iwCLL 2025 | The refined CIRI2-CLL risk index for predicting outcomes after time-limited CLL therapy

So the aim of our study is to validate and refine the CIRI models for CLL in the context of fixed-duration target therapy and to benchmark performance against other established indices. So the idea is that measurable residual disease status after limited duration therapy is an established prognostic factor for survival times, but most prognostic indices rely solely on pretreatment features. So to incorporate dynamic MRD data into prognostic models across cancer types including CLL, the continuous individualized risk index of CIRI was previously proposed. So using Bayesian and Cox models, CIRI dynamically determines outcome probability for individual patients by integrating diverse risk features over time, which includes treatment modality and serial MRD data on and post-treatment. Since developed in the context of chemoimmunotherapy, we here propose a refined version of the CIRI model, the so-called CIRI2-CLL, in the context of fixed-duration target therapy, which includes MRD status on treatment, at end of treatment, and in addition, 12 months post-treatment. 

So after developing model parameters from the CLL8/10/11, and MURANO trials, we applied the refined model to an independent validation site from the CLL14 trial and benchmarked performance against other individual indices. So in the full CLL14 validation set, CIRI2-CLL showed adequate calibration with about 5% difference between observed and predicted event probabilities. So with a 21-31% higher C-statistic compared to CLL-IPI, outperforming MRD and other single-factor indices. So the performance was maintained in CLL14 patients treated first-line with venetoclax and obinutuzumab, or Ven-Obi. 

So additionally, CIRI2-CLL allows for clear separation of high-risk patients from intermediate and low-risk, with corresponding three-year PFS rates of 17%, 70%, and 100%. So furthermore when grouping into tertiles by predicted risk, 16 to 20 percent of patients were recategorized to higher or lower risk by CIRI2-CLL compared to CLL-IPI. 

So MRD status alone missed substantial risk heterogeneities. For example, 46% of Ven-Obi patients with undetectable MRD had intermediate CIRI2-CLL risk. So the performance was maintained for overall survival. 

In conclusion, our results validated CIRI2-CLL in the context of limited-duration treatment and suggest adaptivity with emerging additional longitudinal outcome data. So with CIRI2-CLL, we offer a tool for investigators to reliably identify patients with increased risk of disease progression after Ven-Obi. 

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