Photo by Chad McNeeley
Bone marrow aspirate
New research suggests older individuals with clonal hematopoiesis of indeterminate potential (CHIP) are a safe donor source for allogeneic hematopoietic stem cell transplant (HSCT).
Researchers found that transplants from older donors with CHIP resulted in similar survival as transplants from older donors without CHIP.
HSCT recipients with CHIP donors had a lower risk of relapse or progression but a higher risk of chronic graft-versus-host disease (GHVD), and they were more likely to develop donor-cell malignancies.
Frederik Damm, MD, of Charité – University Medical Center Berlin in Germany, and his colleagues reported these findings in the Journal of Clinical Oncology.
Little is known about the influence of donor CHIP in allogeneic HSCT, according to the researchers.
However, an increasing number of older patients are receiving donations from older, mostly sibling, donors who may have CHIP. CHIP increases with age and is associated with a greater risk of hematologic cancers, cardiovascular disease, and death from coronary heart disease.
With this in mind, Dr. Damm and his colleagues set out to determine how donor CHIP affects the outcome of HSCT.
Between 1993 and 2017, the researchers collected blood samples from 500 healthy, related HSCT donors, age 55 or older, at 10 transplant centers in Germany and France. The researchers sequenced the samples with a 66-gene panel.
The team also assessed overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse/progression (CIR/P), cytomegalovirus (CMV) reactivation, and acute and chronic GVHD in the HSCT recipients.
Mutation analysis
The researchers identified 92 clonal mutations in 80 (16.0%) of the 500 donors. The variant allele frequency was 5.9% (range, 2% to 43%). In 20 patients, 25 variant alleles were present at a frequency of 10% or greater.
The researchers detected a single gene mutation in 70 donors, nine donors had two mutations, and one donor had four mutations. The most frequently mutated genes were DNMT3A (40/500, 8%), TET2 (11/500, 2.2%), and ASXL1 (7/500, 1.4%).
Baseline characteristics such as age, sex, or stem cells harvested per kilogram of body weight were similar between donors with and without CHIP.
Recipient characteristics were also evenly distributed regarding donor CHIP status and baseline characteristics.
However, the researchers noted that donor CHIP was present significantly more often in donors for recipients with myeloid compared to lymphoid neoplasms—19.2% and 6.3%, respectively (P≤0.001).
The prevalence of donor CHIP increased with age, from 10.3% (ages 60 to 64) to 20.3% (ages 65 to 69), 22.5% (ages 70 to 74), and 28.6% (ages 75 to 79).
The researchers observed no statistically significant association between CHIP and age, most likely, they wrote, “because 82% of all donors in our cohort were age 60 to 69 years.”
Transplant outcome
Donor CHIP led to slightly faster leukocyte engraftment, although it did not impact thrombocyte engraftment time.
The cumulative incidence of leukocyte engraftment after 15 days was 64.1% for HSCT recipients with CHIP donors and 51.4% for those with non-CHIP donors (P=0.023).
Chronic GVHD after HSCT was more likely for recipients with CHIP donors, with a 5-year cumulative incidence of 52.9%, compared to 35.7% for patients with non-CHIP donors (P=0.008).
Multivariate analysis showed donor CHIP to be an independent risk factor for chronic GVHD when adjusted for antithymocyte globulin application and donor age.
The researchers identified donor DNMT3A mutation as the predominant CHIP factor for developing chronic GVHD. The incidence of chronic GVHD was 58.5% in patients with DNMT3A-mutated donors and 36.6% in patients with wild-type donors (P=0.006).
The researchers noted that no other CHIP mutations or characteristics affected the development of chronic GVHD.
Donor CHIP status did not impact the incidence of acute GVHD or CMV reactivation.
Transplant recipients with CHIP donors had a lower CIR/P (P=0.027) than recipients with non-CHIP donors. Patients whose donors had CHIP with a DNMT3A mutation also had a lower CIR/P (P=0.029).
Donor CHIP had no effect on NRM.
Neither donor CHIP nor donor DNMT3A mutational status impacted CIR/P or NRM in patients who underwent HSCT while they were in complete response (CR).
However, patients not in CR at the time of HSCT had a lower CIR/P when the donor was CHIP-positive (hazard ratio [HR]=0.49; 95% confidence interval [CI], 0.27 to 0.88; P=0.019) or had a DNMT3A mutation (HR=0.34; 95% CI, 0.15 to 0.81; P=0.015).
Two of 82 patients with CHIP donors developed donor-cell malignancies, but there were no donor-cell malignancies in recipients with non-CHIP donors (P=0.026).
Survival
“To our knowledge, we showed, for the first time, that donor CHIP did not affect the survival of 500 HSCT recipients,” the researchers wrote.
At a median follow-up of 3.3 years, the median OS was 2 years, and the 5-year OS was 37.6%.
The researchers observed no survival differences in patients with CHIP donors or non-CHIP donors (HR=0.88; 95% CI, 0.65 to 1.321; P=0.434). And the same was true for DNMT3A mutation (HR=0.89; 95% CI, 0.58 to 1.35; P=0.573).
The researchers pointed out that patients with myelodysplastic syndromes or acute myeloid leukemia who were not in CR when they underwent HSCT had a survival benefit with donor CHIP (HR=0.49; 95% CI, 0.28 to 0.86; P=0.011).
“This finding could implicate an important clinical potential in this difficult-to-treat subgroup,” the researchers noted.
However, this was not the case for patients with myeloproliferative neoplasia, for whom donor CHIP tended to reduce survival (P=0.077).
The research team recommended future studies be conducted in younger and unrelated donors to confirm the results of this study.
The research was funded by numerous grants and fellowships, and the researchers reported no relevant conflicts of interest.