A refined dynamic prognostic model incorporating longitudinal measurable residual disease (MRD) assessments may improve prediction of progression-free survival and overall survival in patients with chronic lymphocytic leukemia (CLL) receiving limited-duration therapy. The findings, reported by Al-Sawaf et al in the Journal of Clinical Oncology, showed that the refined Continuous Individualized Risk Index for CLL (CIRI2-CLL) outperformed conventional pretreatment risk factors and individual MRD assessments in predicting outcomes.
Study Details
Traditional prognostic tools such as the CLL International Prognostic Index (CLL-IPI) rely primarily on pretreatment characteristics and do not account for changes in risk based on treatment response. The investigators sought to refine the previously developed CIRI framework for patients receiving fixed-duration targeted therapy. CIRI2-CLL combines baseline factors—including CLL-IPI and treatment regimen—with MRD measurements obtained during treatment, at the end of treatment, and 12 months after the end of treatment.
Model parameters were developed using patient-level data from the phase III CLL8, CLL10, CLL11, and MURANO trials. The development set comprised 913 patients: 614 with previously untreated CLL from CLL8, CLL10, and CLL11, and 299 with relapsed or refractory CLL from MURANO. Independent validation was performed using 381 patients from the phase III CLL14 trial, including 183 who received venetoclax plus obinutuzumab and 198 who received chlorambucil plus obinutuzumab. Median follow-up in the CLL14 validation cohort was 80 months.
Key Results
Among patients treated with venetoclax plus obinutuzumab in CLL14, conventional CLL-IPI stratification distinguished the lowest- and highest-risk groups, with 3-year progression-free survival rates of 100.0% and 66.7%, respectively (hazard ratio = 8.97, 95% confidence interval [CI] = 2.01–40.1; P < .001). However, differences between adjacent higher-risk categories were not statistically significant. In contrast, CIRI2-CLL demonstrated C-statistics ranging from 0.82 to 0.98 across assessed time points and separated patients receiving venetoclax plus obinutuzumab into low-, intermediate-, and high-risk groups with 3-year progression-free survival rates of 100.0%, 70.2%, and 10.8%, respectively.
Compared with CLL-IPI, CIRI2-CLL improved progression-free survival prediction by 17% to 37% in C-statistic from years 2 through 5 (P < .001) in the overall CLL14 validation cohort. It also outperformed individual predictors, including treatment choice and MRD status measured at interim, end-of-treatment, and 12-month posttreatment time points. CIRI2-CLL reclassified some patients compared with baseline CLL-IPI: 18.8% of patients receiving venetoclax plus obinutuzumab who had high-risk CLL-IPI were classified as low risk by CIRI2-CLL. The model also showed predictive value for overall survival, with C-statistics ranging from 0.77 to 0.98.
The investigators concluded: “These results validate CIRI2-CLL in the context of limited-duration CLL therapy. Our approach suggests the models' adaptability to emerging additional longitudinal MRD and/or outcome data. By introducing CIRI2-CLL, we offer a dynamic tool for investigators to reliably identify patients with increased risk of disease relapse after limited-duration therapy with venetoclax and obinutuzumab, freely accessible at CIRI2 (Stanford University), with important implications for informed decision making and for future risk-adapted CLL trial design.”
Othman Al-Sawaf, MD, PhD, of Department I of Internal Medicine and Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, German CLL Study Group, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by F. Hoffmann–La Roche and others. For full disclosures of the study authors, visit ascopubs.org.
