Telomeres significantly shorten in the first 3 months post-HCT (average 450 basepairs; bp). Longer donor telomere length (TL) and intermediate magnitude of telomere attrition by day +100 have been associated with superior survival outcomes after HCT. Telomere dynamics beyond day +100 are not well understood and may further inform immunologic recovery and its impact on outcomes. TL was measured by Flow FISH in total lymphocytes and cell-subsets in serial samples collected from 47 patients, half of whom had cGVHD, from the Longitudinal Study of Immune Mediated Disorders After Allogeneic Hematopoietic Cell Transplantation. TL was measured at day 100 (TL-100d) for all patients, at cGVHD diagnosis and 3 months after, or at 6 months post-HCT for those without cGVHD. TL-100d was compared by demographics, transplant characteristics, and subsequent cGVHD diagnosis using linear regression with robust variance estimator. Ratio of observed TL-100d to expected for donor age (O/E) was used as a proxy measure of extent of telomere attrition at day +100. TL trajectories after day +100 were characterized by estimating differences between measurements within patients. Patient median age at HCT was 53 years (range (R): 20, 73), majority were men (77%), and most received HCT for acute leukemia or MDS (81%) and PBSC as graft source (66%). Median TL-100d was longest in B cells (7.3 kilobases (kb); R: 5.1, 10.0) and shortest in NK cells (6.5kb; R: 4.1, 11.1). In contrast, O/E TL-100d suggested limited telomere attrition in memory T cells (median 1.01; R: 0.76, 1.52) and highest attrition in naïve T cells (median 0.84; R: 0.62, 1.09). Longer TL-100d (median 8.6kb vs. 6.7kb, p<0.001) and higher magnitude of attrition (median O/E 0.83 vs. 0.94, p=0.003) were observed in the 9 patients who received cord transplants than other graft sources. In contrast, reduced intensity regimens were associated with shorter TL-100d (median 6.7kb vs. 7.2kb, p=0.001) and greater attrition (median 0.86 O/E vs. 0.95, p=0.001) than myeloablative regimens. In multivariable analysis, adjusted for donor age, graft source, and conditioning intensity, no association between TL parameters at day +100 and cGVHD was found (TL-100d β=0.39kb, p=0.31; and O/E β=0.06, p=0.24). Lymphocyte TL difference between day+ 100 and 180 (Figure 1) appeared higher in patients with cGVHD than cGVHD-free (median= 262 vs. 39bp; p=0.08). Total lymphocyte TL declined a median of 51bp in the first 3 months after cGVHD diagnosis, roughly equivalent to 1 year of attrition in healthy individuals. TL dynamics after HCT are affected by conditioning regimen intensity, graft source, and possibly cGVHD. In cGVHD-free patients, TL after day+ 100 appears to plateau. Observed total lymphocyte TL dynamic differences between patients with and without cGVHD may be explained by variations in immune cell subset composition or chronic activation/proliferation. A larger study is warranted.
Pirsl et al. (Sun,) studied this question.