Long-Term Outcomes of Accelerated Telomere Shortening in Acquired Aplastic Anemia
Authors: Kulagin Alexander , Borisov Vyacheslav , Pronkina Natalia , Kruchkova Irina , Lisukov Igor , Afanasyev Boris 
Published: October 2019

Abstract
Introduction: Accelerated telomere shortening (TS) in blood cells has been well documented in both dyskeratosis congenita and acquired aplastic anemia (AA). The present study investigated the incidence and long-term outcomes of TS in AA patients treated with ATG plus cyclosporine immunosuppressive therapy (IST).
Methods: A total of 53 patients (31 M and 22 F, median age 24, 9-62) with moderate (MAA 15), severe (SAA 22) and very severe (vSAA 16) AA were included in cross-sectional study of telomere length (TEL) between 2008 and 2009 and then followed prospectively for 5 years. Treatment-naïve, recovering after IST and refractory AA were in 13, 35 and 5 patients respectively. There were no cases with physical abnormalities or family history of hematological disorders. TEL in granulocytes was assessed by Flow-FISH method with calculation of absolute and age-adjusted (DeltaTEL) values. TS was defined as absolute TEL value below the normal 99% confidence interval in age matched healthy donors (n=71). Outcome measures were response rate in treatment-naïve patients, cumulative incidence (CI) of relapse and clonal evolution, overall (OS) and failure-free survival (FFS). Adult patients or parents of children signed informed consent.
Results: TS was detected in 24 patients (45%) with a median DeltaTEL of -1.715 kbp compared to -0.009 kbp in 29 patients with normal telomere length (TN) (Table 1).
Table 1. Patient and disease characteristics in cross-sectional study TS (n=24) TN (n=29) P DeltaTEL, kbp, median (range) -1.715 (-5.100 – -0.983) -0.009 (-0.760 – 4.142) <0.001 Age, years, median (range) 22.5 (9-37) 26 (14-62) 0.102 Gender, M/F, n 15/9 16/13 0.780 Severity, n (%) MAA 10 (42%) 5 (17%) 0.0485 SAA/vSAA 14 (58%) 24 (83%) Response to prior IST, n (%) Treatment-naïve 4 (17%) 9 (31%) 0.338 Partial response 7 (29%) 9 (31%) Complete response 8 (33%) 11 (38%) Refractory 5 (21%) 0 (0%) 0.047 PNH positive, n/n (%) 12/24 (50%) 13/28 (46%) 1.000 Interval between AA onset and IST, days, median (range) 92 (17-508) 102 (26-585) 0.848 Interval between AA onset and TEL testing, days, median (range) 1093 (49-3792) 785 (64-3494) 0.173
TS was associated with MAA (p = 0.049) and refractory disease (p=0.047) in cross-sectional study. No significant differences in gender, median age, baseline blood counts, PNH positivity or interval from AA onset and IST were observed between the two groups.
Median follow-up after IST start and TEL testing were 90 and 67 months respectively. Response rates to IST were similar in TS (3/4, 75%) and TN (6/9, 67%) patients evaluated prospectively (p=1.0). TS and TN patients showed similar 10-year CI of relapse (16% vs 14%, p=0.905) and hemolytic PNH (28% vs 20%, p=0.532). However, all 3 cases of MDS /AML occurred in patients with TS with CI of 15.4% vs. 0% in the TN (p = 0.063). Compared patient groups have similar high probability of 10-year OS (TS 86.9% vs TN 92.6%, p=0.571) due to the large proportion of patients responding to treatment. The FFS rates were much lower (38.5% and 57.5% respectively, p=0.510).
Conclusions: TS is a relatively common phenomenon in patients with otherwise typical acquired AA and more frequently detected in MAA and refractory to IST cases in cross-sectional study. Our data confirm the previously reported association of TS and increased risk of MDS/AML, which should be considered for a more careful monitoring and treatment planning, including allogeneic BMT as a curative approach.

Disclosures
No relevant conflicts of interest to declare.