Abstract
The heterogeneity of early stage CLL challenges prognostication, and refinement of prognostic indices for risk-adapted management in this population is essential. The aim of the multicenter, prospective CLL1 trial was to explore a novel prognostic model (CLL1-PM) developed to identify risk groups, separating patients with favorable from others with dismal prognosis. A cohort of 539 clinically, biochemically, and genetically characterized Binet stage A patients were observed until progression, first-line treatment, or death. Multivariate analysis identified six independent factors associated with overall survival (OS) and time-to-first treatment (TTFT): del(17p), unmutated IGHV, del(11q), ß2-microglobulin >3.5 mg/dL, lymphocyte doubling time (LDT) <12 months, and age >60 years. These factors were integrated into the CLL1-PM, which stratified patients into four risk groups. The CLL1-PM was prognostic for OS and TTFT, e.g., the risk of treatment at 5 years was 85.9, 51.8, 27.6, and 11.3% for very low (0–1.5), low (2–4), high (4.5–6.5), and very high-risk (7–14) scores, respectively (P < 0.001). Notably, in addition to factors comprising CLL-IPI, we substantiated del(11q) and LDT as prognostic factors in early CLL. Altogether, our findings would be useful to effectively stratify Binet stage A patients, particularly within the scope of clinical trials evaluating novel agents.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198–206.
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219–34.
Baliakas P, Hadzidimitriou A, Sutton LA, Rossi D, Minga E, et al. Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015;29:329–36.
Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987;60:2712–6.
Montserrat E, Sanchez-Bisono J, Vinolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986;62:567–75.
Rozman C, Montserrat E, Rodríguez-Fernández JM, Ayats R, Vallespí T, Parody R, et al. Bone marrow histologic pattern–the best single prognostic parameter in chronic lymphocytic leukemia: a multivariate survival analysis of 329 cases. Blood. 1984;64:642–8.
Hallek M, Langenmayer I, Nerl C, Knauf W, Dietzfelbinger H, Adorf D, et al. Elevated serum thymidine kinase levels identify a subgroup at high-risk of disease progression in early, nonsmoldering chronic lymphocytic leukemia. Blood. 1999;93:1732–7.
Magnac C, Porcher R, Davi F, Nataf J, Payelle-Brogard B, Tang RP, et al. Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL. Leukemia. 2003;17:133–7.
Hallek M, Wanders L, Ostwald M, Busch R, Senekowitsch R, Stern S, et al. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk Lymphoma. 1996;22:439–47.
Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, et al. Characteristics associated with important clinical end points in patients with chronic lymphocytic leukemia at initial treatment. J Clin Oncol. 2009;27:1637–43.
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;343:1910–6.
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;348:1764–75.
Rassenti LZ, Jain S, Keating MJ, Wierda WG, Grever MR, Byrd JC, et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood. 2008;112:1923–30.
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;94:1848–54.
Zenz T, Kröber A, Scherer K, Häbe S, Bühler A, Benner A, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112:3322–9.
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.
Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121:1403–12.
Hu B, Patel KP, Chen HC, Wang X, Luthra R, Routbort MJ, et al. Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients. Br J Haematol. 2019. https://doi.org/10.1111/bjh.16042.
Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019;133:1205–16.
The 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.
Gentile M, Shanafelt TD, Rossi D, Laurenti L, Mauro FR, Molica S, et al. Validation of the CLL-IPI and comparison with the MDACC prognostic index in newly diagnosed patients. Blood. 2016;128:2093–5.
da Cunha-Bang C, Christiansen I, Niemann CU. The CLL-IPI applied in a population-based cohort. Blood. 2016;128:2181–3.
Molica S, Shanafelt TD, Giannarelli D, Gentile M, Mirabelli R, Cutrona G, et al. The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016;91:1090–5.
Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, et al. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017;31:2833–7.
Molica S, Mauro FR, Callea V, Giannarelli D, Lauria F, Rotoli B, et al. The utility of a prognostic index for predicting time to first treatment in early chronic lymphocytic leukemia: the GIMEMA experience. Haematologica. 2010;95:464–9.
Shanafelt TD, Jenkins G, Call TG, Zent CS, Slager S, Bowen DA, et al. Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer. 2009;115:363–72.
Letestu R, Lévy V, Eclache V, Baran-Marszak F, Vaur D, Naguib D, et al. Prognosis of binet stage A chronic lymphocytic leukemia patients: the strength of routine parameters. Blood. 2010;116:4588–90.
Bulian P, Tarnani M, Rossi D, Forconi F, Del Poeta G, Bertoni F, et al. Multicentre validation of a prognostic index for overall survival in chronic lymphocytic leukaemia. Hematol Oncol. 2011;29:91–9.
Wierda WG, O’Brien S, Wang X, Faderl S, Ferrajoli A, Do KA, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109:4679–85.
Pepper C, Majid A, Lin TT, Hewamana S, Pratt G, Walewska R, et al. Defining the prognosis of early stage chronic lymphocytic leukaemia patients. Br J Haematol. 2012;156:499–507.
Morabito F, Cutrona G, Gentile M, Matis S, Todoerti K, Colombo M, et al. Definition of progression risk based on combinations of cellular and molecular markers in patients with Binet stage A chronic lymphocytic leukemia. Br J Haematol. 2009;146:44–53.
Gentile M, Cutrona G, Mosca L, Matis S, Fabris S, Lionetti A, et al. Prospective validation of a risk score based on biological markers for predicting progression free survival in Binet stage A chronic lymphocytic leukemia patients: results of the multicenter O-CLL1-GISL study. Am J Hematol. 2014;89:743–50.
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.
Pflug N, Bahlo J, Shanafelt TD, Eichhorst BF, Bergmann MA, Elter T, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124:49–62.
Baliakas P, Mattson M, Stamatopoulos K, Rosenquist R. Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed? J Intern Med. 2016;279:347–57.
Gruber M, Bozic I, Leshchiner I, Livitz D, Stevenson K, Rassenti L, et al. Growth dynamics in naturally progressing chronic lymphocytic leukaemia. Nature. 2019;570:474–9.
Acknowledgements
The authors would like to thank Anne Westermann, Ute Elberskirch, Anna Fink, MD, Can Zhang, PhD, Thu-Trang Pham, PhD, Emily Koeneke, PharmD, and Katrin Klein for their contribution to this work. The trial was supported by grants from Deutsche Krebshilfe (German Cancer Aid) (70–2434 and 106116), Wilhelm-Sander-Foundation (2001.004.1 and 2001.004.2), and BayerSchering Pharma AG. Study drug was provided by BayerSchering Pharma AG, which did not have a role in the design or conduct of the study, writing of the manuscript, or the decision to submit the manuscript for publication. Data collection was supported by the Kompetenznetz Maligne Lymphome e.V. (Secretary: Birgit Fath, PhD).
Funding
The trial was funded by Deutsche Krebshilfe (German Cancer Aid) (70–2434 and 106116), Wilhelm-Sander-Foundation (2001.004.1 and 2001.004.2), and BayerSchering Pharma AG.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Hoechstetter, M.A., Busch, R., Eichhorst, B. 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 34, 1038–1051 (2020). https://doi.org/10.1038/s41375-020-0727-y
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-020-0727-y
This article is cited by
-
Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL
Leukemia (2022)
-
Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia
Journal of Hematology & Oncology (2021)
-
Biological significance of monoallelic and biallelic BIRC3 loss in del(11q) chronic lymphocytic leukemia progression
Blood Cancer Journal (2021)
-
Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia
Biomarker Research (2020)
-
Time to first treatment and P53 dysfunction in chronic lymphocytic leukaemia: results of the O-CLL1 study in early stage patients
Scientific Reports (2020)