Elsevier

The Lancet Oncology

Volume 17, Issue 6, June 2016, Pages 779-790
The Lancet Oncology

Articles
An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data

https://doi.org/10.1016/S1470-2045(16)30029-8Get rights and content

Summary

Background

The management of patients with chronic lymphocytic leukaemia is currently undergoing improvements due to novel therapies and a plethora of biological and genetic variables that add prognostic information to the classic clinical staging systems. We established an international consortium with the aim to create an international prognostic index for chronic lymphocytic leukaemia (CLL-IPI) that integrates the major prognostic parameters.

Methods

We used results from a systematic search of the Cochrane Haematological Malignancies Group of MEDLINE, Embase, and Central databases for prospective, clinical phase 2 and 3 trials of chronic lymphocytic leukaemia, published between Jan 1, 1950, and Dec 31, 2010, which identified 13 trials. We contacted the principal investigators of these 13 trials, of which eight agreed to include individual patient data. We used the individual patient data from these phase 3 trials from France, Germany, Poland, the UK, and the USA to create the full analysis dataset. The full analysis dataset was randomly divided, using a random sample procedure, into training and internal-validation datasets. We did a univariate analysis and multivariate analyses using 27 baseline factors and overall survival as an endpoint. We assigned weighted risk scores to each factor included in the final multivariable model. We assessed the discriminatory value using C-statistics and also the validity and reproducibility of the CLL-IPI by subgroup analysis. We used two additional datasets from the Mayo Clinic (Rochester, MN, USA; MAYO cohort) and the SCALE Scandinavian population-based case-control study (SCAN cohort) as the external-validation datasets.

Findings

3472 treatment-naive patients were included in the full analysis dataset; 2308 were randomly segregated into the training dataset and 1164 into the internal-validation dataset. 838 patients were included in the MAYO cohort and 416 in the SCAN cohort. Median age of patients in the full analysis dataset was 61 years (range 27–86). Five independent prognostic factors were identified in the training dataset: TP53 status (no abnormalities vs del[17p] or TP53 mutation or both), IGHV mutational status (mutated vs unmutated), serum β2-microglobulin concentration (≤3·5 mg/L vs >3·5 mg/L), clinical stage (Binet A or Rai 0 vs Binet B–C or Rai I–IV), and age (≤65 years vs >65 years). Using a weighted grading of the independent factors, a prognostic index was derived that identified four risk groups within the training dataset with significantly different overall survival at 5 years: low (93·2% [95% CI 90·5–96·0]), intermediate (79·3% [75·5–83·2]), high (63·3% [57·9–68·8]), and very high risk (23·3% [12·5–34·1]; log-rank test comparing survival across the four risk groups p<0·0001; C-statistic, c=0·723 [95% CI 0·684–0·752]). These risk groups were confirmed in the internal-validation and external-validation datasets.

Interpretation

The CLL-IPI combines genetic, biochemical, and clinical parameters into a prognostic model, discriminating four prognostic subgroups. The CLL-IPI will allow a more targeted management of patients with chronic lymphocytic leukaemia in clinical practice and in trials testing novel drugs.

Funding

José Carreras Leukaemia Foundation

Introduction

The clinical staging systems for chronic lymphocytic leukaemia were developed by Rai1 and Binet2 nearly 40 years ago and represent the backbone of prognostication in clinical practice and trials. In the past two decades, the introduction of novel therapies and greater insight into the genetic and molecular biology of this cancer have led to the identification of various markers associated with survival, providing prognostic information that is complementary to the classic staging systems.3, 4 In particular, molecular investigations of chronic lymphocytic leukaemia cells have shown that the deletion of the short arm of chromosome 17 (del[17p]) or mutations of the tumour suppressor gene TP53 predict both an aggressive disease course and refractoriness to chemoimmunotherapy.5, 6, 7 The mutational status of the immunoglobulin heavy chain IGHV genes is also associated with survival, whereby patients with unmutated IGHV genes have a more aggressive disease course than do those with mutated IGHV genes.8, 9 Other prognostic parameters include expression of ZAP-7010, 11 and CD38,11 and biochemical parameters (eg, lactate dehydrogenase and β2-microglobulin).12 Finally, use of next-generation sequencing has identified novel gene mutations or deletions, including mutations or deletions in NOTCH1 and SF3B1,3, 13, 14 which might be associated with reduced survival. The abundance of prognostic markers, the insufficiency of comprehensive studies on their independent prognostic value, and the small number of proposed models showing an optimised combined use have, so far, delayed the translation of these biomarkers into general practice.

Research in context

Evidence before this study

Refining prognostication of chronic lymphocytic leukaemia has become essential, as therapeutic concepts are changing from chemoimmunotherapy to targeted drugs. Provision of a more accurate, comprehensive tool to predict the heterogeneous clinical course of this cancer would be relevant both for patient counselling and designing of future clinical trials. Between Jan 1, 2009, and Dec 31, 2010, the Cochrane Haematological Malignancies Group did a systematic database search of MEDLINE, Embase, and Central for prognostic factors in chronic lymphocytic leukaemia published between Jan 1, 1950, and Dec 31, 2010, evaluating at least one of the following new prognostic factors: del(17p), del(11q), trisomy 12, del(13q), del(6q), IGHV mutational status, ZAP-70, CD38, or TP53 mutational status. Their search identified 13 eligible phase 3 clinical trials.

Added value of this study

Our meta-analysis used the individual patient data of eight trials identified in the Cochrane systematic search and two additional prospective cohorts to evaluate the currently known prognostic markers including novel gene mutations. The results allowed us to propose an easily applied prognostic model—the chronic lymphocytic leukaemia international prognostic index (CLL-IPI)—based on five widely available parameters defining four distinct groups of patients with very different prognoses.

Implications of all the available evidence

The CLL-IPI will allow uniform reporting of patients in clinical trials internationally with a classification that includes modern prognostic factors beyond clinical staging. It also prepares clinical staging of chronic lymphocytic leukaemia, for a potentially bright future of more targeted and more efficacious therapies, and will improve the precision of prognostic counselling of patients with chronic lymphocytic leukaemia regarding the implications of their disease.

To address this problem, as an international group of chronic lymphocytic leukaemia investigators, we did a comprehensive analysis using individual patient data available from prospective, controlled, randomised clinical trials with the aim to develop a prognostic index based on the most widely used clinical, biological, and genetic prognostic parameters in chronic lymphocytic leukaemia. The prognostic index will allow uniform reporting of patients across clinical trials with a classification that includes modern prognostic factors beyond clinical staging.

Section snippets

Search strategy, selection criteria, and study population

Between Jan 1, 2009, and Dec 31, 2010, the Cochrane Haematological Malignancies Group did a systematic search of MEDLINE, Embase, and Central databases for prospective, clinical phase 2 and 3 trials of chronic lymphocytic leukaemia, published between Jan 1, 1950, and Dec 31, 2010, which included at least one of the following new prognostic factors: del(17p), del(13q), del(6q), del(11q), trisomy 12, TP53 and IGHV mutational status, and ZAP-70 and CD38 expression. No language restrictions were

Discussion

To our knowledge, our meta-analysis represents the largest treatment-naive population of patients with chronic lymphocytic leukaemia analysed for prognostic factors. We used individual patient data from eight randomised, phase 3 clinical trials to validate the currently known prognostic markers, including novel gene mutations. The results allowed us to propose an easily applied prognostic model—the CLL International Prognostic Index (CLL-IPI)—based on five widely available parameters defining

References (34)

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Members of The International CLL-IPI working group are listed in the appendix

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