We rarely encounter therapeutic sequencing challenges in patients with TP53-mutated MCL because none of the standard therapies work very well. I do not think that any of us know how to best treat these patients right now. For our young patients, for whom you might be considering an intensive treatment approach, the data are convincing that, if you do go with the intensive approach and they have a TP53 mutation, the outcomes will be disappointing. It begs the question of whether it is worth putting a patient through that type of intensive treatment for such dismal results. My opinion is that it is not worth it. For my young patients who are TP53 mutated, I would likely recommend something gentler than intensive chemotherapy and stem cell transplantation. It is not as if chemotherapy does not work at all, it just does not work very well; remissions are not very deep, and they do not last very long. I might start with something such as bendamustine and rituximab, and then get lined up and ready to go with second-line therapy, such as a BTK inhibitor or chimeric antigen receptor (CAR) T-cell therapy. We do not truly have the sequencing dilemmas in these high-risk patients that one might see in other malignancies in that they progress rapidly, and we draw on all of our available tools.

There are currently no randomized trials or strong data to help guide us in the treatment of these high-risk individuals. In patients with TP53 mutations, I would generally use a BTK inhibitor with lenalidomide or venetoclax early in the course of treatment, as either initial or second-line therapy. Now that we have CAR T cells for the treatment of MCL, I would also consider this approach. Select patients with high-risk MCL respond very well to CAR T-cell therapy, but there is no clear paradigm on how or when to use this therapy in high-risk patients. Intensive chemotherapy is not an attractive option because the toxicity does not justify the poor response rates. 

We have a lot of evidence on what does not work, but not much evidence on what does work. We have little more than anecdotal evidence that some of the novel agents and CAR T cells can work in this setting. We have promising data on bispecific antibodies and antibody-drug conjugates, but they are very preliminary and I do not think that we can make very strong data-driven recommendations at this time.

Individual patients have different goals, but, in general, for these high-risk patients with MCL, sequencing is done hopefully toward an end goal of trying to get to either a CAR T-cell therapy or an allogeneic stem cell transplantation, if they are the right options. Of course, many patients will be unable to receive these definitive treatments.

It is important to try to incorporate the novel therapies in patients with high-risk MCL. I think that the BTK inhibitors and venetoclax are all reasonable options to consider. These approaches can provide therapeutic responses in very high-risk patients. Sometimes the responses are durable, but I use these therapies as a sequencing approach to get patients to 1 of the definitive therapies. Of course, sequencing these therapies could lead to the development of resistance, which could impact the use of definitive therapies such as CAR T cells. We cannot control biology, but we must try to stay ahead of the curve. In the original study by Wang and colleagues, primary resistance to BTK inhibitors was observed in approximately 30% of patients with MCL, while subsequent reports have ranged from 10.2% to 35%. Essentially, all patients who are treated with BTK inhibitors eventually develop secondary resistance and disease progression. The R-BAC regimen (rituximab, bendamustine, and cytarabine) is often used as a bridge to definitive therapy in patients with MCL who have not received prior bendamustine or cytarabine. The bispecific antibodies, T-cell engagers, and antibody-drug conjugates are exciting, but we have a lot of work to do to clarify their roles in high-risk patients.