Telomere Shortening At Diagnosis Of Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Is Significantly More Pronounced In Patients With Less-Than-Optimal Versus Optimal Molecular Response (ELN criteria) After 12 Months Of Treatment With Nilotinib
Authors: Wenn Katrin , Tomala Lena , Beier Fabian , Wilop Stefan , Vankann Lucia , Hasenbank Christian , Frank Oliver , Walasek Claudia , Hochhaus Andreas , Giles Frank , Koschmieder Steffen , Ziegler Patrick , Brümmendorf Tim H. 
Published: October 2019

Abstract

Introduction
Chronic myeloid leukemia (CML) is a clonal stem cell disorder characterized by the BCR-ABL translocation. Telomere length (TL) reflects the replicative history of eukaryotic cells and progressive telomere shortening is associated with genetic instability. Clinically, accelerated telomere shortening has been demonstrated in patients with CML and was found to correlate with disease progression and clinical risk score in the pre-tyrosine kinase inhibitor (TKI) era. The aim of the current study was to investigate whether telomere length (TL) at diagnosis might predict response to treatment in patients receiving nilotinib as first line treatment of chronic phase CML on the ENEST1st study (NCT01061177)

Methods and Patients
TL analysis of peripheral blood leukocytes was analyzed using monochrome multiplex quantitative PCR in blood samples from 93 newly diagnosed CML patients enrolled on study in Germany. One extreme outlier was excluded from the analysis. 89 healthy controls were used for age-adaption of TL. Median age of the analyzed CML patients was 49.6 years (range: 19-83), Sokal (32 low, 31 intermediate, 13 high risk) and Euro (34 low, 36 intermediate, 6 high risk) scores were available in 76 patients. Response to treatment according to standard criteria was available at 3 month (mo, n=79 patients), 6 mo (n=75), 12 mo (n=71) and 18 mo (n=55) after treatment start.

Results
Mean age-adjusted TL in CML patients was significantly shortened compared to normal individuals (ΔT/S ratio: -0.30 +/- 0.67, p=<0.001). Interestingly, whereas TL followed an expected linear decline over time in the control population of healthy individuals, this age-correlation was no longer detectable in CML patients pointing to a significantly more pronounced TL deficit in younger as opposed to older patients with CML. In univariate analysis, no significant correlation between age-adjusted TL at diagnosis and Euro or Sokal risk score nor with any standard individual prognostic parameters was detected with the exception of the peripheral blast count which was shown to be inversely correlated with age adjusted telomere (ΔT/S ratio) length by linear regression (p=0.01).
When ΔT/S ratio measured at diagnosis was correlated with response to treatment at defined time points according to the ELN criteria 2013 (i.e. <10% BCR-ABL/ABL ratio at 3 mo, <1% at 6 mo, and <0.1% at 12 mo), we could demonstrate that while all cohorts had shortened telomere length compared to age-adjusted controls, less-than-optimal responders had more accelerated telomere shortening compared to optimal responders, i.e. ΔT/S -0.66 (n=4) vs. -0.25 (n=75) at 3 mo; ΔT/S -0.37 (n=10) vs. -0.28 (n=65) at 6 mo and ΔT/S -0.67 (n=15) vs. -0.21 (n=56) at 12 mo. While this pattern seems rather consistent, only the difference at the 12 mo time point reached statistical significance (p=0.028), potentially due to the imbalance of the groups induced by the low number of less-than-optimal responders to treatment according to ELN criteria observed under nilotinib first line treatment.

Conclusions
These data were generated on the first prospective study of the role of telomere length as a potential biomarker for TKI treatment in CML. We could confirm that TL is significantly shortened in CML patients at diagnosis. Even more so, telomere shortening seems to be significantly more accelerated in younger as opposed to older patients pointing to a threshold value of telomere length in CML similar to observations in patients with bone marrow failure syndromes. Furthermore, telomere shortening tends to be more pronounced in patients not meeting the criteria for optimal response according to ELN 2013. Further follow up will reveal whether TL has the potential to serve as a long-term predictive biomarker for frequency and durability of response as well as for the sustainability of treatment cessation in CML patients responding well to TKI treatment.

Disclosures:
Frank: Novartis: Employment. Walasek:Novartis: Employment. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding, Travel Other; BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria. Giles:Novartis: Consultancy, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Brümmendorf:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bristol Myer Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy.