In an AACR 2021 symposium,  speakers discussed current understanding of clonal hematopoiesis, defined by the presence of somatic mutations in blood cells, and its association with aging and both malignant and nonmalignant disease.

A recording of the session, Implications of Clonal Hematopoiesis in Human Health, and companion panel discussion will be available to registered attendees until June 21.

Clonal hematopoiesis in human aging and disease

Siddhartha Jaiswal, MD, PhD, Stanford University, discussed the prevalence of clonal hematopoiesis and its newly recognized link to aging, cardiovascular disease, and other nonmalignant disorders.

“Mutations conferring clonal hematopoiesis are rare below the age of 40, but increase in prevalence with each decade of life, such that when you look at people who are 70 years of age or older, more than 10 percent of them have clonal hematopoiesis,” Jaiswal said. “This finding has been replicated many times, and it seems to be a universal facet of human aging. On the basis of these findings, we proposed a novel clinical entity that we termed ‘clonal hematopoiesis of indeterminate potential,’ or ‘CHIP.’”

CHIP is defined as a cancer-associated clonal mutation present at a variant allele fraction (VAF) of greater than 2 percent in the blood of healthy individuals who do not have a known hematologic disorder, Jaiswal said. Among the most frequently mutated genes are DNMT3A and TET2.

“These most commonly mutated genes in CHIP are also commonly mutated genes in hematologic cancers, especially myeloid malignancies, and so one would predict that individuals who harbor these mutations would be at elevated risk of developing blood cancers in the future,” Jaiswal said. “And indeed, this has been shown.”

He also said that CHIP is associated with an increased risk of atherosclerotic cardiovascular disease.

“This increased risk appears to be due to enhanced inflammation, and we hypothesize that CHIP carriers may preferentially respond to drugs targeting inflammatory pathways,” Jaiswal said.

Clonal hematopoiesis as a premalignant state

Koichi Takahashi, MD, PhD, UT MD Anderson Cancer Center, discussed the presence of clonal hematopoiesis in a premalignant state and emphasized the importance of an individual patient’s clinical context in understanding the risks associated with this condition.

“Unlike solid tissue, clonal hematopoiesis is not something that we can visualize morphologically—it’s not like a polyp where you can visualize the mass,” Takahashi said.

“Clonal hematopoiesis can take different forms depending on what method you use to detect it. Most recently, next-generation sequencing has been widely used to detect clonal hematopoiesis by detecting subclonal gene mutations.”

He cited findings from seminal studies in which investigators analyzed SNP array data from large cohorts of health individuals and found that a significant fraction of participants had subclonal copy number alterations in certain chromosome arms.

“And those chromosome abnormalities were precisely the same abnormalities that we often detect in fully developed malignancy like AML, MDS, or CLL,” Takahashi said. “These alterations were found subclonally in the healthy individuals’ blood, which suggests that these chromosomal abnormalities preceded the actual development of the disease.”

Additionally, he noted that the incidence of this mosaic chromosome alteration was age proportionate.

“There is growing evidence on risk stratification of clonal hematopoiesis, which is enabling us to identify this high-risk clonal hematopoiesis population and potential targets for future intervention,” Takahashi said.

Clonal hematopoiesis in patients with cancer

Rafael Bejar, MD, PhD, Moores Cancer Center at UC San Diego Health, discussed some of the unique clinical considerations raised by clonal hematopoiesis in cancer patients, including how it can affect their outcomes and how clinicians might address the condition.

“It’s important to point out that having clonal hematopoiesis alone does not constitute a disease,” Bejar said. “But the clinical context in which it occurs does matter.”

In some situations, he said, clonal hematopoiesis may represent an important premalignancy, while in others, it may have other significant adverse health effects that need to be considered.

“Clonal hematopoiesis is more common in cancer patients, particularly after exposure to cytotoxic therapy, where certain mutations are selected for, particularly those in DNA damage response elements such as TP53 and PPM1D,” Bejar said. “And clonal hematopoiesis can have adverse health effects even in the absence of therapy-related neoplasms; in fact, most of the negative outcomes are independent of that transformation.”

Certain risk factors are important to keep in mind, he said, such as greater variant allele frequency, multiple mutations, and certain genes—TP53, for example—that are associated with greater risk of transformation.

“One thing we need to think about is whether there are situations where we can avoid hematopoietic stress in patients with clonal hematopoiesis to prevent further clonal selection,” Bejar said. “If there’s a TP53 mutation, for example, are there certain types of chemotherapy that we might try to avoid, and are there certain types of therapies we might want to use instead?”

Targeted therapies and immune therapies seem to have less impact on clonal expansion, he noted, suggesting those would be preferred.

“But ultimately, the clinical context is going to be key for interpreting the risks of clonal hematopoiesis,” Bejar said. “The same gene mutation in a different patient in a different context may have a very different implication.”