The telomere complex consists of repetitive DNA sequences and associated proteins and is located at the end of eukaryotic chromosomes. Telomeres shorten with every cell division and thereby both reflect and restrict the proliferative capacity of somatic cells. Critically short telomeres are associated with genetic instability and eventually, replicative senescence. In chronic myeloid leukemia (CML), increased cellular turnover of clonal breakpoint cluster region-Abelson Murine Leukemia Viral Oncogene Homolog 1 (BCR-ABL)-positive hematopoietic stem and progenitor cells leads to significantly shortened telomeres in peripheral blood myeloid cells. 1 Accelerated telomere shortening was found to correlate with disease stage, cytogenetic remission status, progression to accelerated phase and blast crisis as well as clinical risk score at diagnosis in retrospective trials (refs 1-3, reviewed in ref. 4). However, whether telomere length (TL) can be used as prognostic indicator and/or to predict for depth and kinetics of response to tyrosine kinase inhibitor therapy in patients with CML has not been studied prospectively to date. Consequently, the aim of this substudy within the ENEST1st trial (NCT01061177) was to investigate, whether average TL in peripheral blood leukocytes at diagnosis measured by monochrome multiplex quantitative PCR (MM-qPCR) can be used as an independent prognostic and/or predictive biomarker in patients with CML undergoing first-line treatment with nilotinib. TL from 96 newly diagnosed CML patients before treatment initiation within the ENEST1st trial was measured using MM-qPCR and results were expressed as the standardized T/S ratio. 5 One extreme outlier was excluded from the analysis. Age adaption of TL, indicated as ΔT/S ratio, was performed using data from 89 healthy controls, representing blood donors. 6 The average intra-assay variability expressed as CV Intra-assay for all samples (n = 184; control and CML samples included) was 10.5%. In addition, to monitor plate-to-plate variation, eight reference blood samples from healthy volunteers (age range 24-83 years) were included in each run. The resulting average CV Inter-assay for all eight reference samples was 15.3%. Characteristics of healthy controls and patients are shown in Supplementary Material. The 89 control individuals (unfilled circles, Figure 1a) showed the expected decline in TL with increasing age-a characteristic no longer detectable in CML patients (filled circles). Mean age adjusted TL (ΔT/S ratio) of CML patients was more spread within different age groups and significantly shorter (ΔT/S: − 0.3097 ± 0.6644, n = 95, Po0.001). This is in line with previous studies suggesting accelerated telomere shortening in CML mostly due to an increased turnover of the leukemic as opposed to the coexisting normal stem cell compartment (ref. 1, reviewed in ref. 7). Of note, the analysis of ΔT/S versus age resulted in a positive correlation, indicating a more pronounced TL deficit in younger CML patients (P = 0.0017).
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.
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