Developing MRD as an early endpoint for accelerated approval in CLL

This review article focuses on measurable residual disease (MRD) in chronic lymphocytic leukemia (CLL). Recent therapeutic advances in CLL have resulted in median progression-free survival (PFS) outcomes of ≥ 6 to 9 years, which threatens to slow further therapeutic progress, as it will take many years of follow-up for randomized trials to demonstrate improvements in PFS. Given growing evidence that undetectable MRD at < 10⁻⁴ limit of detection (uMRD4) is strongly associated with PFS outcomes in patients with CLL receiving fixed-duration therapies, MRD warrants evaluation for use as an early endpoint in CLL. Herein, we summarize Food and Drug Administration guidance regarding surrogate endpoints and intermediate endpoints, describe currently utilized MRD assays in CLL, review clinical trials data evaluating the prognostic impact of uMRD4 on survival outcomes in CLL, address questions regarding its prognostic role across regimens with different mechanisms of action, and highlight an ongoing effort to develop end-of-treatment uMRD4 as an early endpoint for accelerated approval of fixed-duration therapies in treatment-naïve CLL.