Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Chronic Lymphocytic Leukemia

Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia

Leukemia volume 23, pages 1062–1072 (2009)Cite this article

Abstract

Telomere length (TL) has been associated with outcome in chronic lymphocytic leukemia (CLL). The aim of this extensive analysis carried out on 401 CLL patients was to assess TL conclusively as a prognostic biomarker. Our study included two cohorts used as learning (191 patients) and blinded validation series (210 patients). A TL cutoff of 5000 bp was chosen by receiver operating characteristic (ROC) analysis and Youden's index in the learning series. In this series, TL⩽5000 bp was independently associated to a worse outcome for both overall survival (OS; 105.5 vs 281 months, P<0.001) and treatment-free survival (TFS; 24.6 vs 73 months, P<0.001). In the blinded validation series, TL⩽5000 bp was confirmed as an independent outcome predictor for OS (79.8 vs not reached, P<0.001) and TFS (15.2 vs 130.8 months, P<0.001). Moreover, TL⩽5000 bp independently predicted the risk of Richter's syndrome (5-year risk: 18.9 vs 6.4%, P=0.016). Within CLL subsets defined by biological predictors, TL consistently identified patient subgroups harboring unfavorable prognosis. These results demonstrate that TL is a powerful independent predictor of multiple outcomes in CLL, and contributes to refine the prognostic assessment of this disease when utilized in combination with other prognostic markers. We thus believe that this prognostic biomarker has the potential for a more widespread use in CLL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Binet JL, Caligaris-Cappio F, Catovsky D, Cheson B, Davis T, Dighiero G et al. Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 2006; 107: 859–861.

    Article  CAS  PubMed  Google Scholar 

  2. Ghia P, Ferreri AM, Caligaris-Cappio F . Chronic lymphocytic leukemia. Crit Rev Oncol Hematol 2007; 64: 234–246.

    Article  PubMed  Google Scholar 

  3. Dighiero G, Hamblin TJ . Chronic lymphocytic leukaemia. Lancet 2008; 371: 1017–1029.

    Article  CAS  PubMed  Google Scholar 

  4. Moreno C, Montserrat M . New prognostic markers in chronic lymphocytic leukemia. Blood Rev 2008; 22: 211–219.

    Article  CAS  PubMed  Google Scholar 

  5. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000; 343: 1910–1916.

    Article  PubMed  Google Scholar 

  6. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840–1847.

    CAS  PubMed  Google Scholar 

  7. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK . Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848–1854.

    CAS  PubMed  Google Scholar 

  8. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348: 1764–1775.

    Article  CAS  PubMed  Google Scholar 

  9. Rassenti LZ, Huynh L, Toy TL, Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med 2004; 351: 893–901.

    Article  CAS  PubMed  Google Scholar 

  10. Kröber A, Bloehdorn J, Hafner S, Bühler A, Seiler T, Kienle D et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol 2006; 24: 969–975.

    Article  PubMed  Google Scholar 

  11. Orchard JA, Ibbotson RE, Davis Z, Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 2004; 363: 105–111.

    Article  CAS  PubMed  Google Scholar 

  12. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002; 99: 1023–1029.

    Article  CAS  PubMed  Google Scholar 

  13. Capello D, Guarini A, Berra E, Mauro FR, Rossi D, Ghia E et al. Evidence of biased immunoglobulin variable gene usage in highly stable B-cell chronic lymphocytic leukemia. Leukemia 2004; 18: 1941–1947.

    Article  CAS  PubMed  Google Scholar 

  14. Gattei V, Bulian P, Del Principe MI, Zucchetto A, Maurillo L, Buccisano F . Relevance of CD49d protein expression as overall survival and progressive disease prognosticator in chronic lymphocytic leukemia. Blood 2008; 111: 865–873.

    Article  CAS  PubMed  Google Scholar 

  15. Rossi D, Cerri M, Capello D, Deambrogi C, Rossi FM, Zucchetto A et al. Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome. Br J Haematol 2008; 142: 202–215. [e-pub ahead of print].

    Article  CAS  PubMed  Google Scholar 

  16. Meyerson M . Role of telomerase in normal and cancer cells. J Clinic Oncol 2000; 18: 2626–2634.

    Article  CAS  Google Scholar 

  17. Moon IK, Jarstfer MB . The human telomere and its relationship to human disease, therapy, and tissue engineering. Front Biosci 2007; 12: 4595–4620.

    Article  CAS  PubMed  Google Scholar 

  18. Lansdorp PM . Telomeres, stem cells, and hematology. Blood 2008; 111: 1759–1766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL et al. Specific association of human telomerase activity with immortal cells and cancer. Science 1994; 266: 2011–2015.

    Article  CAS  PubMed  Google Scholar 

  20. Harley CB, Kim NW, Prowse KR, Weinrich SL, Hirsch KS, West MD et al. Telomerase, cell immortality and cancer. Cold Spring Harb Symp Quant Biol 1994; 59: 307–315.

    Article  CAS  PubMed  Google Scholar 

  21. Hahn WC . Role of telomeres and telomerase in the pathogenesis of human cancer. J Clin Oncol 2003; 21: 2034–2043.

    Article  CAS  PubMed  Google Scholar 

  22. Cheung AL, Deng W . Telomere dysfunction, genome instability and cancer. Front Biosci 2008; 13: 2075–2090.

    Article  CAS  PubMed  Google Scholar 

  23. Poncet D, Belleville A, t'kint de Roodenbeke C, Roborel de Climens A, Ben Simon E, Merle-Beral H et al. Changes in the expression of telomere maintenance genes suggest global telomere dysfunction in B-chronic lymphocytic leukemia. Blood 2008; 111: 2388–2391.

    Article  CAS  PubMed  Google Scholar 

  24. Bechter OE, Eisterer W, Pall G, Hilbe W, Kühr T, Thaler J et al. Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia. Cancer Res 1998; 58: 4918–4922.

    CAS  PubMed  Google Scholar 

  25. Damle RN, Batliwalla FM, Ghiotto F, Valetto A, Albesiano E, Sison C et al. Telomere length and telomerase activity delineate distinctive replicative features of the B-CLL subgroups defined by immunoglobulin V gene mutations. Blood 2004; 103: 375–382.

    Article  CAS  PubMed  Google Scholar 

  26. Hultdin M, Rosenquist R, Thunberg U, Tobin G, Norrback KF, Johnson A et al. Association between telomere length and V(H) gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications. Br J Cancer 2003; 88: 593–598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Terrin L, Trentin L, Degan M, Corradini I, Bertorelle R, Carli P et al. Telomerase expression in B-cell chronic lymphocytic leukemia predicts survival and delineates subgroups of patients with the same igVH mutation status and different outcome. Leukemia 2007; 21: 965–972.

    Article  CAS  PubMed  Google Scholar 

  28. Grabowski P, Hultdin M, Karlsson K, Tobin G, Aleskog A, Thunberg U et al. Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status. Blood 2005; 105: 4807–4812.

    Article  CAS  PubMed  Google Scholar 

  29. Ricca I, Rocci A, Drandi D, Francese R, Compagno M, Lobetti Bodoni C et al. Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients. Leukemia 2007; 21: 697–705.

    Article  CAS  PubMed  Google Scholar 

  30. Tsimberidou AM, Keating MJ . Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 2005; 103: 216–228.

    Article  CAS  PubMed  Google Scholar 

  31. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que TH et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994; 8: 1640–1645.

    CAS  PubMed  Google Scholar 

  32. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87: 4990–4997.

    CAS  PubMed  Google Scholar 

  33. Stamatopoulos K, Belessi C, Moreno C, Boudjograh M, Guida G, Smilevska T et al. Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 2007; 109: 259–270.

    Article  CAS  PubMed  Google Scholar 

  34. Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) World Health Organization Classification of Tumours, Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001.

    Google Scholar 

  35. Ladetto M, Compagno M, Ricca I, Pagano M, Rocci A, Astolfi M et al. Telomere length correlates with histopathogenesis according to the germinal center in mature B-cell lymphoproliferative disorders. Blood 2004; 103: 4644–4649.

    Article  CAS  PubMed  Google Scholar 

  36. Murray F, Darzentas N, Hadzidimitriou A, Tobin G, Boudjogra M, Scielzo C et al. Stereotyped patterns of somatic hypermutation in subsets of patients with chronic lymphocytic leukemia: implications for the role of antigen selection in leukemogenesis. Blood 2008; 111: 1524–1533.

    Article  CAS  PubMed  Google Scholar 

  37. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  38. Cox DR . Regression models and life tables. J R Stat Assoc 1972; 34: 187–220.

    Google Scholar 

  39. Weng NP, Granger L, Hodes RJ . Telomere lengthening and telomerase activation during human B cell differentiation. Proc Natl Acad Sci USA 1997; 94: 10827–10832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bisoffi M, Heaphy CM, Griffith JK . Telomeres: prognostic markers for solid tumors. Int J Cancer 2006; 119: 2255–2260.

    Article  CAS  PubMed  Google Scholar 

  41. Svenson U, Nordfjäll K, Stegmayr B, Manjer J, Nilsson P, Tavelin B et al. Breast cancer survival is associated with telomere length in peripheral blood cells. Cancer Res 2008; 68: 3618–3623.

    Article  CAS  PubMed  Google Scholar 

  42. Satyanarayana A, Manns MP, Rudolph KL . Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology 2004; 40: 276–283.

    Article  CAS  PubMed  Google Scholar 

  43. Frías C, García-Aranda C, De Juan C, Morán A, Ortega P, Gómez A et al. Telomere shortening is associated with poor prognosis and telomerase activity correlates with DNA repair impairment in non-small cell lung cancer. Lung Cancer 2008; 60: 416–425.

    Article  PubMed  Google Scholar 

  44. Unryn BM, Hao D, Glück S, Riabowol KT . Acceleration of telomere loss by chemotherapy is greater in older patients with locally advanced head and neck cancer. Clin Cancer Res 2006; 12: 6345–6350.

    Article  CAS  PubMed  Google Scholar 

  45. Feldser DM, Hackett JA, Greider CW . Telomere dysfunction and the initiation of genome instability. Nat Rev Cancer 2003; 3: 623–627.

    Article  CAS  PubMed  Google Scholar 

  46. Blasco MA . The epigenetic regulation of mammalian telomeres. Nat Rev Genet 2007; 8: 299–309.

    Article  CAS  PubMed  Google Scholar 

  47. Roos G, Kröber A, Grabowski P, Kienle D, Bühler A, Döhner H et al. Short telomeres are associated with genetic complexity, high-risk genomic aberrations, and short survival in chronic lymphocytic leukemia. Blood 2008; 111: 2246–2252.

    Article  CAS  PubMed  Google Scholar 

  48. Solal-Céligny P, Roy P, Colombat P . Follicular lymphoma international prognostic index. Blood 2004; 104: 1258–1265.

    Article  PubMed  Google Scholar 

  49. Shaughnessy Jr JD, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007; 109: 2276–2284.

    Article  CAS  PubMed  Google Scholar 

  50. Tsimberidou AM, Keating MJ . Richter's transformation in chronic lymphocytic leukemia. Semin Oncol 2006; 33: 250–256.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by Compagnia di San Paolo (Torino, Italy), Ministero Italiano Universitá e Ricerca (MIUR) (PRIN 2006 and Ricerca locale), Rome, Italy; by Fondazione Neoplasie del sangue (FO. NE. SA), Torino Italy; Ricerca Sanitaria Finalizzata, Regione Piemonte, Torino, Italy; Progetto Alfieri—Fondazione CRT, Torino, Italy; Novara-AIL Onlus, Novara, Italy; Associazione Franca Capurro per Novara Onlus, Novara, Italy.

We thank Antonella Fiorillo for secretarial support.

Author information

Authors and Affiliations

  1. Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

    D Rossi, M Cerri, C Deambrogi, D Capello, L De Paoli & G Gaidano

  2. Division of Hematology, Department of Experimental Medicine and Oncology, University of Turin, Turin, Italy

    C Lobetti Bodoni, E Genuardi, L Monitillo, D Drandi, I Ricca, A Rocci, S Ferrero, E Bernocco, L Bergui, M Boi, P Omedè, M Massaia, C Tarella, M Boccadoro & M Ladetto

  3. Nuclear Medicine Department, Azienda Ospedaliera San Giovanni Battista, Turin, Italy

    R Passera

Authors
  1. D Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C Lobetti Bodoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Genuardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Monitillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D Drandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Cerri
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Deambrogi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. I Ricca
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Rocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Ferrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. E Bernocco
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. D Capello
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L De Paoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. L Bergui
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. M Boi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. P Omedè
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. M Massaia
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. C Tarella
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. R Passera
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. M Boccadoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. G Gaidano
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. M Ladetto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Ladetto.

Additional information

Contributions: M Ladetto designed and performed research, supervised laboratory experiments, analyzed data and wrote the paper. D Rossi performed research, analyzed data, performed statistical analysis and wrote the paper. G Gaidano designed and performed research, analyzed data and wrote the paper. C Lobetti Bodoni performed research, made laboratory experiments, collected clinical information, analyzed data and wrote the paper. R Passera performed statistical analysis. E Genuardi, L Monitillo, D Drandi, M Cerri, C Deambrogi, I Ricca, A Rocci, S Ferrero, E Bernocco, D Capello, L De Paoli, M Boi and P Omedè made laboratory experiments. L Bergui provided patient samples and clinical information. M Massaia, C Tarella and M Boccadoro provided critical organizational support.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rossi, D., Lobetti Bodoni, C., Genuardi, E. et al. Telomere length is an independent predictor of survival, treatment requirement and Richter's syndrome transformation in chronic lymphocytic leukemia. Leukemia 23, 1062–1072 (2009). https://doi.org/10.1038/leu.2008.399

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.399

Keywords

This article is cited by

Search

Advanced search

Quick links