When we talk about the biology of MCL in general, a number of clinical prognostic scores can help predict outcomes. Mutations in TP53 are associated with less favorable outcomes. In general, we know that patients with TP53 mutations do worse than other patients from the beginning of treatment. Right now, TP53 mutation status is the most clinically relevant factor for disease recurrence because we know that chemotherapy does not work well in those with TP53 mutations. The question is: What new therapy should these patients receive? And that is something that is under active investigation. We are also trying to understand why residual cells are residual and do not get killed during treatment. 

Patients with MCL who achieve minimal residual disease (MRD) negativity after induction chemotherapy tend to do better than those with MRD positivity. That is not at all a surprise because MRD status reflects the lymphoma’s sensitivity to treatment. Although MRD negativity correlates with better treatment outcomes, we do not know whether selecting treatment based on MRD status makes a difference in terms of overall survival. We also do not know the importance of MRD status in patients who have TP53 mutations or other adverse prognostic features.

We have been interested in the diagnosis-to-treatment interval (DTI) and what it may signify in MCL. Based on experiences in solid tumors, one might ask: Does a longer DTI predict worse outcomes and/or a greater likelihood of early recurrence in MCL? Longer DTI has been linked to worse outcomes in solid tumors, as it reflects other determinants of health. For example, people may have difficulty accessing care, trouble receiving a diagnosis because their disease has a complex presentation, or some other factor that would delay treatment. And that would be a bad thing, particularly if patients got sicker during the DTI. However, when you examine this question retrospectively in MCL and in other lymphomas, it turns out that a longer DTI is often associated with better outcomes. This likely reflects that a patient who can wait a long time to receive treatment is somebody whose disease is not rapidly progressing to the point of making them sick. So, there is an association between better disease biology and longer DTI, which is not always intuitive.

In some ways, I think of MCL as having a biology that is unique, with a bit more genomic instability compared with many other lymphomas. Mutational profiling studies show that mutations in the ATM gene accumulate, and then you start to see mutations in the TP53 gene accumulate. And these alterations become more common with subsequent relapses. When MCL acquires a TP53 mutation, it becomes quite difficult to manage. Treatments that work in MCL do not work as well in TP53-mutated disease, and that is especially true of chemotherapy. Some targeted agents, such as Bruton tyrosine kinase (BTK) inhibitors and probably chimeric antigen receptor (CAR) T-cell therapy, seem to work better than chemotherapy in TP53-mutated MCL, but even those targeted agents lose some of their activity. Right now, there just is not any way to overcome that bad biology. 

There may be a day when MRD testing is used to personalize the amount of therapy that is offered to an individual patient. It might give you guidance on when you need to keep going or when you could stop. That is how I could see MRD status as having value for individual patients with MCL, but we do not have the data yet to tell us how to use it. When you have a curable lymphoma, such as diffuse large B-cell lymphoma, MRD testing might be valuable to ensure that you have achieved a high-quality complete remission that would increase the likelihood of a cure. An ongoing trial is evaluating whether patients who have achieved a deep high-quality remission and MRD negativity can subtract some treatment but preserve a good outcome.

MCL seems to develop mutations more frequently and earlier than other lymphomas. For example, chronic lymphocytic leukemia does not seem to develop TP53 mutations as much or as soon as MCL, for reasons we do not understand. Once these mutations do develop, it is very difficult to treat them, certainly with any chemotherapy. CAR T-cell and BTK inhibitor therapies have some activity in patients with TP53-mutated disease, but, unfortunately, they are not as successful in MCL as they are in some other cancers. So, I think that we need a whole new area of therapeutic endeavors for those types of patients.

MRD testing is certainly being done in clinical trials, but it is not performed as much in clinical practice. The issue is that MRD reflects the amount of disease remaining in a patient after treatment. If a patient is MRD positive, it would make sense to treat them with rituximab maintenance, for example, and that could possibly improve the outcome. But, since we just do not yet know how much it helps long-term survival, it makes sense that MRD testing is not routinely performed on a day-to-day basis.

It is too early to know if there is anything important that we can learn from the fact that patients with relapsed/refractory MCL can respond to pirtobrutinib or if the combination of lenalidomide plus rituximab overcomes rituximab resistance. I would be happy if these treatments are proven effective in patients with residual disease, but we just do not know. Unfortunately, MCL is difficult to study because it is a relatively rare lymphoma, and studying this type of rare disease needs to be done on a national or international level.