A recent study found that clonal hematopoiesis (CH) was not an uncommon feature in donors involved in allogeneic hematopoietic stem cell transplantations (HSCTs), with varied outcomes for transplant recipients based on CH features. The study’s results were published in the Journal of Clinical Oncology.
The study included 2 cohorts of patients undergoing allogeneic HSCT between 2000 and 2016, with cohort 1 being treated at Dana-Farber Cancer Institute in Boston, MA, and cohort 2 being treated at Johns Hopkins University in Baltimore, MD. Included patients were at least 40 years of age. Samples from donors were subjected to sequencing of a total of 46 genes associated with mutations in CH and myeloid malignancies. The primary end point of the study was progression-free survival (PFS) in transplant recipients, and multiple other outcomes were additionally assessed.
Samples from 1727 donors were evaluated in this study. From these, 388 (22.5%) showed evidence of CH with a variant allele fraction of ≥0.005. CH prevalence was associated with donor age, ranging from 12.6% in donors from 40 to 49 years of age to 41.2% in donors 60 years of age or older.
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There were 4 genes found to be mutated in more than 10 donors. The most common was DNMT3A, which accounted for 302 of 501 total mutations and was mutated in 253 donors (14.6% of the total donors). TET2 accounted for 96 mutations in 89 donors (5.2% of the total), ASXL1 accounted for 22 mutations in 22 donors, and PPM1D accounted for 14 mutations in 14 donors.
Recipient PFS was significantly better with donor CH involving DNMT3A and a variant allele fraction (VAF) of ≥0.01 (hazard ratio [HR], 0.72; 95% CI, 0.58-0.89; P =.003). DNMT3A-CH and a VAF ≥0.01 was also associated with both better recipient overall survival (HR, 0.78; 95% CI, 0.62-0.98; P =.037) and reduced relapse risk (subdistribution HR, 0.74; 95% CI, 0.57-0.96; P =.022). However, posttransplant outcomes also showed relationships with graft-versus-host disease prophylaxis options.
The 10-year cumulative incidence of donor cell leukemia (DCL) in this study was 0.7%. DCL occurred with a median latency of 5.2 years (range, 0.3-10.3) between transplantation and DCL diagnosis. Increased donor age appeared to be associated with development of DCL in recipients (P =.037). TP53 mutations, myelodysplastic syndrome-associated splicing factor mutations, or germline DDX41 mutations were seen with donor CH in cases of DCL in recipients.
“We find that the presence of DNMT3A-CH or TET2-CH in stem-cell donors does not adversely affect recipient outcomes and that DNMT3A-CH is independently associated with improved survival in recipients as a consequence of reduced relapse,” the study authors wrote in their report. However, they considered CH involving splicing factors, TP53 mutations, or DDX41 mutations to have potential to be linked to a higher DCL risk.
Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.
Reference
Gibson CJ, Kim HT, Zhao L, et al. Donor clonal hematopoiesis and recipient outcomes after transplantation. J Clin Oncol. Published online November 18, 2021. doi:10.1200/JCO.21.02286
