A new prognostic model combining genetic, biochemical, and clinical parameters can enable a more targeted management of chronic lymphocytic leukemia (CLL) in both clinical practice and clinical trials, according to a report published in Lancet Oncology. The revised staging system, called the CLL-International Prognostic Index (CLL-IPI), represents a collaboration among multiple international study groups.
“The management of patients with CLL is undergoing improvements due to novel therapies and a plethora of biologic and genetic variables that add prognostic information to the classic clinical staging systems,” the authors, members of the International CLL-IPI Working Group, wrote. CLL-IPI, which was developed following an analysis of 27 prognostic factors for overall survival, could serve as a simple, reliable, and easily applicable method of risk stratification for patients with CLL, they added.
The international group of researchers conducted a literature search for phase II and phase III clinical trials of CLL published between January 1, 1950, and December 31, 2010, including eight prospective trials in their analyses. In total, the studies included 3,473 treatment-naïve patients at both early and advanced CLL stages (median age, 61 years; range, 27-86 years) from France, Germany, Poland, the United Kingdom, and the United States. Patients were followed for a median of 80 months.
The full analysis dataset was randomly divided into training (n=2,308; 67%) and internal-validation (n=1,164; 33%) datasets. The researchers externally validated the model in two additional datasets: a cohort from the Mayo Clinic in Rochester, Minnesota (n=838), and the SCALE Scandinavian population-based case-control study (n=416). Mean patient age in these cohorts was 62 years (range = 25-89 years), and these patients were followed for a median of 63 months.
From the group of 27 baseline factors the CLL-IPI researchers examined in the training dataset, five emerged as independent prognostic markers for overall survival (OS):
- TP53 status (no abnormalities vs. del17p, TP53 mutations, or both)
- IGHV mutational status (mutated vs. unmutated)
- Serum ß2-microglobulin (B2M) 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)
- Age (≤65 years vs. >65 years)
Each variable was then assigned an individual weight (TABLE). The researchers then added all of these factors together, derived a prognostic score ranging from 0-10, and identified four risk groups with significantly different rates of OS at five years (p<0.001 for all):
- Low-risk patients (score = 0-1): 93.2% (95% CI 90.5-96.0)
- Intermediate risk (score = 2-3): 79.3% (95% CI 75.5-83.2)
- High risk (score = 4-6): 63.3% (95% CI 57.9-68.8)
- Very-high risk (score = 7-10): 23.3% (95% CI 12.5-34.1)
When the five-year OS was assessed in the external validation cohorts, rates in each risk group were similar to those in the training cohort: 94 percent (low risk), 91 percent (intermediate risk), 68 percent (high risk), and 21 percent (very high risk), respectively (p<0.001 for all).
Earlier results of the CLL-IPI study were presented at the 2015 American Society of Clinical Oncology Annual Meeting, where Nadine Kutsch, MD, from the University Hospital of Cologne, in Germany, discussed the implications of CLL-IPI for the management of CLL with ASH Clinical News.
“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 discriminate enough,” Dr. Kutsch said. “[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,” she added, meaning that any new prognostic marker could easily be validated and incorporated into the score.
She also provided treatment recommendations for the different patient risk subgroups:
- Low: 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 with non-cytotoxic drugs, if possible (no chemotherapy or chemoimmunotherapy)
However, it is unknown how newly developed CLL therapies and newly identified molecular mutations would be incorporated into this revised staging system.
International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;S1470-2045:30029-8.
|TABLE. Multivariate Analysis of Independent Predictors for Overall Survival in the CLL-IPI System|
|Variable||Adverse factor||Coefficient||Hazard ratio||Grading|
|Clinical stage||Binet B/C or Rai I-IV||0.499||1.6||1|
|Del17p and/orTP53 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|
|CLL-IPI = Chronic Lymphocytic Leukemia-International Prognostic Index|