Effect of Donor Clonal Hematopoiesis of Indeterminate Potential in Allogeneic Hematopoietic Stem Cell Transplantation
In a study reported in the Journal of Clinical Oncology, Frick et al found that allogeneic hematopoietic stem cell transplantation (HSCT) from donors with clonal hematopoiesis of indeterminate potential (CHIP) appears safe and not associated with poorer survival when donors are older, related donors. As noted by the investigators, CHIP, which occurs in the blood of approximately 20% of older persons, is associated with an increased risk of hematologic malignancies and all-cause mortality.
In the study, blood samples were collected from 500 healthy, related HSCT donors aged ≥ 55 years at the time of stem cell donation for targeted sequencing with a 66-gene panel. The 500 donor-recipient couples were from 10 transplantation centers in Germany and France. The effect of donor CHIP on recipient outcomes was assessed, including graft-vs-host disease (GVHD), cumulative incidence of relapse/progression, and overall survival.
Prevalence and Effect of CHIP in Donors
In total, 80 donors (16.0%) had CHIP, represented by a total of 92 clonal mutations with a median variant allele frequency of 5.9%. Donor CHIP prevalence increased by age from 10.3% among donors aged 60 to 64 years to 20.3% at 65 to 69 years, 22.5% at 70 to 74 years, and 28.6% at 75 to 79 years. CHIP prevalence was higher in donors related to patients with myeloid vs lymphoid malignancies (19.2% vs 6.3%, P ≤ .001).
In patients receiving allografts from donors with vs without CHIP, the cumulative incidence of chronic GVHD was higher on multivariate analysis (hazard ratio [HR] = 1.73, P = .003) and cumulative incidence of relapse/progression was lower on both univariate analysis (HR = 0.62, P = .027) and multivariate analysis (HR = 0.63, P = .042), with no difference in nonrelapse mortality being observed (P = .464). Serial quantification of 25 clonal mutations showed engraftment of 24 and a disproportionate expansion in half of the clones. Donor-cell leukemia occurred in 2 recipients from CHIP donors.
Median follow-up was 3.3 years in patients remaining alive. Among all patients, median overall survival was 2 years and the 5-year rate was 37.6%. There was no significant difference in overall survival for recipients with vs without CHIP donors (HR = 0.88, P = .434).
The investigators concluded, “Allogeneic HSCT from donors with CHIP seems safe and results in similar survival in the setting of older, related donors. Future studies in younger and unrelated donors are warranted to extend these results. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that donor CHIP might foster [chronic] GVHD development and reduce relapse/progression risk.”
The study was supported by Deutsche Forschungsgemeinschaft and others.
Frederik Damm, MD, of the German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: See study authors’ full disclosures at jco.ascopubs.org.
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