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

Background: CLL is a heterogeneous disease with several prognostic models proposed for risk stratification. The validated CLL-IPI model (Lancet Oncology; 2016) integrates weighted key markers: TP53 dysfunction (del17p or TP53 mutation) = 4 points, unmutated IGHV= 2 points, β2M >3.5 mg/L = 2 points, Binet stage ≥B or Rai stage ≥I = 1 point, and age >65 years = 1 point. The CLL-IPI divides patients into 4 risk groups with differential survival outcomes, but it was developed based on patients receiving chemoimmunotherapy, not novel agents, such as ibrutinib. Whether the CLL-IPI applies to patients receiving ibrutinib is unknown. We sought to examine how the CLL-IPI impacts pts receiving ibrutinib monotherapy in the front line setting.

Patients and Methods: A retrospective cohort analysis of CLL pts treated with front-line ibrutinib across 19 community and academic centers was conducted. We analyzed demographics, prognostic factors, CLL-IPI scores, and survival outcomes. The primary endpoint was progression-free survival (PFS) measured from the time of ibrutinib initiation until CLL progression, death, or last follow up as estimated by the Kaplan Meier method. Using Cox regression, we examined the CLL-IPI score and its individual components as predictors of PFS. Descriptive statistics were used for demographic data.

Results: A total of 326 CLL pts treated with front-line ibrutinib monotherapy were included in this analysis. Median age at ibrutinib initiation was 68 years (range, 36-96), 63% were males. Median follow up on ibrutinib was 12 months (range, 1-76). Frequency of the CLL-IPI adverse variable testing and presence is displayed in Table 1. Of pts tested, 32% had TP53 dysfunction (del17p or TP53 mutation), 67% were IGHV unmutated, 76% had β2M >3.5 mg/L, 96% had advanced clinical stage, and 45% were age >65 years. In total, 79 pts (24%) had all variables available to accurately calculate the CLL-IPI. Of these, 2.5% were low risk, 20% intermediate risk, 49.5% high risk, and 28% very high risk. The 12 month PFS on frontline ibrutinib for intermediate, high, and very high risk groups was 86%, 94%, and 94%, respectively. These differences were not significant (Figure). On univariate analyses of individual CLL-IPI variables, only the presence of del17p and/or TP53 mutation was significantly associated with inferior PFS (HR 2.2, p=.01).

Conclusions: In the largest cohort of 326 frontline ibrutinib-treated CLL pts reported to date, only 79 patients had all CLL-IPI variables available. β2M was missing in 63% and IGHV mutational analysis was missing in 44%. Contrary to pts treated with chemoimmunotherapy, CLL-IPI did not distinguish 12 month PFS in ibrutinib-treated pts. Only del17p and/or TP53 mutation was associated with inferior PFS. Our analysis suggests the need for different prognostic models in pts treated with ibrutinib and confirms that testing of all CLL-IPI prognostic variables is not commonly performed in the real world.

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