CLL-IPI: A New and Improved Staging System for CLL?

In a recent study examining the validity of prognostic markers for patients with chronic lymphocytic leukemia (CLL), researchers believe they have developed an internationally applicable prognostic index for patients with CLL. Called CLL-IPI (International Prognostic Index), the newly developed scoring system represents a collaboration among multiple international study groups.

Nadine Kutsch, MD, from the University Hospital of Cologne, in Germany, presented the new CLL-IPI system at the 2015 American Society of Clinical Oncology Annual Meeting. “In times of novel therapies and improved prognosis for patients with CLL, the traditional staging system developed by Rai and Binet more than 30 years ago no longer discriminates enough,” Dr. Kutsch said. “In order to allow better information on survival, a number of new prognostic markers have been introduced, but there is no broadly applicable system integrating all of these markers.”

Furthermore, many of these prognostic tests rely on complex (and costly) molecular and biologic assays and are not available to all patients with CLL.

The CLL-IPI, which was developed based on analyses of 26 prognostic factors, could serve as a simple, reliable, and easily applicable method of risk stratification for patients with CLL.

The international group of researchers collected data from eight phase III clinical trials from France, Germany, the United Kingdom, the United States, and Poland. The studies included 3,472 treatment-naïve patients at both early and advanced CLL stages (median age, 61 years; range, 27-86 years). Patients were followed for a median of 80 months.

The full analysis set was randomly divided into training and internal validation datasets (training: n=2,308, 67%; internal validation: n=1,164, 33%). The study’s model was externally validated in a third dataset that included 845 newly diagnosed CLL patients from the Mayo Clinic in Rochester, Minnesota; these patients had a median age of 62 years (range, 25-89 years) and were observed for a median of 63 months.

Of the 1,192 patients from the training dataset (52%), five independent predictors for overall survival (OS) were identified: age, clinical stage, del(17p) and/or TP53 mutation status, IGHV mutation status, and ß2-microglobulin (B2M) level. Each variable was then assigned an individual weighted grade (TABLE).

Adding all of these factors together results in a prognostic score ranging from 0-10, with four different risk groups: low (score 0-1), intermediate (score 2-3), high (score 4-6), and very high (score 7-10). Patients in these four groups had significantly different rates of five-year OS (95% CI 0.69-0.76; p<0.001):

  • Low-risk patients (n=340): 93.2 percent
  • Intermediate risk (n=464): 79.4 percent
  • High risk (n=326): 63.6 percent
  • Very high risk (n=62): 23.3 percent

The results “were nicely confirmed” by the internal validation dataset as well as in a subgroup analysis of Rai stages, Dr. Kusch noted. “Applying the analysis to the external validation data from the Mayo Clinic cohort, we found a high replication of the developed prognostic index – across all Rai stages.” Five-year OS rates were 94 percent, 91 percent, 68 percent, and 21 percent among the low to very high-risk groups (95% CI 0.74-0.85; p<0.001).

How would the CLL-IPI score be applied in the clinic? Dr. Kutsch and colleagues provided the following treatment recommendations:

  • Low: Do not touch (watch-and-wait approach)
  • Intermediate: Do not treat (except when the patient is symptomatic)
  • High: Treat (except when the patient is asymptomatic)
  • Very high: Treat in experimental protocol or with non-cytotoxic drugs if possible (no chemotherapy or chemoimmunotherapy)

“[The use of CLL-IPI] leads to an advancement of the classic clinical staging systems and a refinement in prognosis for CLL. “Importantly, this is a modular score,” Dr. Kutsch noted, meaning that any new prognostic marker could easily be validated and incorporated into the score.


Reference

Kutsch N, Bahlo J, Byrd JC, et al. The international prognostic index for patients with CLL (CLL-IPI): An international meta-analysis. Abstract #7002. Presented at the American Society of Clinical Oncology 2015 Annual Meeting, Chicago, Illinois, May 30, 2015.

TABLE. Multivariate Analysis of Independent Predictors for Overall Survival in the CLL-IPI System
Variable Adverse factor Coefficient Hazard ratio Grading
Age >65 years 0.555 1.7 1
Clinical stage Binet B/C or Rai I-IV 0.499 1.6 1
Del(17p) and/or TP53 mutation Deleted and/or mutated 0.665 2.0 4
IGHV mutation status Unmutated 0.941 2.6 2
B2M level, mg/L >3.5 mg/L 1.442 4.2 2

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