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Open Access Research

IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

Pietro Bulian1*, Davide Rossi2, Francesco Forconi3, Giovanni Del Poeta4, Francesco Bertoni5, Emanuele Zucca5, Marco Montillo6, Gabriele Pozzato7, Giovanni D'Arena8, Dimitar G Efremov9, Roberto Marasca10, Francesco Lauria3, Gianluca Gaidano2, Valter Gattei1 and Luca Laurenti11

  • * Corresponding author: Pietro Bulian pbulian@cro.it

  • † Equal contributors

Author Affiliations

1 Clinical and Experimental Onco-Hematology Unit, IRCCS Centro di Riferimento Oncologico, via Franco Gallini 2, 33170 Aviano (PN), Italy

2 Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

3 Division of Hematology and Transplant, University of Siena, Siena, Italy

4 Hematology, Tor Vergata University, Rome, Italy

5 Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

6 Department of Oncology/Hematology, Niguarda Ca'Granda Hospital, Milan, Italy

7 Department of Internal Medicine and Haematology, Maggiore Hospital, Trieste, Italy

8 Onco-Hematology Department, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (Pz), Italy

9 CNR Campus "A. Buzzati-Traverso", ICGEB Outstation-Monterotondo, Rome, Italy

10 Department of Medical Sciences, Section of Internal Medicine and Hematology, University of Modena and Reggio Emilia, Modena, Italy

11 Institute of Haematology, Catholic University of the Sacred Heart, Rome, Italy

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Journal of Translational Medicine 2012, 10:18  doi:10.1186/1479-5876-10-18

Published: 30 January 2012

Abstract

Background

Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed.

Methods

Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions.

Results

IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed.

Conclusions

Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical-demographic variables in new prognostic tools to estimate overall survival.

Keywords:
Chronic lymphocytic leukaemia; Prognosis; Prognostic score; Nomogram