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Chronic lymphocytic leukemia

Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients


The prognostic significance of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was identified when the biology of the disease was poorly understood and therapy was not effective. We assessed the clinical and biological significance of LDT in 848 CLL patients in a real-life setting and the context of new biomarkers and effective therapy. A short LDT (≤12 months) was enriched for adverse biomarkers. Patients with a rapid LDT did need therapy shortly after diagnosis (median 23 months vs. not reached; p < 0.001) and had a poorer overall survival (median 95 months vs. not reached p < 0.001). LDT, IGHV mutational status, Beta-2 microglobulin, and Rai clinical stage were independent predictors for time to first treatment in the whole series and in Binet stage A patients. No correlation was observed between LDT and response to chemoimmunotherapy. However, a short LDT along with age ≥65 years, high-risk FISH (del(17p), del(11q)), unmutated IGHV, increased Beta-2 microglobulin, and TP53 mutations predicted short survival. Moreover, the prognostic significance of LDT was independent of the CLL-IPI and the Barcelona/Brno prognostic model. LDT remains an important outcome marker in the modern CLL era and should be incorporated into the clinical assessment and stratification of CLL patients.

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Fig. 1: Outcomes according to LDT.


  1. Montserrat E, Sánchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986;62:567–75.

    CAS  Article  Google Scholar 

  2. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131:2745–60.

    CAS  Article  PubMed  Google Scholar 

  3. Eichhhorst B, Robak T, Montserrat E, Ghia P, Niemann C, Kater AP, et al. on behalf of the ESMO Guidelines Committee. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32:22–33.

  4. Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987;60:712–2716.

    Article  Google Scholar 

  5. Dhodapkar M, Tefferi A, Su J, Phyliky RL. Prognostic features and survival in young adults with early/intermediate chronic lymphocytic leukemia (B-CLL): a single institution study. Leukemia. 1993;7:1232–5.

    CAS  PubMed  Google Scholar 

  6. Axdorph U, Nilsson BI, Nilsson BR, Björkholm MX. Leucocyte doubling time is a useful predictor of progression-free survival in chronic lymphocytic leukaemia. J Intern Med. 1995;237:205–9.

    CAS  Article  PubMed  Google Scholar 

  7. Ghia P, Stamatopoulos K, Belessi C, Moreno C, Stilgenbauer S, Stevenson F, et al. ERIC recommendations on IGHV gene mutational status analysis in chronic lymphocytic leukemia. Leukemia. 2007;21:1–3.

    CAS  Article  PubMed  Google Scholar 

  8. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole- genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475:101–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17:779–90.

    Article  Google Scholar 

  10. Delgado J, Doubek M, Baumann T, Kotaskova J, Molica S, Mozas P, et al. Chronic lymphocytic leukemia: a prognostic model comprising only two biomarkers (IGHV mutational status and FISH cytogenetics) separates patients with different outcome and simplifies the CLL-IPI. Am J Hematol. 2017;92:375–80.

    CAS  Article  PubMed  Google Scholar 

  11. Rossi D, Gerber B, Stüssi G. Predictive and prognostic biomarkers in the era of new targeted therapies for chronic lymphocytic leukemia. Leuk Lymphoma. 2017;58:1548–60.

    CAS  Article  PubMed  Google Scholar 

  12. Montserrat E, Gale RP. Predicting the outcome of patients with chronic lymphocytic leukemia: progress and uncertainty. Cancer. 2019;125:3699–705.

    Article  PubMed  Google Scholar 

  13. Galton DAG. The pathogenesis of chronic lymphocytic leukemia. Canad Med Ass J. 1966;94:1005–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Theml H, Ziegler-Heitbrock HWL. Management of CLL and allied disorders with reference to their immunology and proliferation kinetics. Recent Results Cancer Res. 1984;93:240–58.

    CAS  Article  Google Scholar 

  15. Simonsson B, Nilsson K. 3H-Thymidine uptake in chronic lymphocytic leukemia cells. Scand J Hematol. 1980;24:169–73.

    CAS  Article  Google Scholar 

  16. Orfao A, Ciudad J, González M, San Miguel M, García AR, López-Berges MC, et al. Prognostic value of S-phase white blood cell count in B-cell chronic lymphocytic leukemia. Leukemia. 1992;6:47–51.

    CAS  PubMed  Google Scholar 

  17. Messmer BT, Messmer D, Allen SL, Kolitz JE, Kudalkar P, Cesar D, et al. In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells. J Clin Invest. 2005;115:755–64.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Gruber M, Bozic I, Leschiner I, Livitz D, Stevenson K, Rassenti L, et al. Growth dynamics in naturally progressing chronic lymphocytic leukaemia. Nature. 2019;570:474–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Nadeu F, Diaz-Navarro A, Delgado J, Puente XS, Campo E. Genomic and epigenomic alterations in chronic lymphocytic leukemia. Annu Rev Pathol. 2020;15:149–77.

    CAS  Article  PubMed  Google Scholar 

  20. Burger J. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383:460–73.

    CAS  Article  PubMed  Google Scholar 

  21. Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Bahlo J, et al. Prognostic model for newly diagnosed CLL patients in Binet stage A: results of the multicenter, prospective CLL1 trial of the German CLL study group. Leukemia. 2020;34:1038–51.

    CAS  Article  PubMed  Google Scholar 

  22. Lad DP, Tejaswi V, Jindal N, Malhotra P, Khadwal A, Prakash G, et al. Modified CLL International Prognostic Index (CLL-LIPI) using lymphocyte doubling time (LDT) in place of IgHV mutation status in resource limited settings predicts time to first treatment and overall survival. Leuk Lymphoma. 2020;61:1512–5.

    CAS  Article  PubMed  Google Scholar 

  23. Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P. et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020.

    Google Scholar 

  24. Mozas P, Rivas-Delgado A, Baumann T, Villamor N, Ortiz-Maldonado V, Aymerich M, et al. Analysis of criteria for treatment initiation in chronic lymphocytic. Leuk Cancer J. 2018;8:1–5.

    Google Scholar 

  25. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med. 2015;175:1389–98.

    Article  Google Scholar 

  26. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer CH, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928–42.

    CAS  Article  Google Scholar 

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This study was supported by Janssen research grant; Swiss Cancer League, ID 3746, 4395 4660, and 4705, Bern, Switzerland; European Research Council (ERC) Consolidator Grant CLLCLONE, ID: 772051; Swiss National Science Foundation, ID 320030_169670/1 and 310030_192439, Berne, Switzerland; The Leukemia & Lymphoma Society, Translational Research Program, ID 6594-20, New York. AIRC 5 × 1000 No. 21198, Associazione Italiana per la Ricerca sul Cancro Foundation Milan, Italy; the AGING Project—Department of Excellence—DIMET, Università del Piemonte Orientale, Novara, Italy; Ricerca Finalizzata 2018 (project RF-2018-12365790), MoH, Rome, Italy.

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Correspondence to Emili Montserrat.

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Baumann, T., Moia, R., Gaidano, G. et al. Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients. Leukemia 35, 2325–2331 (2021).

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