Characteristics of Donor and Recipient Clonal Hematopoiesis in Nonmyeloablative Transplant for Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic hemolytic anemia, painful vaso-occlusive episodes, and end-organ damage. Cellular therapies, including allogeneic hematopoietic cell transplant (allo-HCT) and gene therapy, are potentially curative treatments for SCD. Cases of myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) occurring after cellular therapy for SCD and reports of an increased relative risk of AML in populations with SCD have raised questions about the association between SCD and clonal hematopoiesis (CH), a recognized precursor state for MDS/AML. We used error-corrected DNA sequencing to detect CH variants at a variant allele fraction > 0.0005 in blood samples from 98 individuals with SCD and 72 non-SCD donor controls who underwent HCT at the NIH between July 2004 and June 2023. Baseline CH prevalence was similar in recipients and donors; however, SCD recipients had 3.8-fold higher odds of DNA Damage Response (DDR)-mutant CH, involving TP53, PPM1D, ATM, and CHEK2, compared with non-SCD donors. Following HCT, the proportion of SCD recipients with CH increased, driven primarily by mutations in DNMT3A/TET2 and TP53. Post-HCT CH arose from newly emergent variants undetectable at baseline in both recipient and paired donor samples, engrafted donor-derived CH, and persistent recipient CH. All cases of donor-derived CH involved DNMT3A/TET2 mutations, while persistent-recipient CH involved DDR mutations. Hematologic malignancies were rare but included 3 cases of fatal TP53-mutant MDS/AML. Larger cohort studies are needed to identify risk factors for developing DDR-CH and MDS/AML in SCD and to optimize cellular therapy safety in this population.