A study presented by Christopher Gibson, MD, and colleagues at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 80) has revealed for the first time that clonal hematopoiesis may confer a health benefit in allogeneic stem cell or bone marrow transplants. Researchers reported that patients who received transplants from donors aged 40 and older with clonal hematopoiesis had a lower risk of relapse and longer survival compared with patients who received transplants from donors without clonal hematopoiesis.
Christopher Gibson, MD
“Because clonal hematopoiesis in the nontransplant setting is associated with adverse outcomes, we initially expected to see something similar in recipients of transplants from donors with clonal hematopoiesis,” said presenting author Dr. Gibson, of Dana-Farber Cancer Institute. “However, we largely found the opposite: donor clonal hematopoiesis is actually associated with better survival in most transplant recipients due to a reduced risk of relapse from their underlying cancer.”
More on Clonal Hematopoiesis
Clonal hematopoiesis is a recently identified condition in which mutations associated with blood cancers are detected in the blood of some healthy, usually older, individuals without a cancer diagnosis. People with clonal hematopoiesis, while asymptomatic, have an elevated risk of developing blood cancers and other negative health outcomes, including heart attacks and strokes.
The term clonal hematopoiesis refers to a genetically distinct subpopulation, or clone, of blood cells that share a unique mutation. Its prevalence is low in younger people but it is estimated to occur in 10% to 20% of the population over age 70.
Previous research has shown that clonal hematopoiesis may be unknowingly passed from donor to recipient during transplantation. “The only way to detect clonal hematopoiesis is to perform genetic sequencing of blood, which is not a routine part of the workup for prospective transplant donors,” said Dr. Gibson. “We were the first to show that passing clonal hematopoiesis from donor to recipient can occur without causing a new leukemia to arise in donor cells, but our study was not powered to assess the impact on other outcomes. We’ve been working on the follow-up study ever since.”
Study Findings
KEY POINTS
- The investigators identified clonal hematopoiesis in 388 of the 1,727 donor samples. The most common mutations found in the donor samples were in the gene DNMT3A.
- Those mutations were specifically associated with the improved overall survival and reduced risk of relapse in transplant recipients.
The investigators evaluated the impact of clonal hematopoiesis in donors age 40 or older on recipient clinical outcomes in 1,727 donor-recipient pairs. The investigators identified clonal hematopoiesis in 388 of the 1,727 donor samples. The most common mutations found in the donor samples were in the gene DNMT3A. Those mutations were specifically associated with improved overall survival and reduced risk of relapse in transplant recipients. Other gene mutations found in the samples were not associated with the survival benefit.
“We are not yet sure why donor DNMT3A mutations reduce the risk of relapse, but our data suggest that they improve the immune activity of donor T cells, which are one of the most critical determinants of transplant efficacy,” said Dr. Gibson. This theory fits with data from the trial showing that transplant recipients who received cyclophosphamide to prevent graft-vs-host disease did not benefit from transplants from donors with clonal hematopoiesis. That was likely because cyclophosphamide eliminates donor T cells from the graft as a means of preventing chronic graft-vs-host disease. In all other patients, on balance, despite the higher risk of chronic graft-vs-host disease, the reduction in relapse outweighed that negative outcome and yielded better survival with the clonal hematopoiesis donors.
“Our findings are exciting because they have the potential for an immediate impact on clinical care,” said Dr. Gibson. For example, some transplant centers have been excluding potential donors found to have clonal hematopoiesis during their pretransplant workup. Dr. Gibson said the new findings show that this is not necessary, and, in certain circumstances, donors with DNMT3A mutations could be preferable to similar donors without that mutation.
Disclosure: For full disclosures of the study authors, visit ash.confex.com.
