CHICAGO, IL—A comprehensive meta-analysis of 26 factors has resulted in an internationally applicable prognostic index for patients with chronic lymphocytic leukemia (CLL), study results presented at 2015 American Society of Clinical Oncology (ASCO) Annual Meeting have shown.
The two established clinical staging systems for CLL, Rai and Binet, “do not accurately discriminate between prognostic groups,” said Nadine Kutsch, MD, of the International CLL-IPI Working Group.
In addition, “there are several new prognostic markers, but no system integrates the major clinical, biological, and genetic variables into one widely accepted score,” added Dr. Kutsch, who is also with Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn and University Hospital Cologne in Cologne, Germany.
The resulting International Prognostic Index for patients with CLL and CLL-IPI, “combines the most important genetic risk factors (IGHV, del(17p)/TP53 mutation) with clinical stage, age, and β2-microglobulin (B2M) into an easily applicable prognostic score for CLL patients,” she said. “Moreover, it both discriminates between prognostic groups and is informative regarding current treatment recommendations.”
The full analysis set was collected from eight phase 3 trials in France, Germany, the United Kingdom, the United States, and Poland. The trials comprised 3,472 patients and both early and advanced stages of CLL; the median age was 61 years (range: 27-86 years). A total of 89% of patients had received treatment for CLL and median overall survival (OS) was 95 months.
The investigators randomly divided the full analysis set into training (2,308 patients, 66.5%) and internal validation datasets (1,164 patients, 33.5%). Missing data required a complete case analysis. The primary end point was OS. The model was externally validated in a third dataset comprising 845 patients with newly diagnosed CLL from the Mayo Clinic; median age was 62 years (range: 25-89 years). In this cohort, 39% had received treatment for CLL. Median OS was not reached; 10 year OS was 61%.
Based on 1,192 patients (52%) from the training set, the final model of multivariate analysis identified 5 independent predictors for OS: TP53 (17p) mutation (deleted and/or mutated; hazard ratio [HR]: 4.2); IGHV mutation status (unmutated, HR: 2.6); B2M (>3.5 mg/L; HR: 2.0); clinical stage (Binet B/C or Rai I-IV, HR: 1.6); and age (>65 years, HR: 1.7). Using weighted grading, a prognostic score from 0 to 10 was derived that separated the patients into four different groups: low risk (score 0-1), intermediate risk (score 2-3), high risk (score 4-6), and very high risk (score 7-10).
At 5 years, significantly different rates of OS were observed for the low to the very high risk group, 93%, 79%, 64%, and 23%, respectively (P<0.001; C-statistic c=0.72 [95% CI: 0.69, 0.76]).
Dr. Kutsch said this multivariable model was confirmed on the internal validation datasets; in addition, the four risk groups were reproduced with on the Mayo dataset, with 5-year OS rates of 97%, 91%, 68% and 21%, respectively (P<0.001; C-statistic c=0.79 [95% CI: 0.74, 0.85]).
She proposed a clinical application for these four risk groups, with an associated treatment recommendation. For those at low risk, “do not touch”; intermediate risk, “do not treat” (except symptomatic); high risk, “treat” (except asymptomatic); and very high risk, “treat in experimental protocol or with noncytotoxic drugs if possible,” avoiding chemotherapy or chemoimmunotherapy.
Wendy Stock, MD, of The University of Chicago Medical Center in Chicago, IL, the discussant for this abstract, said the clinical implications include that “we have five variables [that are] easily applicable that have been evaluated using this IPI-CLL, and this weighted scoring, in particular, helps to clarify the impact of a single poor risk feature in otherwise ‘low risk’ patient, which I think can be very useful. It provides an important framework for treatment recommendations and also, the identification of these very poor risk groups, who have not benefited from traditional chemo/immunotherapeutic approaches, who may well be the ones where we would really like to test some of the many exciting and novel therapies in CLL.”
1. Kutsch N, Bahlo J, Byrd JC, et al. The international Prognostic Index for patients with CLL (CLL-IPI): An international meta-analysis. J Clin Oncol. 2015;33:(suppl; abstr 7002).