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.
Highlights
In patients with chronic lymphocytic leukemia (CLL) treated with fixed-duration regimens, such as chemoimmunotherapy (CIT), end-of-treatment response by standard criteria correlates with time-to-event endpoints, including progression-free (PFS) and overall survival (OS) [1–5]
Reporting the MRD4 rate often use an assay with a detection limit of 1 CLL cell in 100,000 or 1 million leukocytes), it is more informative to follow the approach recommended by the CML community [17] and use detectable/undetectable to provide additional information on assay sensitivity and whether disease is detectable below the reporting threshold
A large body of evidence indicates that Measurable residual disease (MRD) status is independently prognostic for time-to-event outcomes (Table 1)
Summary
In patients with chronic lymphocytic leukemia (CLL) treated with fixed-duration regimens, such as chemoimmunotherapy (CIT), end-of-treatment response by standard criteria correlates with time-to-event endpoints, including progression-free (PFS) and overall survival (OS) [1–5]. Extended author information available on the last page of the article is associated with superior outcomes. Achieving this depth of response has been the therapeutic goal. Low but measurable persistent CLL is present in many CIT-treated patients, including those achieving CR. Measurable residual disease (MRD; often referred to as “minimal residual disease”) is distinct from standard response, providing additional independent prognostic information. MRD is a sensitive reflection of disease burden during and after fixed-duration treatment and has been correlated with PFS and OS (Table 1).
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