective analyses in prospective studies.”

From October 2020 to April 2023, the registry enrolled 181 patients with no active hematologic malignancy, aged over 40 years or over 18 years and with a known risk factor for CH. Patients were enrolled directly from a CH clinic or via referral from collaborators in numerous specialties.

Genotyping revealed that 99 patients had at least one CH mutation (50.5% males; median age = 71.9) and 82 patients had no CH mutations (29.3% males; median age = 62.9). The registry recorded the participants’ clinical and genetic data and collected blood samples at six- and 12-month intervals.

The most commonly mutated genes were DNMT3A, TET2, ASXL1, and TP53. Most patients with CH presented with a single mutation in either DNMT3A or TET2 genes, while 28.9% presented with multiple mutations. Patients with CH had higher rates of end-organ dysfunction, mainly chronic kidney disease, at 41.2% versus 18.3% for those without CH (p=0.002). Similarly, patients with CH were more likely to have a history of coronary artery disease (55.7% vs. 32.9%; p=0.004), hypertension (79.4% vs. 52.4%; p<0.01), and heart failure (22.7% vs. 9.8%; p=0.035) compared to those without CH, respectively.

Among the patients with CH, 4.7% progressed to hematologic malignancy, of which variant allele frequency (p=0.010) and the accrual of multiple distinct high-risk clone features were independently associated (p=0.004). These genetic characteristics were also associated with cytopenias (p=0.008, p=0.013, respectively). Unexpectedly, around 30% of patients enrolled from CH clinics were considered CHIP-negative, which the authors suggest highlights the need for molecular standards and purpose-built CH assays.

“Treating CHIP is attractive as it gets at the ‘seedling’ of the forest of weeds that is myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). However, only a very small portion of patients with CHIP ever develop MDS or AML,” Dr. Savona said.

“Treating CHIP comes down to either: a) exposing a large healthy population to whatever toxicities (and there are always toxicities) that come with a secondary preventative therapy, at considerable use of resources and expense; or b) determining a priori which CHIP mutations, in which contexts, are actually dangerous, and focusing on them” — the far more appealing alternative, Dr. Savona said. 

The single-center design limited the study, contributing to inadequate ethnic diversity and a female skew, the authors noted. Another limitation of the study was the small number of patients.

“It is hoped that CHIVE can grow to provide sufficient samples from various CHIP variants from a diverse population of study subjects to help us discern ‘benign’ from ‘dangerous’ CHIP,” Dr. Savona added. Efforts are underway to grow CHIVE across the U.S. “to magnify and accelerate the accomplishment of these objectives.”

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Shannon ML, Heimlich JB, Olson S, et al. Clonal Hematopoiesis and Inflammation in the VasculaturE (CHIVE): a prospective, longitudinal cohort and biorepository [published online ahead of print, 2024 April 12]. Blood Adv. doi: 10.1182/bloodadvances.2023011510.

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