Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations

Abstract

Assessment of measurable residual disease (often referred to as "minimal residual disease") has emerged as a highly sensitive indicator of disease burden during and at the end of treatment and has been correlated with time-to-event outcomes in chronic lymphocytic leukemia. Undetectable-measurable residual disease status at the end of treatment demonstrated independent prognostic significance in chronic lymphocytic leukemia, correlating with favorable progression-free and overall survival with chemoimmunotherapy. Given its utility in evaluating depth of response, determining measurable residual disease status is now a focus of outcomes in chronic lymphocytic leukemia clinical trials. Increased adoption of measurable residual disease assessment calls for standards for nomenclature and outcomes data reporting. In addition, many basic questions have not been systematically addressed. Here, we present the work of an international, multidisciplinary, 174-member panel convened to identify critical questions on key issues pertaining to measurable residual disease in chronic lymphocytic leukemia, review evaluable data, develop unified answers in conjunction with local expert input, and provide recommendations for future studies. Recommendations are presented regarding methodology for measurable residual disease determination, assay requirements and in which tissue to assess measurable residual disease, timing and frequency of assessment, use of measurable residual disease in clinical practice versus clinical trials, and the future usefulness of measurable residual disease assessment. Nomenclature is also proposed. Adoption of these recommendations will work toward standardizing data acquisition and interpretation in future studies with new treatments with the ultimate objective of improving outcomes and curing chronic lymphocytic leukemia.

Fig. 1. Landmark analysis in the German CLL Study Group CLL8 and CLL10 trials.

PFS (A and C) and OS (B and D) at end of treatment by PB MRD and additional response status. Reprinted with permission from Kovacs G, Robrecht S, Fink AM, et al. Minimal residual assessment improves prediction of outcome in patients with chronic lymphocytic leukemia (CLL) who achieve partial response: comprehensive analysis of two-phase III studies of the German CLL Study Group. J Clin Oncol. 2016;31:3758–3765. BM, bone marrow; CR, complete response; MRD-, minimal residual disease negative; MRD+, minimal residual disease positive; OS, overall survival; PFS, progression-free survival; PR, partial response.