Association Between Donor Leukocyte Telomere Length and Survival After Unrelated Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Gadalla, Shahinaz M.; Wang, Tao; Haagenson, Michael; Spellman, Stephen R.; Lee, Stephanie J.; Williams, Kirsten M.; Wong, Jason; Vivo, Immaculata De; Savage, Sharon A.

doi:10.1001/jama.2015.7

Cited by 80 publications

(74 citation statements)

References 35 publications

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“…Moreover, others have reported that longer donor telomere length correlates with survival, but only in patients transplanted for aplastic anemia. 10 We failed to find a correlation between donor telomere length and TRM or OS (data not shown), suggesting that such influences on transplant outcomes may only occur in aplastic anemia patients. As telomere erosion may be etiologic in aplastic anemia and is genetically determined by mutations in telomere-associated genes, donor telomere length may act as a surrogate for the donor's silent genetic status, which may result in a limited stem cell reserve.…”

Section: Discussionmentioning

confidence: 81%

“…More recently, we and others have reported on the correlation of recipient or donor telomere length with OS and TRM. 9,10 A number of clinical and biological factors may be used to inform transplantation-related decision making. However, clinical and biological data, including pretransplant telomere length and comorbidity index scores, are mostly assessed separately, making it difficult to gauge each factor's contribution to TRM.…”

Section: Introductionmentioning

confidence: 99%

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Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT

et al. 2017

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Section: Discussionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT

et al. 2017

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“…Short telomeres after HCT were more common in females and those with cGVHD, 164 and pre-HCT short telomere length in recipients has been associated with transplant-related mortality. 165,166 Finally, in a longitudinal study including 287 lymphoma patients, accelerated telomere shortening was associated with MDS/AML risk after autologous HCT. 167 …”

Section: Non-transplant-related Risk Factorsmentioning

confidence: 99%

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Morton

Saber

Baker

et al. 2017

Biology of Blood and Marrow Transplantation

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Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists in order to reduce the burden of SN in the rapidly growing population of HCT survivors.

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“…The fruits of this research over the past 30-plus years are now being directed toward clinical practice (2). An important component for successful telomere analysis in a clinical laboratory environment is a validated, scalable, and reproducible assay for average telomere length measurement.…”

mentioning

confidence: 99%

“…Quantitative PCR (qPCR) 2 based assays for telomere length measurement are high-throughput techniques that require low nanogram amounts of DNA (9,10). Previous studies have used qPCR methodology developed by Cawthon's laboratory (9,10), which reports relative average telomere length (rATL) by taking the ratio of a telomere signal to a normalizing single copy gene signal (the T/S ratio).…”

mentioning

confidence: 99%

Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment

Blauwkamp¹,

Fasching²,

Lin³

et al. 2017

The Journal of Applied Laboratory Medicine

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Background Average telomere length in whole blood has become a biomarker of aging, disease, and mortality risk across a broad range of clinical conditions. The most common method of telomere length measurement for large patient sample sets is based on quantitative PCR (qPCR). For laboratory-developed tests to be performed on clinical samples, they must undergo a rigorous analytical validation, currently regulated under CLIA. Methods Whole blood samples from 40 donors were used in the analytical validation of methods for relative average telomere length (rATL) measurement. Three technical replicate DNA samples were extracted from each whole blood sample and placed in three independent wells on a sample plate. Each of these sample plates was assayed 12 times during the validation process. The study was conducted over a 20-day period, once in the morning and once in the evening, using 3 different operators. Results Our process of rATL measurement beginning with DNA extraction followed by qPCR-based assay resulted in repeatability and reproducibility CV of <5% and amplification efficiencies near 100%. The validated assay was used to establish a reference interval derived from 2 cohorts of individuals: (a) San Francisco Bay area (n = 504) and (b) a US cross-sectional, demographic population (n = 357). Conclusions We present advances in the establishment of a highly reproducible analytically validated process for determining rATLs in a CLIA laboratory environment.

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Association Between Donor Leukocyte Telomere Length and Survival After Unrelated Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Cited by 80 publications

References 35 publications

Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT

Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment

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