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Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial

Leukemia volume 29, pages 2411–2414 (2015)Cite this article

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Telomere erosion and fusion have an important role in the pathology of many common human malignancies including chronic lymphocytic leukemia (CLL).1, 2 Previous studies in CLL have shown that short telomeres defined on the basis of the median value or receiver operating characteristic analysis are associated with unmutated IGHV genes, poor-risk genomic abnormalities, genomic complexity and high expression of CD38, CD49d and ZAP70 whereas long telomeres are associated with increasing IGHV mutational load, isolated deletion of 13q and low CD49d expression. In addition, in predominantly diagnostic or mixed patient cohorts, telomere length (TL) predicts time to first treatment and/or overall survival (OS) in multivariate analyses of models incorporating established biomarkers.3, 4, 5, 6, 7 However uncertainties about the most clinically relevant measure of TL, the optimal choice of assay, the need for assay standardisation and the lack of published data on the prognostic value of TL in patients entered into randomised trials have hindered the implementation of TL measurement into routine clinical practice. We have attempted to address these issues by measuring TL using monochrome multiplex Q-PCR (MMQ-PCR) in 384 patients at randomisation into the UK LRF CLL4 phase 3 chemotherapy trial (Supplementary Table S1), of whom 111 samples were also screened by single telomere length analysis (STELA). TL and established biomarkers were measured as previously described.8, 9, 10, 11, 12, 13

The mean TL assessed by MMQ-PCR in 384 cases was 3.57 TLU (TL units, range 0.61–19.05). For 111 patients randomised to the fludarabine plus cyclophosphamide arm analysed by both MMQ-PCR and STELA, we showed an excellent correlation between these two TL measurements (Spearman correlation 0.80; Supplementary Fig. S1), permitting the calibration of the mean TLU to a mean absolute TL of 3.39 kb (range 1.93–11.06 kb, median 2.92 kb (inter quartile range: 2.58, 3.60)) for our cohort. All subsequent analyses were based on data derived from MMQ-PCR expressed in kb rather than TLU. TL was found to be significantly associated with IGHV mutation status, ZAP70 and CD38 expression, serum beta-2 microglobulin, TP53 abnormality, 11q deletion, genomic complexity, ATM and SF3B1 mutation but not trisomy 12 or NOTCH1 mutation (Supplementary Table S2).

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Author notes

  1. J C Strefford and L Kadalayil: These authors contributed equally to this study and share first authorship.

Authors and Affiliations

  1. Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    J C Strefford, J Forster, M J J Rose-Zerilli, A J Steele, H Parker & D G Oscier

  2. Genetic Epidemiology and Bioinformatics, Faculty of Medicine, University of Southampton, Southampton, UK

    L Kadalayil & A Collins

  3. Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK

    A Parker, A Gardiner, Z Davies & D G Oscier

  4. CLL Research Group, Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK

    T T Lin, N Heppel, K Norris, C Pepper, C Fegan & D Baird

  5. Division of Molecular Pathology, Haemato-oncology Research Unit, The Institute of Cancer Research, London, UK

    D Gonzalez de Castro, M Else & D Catovsky

  6. Division of Cancer Sciences, School of Medicine, University of Birmingham, Birmingham, UK

    T Stankovic

Authors
  1. J C Strefford
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  2. L Kadalayil
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  3. J Forster
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  16. C Pepper
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  18. D Baird
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  19. A Collins
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  20. D Catovsky
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Corresponding authors

Correspondence to J C Strefford or D G Oscier.

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The authors declare no conflict of interest.

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Strefford, J., Kadalayil, L., Forster, J. et al. Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Leukemia 29, 2411–2414 (2015). https://doi.org/10.1038/leu.2015.217

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