HCT Recipients Acquire Rare, Potentially Harmful Clonal Mutations Harbored by Younger Donors

Some patients with acute myeloid leukemia (AML) who received a hematopoietic cell transplantation (HCT) from young donors acquired rare, yet potentially harmful, clonal mutations associated with pathogenic processes, according to findings from a small pilot study. While this phenomenon has previously been observed in older donors, the HCT donors were younger, with a median age of 26 years.

These findings, which were published in Science Translational Medicine by Wing Hing Wong, PhD, from the Washington University School of Medicine, and colleagues, also suggest that some of these genetic mutations expand over the first year post-HCT. These engrafted mutations could increase a recipient’s risk of developing cardiovascular damage, graft-versus-host disease, and even new leukemias.

“Based on our sensitive tool for genetic sequencing, we have found that by the time people reach their 50s, everyone has somatic genetic mutations in their blood,” corresponding study author Todd Druley, MD, PhD, told ASH Clinical News. “They’re much more common than people have previously thought.”

In this retrospective pilot study, researchers from the Washington University School of Medicine identified and analyzed pre-HCT bone marrow specimens from 25 adult patients with AML, as well as samples collected at 30 days, 100 days, and 1 year post-HCT.

Using data from the Center for International Blood and Marrow Transplant Research repository, the researchers also obtained and sequenced pre-HCT samples from 25 corresponding unrelated donors. Healthy donors in this study were between the ages of 20 and 58 years, representing a relatively young population where clonal hematopoiesis meeting ≥2% variant allele frequency (VAF) criteria for clonal hematopoiesis of indeterminate potential (CHIP) is uncommon.

Samples were sequenced to identify genetic variants across 80 genes frequently mutated in pediatric and adult patients with AML and present in the bone marrow of donors and recipients. The researchers used error-corrected sequencing, a technique invented in Dr. Druley’s lab, to find rare DNA mutations that are typically below the detection limit of conventional high-throughput genome sequencing methods. The detection limit of the error-corrected sequencing technique is around 0.0001 (0.01% VAF), meaning it can identify mutations present in as few as 1 out of 10,000 cells, Dr. Druley explained, while many next-generation sequencing techniques correctly identify mutations in 1 out of 100 cells (1% VAF).

In this analysis, Dr. Wong and investigators found 19 somatic clonal hematopoietic mutations in 11 donors (44%; median age = 35 years), with a corresponding median VAF of 0.247%. Approximately 84% of the mutations detected in these samples were found to be molecularly pathogenic. In addition, all of the detected mutations engrafted in the HCT recipients, as demonstrated by post-HCT clonal mutation profiling. Many of the mutations also expanded over time, the researchers noted, and approximately 74% of the 19 engrafted mutations persisted 1 year after transplant. The researchers also observed de novo clonal mutations in recipients appearing within 100 days of HCT.

Although donor-derived leukemia was not observed, given the relatively short follow-up the findings suggest new health problems associated with these genetic mutations may occur in HCT recipients in the future. For example, Dr. Druley explained, more than 20% of the bone marrow transplant recipients in this study ended up with TET2 mutations, which are associated with poor cardiac outcomes and atherosclerosis. “There may be a correlation between the people who have long-term cardiac problems after a bone marrow transplant and the clones they inherited from their donors,” he said.

While the study highlights important implications of HCT, it also raises new questions that Dr. Druley and his colleagues hope to explore further. “These findings make us ask ourselves how we can make bone marrow transplants safer and how can we do a better job in surveillance – not only for recurrence of the leukemia, but also to potentially protect the recipient from unwanted side effects, such as graft-versus-host disease and cardiac difficulties.”

The authors report no relevant conflicts of interest.

Reference

Wong WH, Bhatt S, Trinkaus K, et al. Engraftment of rare, pathogenic donor hematopoietic mutations in unrelated hematopoietic stem cell transplantation. Sci Transl Med. 2020;12(526).