A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL

Natalie Dimier, Paul Delmar, Carol Ward, Rodica Morariu-Zamfir, Günter Fingerle-Rowson, Jasmin Bahlo, Kirsten Fischer, Barbara Eichhorst, Valentin Goede, Jacques J. M. van Dongen, Matthias Ritgen, Sebastian Böttcher, Anton W. Langerak, Michael Kneba and Michael Hallek

Key Points

  • Meta-analysis of 3 randomized clinical trials shows a statistically significant relationship between treatment effects on PFS and MRD.

  • Meta-regression model supports use of MRD as a primary end point in clinical trials of chemoimmunotherapy in CLL.

Publisher's Note: There is a Blood Commentary on this article in this issue.


Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials ( identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD rates between arms, the log of the PFS hazard ratio decreased by −0.188 (95% confidence interval, −0.321 to −0.055; P = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.

  • Submitted June 21, 2017.
  • Accepted November 29, 2017.
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