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 T cell clones will display variable TL; these differences across the population are not represented when examining average 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 TeLSA PCR technique that provided discrete measurments of individual telomeres for each DNA sample for 72 stem cell transplant (SCT) donor-recipient pairs. Donor and recipient TeSLA TL measurements was performed on samples taken before and 90 days post HCT, respectively. Set correspondence mathematical techniques and area under the curve (AUC) calculations were used to measured donor-recipient TL differences (delta-TL) incorporating the full distribution of measured TL from each sample.

Results. Telomere band lengths ranged from 350 basepairs (BP) to 16.7 kilobases with a logarithmically declining distribution in all samples when arrayed in a descending order. Set correspondence methods yielded TL averages which were highly correlated with AUC calculations (r >0.9, p<0.001 for all) The AUC delta-TL method predicted patient overall survival (P-log rank <0.0001). HCT recipients with intermediate degrees of telomere attrition (25th-75th percentile) post-HCT experienced the best outcomes (2 years overall survival; OS=92%), whilst donors with the least (<25th percentile; 2 years OS=33%; adjusted HR vs. intermediate shortening=9.3, p=0.001) and the greatest (>75th percentile; 2 years OS=59%; adjusted HR=6.0, p=0.01) shortening had worse outcomes. By contrast, using the traditional method based on donor-recipient difference in TeSLA mean telomere length did not demonstrate survival association in this small sample set (p log-rank=0.95).

Conclusion. The findings described herein suggest that the degree of donor telomere attrition may reflect T cell proliferation and alloreactivity following transplant. Accounting for the entire span of telomere lengths, could better identify post-transplant risk groups.

The authors have declared no competing interest.

The study is funded by the NIH grant U01AG066529 (The Telomere Research Network), and by the intramural program of the National Cancer Institute, NIH. The Center for International Blood and Marrow Transplant Research (CIBMTR) is supported primarily by Public Health Service U24CA076518 from the NCI, the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases; HHSH250201700006C from the Health Resources and Services Administration; and N00014-21-1-2954 and N00014-20-1-2832 from the Office of Naval Research. Support for this study was provided by grants U10HL069294 and U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) from the National Heart, Lung, and Blood Institute and the National Cancer Institute. T.P.L work was supported by NSF grant 2032119, NIH grants 1U01AG066529, 3U01AG066529-02S1, NCI contract 75N91019P00829, and New Jersey Alliance for Clinical and Translational Science Career Development Award NJACTS KL2 TR003018.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The research use of blood samples and clinical Information was approved by the National Marrow Donor Program IRB. All study participants provided written informed consent for participation in the BMT-CTN 1202 protocol (NCT01879072) and the CIBMTR repository and database protocols (NCT00495300, and NCT01166009, respectively).The research use of blood samples and clinical Information was approved by the National Marrow Donor Program IRB. All study participants provided written informed consent for participation in the BMT-CTN 1202 protocol (NCT01879072) and the CIBMTR repository and database protocols (NCT00495300, and NCT01166009, respectively).

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All data produced in the present study are available upon reasonable request to the authors