The study investigates the link between clonal hematopoiesis and treatment-related blood cancer risk

Reviewed by Emily Henderson, B.Sc.October 27, 2020

In recent years, improvements in cancer therapy have led to a significant increase in cancer survival. Experts estimate that by 2022 the United States will have 18 million cancer survivors, but a subset of these survivors will have long-term health problems to address.

A rare complication of cancer treatment is the development of a secondary blood cancer – therapy-related acute myeloid leukemia or myelodysplastic syndrome. These blood cancers are very aggressive and do not respond well to treatment.

Historically, doctors thought that cancer treatments like chemotherapy and radiation caused a buildup of mutations in the blood that led to these therapy-related tumors.

In recent years, however, researchers have found that these mutations in the blood can also occur spontaneously with increasing age. This phenomenon is called clonal hematopoiesis (CH) and is found in 10-20% of all people over the age of 70.

The presence of CH increases the risk of developing blood cancer. Using data from MSK-IMPACTTM, Memorial Sloan Kettering’s clinical genomic sequencing test, the researchers demonstrated that CH is also common in cancer patients.

In a study published in Nature Genetics On October 26, 2020, MSK researchers sought to understand the relationship between CH in cancer patients and the risk of later developing treatment-related blood cancer. The study included data from 24,000 people treated at MSK. The researchers found CH in about a third of them.

Because many people treated at MSK have performed genetic testing using MSK-IMPACT, we have this amazing resource that allows us to study CH in cancer patients in a setting that no one else has been able to do. “

Kelly Bolton, lead author of the study e Doctor-scientist, Memorial Sloan Kettering Cancer Center

Decoding specific genetic changes for cancer treatment

Focusing on a subset of patients on whom they had more detailed data, the researchers observed increased rates of CH in people who had already received treatment. They have established specific connections between cancer therapies such as radiotherapy and particular chemotherapies – for example certain platinum-based drugs or agents called topoisomerase II inhibitors – and the presence of CH.

Unlike the CH changes found in the general population, the team found that CH mutations after cancer treatment occur more frequently in genes whose protein products protect the genome from damage. One of these genes is TP53, which is often referred to as “the guardian of the genome”.

The work was supported by the Precision Interception and Prevention (PIP) program at MSK, a multidisciplinary research program focused on identifying people who have the highest risk of developing cancer and improving methods of screening, early detection and evaluation. risk.

The authors undertook a three-year study to understand the relationship between CH and cancer therapy. For this part of the research, more than 500 people were screened for CH when they first arrived on MSK and then at a later time during treatment.

A finding from the study was that people with pre-existing CH whose blood carried DNA damage repair-related mutations such as TP53 were more likely to grow those mutations after receiving cancer therapies than people who did not. care.

“This discovery provides a direct link between the type of mutation, the specific therapies and how these cells progress to becoming a blood cancer,” says Elli Papaemmanuil of MSK’s Center for Computational Oncology, one of the two authors. senior of the firm. “Our hope is that this research will help us understand the implications of having CH, and to begin developing models that predict who with CH is at greatest risk of developing blood cancer.”

For a subset of CH patients who developed therapy-related blood cancers, the researchers showed that blood cells acquired further mutations over time and progressed to leukemia. “We are now routinely screening our patients for the presence of CH mutations,” adds computational biologist Ahmet Zehir, director of clinical bioinformatics and senior co-author of the study.

The ability to introduce real-time CH screening to our patient population has enabled us to establish a clinic dedicated to the care of cancer patients with CH. As we continue to study more patients in the clinic, we expect to learn more about how to use these findings to find ways to detect treatment-related blood cancers early when they may be more treatable. “

Ahmet Zehir, computational biologist and director of clinical bioinformatics, Memorial Sloan Kettering Cancer Center

Application of results to future treatments

In the future, this research could help guide therapy by indicating whether some chemotherapy drugs are more appropriate than others in people with CH. People at high risk of developing treatment-related leukemia may also benefit from a different treatment program.

“We hope this research will allow us to ultimately map which CH mutations a person has and use that information to tailor their primary care and also mitigate their long-term risk of developing blood cancer,” says Dr. Papaemmanuil.

“We have explored this in collaboration with researchers from the National Cancer Institute, Dana-Farber Cancer Institute, Moffit Cancer Center and MD Anderson, and we have shown that such risk-adjusted treatment decisions could achieve a significant reduction in leukemia risk, without affect outcomes for primary cancer, ”adds Dr. Bolton.

The researchers also hope to use the data from this study to develop better methods for detecting CH-related blood cancers as they begin to form and potentially to develop new interventions that could prevent CH from progressing to cancer.

“We are excited to continue growing and expanding the CH Clinic as part of the integrated vision of PIP,” says physician-scientist Ross Levine, who leads MSK’s CH Clinic and is a member of the Human Oncology and Pathogenesis Program.

“In addition to continuing to follow people who are at higher risk of developing secondary cancer, we want to continue using the clinic as a vehicle for studies like this,” he adds. “Our long-term goal is to move towards therapeutic interventions and prevent disease in a way we have never been able to do before.”