Telomere Lenght and Outcome of Allogeneic Stem Cell Transplantation for Poor Risk Chronic Lymphocytic Leukemia: Results from the GCLLSG CLL3X Trial
Authors: Scheffold Annika , Jebaraj Billy Michael Chelliah , Tausch Eugen , Boettcher Sebastian , Ritgen Matthias , Bunjes Donald , Zeis Matthias , Stadler Michael , Uharek Lutz , Scheid Christof , Hegenbart Ute , Hallek Michael , Kneba Michael , Schmitz Norbert , Doehner Hartmut , Dreger Peter , Stilgenbauer Stephan 
Published: October 2019

Abstract
BACKGROUND: Short telomere length has been described in CLL as independent adverse prognostic factor in multivariate analyses of several single centre series and clinical trial cohorts. However, the clinical impact of short telomeres has not been studied in the context of allogeneic stem cell transplantation (allo-SCT) in CLL.
METHODS: Here, we studied telomere length, its associations and impact on outcome in the multicentre CLL3X trial evaluating efficacy of allo-SCT after reduced intensity conditioning in patients with poor-risk CLL (Table 1). Telomere length was analyzed using quantitative PCR on DNA from peripheral blood mononuclear cells (PBMCs) of 69 patients and this cohort was representative of the full trial population. The technique was validated using terminal restriction fragment length analysis (TRF) (R2=0.859, P<0.001) in an independent control sample set (n=18) and 6 of these samples were included in every batch as controls.
RESULTS: Telomere length in the CLL3X cohort was found to be highly variable (1.9 kb – 21 kb). Correlation of telomere length with disease characteristics was performed by defining short and long telomere subgroups, based on median telomere length (median=5.35kb). In contrast to several reports on untreated CLL cohorts, telomere length showed no significant associations with age (P=0.400), sex (P=0.306), presence of high leukocyte count (P=0.765), ECOG status (P=1.000), and prior resistance to fludarabine-based therapy (P=0.955) or other clinical characteristics.
Analysis of telomere length association with genetic characteristics showed a trend towards association with del(17p) (P=0.088) while no association was observed with del(11q) (P=0.834), 12q trisomy (P=0.650), normal karyotype (P=0.450) and del(13q) (P=0.792). Also, no association of telomere length with mutations of TP53 (P=0.280), NOTCH1 (P=0.2470) and SF3B1 (P=0.819) was observed.
With a median observation time of 6 years, analysis of the impact of telomere length below the median on outcome showed no significant association with non-relapse mortality (HR 2.11, P=0.199), event-free survival (EFS) (HR=1.22, P=0.53, Fig.1a) and time to relapse (HR=0.92, P=0.82). Nevertheless, patients with short telomere length tended to have inferior overall survival (OS) (HR=2.04, 95%CI 0.92 - 4.5, P=0.079, Fig. 1b). The OS benefit associated with long telomeres could be largely explained by superior survival after relapse in this subset (HR=3.04, 95%CI 0.96 - 9.57, P=0.058) indicative of better efficacy of salvage treatment.
CONCLUSION: In contrast to several reports on treatment naïve CLL cohorts, telomere length in the poor-risk patient selection of the CLL3X trial was not significantly associated with any known clinical and genetic baseline disease characteristics. While EFS was unaffected by telomere length, short telomeres were associated with poor OS, largely due to inferior survival after CLL relapse, suggesting that rescue treatment after post-transplant disease recurrence was less effective in the presence of short telomeres.
Table 1: Patient Characteristics N % Unmutated IGHV 60/65 92.3 Presence of 11q or 17p- 38/64 59.4 Fludarabine refractory 30/45 66.7 Early relapse 26/63 41.3 Previous regimens >1 (Mean = 4 regimens/patient) 57/63 90.5
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.