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Chronic lymphocytic leukemia

Validation of a biological score to predict response in chronic lymphocytic leukemia patients treated front-line with bendamustine and rituximab

Leukemia volume 32, pages 1869–1873 (2018)Cite this article

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During the the last two decades several biological prognostic markers have been identified in chronic lymphocytic leukemia (CLL) [1]. Some, like the IGHV mutational status and TP53 disruption, are also predictive of response to chemo-immunotherapy [2,3,4,5,6]. Rossi et al. reported an observational retrospective analysis on 404 CLL patients treated front-line with fludarabine-cyclophosphamide-rituximab (FCR) [6]. Based on the IGHV mutational status and FISH cytogenetics, patients were stratified into low risk (mutated IGHV and no adverse FISH cytogenetics [del(17p), del(11q)]), intermediate risk (unmutated IGHV and/or del11q in the absence of del17p), and high risk (del17p independent of co-occurring del11q or unmutated IGHV). This simple biologically based prognostic score based on the combination of three widely utilized biomarkers allowed to stratify patients with a significantly different progression-free survival (PFS) and overall survival (OS) after FCR treatment. In addition, they also demonstrated that low-risk patients had a durable remissions after FCR, with a life expectancy overlapping that observed in the age-matched general population [6]. Similarly, Laurenti et al. recently published a retrospective study on 102 patients with CLL treated front-line with chlorambucil-rituximab [7]. This analysis also showed that the above-mentioned biological score could distinguish patients with a different PFS. A trend toward a better OS was also observed.

With the aim of investigating whether this biological score could also segregate CLL patients treated with bendamustine-rituximab (BR), we performed a retrospective study on previously untreated CLL patients who received BR as primary therapy. The cohort included 418 patients with progressive CLL from 34 different hematology centers (29 Italian, 3 Israeli, 1 German, and 1 American) who received at least one dose of BR as front-line treatment during the period 2008–2014; 279 of the 418 patients have been included in a previous multicenter study which reported on the front-line treatment of CLL patients with BR outside of clinical trials [8]. Relative survival, defined as the ratio between the actuarial survival observed in the CLL cohort and the expected survival of the general population matched by sex, age, nationality, and calendar year of starting BR was calculated using the Ederer II method. Expected survival estimates were calculated according to Italian, Israel, German, and American life expectancy tables (Human Mortality Database; http://www.mortality.org/, accessed 18 September 2017). Observed and expected survivals were compared using the Fisher test. Data analysis was carried out by STATA 13.1 (by StataCorp 4905 Lakeway Drive College Station, TX 77845, USA) (further details are in the Supplemental Appendix).

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Author contributions

MG, TDS, FRM, LL, DR, SM, AN, YH, LS, TT, GDP, MF, FDR, GG, AC, RF, AP, and FM designed the study, analyzed and interpreted data, and wrote the manuscript; MG, GT, GD’A, KGC, and FM performed statistical analysis; GC, AGR, AN, and MF performed central laboratory tests; GR, KZ, SC, IDP, NDR, FA, MC, AC, AG, SAP, GU, II, and EV provided the patients and collected clinical data; and all authors gave final approval for the manuscript.

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Authors and Affiliations

  1. Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy

    Massimo Gentile, Giuseppina Uccello & Ernesto Vigna

  2. Department of Medicine, Division of Hematology, Stanford University, Stanford, CA, USA

    Tait D. Shanafelt

  3. Hematology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy

    Gianluigi Reda, Agostino Cortelezzi & Antonino Neri

  4. Hematology, Department of Cellular Biotechnologies and Hematology, ‘Sapienza’ University, Rome, Italy

    Francesca Romana Mauro & Robin Foà

  5. Department of Haematology and Oncology, University Medical Centre Freiburg, Freiburg, Germany

    Katja Zirlik

  6. University of Florence, Florence, Italy

    Stefania Ciolli

  7. Department of Hematology, Catholic University Hospital “A. Gemelli”, Rome, Italy

    Luca Laurenti & Idanna Innocenti

  8. Ematologia, Dipartimento di Biomedicina e Prevenzione, Università degli studi di Roma “Tor Vergata”, Rome, Italy

    Maria Ilaria Del Principe & Giovanni Del Poeta

  9. Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland

    Davide Rossi

  10. Unità di Ematologia, Ospedale Vito Fazzi, Lecce, Italy

    Nicola Di Renzo

  11. Department of Oncology and Haematology, Pugliese-Ciaccio Hospital, Catanzaro, Italy

    Stefano Molica

  12. Department of Hematology, Ospedale Santo Spirito, Pescara, Italy

    Francesco Angrilli

  13. Division of Haematology, University of Torino, A.O. Città della Salute e della Scienza di Torino, Torino, Italy

    Marta Coscia

  14. Department of Biomedical Sciences, Division of Haematology, University of Catania and Ferrarotto Hospital, Catania, Italy

    Annalisa Chiarenza & Francesco Di Raimondo

  15. Ematologia-Azienda Ospedaliero-Universitaria, Policlinico Consorziale di Bari, Bari, Italy

    Annamaria Giordano

  16. UO Molecular Pathology, Ospedale Policlinico San Martino IRCCS, Genova, Italy

    Giovanna Cutrona

  17. Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA

    Kari G. Chaffee

  18. Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Sameer A. Parikh

  19. Consiglio Nazionale delle Ricerche, Instituto di Biomedicina ed Immunologia Molecolare, Reggio Calabria, Italy

    Giovanni Tripepi, Graziella D’Arrigo & Fortunato Morabito

  20. Biotechnology Research Unit, Azienda Sanitaria Provinciale di Cosenza, Aprigliano, Italy

    Anna Grazia Recchia

  21. Department of Hematology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Yair Herishanu

  22. Hematology Institute, Kaplan Medical Center, Rehovot, Israel

    Lev Shvidel

  23. Hematology Unit, Bnai-Zion Medical Center, Haifa, Israel

    Tamar Tadmor

  24. Division of Haematology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

    Gianluca Gaidano

  25. Direzione Scientifica Ospedale Policlinico San Martino IRCCS, Genova, Italy

    Manlio Ferrarini

  26. Department of Hematology, Hadassah University, Hospital and Hebrew University Medical School, Jerusalem, Israel

    Aaron Polliack

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  1. Massimo Gentile
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Correspondence to Massimo Gentile.

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Gentile, M., Shanafelt, T.D., Reda, G. et al. Validation of a biological score to predict response in chronic lymphocytic leukemia patients treated front-line with bendamustine and rituximab. Leukemia 32, 1869–1873 (2018). https://doi.org/10.1038/s41375-018-0100-6

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