Most patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.

Augusta Victoria Hospital Jerusalem Israel

Azienda Ospedaliera of Cosenza Cosenza Italy

Biotechnology Research Unit Aprigliano Cosenza Italy

Cancer Sciences Division University of Southampton Southampton United Kingdom

Center of Integrated Oncology Cologne Bonn and German CLL Study Group University of Cologne Cologne Germany

Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Experimental Medicine University of Genoa Genoa Italy

Department of Internal Medicine 3 University Hospital of Ulm Ulm Germany; and

Department of Oncology and Hemato Oncology University of Milan Milan Italy

Division of Hematology Department of Translational Medicine University of Eastern Piedmont Novara Italy

Division of Hematology Sapienza University Rome Italy

Hospital Clinic Barcelona Spain

Hospital Munich Schwabing German CLL Study Group Munich Germany

Institute of Hematology and Oncology University of Barcelona Barcelona Spain

Institute of Oncology Research Università della Svizzera Italiana Bellinzona Switzerland

Interní Hematologická a Onkologická Klinika University Hospital Brno and Medical Faculty Masaryk University Brno Czech Republic

IRCCS Ospedale Policlinico San Martino Genoa Italy

Karolinska Institute Stockholm Sweden

Mayo Clinic Rochester MN

Oncology Institute of Southern Switzerland Bellinzona Switzerland

Southampton University Hospital Trust Southampton United Kingdom

The 1st Affiliated Hospital of Nanjing Medical University Jiangsu Province Hospital Nanjing China

University of Texas MD Anderson Cancer Center Houston TX

Uppsala University Hospital Uppsala Sweden

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Blood. 2020 May 21;135(21):1820-1821. doi: 10.1182/blood.2020005426. PubMed

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Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR. 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA Cancer J Clin. 2016;66(6):443–459. PubMed

Abrisqueta P, Pereira A, Rozman C, et al. Improving survival in patients with chronic lymphocytic leukemia (1980-2008): the Hospital Clinic of Barcelona experience. Blood. 2009;114(10):2044–2050. PubMed

Cheson BD, Bennett JM, Grever M, et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996;87(12):4990–4997. PubMed

Hallek M, Cheson BD, Catovsky D, et al. International Workshop on Chronic Lymphocytic Leukemia Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–5456. PubMed PMC

Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(Suppl 5):v78–v84. PubMed

Shustik C, Mick R, Silver R, Sawitsky A, Rai K, Shapiro L. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988;6(1):7–12. PubMed

Dighiero G, Maloum K, Desablens B, et al. French Cooperative Group on Chronic Lymphocytic Leukemia Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998;338(21):1506–1514. PubMed

Schweighofer CD, Cymbalista F, Müller C, et al. Early versus deferred treatment with combined fludarabine, cyclophosphamide and rituximab (FCR) improves event-free survival in patients with high-risk Binet stage A chronic lymphocytic leukemia – first results of a randomized German-French Cooperative Phase III Trial. Blood. 2013;122(21):524.

Hoechstetter MA, Busch R, Eichhorst B, 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(12):2833–2837. PubMed

Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst. 1999;91(10):861–868. PubMed

Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018;391(10129):1524–1537. PubMed

Sant M, Allemani C, Tereanu C, et al. HAEMACARE Working Group Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116(19):3724–3734. PubMed

Langerbeins P, Bahlo J, Rhein C, et al. Ibrutinib versus placebo in patients with asymptomatic, treatment-naïve early stage CLL: primary endpoint results of the phase 3 double-blind randomized CLL12 trial. Hematol Oncol. 2019;37(S2):38–40. PubMed

Wierda WG, O'Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia. J Clin Oncol. 2011;29(31):4088–4095. PubMed PMC

Molica S, Giannarelli D, Gentile M, et al. External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia. Cancer. 2013;119(6):1177–1185. PubMed

Mansouri L, Cahill N, Gunnarsson R, et al. NOTCH1 and SF3B1 mutations can be added to the hierarchical prognostic classification in chronic lymphocytic leukemia. Leukemia. 2013;27(2):512–514. PubMed

Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121(8):1403–1412. PubMed PMC

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(6):779–790. PubMed

Delgado J, Doubek M, Baumann T, 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(4):375–380. PubMed

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics Reporting recommendations for tumor marker prognostic studies (REMARK) J Natl Cancer Inst. 2005;97(16):1180–1184. PubMed

Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745–2760. PubMed

Bain BJ. Ethnic and sex differences in the total and differential white cell count and platelet count. J Clin Pathol. 1996;49(8):664–666. PubMed PMC

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

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(6):1848–1854. PubMed

Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood. 2006;107(5):1747–1750. PubMed PMC

Rossi D, Condoluci A, Spina V, Gaidano G. Methods for measuring ctDNA in lymphomas. Methods Mol Biol. 2019;1881:253–265. PubMed

Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53(282):457–481.

Thabane L, Mbuagbaw L, Zhang S, et al. A tutorial on sensitivity analyses in clinical trials: the what, why, when and how. BMC Med Res Methodol. 2013;13(1):92. PubMed PMC

Dignam JJ, Kocherginsky MN. Choice and interpretation of statistical tests used when competing risks are present. J Clin Oncol. 2008;26(24):4027–4034. PubMed PMC

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

Simon N, Friedman J, Hastie T, Tibshirani R. Regularization paths for Cox's proportional hazards model via coordinate descent. J Stat Softw. 2011;39(5):1–13. PubMed PMC

Schoenfeld D. Partial residuals for the proportional hazard regression model. Biometrika. 1982;69(1):239–241.

Ciampi A, Negassa A, Lou Z. Tree-structured prediction for censored survival data and the Cox model. J Clin Epidemiol. 1995;48(5):675–689. PubMed

Harrell FE., Jr . Regression modeling strategies. Springer-Verlag; New York, NY: 2001.

Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219–234. PubMed

Wierda WG, O'Brien S, Wang X, et al. Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood. 2007;109(11):4679–4685. PubMed

Pflug N, Bahlo J, Shanafelt TD, et al. Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood. 2014;124(1):49–62. PubMed PMC

Gentile M, Shanafelt TD, Cutrona G, et al. A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients. Leukemia. 2016;30(6):1440–1443. PubMed

Molica S, Giannarelli D, Mirabelli R, et al. Reliability of six prognostic models to predict time-to-first-treatment in patients with chronic lymphocytic leukaemia in early phase. Am J Hematol. 2017;92(6):E91–E93. PubMed

Montserrat E, Gale RP. Predicting the outcome of patients with chronic lymphocytic leukemia: Progress and uncertainty. Cancer. 2019;125(21):3699–3705. PubMed

Best OG, Gardiner AC, Davis ZA, et al. A subset of Binet stage A CLL patients with TP53 abnormalities and mutated IGHV genes have stable disease. Leukemia. 2009;23(1):212–214. PubMed

Tam CS, Shanafelt TD, Wierda WG, et al. De novo deletion 17p13.1 chronic lymphocytic leukemia shows significant clinical heterogeneity: the M. D. Anderson and Mayo Clinic experience. Blood. 2009;114(5):957–964. PubMed PMC

Hu B, Patel KP, Chen HC, et al. Association of gene mutations with time-to-first treatment in 384 treatment-naive chronic lymphocytic leukaemia patients. Br J Haematol. 2019;187(3):307–318. PubMed

Nadeu F, Delgado J, Royo C, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122–2130. PubMed PMC

Montserrat E, Bauman T, Delgado J. Present and future of personalized medicine in CLL. Best Pract Res Clin Haematol. 2016;29(1):100–110. PubMed

Baliakas P, Hadzidimitriou A, Sutton LA, et al. European Research Initiative on CLL (ERIC) Recurrent mutations refine prognosis in chronic lymphocytic leukemia. Leukemia. 2015;29(2):329–336. PubMed

Wierda WG, Byrd JC, Abramson JS, et al. NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2019. J Natl Compr Canc Netw. 2019;17(1):12–20. PubMed

Gruber M, Bozic I, Leshchiner I, et al. Growth dynamics in naturally progressing chronic lymphocytic leukaemia. Nature. 2019;570(7762):474–479. PubMed PMC

Montserrat E, Sánchez-Bisonó J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986;62(3):567–575. PubMed

Mozas P, Rivas-Delgado A, Baumann T, et al. Analysis of criteria for treatment initiation in patients with progressive chronic lymphocytic leukemia. Blood Cancer J. 2018;8(1):10. PubMed PMC

Sharma S, Rai KR. Chronic lymphocytic leukemia (CLL) treatment: So many choices, such great options. Cancer. 2019;125(9):1432–1440. PubMed

Hallek M, Fürstenau M. How to approach CLL in clinical practice. Hematol Oncol. 2019;37(Suppl 1):38–42. PubMed

International Non-Hodgkin's Lymphoma Prognostic Factors Project A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987–994. PubMed

Solal-Céligny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104(5):1258–1265. PubMed

Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27(27):4555–4562. PubMed

Hoster E, Dreyling M, Klapper W, et al. European Mantle Cell Lymphoma Network A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558–565. PubMed

Hosmer DW, Lemeshow S. Applied logistic regression. 2nd ed. John Wiley & Sons; New York: 2000.

ERIC recommendations for TP53 mutation analysis in chronic lymphocytic leukemia-2024 update

Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY

The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms

Chemoimmunotherapy in the First-Line Treatment of Chronic Lymphocytic Leukaemia: Dead Yet, or Alive and Kicking?