Donor cells with clonal hematopoiesis may improve bone marrow transplant outcomes

Clonal hematopoiesis, a condition in which mutations associated with blood cancers are found in the blood of healthy people, is common with aging. When looking for appropriate stem cell/bone marrow donors, clinicians tend to stay away from older donors with clonal hematopoiesis (CH) because of concerns about passing potentially premalignant stem cells to the recipient.

However, a new study, co-authored by researchers at the Johns Hopkins Kimmel Cancer Center and Dana-Farber Cancer Institute in Boston, found an interesting curve: In some patients who have received a stem cell transplant, donor cells with CH can improve overall and disease-free survival and reduce the risk of relapse.

A report on the research, published Nov. 18 in the Journal of Clinical Oncology in the Journal of Clinical Oncology, provides scientific evidence that individuals age 40 or older with CH should not necessarily be excluded from stem cell donation. Since matched related siblings are often considered the best available options for patients undergoing stem cell transplantation, the presence of CH, particularly in older siblings, should not necessarily be an exclusion criteria for donation, says study co-author Lukasz Gondek, M.D., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine.

The paper provides evidence that donors with mutations in DNMT3A, the most commonly affected gene in CH, can be safely used. Moreover, in some instances, using the donors with DNMT3A mutations may be beneficial, as mutated donor immune cells may provide a better anti-leukemic effect."

Lukasz Gondek, M.D., Ph.D., assistant professor of oncology, Johns Hopkins University School of Medicine

However, other rarer types of CH may produce undesirable outcomes, Gondek points out.

For the study, investigators evaluated the impact of CH from donors age 40 or older on clinical outcomes in recipients. Using next generation sequencing techniques, researchers identified CH in 388 (22.5%) of 1,727 donor-recipient pairs treated at the Johns Hopkins Kimmel Cancer Center or Dana-Farber Cancer Institute between 2000 and 2016. The prevalence increased with the age of the donors, so CH was present in 12.6% of donors ages 40-49; 26.6% of donors ages 50-59; and 41.2% of donors age 60 or older.

Overall, CH was present in 22.5% of donors, with mutations in the DNMT3A (14.6%) and TET2 (5.2%) genes being the most common. Both genes are associated with acute myeloid leukemia. Researchers found 302 mutations in DNMT3A in 253 donors and 96 mutations in TET2 in 89 donors. Out of all donors with CH, 301 (77.5%) had only one mutation.

In non-transplant settings, DNMT3A and TET2 mutations have driven the bulk of association with inflammatory outcomes like cardiovascular disease, while other mutations have been associated with a higher risk of progression to blood cancers, Gondek says. Because of this, investigators looked specifically for outcomes associations from donors with only DNMT3A mutations, only TET2 mutations, and mutations in genes other than DNMT3A and TET2.

Donor DNMT3A CH was found to be significantly associated with recipients' outcomes. Those whose donors had DNMT3A CH had improved overall survival, progression-free survival (survival without progression of disease), and a reduced risk of relapse when compared with recipients whose donors did not have CH.

Investigators looked at donor immune cells and graft-versus-host disease (when donor cells attack recipient tissues), and with graft-versus-leukemia activity, the ability of donor immune cells to target and eliminate any circulating leukemia cells in recipients. DNMT3A CH was associated with an increased risk of chronic graft-versus-host disease in recipients who received standard graft-vs-host disease prophylaxis. Moreover, the presence of DNMT3A CH was associated with better overall and disease-free survival (HR for death 0.78, 95% CI 0.62-0.98, P=0.037) and reduced risk of relapse (HR for relapse 0.74, 95% CI 0.57-0.96, P=0.022). By contrast, there was no effect on recipients' outcome in those who received cyclophosphamide as a graft-vs-host disease prophylaxis. Since graft-vs-host disease is frequently associated with antileukemic effect, it is likely that donor immune cells carrying DNMT3A mutations augment anti-tumor activity. Post-transplant cyclophosphamide that provides a very effective graft-vs-host disease control may significantly suppress or eliminate donor lymphocytes and nullify the effect of DNMT3A mutation.

Given the fact that CH has been associated with hematologic cancers, the study looked at the risk of donor-cell leukemia, a condition in which "healthy" donor cells give rise to leukemia in the recipients. Eight recipients developed donor-cell leukemia, none of them arising from donor CH with a single DNMT3A or TET2 mutation. Hereditary genetic predisposition and mutations in spliceosome genes such as SRSF2, U2AF1, SF3B1 and TP53 were associated with donor-cell leukemia. Spliceosomes are RNA-editing cellular machinery that influence protein production.

Research is ongoing, Gondek says.

In addition to Gondek, scientists who contributed to the work include Lin Zhao, Bryan Hambley, Rafael Madero-Marroquin, Shiyu Wang, Christopher D. Gocke, Amy E. DeZern, and Richard J. Jones. Additional authors were from Brigham and Women's Hospital, Boston; Harvard University, Boston; the Broad Institute of MIT and Harvard, Cambridge, Massachusetts; the University of Washington, Seattle; and Massachusetts General Hospital, Boston.

The work was supported by the National Institutes of Health (grants K08CA204734, P01CA229092, K08HL136894, R01HL156144), the Damon Runyon Cancer Research Foundation, the Alan and Lisa Dynner Fund, the James A. and Lois J. Champy Family Fund, the Jock and Bunny Adams Education and Research Fund, the Ted and Eileen Pasquarello Tissue Bank in Hematologic Malignancies, and the Connell and O'Reilly Families Cell Manipulation Core Facility.

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