Clonal hematopoiesis in donors and long-term survivors of related allogeneic HSCT

Boettcher S, Wilk CM, Singer J, Beier F, Burcklen E, Beisel C, Ventura Ferreira MS, Gourri E, Gassner C, Frey BM, Schanz U, Skoda RC, Ebert BL, Brümmendorf TH, Beerenwinkel N, Manz MG.

Abstract Clonal hematopoiesis is associated with age and an increased risk of myeloid malignancies, cardiovascular risk and all-cause mortality. We tested presence of CH (defined as VAF ≥0.01 in granulocytes using a next-generation DNA sequencing panel targeting 102 genes) in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, i.e. in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n=42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range: 10-32 years), we found a total of 35 mutations in 23/84 (27.4%) study participants. 10/42 (23.8%) donors, and 13/42 (31%) recipients had CH. CH was associated with older donor and recipient age. We identified five cases of donor-engrafted CH, with one case progressing into myelodysplastic syndrome in both donor and recipient. 4/5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH: i) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; ii) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; iii) while telomere shortening determined in granulocytes suggested about 20 years of added proliferative history of HSCs in recipients compared with their donors, telomere length in CH versus non-CH CFUs showed varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.