Navigating Measurable Residual Disease as a Surrogate Endpoint in Chronic Lymphocytic Leukemia

Measurable residual disease (MRD) has established itself as an essential post-treatment biomarker in chronic lymphocytic leukemia (CLL). While achieving undetectable MRD (uMRD) reliably predicts prolonged progression-free survival (PFS) for individual patients across clinical trials, establishing MRD as a universal, trial-level regulatory surrogate endpoint across contemporary targeted therapies remains a formidable biostatistical hurdle. This perspective addresses the "atomistic fallacy" underlying the apparent erosion of trial-level surrogacy observed in aggregate meta-analyses. We demonstrate that the attenuation of trial-level surrogacy stems from fundamental biological effect modification-specifically the distinction between cytostatic therapies (e.g., continuous Bruton tyrosine kinase inhibitors) and cytotoxic, deep-remission regimens (e.g., fixed-duration venetoclax combinations)-as well as operational confounders introduced by modern adaptive trial designs. Reconciling these individual- and trial-level observations requires transitioning from a binary endorsement model to a mechanism-dependent, context-specific framework for surrogate endpoint validation in CLL.