Telomere length and clonal hematopoiesis interact to influence outcomes in hematopoietic stem cell transplantation

Clonal hematopoiesis (CH), the clonal expansion of a hematopoietic stem cell and its progeny driven by somatic mutations, has been associated with inferior survival outcomes among recipients of autologous stem cell transplants (ASCT). Leukocyte telomere length (LTL) has a complex but well-documented interaction with CH, but the impact of this interaction on stem cell transplantation has not been adequately examined. We measured LTL in graft cell DNA from 452 patients undergoing ASCT for myeloma, for whom targeted DNA sequencing for CH driver gene mutations was available. We interrogated clinical and longitudinal large-scale laboratory data for these patients to understand the impact of graft LTL on progression-free survival (PFS) and overall survival after transplantation, as well as blood count indices and their trajectories. In multivariate analyses, longer LTL was associated with increased PFS among patients without CH. However, this protective association was not seen in patients with CH. We also report that among patients with CH, longer LTL was associated with an increased red cell distribution width before myeloablative chemotherapy and after ASCT. Collectively, these data reveal hitherto undescribed interactions between LTL, CH, and ASCT outcomes.