Q: What is the significance of MRD negativity in CLL? Please discuss its use as an end point in clinical trials.

In chemoimmunotherapy trials, complete response (by International Workshop on Chronic Lymphocytic Leukemia criteria) and achievement of MRD status is correlated with prolonged progression-free and overall survival. So, while MRD negativity may be a clinically important end point in potentially curative strategies, MRD analysis is not a part of routine practice in the current standard of care. It is also important to note that the risk-benefit ratio of various treatment regimens can differ greatly, and, for individual patients, maintaining a good quality of life with excellent control of CLL may be of greater importance than achieving MRD negativity.

MRD negativity also depends on the type of therapy because it is a post-therapy measure rather than something that we assess prior to starting treatment. As Dr Mato noted, with chemoimmunotherapy, MRD negativity as measured by 4-color flow cytometry is quite predictive of better progression-free and overall survival. It seems likely that MRD negativity is also important in the setting of venetoclax therapy, although the extent of the data is not as great. It is really with the B-cell receptor pathway inhibitors, including ibrutinib and idelalisib, where the role of MRD negativity has not been established, and it is rare when patients have been treated with single agents or even with single agents plus antibody.

MRD negativity is also used as an end point in clinical trials investigating combination therapy. For example, at the last American Society of Hematology Annual Meeting and Exposition, there was discussion of early data from a trial investigating the combination of ibrutinib and venetoclax for high-risk patients, and there the goal is to achieve MRD negativity in a high fraction of patients. The data are premature at this point, so all that we can say is that, based on high response rates and MRD negativity, it looks like a promising strategy, but we do not have progression-free survival data at this point for combinations of a Bruton’s tyrosine kinase inhibitor with a B-cell lymphoma-2 antagonist that show superiority to sequential therapy.