Minimal Residual Disease in Chronic Lymphocytic Leukemia in the Era of Novel Agents: A Review.

IMPORTANCE: The landscape of chronic lymphocytic leukemia (CLL) treatment has changed considerably since the first reported assessment of minimal residual disease (MRD) by flow cytometry in 1992. Chemoimmunotherapy (CIT) combinations have become the standard of care for most patients, and novel targeted agents are rapidly being incorporated into the front-line and relapsed settings. Minimal residual disease status has been shown to be a predictor of both progression-free survival (PFS) and overall survival (OS) at the time of response assessment following CIT, but less is known about the relationship between MRD and outcomes after novel oral therapeutics. Herein, we review current methods for MRD testing and present relevant clinical data for MRD for current treatment regimens focusing on novel oral agents as monotherapies and in combination. OBSERVATIONS: Flow cytometry and polymerase chain reaction are the 2 methods most frequently used to measure MRD, although high-throughput sequencing and more specific assays are being refined. Minimal residual disease status is an independent predictor of PFS and OS for patients receiving CIT, and emerging data for venetoclax suggest a relationship between MRD negativity and outcomes. The prognostic value of MRD status for kinase inhibitors remains unknown. CONCLUSIONS AND RELEVANCE: Minimal residual disease as a clinical trial end point must be validated in prospective studies prior to being used as a surrogate for survival. Given the heterogeneity of CLL biology and therapies, this validation must be regimen specific. Minimal residual disease assessments should be performed in clinical trial patients with both partial and complete responses. Following CIT, MRD status has prognostic value in all responders and this observation is important to validate with novel agents because most patients obtain partial remission. Further research is required to validate the use of MRD status as a decision point in guiding therapy in clinical practice.