Abstract
Telomeres are tandem nucleotide repeats and a protein complex located at the end of the chromosomes maintaining genomic stability. Their potential as a predictive biomarker for outcomes after allogeneic hematopoietic cell transplant (HCT) in hematologic malignancies is still unclear. From the Center for International Blood and Marrow Transplant Research (CIBMTR), we randomly selected 536 acute leukemia (AL) patients from those who underwent myeloablative 8/8 HLA-matched unrelated donor HCT between 2005 and 2012, and who had an available pre-HCT blood sample in the repository. RTL was measured by real time qPCR. We used Kaplan-Meier and competing risk estimators to calculate survival probability and cumulative incidence, respectively across patient RTL tertiles. Cox proportional hazard regression was used for adjusted analyses. The study included 396 AML and 140 ALL patients. Median age at HCT=41 years, range 0.5–66 years, and median follow-up for survivors=5.1 years (range= 0.4–8.3). Significant inverse correlations between age and RTL were observed in patients with AML (r=−0.44, p<0.0001), and ALL (r=−0.48 p<0.0001). Patients with ALL had longer RTL than those with AML (mean T/S= 0.48 vs. 0.43, respectively); the difference was not statistically significant after adjusting for patient age (p=0.96). Pre-HCT RTL in AL patients was not statistically significantly associated with overall survival (HR for longest RTL compared with shortest=0.91, 95% CI=0.65–1.28), disease free survival (HR=0.90, 95% CI=0.64–1.25), transplant related mortality (HR=0.97, 95% CI=0.60–1.59), incidence of relapse (HR=0.89, 95% CI=0.56–1.40), neutrophil engraftment (HR=1.06, 95% CI=0.85–1.32), or acute (HR=1.11, 95% CI=0.81–1.53 for grade II–IV, HR=0.92, 95% CI=0.54–1.59 for grade III–IV) and chronic graft-versus-host disease (HR=1.10, 95% CI=0.81–1.50). In this study, recipient pre-HCT RTL had no prognostic role in post-transplant outcomes in AL patients.
Keywords: Acute leukemia, Telomere length, Hematopoietic cell transplantation, Survival, Outcome
INTRODUCTION
Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment option for patients with acute leukemia(1, 2). Despite recent advances in HLA matching, conditioning regimens, and supportive care, post-HCT mortality and morbidity risks are still high(3). Leukemia relapse remains the main cause of death in most patients, followed by graft versus host disease (GvHD) and infections(3). Identifying biomarkers for pre-HCT patient risk stratification is needed.
Telomeres are tandem hexanucleotide (TTAGGG)n repeats and a protein complex located at the end of the chromosomes. They shorten with each cell division, and therefore are a marker for cellular aging(4). Critically short telomeres trigger cellular senescence(5), p53 dependent apoptosis(6), and genomic instability(7). Patients with hematological malignancies have been reported to have short telomeres than healthy controls(8, 9). Shorter telomeres in patients with leukemia were associated with the presence of aberrant karyotypes(8), and possibly unfavorable outcomes(10). Telomere length was associated with leukemia outcomes in several small studies.
For example, in a study of 97 pediatric and young adults with AML, shorter telomere length after chemotherapy induction was associated with a delay in neutrophil recovery in later chemotherapy courses(11). In a single center study of 178 patients who underwent myeloablative matched sibling HCT, mainly for hematological malignancy, longer recipient pre-HCT telomere length was associated with a lower risk of treatment related mortality (TRM) (HR=0.4, 95% CI = 0.2–0.8), but no other outcome (12).
In the current study, we evaluated the association between recipient pre-transplant leukocyte RTL and post-transplant outcomes focusing on patients who received an 8/8 HLA-matched unrelated donor HCT for acute leukemia using myeloablative regimens.
MATERIALS AND METHODS
Data source and population selection
Clinical and outcome data and pre-HCT blood samples for acute leukemia patients in this study were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR). The CIBMTR is a research collaboration between the National Marrow Donor Program® (NMDP)/Be The Match® and the Medical College of Wisconsin. It was established in 2004 and includes a large network of more than 500 transplant centers worldwide that report baseline and longitudinal data on clinical parameters and transplant outcome. Reported data go through a rigorous validation and verification process to ensure high data quality.
The study included 536 patients with acute leukemia, randomly selected from patients with the following criteria: 1) underwent an 8/8 HLA-matched unrelated donor HCT, 2) transplanted between 2005 and 2012, 3) received myeloablative conditioning, and 4) had an available pre-HCT blood sample in the repository. The study was approved by the NMDP Institutional Review Board and the NIH office of Human Subjects Research Protections, and all patients provided informed consent.
Telomere length measurement
Genomic DNA were extracted from recipient peripheral blood mononuclear cells or whole blood samples using QIAamp Maxi Kit procedure (QIAGEN Inc., Valencia, CA). Pre-transplant leukocyte RTL was measured using a monoplex quantitative real-time PCR (qPCR) assay adopting the methods described previously (13–15). In brief, the ratio between telomere signal concentration (T) to that of a single-copy gene (S; 36B4) (T/S) was calculated for each sample then divided by the average T/S ratio obtained from the internal QC calibrator samples in the same plate. Final T/S was exponentiated to ensure normal distribution. All telomere and 36B4 reactions were run in triplicate and the average of the measurements was used for all calculations. Details are described elsewhere (16). The mean coefficient of variation for the standardized T/S measure from replicate samples was 5%.
Outcome definitions and end points
Death from any cause was considered an event for overall survival (OS) analysis. Disease-free survival (DFS) was defined as survival without disease relapse. Transplant-related mortality (TRM) was defined as death during continuous complete leukemia remission. Neutrophil engraftment was defined as achieving an absolute neutrophil count ≥0.5 ×109/L for three consecutive days. Acute and chronic GvHD were diagnosed and graded according to previously described criteria (17, 18).
Statistical Analysis
RTL was categorized into tertiles based on the distribution in the entire study cohort (short: RTL <0.37, intermediate: RTL 0.37 −<0.47, and long: RTL ≥0.47). We calculated the probabilities of OS and DFS at 1, 3 and 5 years post-transplant using the Kaplan-Meier estimator. Log-rank test was used to compare probabilities across RTL categories.
For relapse and TRM, we used cumulative incidence functions to account for the presence of competing risks. TRM was treated as a competing risk in the analysis of relapse, and relapse was used as a competing risk in the TRM analysis.
We used Cox proportional hazard regression for multivariate adjusted analysis and calculated the hazard ratios (HRs) and the 95% CI of post-HCT outcomes comparing long and intermediate RTL with short RTL. Follow-up started at the date of HCT and ended at the date of event, death, date of last follow-up, or end of study in October 14, 2014.
We used a stepwise forward-backward conditional procedure to select clinical variables to enter and stay in the model with a threshold of p=0.05. Variables that violated the proportional hazard assumption were adjusted for through stratification. All p-values were two-sided and p<0.05 was considered to be statistically significant. All statistical analyses were conducted using SAS 9.3 (SAS Institute, Cary, NC).
RESULTS
Baseline characteristics
The study included 396 patients with AML and 140 patients with ALL. The median age at HCT for all patients was 41 years (range= 0.5–66 years), for AML patients was 45 years (range=0.6–66 years), and for ALL patients was 30 years (range=0.5–62 years). Most of the patients in this study received HCT in first complete remission (n=359, 67%), and received peripheral blood stem cells (n=382, 71%). The median follow-up for survivors was 5.1 years (range= 0.4–8.3).
RTL negatively correlated with age in all patients (r=−0.47, p<0.0001), patients with AML (r=−0.44, p<0.0001), and ALL (r=−0.48, p<0.0001) (Figure 1). Patients with ALL had longer RTL than those with AML (mean T/S= 0.48 vs. 0.43, respectively, p<0.001). This RTL difference was not statistically significant after adjusting for patient age (p=0.96). Table 1 summarizes patient demographics and clinical factors by recipient RTL.
Figure 1.
Scatter Plots of the correlation between relative telomere length and age in patients with AML and ALL.
Table 1.
Characteristics of recipients with acute leukemia who underwent unrelated donor HCT between 2005 and 2012 by tertiles of pre-transplant leukocyte relative telomere length.
| Variable | N (%) by recipient pre-HCT RTL tertile
|
|||
|---|---|---|---|---|
| Short (T/S< 0.37) |
Intermediate (T/S=0.37-<0.47) |
Long (T/S≥ 0.47) |
p-value1 | |
| Number of Recipients | 179 | 178 | 179 | |
| Recipient age at transplant, Median (range) | 50 (2–66) | 40 (2–66) | 29 (0–60) | <0.001 |
| Recipient sex, Male | 101 (56) | 93 (52) | 85 (47) | 0.24 |
| Karnofsky score | 0.36 | |||
| 10–80 | 50 (28) | 51 (29) | 37 (21) | |
| 90–100 | 120 (67) | 118 (66) | 135 (75) | |
| Missing | 9 (5) | 9 (5) | 7 (4) | |
| Disease at transplant | <0.001 | |||
| AML | 152 (85) | 132 (74) | 112 (63) | |
| ALL | 27 (15) | 46 (26) | 67 (37) | |
| Disease status at transplant | 0.05 | |||
| In 1st complete remission | 129 (72) | 107 (60) | 123 (69) | |
| In 2nd complete remission | 50 (28) | 71 (40) | 56 (31) | |
| Stem cell source | 0.003 | |||
| Marrow | 41 (23) | 45 (25) | 68 (38) | |
| Peripheral blood stem cell | 138 (77) | 133 (75) | 111 (62) | |
| Conditioning regimen | <0.001 | |||
| Bu + Cy +/− Others | 66 (37) | 45 (25) | 39 (22) | |
| Bu +/− Others (No Cy) | 53 (30) | 52 (29) | 31 (17) | |
| Cy + TBI +/− Others | 52 (29) | 71 (40) | 97 (54) | |
| TBI +/− Others | 8 (4) | 10 (6) | 12 (7) | |
| GvHD Prophylaxis | 0.15 | |||
| Tacrolimus ± others | 150 (84) | 148 (84) | 137 (77) | |
| CSA ± others | 29 (16) | 30 (16) | 42 (24) | |
| Donor/Recipient sex matching | 0.55 | |||
| Male/Male | 79 (44) | 67 (38) | 65 (36) | |
| Male/Female | 50 (28) | 59 (33) | 59 (33) | |
| Female/Male | 22 (12) | 26 (15) | 20 (11) | |
| Female/Female | 28 (16) | 26 (15) | 35 (20) | |
| Donor/Recipient CMV serostatus | 0.15 | |||
| Negative/negative | 49 (27) | 65 (37) | 62 (35) | |
| Negative/positive | 73 (41) | 59 (33) | 49 (27) | |
| Positive/negative | 22 (12) | 19 (11) | 28 (16) | |
| Positive/positive | 35 (20) | 35 (20) | 40 (22) | |
| Donor age at donation, Median (range) | 33 (20–59) | 33 (18–61) | 30 (19–59) | 0.11 |
| Year of transplant | 0.48 | |||
| 2005–2006 | 59 (33) | 50 (28) | 59 (33) | |
| 2007–2008 | 54 (30) | 68 (39) | 64 (36) | |
| 2009–2012 | 66 (36) | 60 (33) | 56 (31) | |
| Follow-up among survivors | ||||
| N | 84 | 95 | 101 | |
| Median months (range) | 60 (5–99) | 65 (12–100) | 60 (12–99) | 0.65 |
The Pearson chi-square test was used for comparing discrete variables; the Kruskal-Wallis test was used for comparing continuous variables.
The association between recipient pre-HCT RTL and survival outcomes after HCT
Post-HCT OS and TRM were not associated with patient pre-HCT RTL. For DFS, only 5-year probabilities showed statistically significant differences by pre-HCT RTL (39%, 48% and 54% for the short, intermediate, and long RTL, respectively; p=0.03) (Figure 2 & Table 2).
Figure 2.
Post-HCT leukemia-free survival by tertiles of patient pre-HCT relative telomere length.
Table 2.
Univariate analyses of HCT outcomes for patients with acute leukemia by recipient relative telomere length.
| Outcome | Recipient pre-HCT RTL tertile
|
|||
|---|---|---|---|---|
| Short N=179 |
Intermediate N=178 Prob (95% CI) |
Long N=179 |
p-value | |
| Overall survival | ||||
| 1 year | 67 (60–74) | 72 (65–78) | 75 (68–81) | 0.25 |
| 3 years | 52 (44–59) | 57 (49–64) | 62 (54–69) | 0.18 |
| 5 years | 46 (39–54) | 53 (45–60) | 58 (51–65) | 0.10 |
| Disease free survival | ||||
| 1 year | 59 (52–67) | 64 (57–71) | 66 (59–73) | 0.46 |
| 3 years | 44 (36–52) | 51 (43–58) | 54 (46–61) | 0.17 |
| 5 years | 39 (30–47) | 48 (40–56) | 54 (46–61) | 0.03 |
| Transplant related mortality | ||||
| 1 year | 16 (11–21) | 16 (11–21) | 15 (10–21) | 0.99 |
| 3 years | 25 (18–32) | 23 (17–30) | 21 (16–28) | 0.74 |
| 5 years | 27 (20–35) | 26 (19–33) | 21 (16–28) | 0.44 |
| Relapse | ||||
| 1 year | 25 (19–31) | 20 (15–26) | 19 (14–25) | 0.40 |
| 3 years | 31 (25–39) | 26 (20–33) | 25 (19–31) | 0.36 |
| 5 years | 34 (27–42) | 27 (20–34) | 25 (19–31) | 0.17 |
| Neutrophil Engraftment, 24 days | 94 (90–97) | 92 (88–96) | 90 (86–94) | 0.50 |
| Grade II-IV aGvHD, 100 days | 42 (35–49) | 44 (37–52) | 44 (37–51) | 0.91 |
| cGvHD, 1 year | 48 (41–56) | 51 (44–59) | 50 (43–58) | 0.87 |
In multivariable analyses, no significant association was observed with any survival outcome. The HR comparing the longest with shortest RTL tertile was 0.91 (95% CI=0.65–1.28) for OS; HR=0.97 (95% CI=0.60–1.59) for TRM; and HR=0.90 (95% CI=0.64–1.25) for DFS (Table 3).
Table 3.
Multivariate analysis results of outcomes after unrelated donor HCT for acute leukemia.
| Outcome | N of events/ total | HR (95% CI)1 | p-value |
|---|---|---|---|
| Overall survival | |||
| short RTL | 95/179 | 1.00 (reference) | |
| intermediate RTL | 83/178 | 0.87 (0.64, 1.19) | 0.39 |
| long RTL | 78/179 | 0.91 (0.65, 1.28) | 0.59 |
| Disease free survival | |||
| short RTL | 97/179 | 1.00 (reference) | |
| intermediate RTL | 90/178 | 0.89 (0.66, 1.21) | 0.46 |
| long RTL | 83/179 | 0.90 (0.64, 1.25) | 0.51 |
| Transplant related mortality | |||
| short RTL | 41/179 | 1.00 (reference) | |
| intermediate RTL | 44/178 | 0.95 (0.60, 1.48) | 0.81 |
| long RTL | 39/179 | 0.97 (0.60, 1.59) | 0.92 |
| Relapse | |||
| short RTL | 56/179 | 1.00 (reference) | |
| intermediate RTL | 46/178 | 0.87 (0.58, 1.30) | 0.49 |
| long RTL | 44/179 | 0.89 (0.56, 1.40) | 0.61 |
| aGvHD II-IV | |||
| short RTL | 79/179 | 1.00 (reference) | |
| intermediate RTL | 82/177 | 1.06 (0.77, 1.45) | 0.72 |
| long RTL | 80/178 | 1.11 (0.81, 1.53) | 0.52 |
| aGvHD III-IV | |||
| short RTL | 29/179 | 1.00 (reference) | |
| intermediate RTL | 27/178 | 0.93 (0.55, 1.58) | 0.79 |
| long RTL | 25/179 | 0.92 (0.54, 1.59) | 0.77 |
| cGvHD | |||
| short RTL | 94/174 | 1.00 (reference) | |
| intermediate RTL | 101/177 | 1.06 (0.79, 1.41) | 0.70 |
| long RTL | 93/170 | 1.10 (0.81, 1.50) | 0.52 |
| Neutrophil engraftment | |||
| short RTL | 173/178 | 1.00 (reference) | |
| intermediate RTL | 175/178 | 1.14 (0.92, 1.42) | 0.22 |
| long RTL | 174/178 | 1.06 (0.85, 1.32) | 0.62 |
Hazard ratio and 95% confidence interval. OS models adjusted for conditioning regimen, donor age, GvHD prophylaxis, recipient age, and stratified on graft type; DFS models adjusted for conditioning regimen, donor age, GvHD prophylaxis, recipient age, and stratified on graft type; TRM models adjusted for conditioning regimen, donor age, GvHD prophylaxis, recipient age, and stratified on graft type; Relapse models adjusted for graft type, and stratified on recipient age. Acute GvHD II-IV models adjusted for ATG given, donor Rh, graft type, recipient Rh, donor/recipient sex match and year of transplant; Acute GvHD III-IV models adjusted for graft type, and donor-recipient sex match.; Chronic GvHD models adjusted for ABO, ATG given, alemtuzumab given, conditioning regimen, graft type, and year of transplant; Neutrophil engraftment models adjusted for ABO, GvHD Prophylaxis, and stratified on graft type.
The association between recipient pre-HCT RTL and the incidence of relapse, neutrophil engraftment and GvHD
There was no statistically significant association between recipient RTL and relapse at 3 years (P=0.36), neutrophil engraftment at 24 days (P=0.50), grades II-IV acute GvHD at 100 days (P=0.91), or chronic GvHD at 1 year (P=0.87) (Table 2).
Similar results were noted in multivariable analyses (Table 3). The HR comparing the longest with shortest RTL tertile were: 0.89 (95% CI=0.56–1.40) for relapse; HR=1.06 (95% CI=0.85–1.32) for neutrophil engraftment; HR=1.11 (95% CI=0.81–1.53) for grades II-IV acute GvHD; and HR=1.10 (95% CI=0.81–1.50) for chronic GvHD.
In an exploratory subset analysis stratified by disease type, the data suggested that longer recipient RTL was associated with a higher probability of neutrophil engraftment in patients with ALL, but not in AML. Compared with patients with short RTL, the HR for neutrophil engraftment in ALL patients was 2.06 (95% CI=1.20–3.52, P=0.01) for intermediate, and 1.94 (95% CI=1.10–3.40, P=0.02) for the long RTL, respectively. For AML patients, the HR was 1.02 (95% CI=0.80–1.30, P=0.85) for intermediate, and 1.01 (95% CI=0.79–1.30, P=0.94) for the long RTL, respectively. However, the interaction between disease subtype and RTL was not statistically significant (p for interaction=0.95).
DISCUSSION
Several prior studies have suggested a possible association between telomere length and outcomes after therapy for acute leukemia. Here, we evaluated whether pre-HCT recipient leukocyte telomere length is associated with HCT outcomes in 536 patients who underwent unrelated 8/8 HLA-matched donor HCT with myeloablative regimens for acute leukemia. Our data showed no statistically significant associations with post-HCT survival outcomes, neutrophil engraftment, GvHD, or leukemia relapse.
This finding is consistent with our previous report in 330 patients with SAA in which there was no association between recipient RTL and HCT outcome (19). Specifically, analyses comparing SAA patients with the longest pre-HCT RTL tertile to those with shorter RTL, the HR for OS was 0.91; HR for neutrophil engraftment=1.03; HR for acute GvHD grades III–IV= 1.21; and HR for chronic GvHD= 1.00 (19). Similarly, our results are consistent with another study of 178 matched sibling HCT (153 for malignant diseases, 65% of them had ALL or AML), with the exception of an observed inverse association with TRM (HR=0.4, 95% CI=0.2, 0.8) (12). It is possible that the observed differences in TRM between the two studies could be explained by the HCT advancements leading to a reduction of TRM over the years. Additionally, differences in the patient population of both studies may have contributed to these discrepancies; in our study all patients had acute leukemia versus 65% of the patients in the previous study.
Our study strengths include its large sample size, the availability of pre-transplant blood samples and comprehensive clinical and outcome data uniformly collected by CIBMTR, and the use of the same DNA extraction and handling methods for all samples. The study limitations include lack of information on possible confounders such as pre-HCT chemotherapy, time from chemotherapy to blood collection and transplant, patient cytogenetics and risk classification, and quantity of minimal residual disease at HCT. We used the qPCR assay to measure telomere length. qPCR provides an average measure of TL across cell subtypes, and therefore its measure could possibly be affected by the dominant cell type. Comparing tertiles of RTL did not allow for evaluating possible associations with HCT outcomes when pre-RTL is very short. Our study was restricted to patients with acute leukemia who received unrelated blood or marrow transplant using myeloablative regimens, and therefore may not be generalizable to all patients.
In conclusion, our study showed no associations between recipient pre-HCT RTL and outcomes after transplantation. Future large scale studies with comprehensive information on patients’ pre-transplant clinical profiles are imperative to better understand the role of patient telomere length on transplant outcomes.
HIGHLIGHTS.
Pre-HCT relative telomere length (RTL) is inversely correlated with age in patients with ALL and AML.
Age-adjusted RTL is similar in patients with ALL and AML.
Recipient pre-transplant RTL is not associated with HCT outcomes in patients with acute leukemia.
Acknowledgments
The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute; by a Public Health Service grant (U24-CA76518) from the National Cancer Institute, the National Heart Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases, Heath Resources, and Services Administration (HHSH234200637015C); and by two Grants N00014-15-1-0848 and N00014-16-1-2020 from the Office of Naval Research.
Footnotes
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Conflict of Interest: None.
References
- 1.Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011;117(8):2307–18. doi: 10.1182/blood-2010-10-265603. [DOI] [PubMed] [Google Scholar]
- 2.Khaled SK, Thomas SH, Forman SJ. Allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia in adults. Curr Opin Oncol. 2012;24(2):182–90. doi: 10.1097/CCO.0b013e32834f5c41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: CIBMTR Summary Slides. 2015 [Available from: http://www.cibmtr.org/
- 4.Bekaert S, De Meyer T, Van Oostveldt P. Telomere attrition as ageing biomarker. Anticancer research. 2005;25(4):3011–21. [PubMed] [Google Scholar]
- 5.Campisi J, Kim SH, Lim CS, Rubio M. Cellular senescence, cancer and aging: the telomere connection. Exp Gerontol. 2001;36(10):1619–37. doi: 10.1016/s0531-5565(01)00160-7. [DOI] [PubMed] [Google Scholar]
- 6.Artandi SE, Attardi LD. Pathways connecting telomeres and p53 in senescence, apoptosis, and cancer. Biochem Biophys Res Commun. 2005;331(3):881–90. doi: 10.1016/j.bbrc.2005.03.211. [DOI] [PubMed] [Google Scholar]
- 7.Feldser DM, Hackett JA, Greider CW. Telomere dysfunction and the initiation of genome instability. Nat Rev Cancer. 2003;3(8):623–7. doi: 10.1038/nrc1142. [DOI] [PubMed] [Google Scholar]
- 8.Hartmann U, Brummendorf TH, Balabanov S, Thiede C, Illme T, Schaich M. Telomere length and hTERT expression in patients with acute myeloid leukemia correlates with chromosomal abnormalities. Haematologica. 2005;90(3):307–16. [PubMed] [Google Scholar]
- 9.Blackburn NB, Charlesworth JC, Marthick JR, Tegg EM, Marsden KA, Srikanth V, et al. A retrospective examination of mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study. Oncology reports. 2015;33(1):25–32. doi: 10.3892/or.2014.3568. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Watts JM, Dumitriu B, Hilden P, Kishtagari A, Rapaport F, Chen C, et al. Telomere length and associations with somatic mutations and clinical outcomes in acute myeloid leukemia. Leukemia research. 2016;49:62–5. doi: 10.1016/j.leukres.2016.07.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gerbing RB, Alonzo TA, Sung L, Gamis AS, Meshinchi S, Plon SE, et al. Shorter Remission Telomere Length Predicts Delayed Neutrophil Recovery After Acute Myeloid Leukemia Therapy: A Report From the Children’s Oncology Group. Journal of Clinical Oncology. 2016;34(31):3766–72. doi: 10.1200/JCO.2016.66.9622. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Peffault de Latour R, Calado RT, Busson M, Abrams J, Adoui N, Robin M, et al. Age-adjusted recipient pretransplantation telomere length and treatment-related mortality after hematopoietic stem cell transplantation. Blood. 2012;120(16):3353–9. doi: 10.1182/blood-2012-01-403337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cawthon RM. Telomere measurement by quantitative PCR. Nucleic acids research. 2002;30(10):e47. doi: 10.1093/nar/30.10.e47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Callicott RJ, Womack JE. Real-time PCR assay for measurement of mouse telomeres. Comp Med. 2006;56(1):17–22. [PubMed] [Google Scholar]
- 15.Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic acids research. 2009;37(3):e21. doi: 10.1093/nar/gkn1027. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Gadalla SM, Wang T, Dagnall C, Haagenson M, Spellman SR, Hicks B, et al. Effect of Recipient Age and Stem Cell Source on the Association between Donor Telomere Length and Survival after Allogeneic Unrelated Hematopoietic Cell Transplantation for Severe Aplastic Anemia. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2016;22(12):2276–82. doi: 10.1016/j.bbmt.2016.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone marrow transplantation. 1995;15(6):825–8. [PubMed] [Google Scholar]
- 18.Flowers ME, Kansu E, Sullivan KM. Pathophysiology and treatment of graft-versus-host disease. Hematology/oncology clinics of North America. 1999;13(5):1091–112. viii–ix. doi: 10.1016/s0889-8588(05)70111-8. [DOI] [PubMed] [Google Scholar]
- 19.Gadalla SM, Wang T, Haagenson M, Spellman SR, Lee SJ, Williams KM, et al. Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia. JAMA. 2015;313(6):594–602. doi: 10.1001/jama.2015.7. [DOI] [PMC free article] [PubMed] [Google Scholar]