The concept of a deeper remission and its significance in MCL is somewhat debatable. The first question is: To what extent does a deeper remission matter? And the second question is: How do you achieve such a remission? 

Evidence showing that a deeper remission may matter in MCL comes largely from studies of patients who received intensive induction chemotherapy and proceeded to autologous stem cell transplantation, where MRD negativity was associated with better outcomes. Now, a critique of MRD-driven therapy would be that achieving a deeper remission is associated with improved outcomes but does not actually cause them (eg, MRD negativity might simply be a marker of more easily treated disease). However, a more optimistic interpretation is that getting a patient into an MRD-negative state is a goal that may be linked to better outcomes for that individual patient, and this implies that we should be trying to get patients into deeper remissions. 

Several methods have been used for MRD monitoring in MCL, and this technology is still evolving. The best definition of a deeper remission is one in which the patient is MRD negative and is in complete remission by imaging studies. In the future, the significance of deeper remissions might be clarified by treating patients who do not achieve an MRD-negative state more aggressively and seeing whether their outcomes are improved. Thus, I think that the lesson that should be taken from the intensive approaches is that treatment regimens that provide MRD-negative complete remission states in high percentages will likely be associated with better outcomes as compared with regimens that do not, and, therefore, we should at least consider that potential.

As such, MRD has been used in a variety of studies of targeted therapies, some involving the use of targeted combinations in an attempt to achieve an MRD-negative state. In MCL, the main targeted combination that has been pursued (ie, where combination therapy is more likely to achieve an MRD-negative state than monotherapy) is the combination of a Bruton tyrosine kinase (BTK) inhibitor with venetoclax. This combination seems to have a higher complete remission rate and MRD-negative rate than the BTK inhibitor alone, suggesting that such a regimen would be appropriate to study further. 

While venetoclax is the only BCL-2 inhibitor available, several BTK inhibitors have been developed. Differences among the currently US Food and Drug Administration–approved BTK inhibitors appear to be related more to safety than efficacy. Although the newer BTK inhibitors such as acalabrutinib seem to have less toxicity than ibrutinib, it is important to remember that BTK inhibitors and venetoclax are not standard in the initial treatment of MCL (ie, these are all investigational regimens). Additionally, the duration of treatment with BTK inhibitors in the relapsed/refractory setting is indefinite up to the time of disease progression; however, if effective BTK inhibitor–based combinations were successfully developed, one could argue that treatment discontinuation may be considered at some point, much like the time-limited regimens being pursued in chronic lymphocytic leukemia.