Updated Prognostic Tools Needed in the Era of Novel Therapies for Chronic Lymphocytic Leukemia

Patients with chronic lymphocytic leukemia (CLL) would benefit from an updated risk-stratification tool that predicts response to newer targeted therapies. In a recent study, the CLL-International Prognostic Index (CLL-IPI), a standard prognostic score for patients starting chemoimmunotherapy, failed to differentiate outcomes after frontline ibrutinib.

Danielle M. Brander, MD, of the Division of Hematologic Malignancies and Cellular Therapy at Duke, presented results from the study at the American Society of Hematology's 59th Annual Meeting & Exposition, December 9 to 12, 2017, in Atlanta, GA.

The CLL-IPI score is a validated predictor of overall survival (OS) in patients with newly diagnosed CLL who are starting first-line treatment with chemoimmunotherapy. It is calculated by adding the points assigned for variables associated with adverse outcomes:

  • Age > 65 years: 1 point
  • Higher clinical stage (Binet stage ≥ B or Rai stage ≥ I): 1 point
  • β2-microglobulin > 3.5 mg/L: 2 points
  • Unmutated IGHV: 2 points
  • TP53 dysfunction (del17p or TP53 mutation): 4 points

Based on the total score (range, 0-10 points), the CLL-IPI model categorizes patients into 4 risk groups: low risk (0-1 points), intermediate risk (2-3 points), high risk (4-6 points), and very high risk (7-10 points). The 5-year OS rates for patients with CLL starting chemoimmunotherapy by risk group are 93%, 79%, 63%, and 23%, respectively.

Because the CLL-IPI score was developed in patients receiving chemoimmunotherapy, its role in the setting of novel agents is not clear. Brander and her team examined whether CLL-IPI is a useful prognostic tool for patients who are starting frontline treatment with ibrutinib.

CLL-IPI score in ibrutinib-treated patients
In the retrospective cohort study, 326 patients with CLL were enrolled from 19 international academic centers and community sites. The CLL-IPI risk score was calculated for each patient based on baseline clinical and molecular prognostic factors. The median patient age at diagnosis was 64 years, and the median age at the start of ibrutinib was 68 years. Nearly two-thirds of patients (63%) were men.

All patients were treated with first-line ibrutinib monotherapy. The research team compared CLL-IPI scores as predictors of survival outcomes following frontline ibrutinib. The primary end point was progression-free survival (PFS).

Results showed that the CLL-IPI risk model was not able to differentiate survival outcomes in patients starting first-line ibrutinib monotherapy (Table). The 12-month PFS rates ranged from 97% in the low-risk group to 93% in the very-high-risk group (P = nonsignificant). Similarly, 12-month OS rates in the low-, intermediate-, high-, and very-high-risk groups were 98%, 98%, 92%, and 86%, respectively (P = nonsignificant).

TABLE. Survival Outcomes by CLL-IPI Risk Category

CLL-IPI Category Patients in Risk Category 12-Month PFS 12-Month OS
Low risk 2.5% 97% 98%
Intermediate risk 20% 86% 98%
High risk 49.5% 88% 92%
Very high risk 28% 93% 86%

CLL-IPI = chronic lymphocytic leukemia-International Prognostic Indicator; OS = overall survival; PFS = progression-free survival.

Brander and colleagues also analyzed the individual variables in the composite CLL-IPI score. The only variable that correlated with outcomes following ibrutinib treatment was TP53 dysfunction (the presence of del17p and/or TP53 mutation). Patients with TP53 dysfunction had significantly worse PFS than those who did not harbor these mutations (HR, 2.2; P = .01). The del17p and TP53 mutations were present in 32% and 22% of patients, respectively.

Implications for practice
One of the limitations of the CLL-IPI model involves the challenges of gathering patient information in the real-world clinical setting. Although the CLL-IPI risk score is based on widely available clinical variables such as age and disease stage, 76% of patients were missing at least 1 variable. Most commonly, patients were missing information on β2-microglobulin test results (63%) and IGHV status (44%).

"There is a critical need for prognostic models that integrate variables relevant to survival outcomes in the era of frontline ibrutinib in order to adequately counsel patients on treatment expectations," Brander said.

Better risk models are also needed to identify patients who may not respond well to ibrutinib and other novel targeted therapies, so that clinicians can offer these patients alternative options for CLL management, she concluded.

Source: Brander DM, Rhodes J, Pagel JM, et al. Applicability of the chronic lymphocytic leukemia (CLL)-IPI on patients treated with front-line ibrutinib in the real world: the case for new prognostic models. Presented at: American Society of Hematology 59th Annual Meeting; December 9-12, 2017; Atlanta, GA. Abstract 1719.