Understanding Telomere Biology in Hematopoietic Cell Transplantation: A Dynamical Systems Perspective.

Background: T cell proliferation and repertoire reconstitution is a hallmark of successful hematopoietic cell transplantation (HCT). This process may be modeled as a dynamical system and in such a system, precise telomere length (TL) measurement may reflect the proliferative capacity of donor T cells. TL for different chromosomes span a few orders of magnitude, and different blood cell populations including T cell clones display variable TL; these differences across the cell populations are not represented when examining average leukocyte TL. This study aims to develop a method that integrates the entire spectrum of TL observed within a sample to better understand the influence on clinical outcomes following HCT.

Methods: To better reflect the entire span of TL, we used data generated using the Telomere Shortest Length Assay (TeLSA) that provides discrete measurements of individual telomeres for each blood DNA sample. TeSLA leukocyte TL (LTL) measurements were performed on 72 paired samples collected from the donor pretransplant (D-LTL) and the recipient 90 days following HCT (post-HCT LTL). Area under the curve (AUC) calculations were used to incorporate the full distribution of measured LTL from each sample. The magnitude of LTL shortening after HCT was calculated as the difference between the AUCs for D-LTL and corresponding post-HCT LTL, and referred to as AUC delta-TL.

Results: Telomere band lengths ranged from 350 base pairs to 16.7 kilobases with a logarithmically declining distribution in all samples when arrayed in descending order. The AUC delta-TL predicted patient overall survival (OS; P-log rank <.0001); HCT recipients with an intermediate degree of TL shortening (25^th to 75^th percentile/Q2&3) post-HCT experienced the best outcomes (2 years OS = 92%), whilst donors with minimal (<25^th percentile/Q1; 2 years OS = 33%; adjusted HR versus intermediate shortening = 9.3, P = .001) or maximal (>75^th percentile/Q4; 2 years OS = 59%; adjusted HR = 6.0, P = .01) TL shortening had worse outcomes.

Conclusion: The findings described herein suggest that the degree of donor telomere attrition may correlates with clinical outcomes following transplant, possibly reflecting alloreactive T cell expansion. Accounting for the entire span of telomere lengths, may better identify post-transplant risk groups.