Determining CHIP’s Potential

Researchers have known about clonal hematopoiesis – clonal expansion among hematopoietic stem cells [HSCs], resulting in a population of genetically identical blood cells) for decades. Clonal hematopoiesis is a hallmark of hematologic malignancy, but can also be seen in healthy people. In the mid-1990s, for instance, several groups reported a skewed pattern of X-chromosome inactivation indicating clonal expansion in the peripheral blood (PB) cells of older women.1,2

But it was not until genetic sequencing advanced enough to easily detect driver mutations associated with clonal hematopoiesis that researchers were able to define the prevalence of clonal hematopoiesis in older people and better understand its biological and clinical implications. Now clonal hematopoiesis is one of the most exciting topics in hematology – and cardiovascular – research.

“Clonal hematopoiesis is a common age-related condition in which a substantial fraction of the DNA in a person’s blood is being generated by the clonal progeny of a single cell,” said Steven McCarroll, PhD, Dorothy and Milton Flier Associate Professor of Biomedical Science and Genetics at Harvard Medical School. “That single cell underwent mutation that caused the cell and its progeny to be able to proliferate relative to other such cells.”

The cells that cause clonal hematopoiesis are typically HSCs or progenitors committed to one of the blood-cell lineages, he explained. Research has shown that the presence of clonal hematopoiesis is associated with an increased risk of hematologic malignancies, all-cause mortality, and cardiovascular events; however, many people who have the somatic mutations associated with clonal hematopoiesis never go on to develop negative health events.3-5  

Given this finding, in 2015 researchers proposed the term “clonal hematopoiesis of indeterminate potential,” or CHIP, to describe people who have clonal hematopoiesis defined by a mutation in a malignancy-associated gene, but without evidence of disease.6

As its name implies, the true potential of CHIP remains undetermined, both for an individual patient diagnosed with CHIP and for the overall affected population. Since CHIP was defined, institutions such as the University of California San Diego’s Moores Cancer Center and Memorial Sloan Kettering Cancer Center, have established clinics that will focus solely on this premalignant condition, including identifying patients at the highest risk for developing a malignancy. Other institutions such as the Dana-Farber Cancer Institute have created more general “precursor state” clinics, both for those with CHIP and for patients with analogous premalignant clonal states, including monoclonal B cell lymphocytosis and monoclonal gammopathy of undetermined significance.

ASH Clinical News spoke with researchers and clinicians to learn more about CHIP, the implications of a CHIP diagnosis, and what it means for treatment decisions and follow-up.

Who Does CHIP Target?

After the discovery and subsequent studies of CHIP, “we got a sense of how remarkably common [age-related clonal hematopoiesis with acquired mutations] is,” said Rafael Bejar, MD, PhD, assistant professor in the Division of Hematology and Oncology at University of California San Diego’s Moores Cancer Center. “And we saw how alarming it is that the mutations we’re identifying [in CHIP] are in the exact genes that are [mutated] in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).”

CHIP is more prevalent as people age, but its incidence among the general population is an open question.

“I don’t think we’ve done systematic studies of large enough populations with comprehensive assays [to accurately determine the prevalence],” said Ross Levine, MD, director of the Center for Hematologic Malignancies at Memorial Sloan Kettering Cancer Center.

In one of the largest studies looking at the prevalence of CHIP, Giulio Genovese, PhD, of the Broad Institute in Massachusetts, and colleagues analyzed whole-exome sequencing in the PB cells of 12,380 people who were unselected for cancer or hematologic phenotypes in Swedish national registries.3 Among this group, CHIP occurred in 10.4 percent of individuals over age 65; it was found in just 0.9 percent of those younger than 50.

CHIP is also more prevalent in people with cancer. In a recent analysis of next-generation sequencing data from more than 8,000 individuals, Dr. Levine and colleagues found that a quarter of people with any type of cancer had CHIP.7

Still, the answer to the prevalence question might vary with the type of assays used to detect CHIP. Studies using more sensitive assays suggest that clonal hematopoiesis is present in an even greater population, but researchers say the presence of mutations in very small cell populations is only one part of the equation in determining CHIP’s full impact.

“As we begin to do deeper sequencing, we can find mutations in everybody at low levels,” Dr. Levine said. “It’s not just whether a patient has these mutations, but also whether he or she has mutations at enough of a burden to be clinically relevant. That’s one of the questions the field needs to figure out.”

Defining the Indeterminate

Though many people have CHIP and harbor somatic mutations in genes associated with myeloid neoplasms (MNs; e.g., DNMT3A, TET2, and ASXL1), few will go on to develop a malignancy, according to Daniel C. Link, MD, and Matthew J. Walter, MD, professors at Washington University School of Medicine in St. Louis. “Only a small fraction of individuals (about 4%) subsequently develop a myeloid malignancy, and the size of the mutant clone in CHIP can remain stable for years without disease progression,” the authors wrote.8

Indeed, in the study by Dr. Genovese and co-authors, CHIP was a strong risk factor for subsequent hematologic malignancy: Individuals with CHIP were nearly 13 times more likely to develop the condition than those without (hazard ratio = 12.9; 95% CI 5.8-28.7; p<0.001).3

In a population of patients with solid-tumor malignancies who were undergoing chemotherapy, Nancy K. Gillis, PharmD, post-doctoral fellow at the H. Lee Moffitt Cancer Center in Florida, and co-authors reported that patients who had CHIP at the time of primary diagnosis were almost six times more likely to later develop a therapy-related malignancy (odds ratio = 5.75; 95% CI 1.52-25.09; p=0.013).9

Overall, though, the rate of these mutated cells developing into cancer is still low.

“The risk of going on to get myeloid cancer, like an MDS or an AML, is about 1 percent per year,” Dr. Walter told ASH Clinical News. “By a 30-year follow-up, each individual would have about a 30 percent risk of getting cancer from [CHIP].”

Researchers have started to define risk factors that increase a person’s risk of progressing from a premalignant to a malignant state. In addition to aging, Dr. Walter believes inflammation, other forms of stress, and exposure to chemotherapy or other toxins could play a role in inducing clonal expansion and subsequent cell development. “Putting selective pressure on a person’s system might cause the number of clonal cells to rise and then become detectable,” he said.

Dr. Bejar added that results from the studies that defined CHIP have also provided some insight. “In the short follow-ups of these trials, the patients who progressed were those who had a greater abundance of these mutations, so their variant allele frequency was much higher – about 2.5 times that of the average for the group,” he noted.

The presence of CHIP at the time of non-myeloid cancer diagnosis also increased the likelihood that patients would be diagnosed with secondary, therapy-related MNs (t-MNs), according to a small study by Koichi Takahashi, MD, assistant professor  at the University of Texas MD Anderson Cancer Center, and colleagues.10 In a cohort of patients with lymphoma treated with frontline CHOP-based chemotherapy (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone), CHIP was detected in 80 percent (n=4/5) of patients who developed t-MNs and only 16 percent (n=11/69) of those who did not (p=0.005).

When Your CHIP Comes In

What happens after CHIP is discovered depends, in part, on the clinical context in which the patient presented and their individual risk level. According to Dr. Levine, the first step for any patient is determining whether he or she should be fully evaluated for a myeloid malignancy.

“The second step, given the obvious cardiovascular risk signal with CHIP, would be making sure that people are being properly risk-mitigated for their cardiovascular disease, blood pressure, and lipids,” he said.  Several studies have indicated that patients with CHIP have a significantly increased risk of atherosclerotic disease and acute cardiovascular events due to a pro-inflammatory interaction between clonally-derived cells and the vascular endothelium.

There are no formal standards to guide the management of CHIP, but interviewees agreed that hematologists should focus on cardiovascular risk factors and should be most concerned about the development of a malignancy in patients who present with multiple distinct mutations, high variant allele frequencies, cytopenias, or a non-myeloid form of cancer for which chemotherapy or radiotherapy is being considered.

These types of high-risk patients can be followed with regular bloodwork, supplemented by bone marrow biopsies and genetic sequencing if their bloodwork signals a concern, Dr. Bejar added, noting that “[at Moores Cancer Center], we’ve been recommending that patients have blood counts done every six months, potentially more frequently if they are close to a transfusion threshold.”

For the patients for whom CHIP does not precede a malignant state, the researchers advised caution in considering its implications. All agreed that CHIP is an important biomarker that can predict myeloid malignancies, but that much work needs to be done before it can be considered an “actionable” discovery.

“We need to better identify whether CHIP carries a differential risk – if it changes depending on what the type or number of mutations is – so that we can better identify the people at the highest versus lowest risk for developing leukemia and other complications,” Dr. Levine said.

Researchers also need to determine what makes CHIP cells different, and whether there is a way to intervene to eradicate these clones or prevent CHIP from progressing from a premalignant to malignant state.

The good news is that that investigators’ curiosity has been piqued and considerable amounts of time and effort are being spent uncovering answers to these questions. “This is one of those fields where every week there’s a new discovery,” Dr. Levine said. —By Jill Sederstrom


References

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  2. Raghavachar A, Janssen JW, Schrezenmeier H, et al. Clonal hematopoiesis as defined by polymorphic X-linked loci occurs infrequently in aplastic anemia. Blood. 1995;86:2938-47.
  3. Busque L, Mio R, Mattioli J, et al. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood. 1996;88:59-65.
  4. Genovese G, Kahler AK, Handsaker RE, et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014;371:2477-87.
  5. Jaiswal S, Natarajan P, Silver AJ, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111-21.
  6. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-98.
  7. Steensma DP, Bejar R, Jaiswal S, et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood. 2015;126:9-16.
  8. Coombs C, Zehir A, Devlin S, et al. Therapy-related clonal hematopoiesis in patients with non-hematologic cancers is common and associated with adverse clinical outcomes. Cell Stem Cell. 2017;21:374-82.
  9. Link DC, Walter MJ. ‘CHIP’ping away at clonal hematopoiesis. Leukemia. 2016;30:1633-5.
  10. Gillis NK, Ball M, Zhang Q, et al. Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study. Lancet Oncol. 2017;18:112-21.
  11. Takahashi K, Wang F, Kantarjian H, et al. Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study. Lancet Oncol. 2017;18:100-11.

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