Telomere Length Of Granulocytes Significantly Increases During The First Six Months Of Lenalidomide Treatment In Patients With Isolated 5q- Syndrome
Authors: Beier Fabian , Germing Ulrich , Büsche Guntram , Ziegler Patrick , Wilop Stefan , Vankann Lucia , Gattermann Norbert , Platzbecker Uwe , Giagounidis Aristoteles , Götze Katharina S. , Hofmann Wolf-Karsten , Haase Detlef , Kreipe Hans , Panse Jens , Brümmendorf Tim H. 
Published: October 2019

Abstract

Introduction
Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal stem cell disorders characterized by ineffective hematopoiesis and an increased risk for leukemic transformation. Lenalidomide (LEN) was found to be an effective treatment particularly in a subset of MDS patients with isolated 5q deletion (del5q). Telomere length (TL) predicts replicative potential of eukaryotic cells and dysfunctional telomeres have been found to play an important role in the development of chromosomal instability and malignant transformation. The aim of this study was to investigate telomere biology during LEN treatment as a potential biomarker for clonal evolution and leukemic transformation of patients with MDS del5q.

Methods and Patients
TL of granulocytes and lymphocytes in the peripheral blood of 45 MDS patients enrolled in the LEMON5 study (NCT01081431) and 108 healthy controls (used for age-adaption of TL) were measured using quantitative telomere flow-FISH. Criteria for study inclusion were isolated del5q, IPSS low risk and intermediate-1 as well as transfusion dependence of at least one unit per 8 weeks. Mean age of the MDS patients was 66 years (range 42-88) and follow-up measurement were carried out before as well as 6 and 12 months after treatment start, respectively.

Results
We found that mean age-adjusted TL in granulocytes was only slightly shortened compared to age-adjusted normal individuals (-0.31 kb, n=22). However, under LEN treatment, TL significantly increased during the first six months (ΔTL: +0.71 kb, n=17 p=0.01) and twelve months after treatment start (ΔTL: +0.86 kb, n=16, p=0.02; both time points compared to pre-treatment results, respectively). In contrast, TL of lymphocytes did not change significantly from pre-treatment (ΔTL: -0.11 kb, n=22) compared to months six (ΔTL: +0.15 kb, n=17) and months twelve (ΔTL: +0.04 kb, n=15). Interestingly, in five patients with sequential measurements of granulocytes available, the following pattern was detected: 3/5 patients showed telomere elongation, 1/5 had stable TL and 1/5 expressed telomere shortening (TS) during the first six months. Two patients were further followed up to 12 months after treatment initiation and showed either TS or elongation.

Conclusions
Mean telomere length in granulocytes of patients with MDS and isolated del5q increases significantly during the first year of LEN treatment while in the same time period, TL in lymphocytes remains unchanged. Whether telomere elongation is due to direct effects of LEN on telomerase and/or telomeres in clonal MDS del5q stem cells themselves (e.g. by telomerase upregulation) or due to a shift from dysplastic clonal towards normal hematopoiesis is currently under investigation. Upon validation, absolute TL and/or increase of telomere length under treatment (ΔTL) might become a promising novel biomarker for treatment response to LEN.

Disclosures:
Beier: Celgene: Travel grant Other. Germing:Celgene: Honoraria, Research Funding. Büsche:Celgene: Research Funding. Gattermann:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Platzbecker:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Götze:Celgene Corp.: Honoraria. Hofmann:Celgene: Honoraria, Research Funding. Brümmendorf:Celgene: Honoraria, Research Funding.