There are many different categories of individualization. Testing for the TP53 mutation can help to identify when to recommend and when not to recommend chemoimmunotherapy. A robust body of evidence has demonstrated inferior outcomes for patients with TP53 mutations, which are often associated with a high proliferation rate, following treatment with either intensive chemoimmunotherapy or Bruton tyrosine kinase (BTK) inhibitors.

Additionally, patient preference and individual patient characteristics matter a lot in the treatment of R/R MCL. In older patients, maintaining a good quality of life and minimizing the risk of toxicities are obviously important, and their medical histories beyond MCL must be considered. Do they have hypertension? Are they on anticoagulation treatment? Do they have atrial fibrillation? Are they on a proton pump inhibitor? And so on. The answers will help us to determine which type of treatment should be given to these patients. The same approach applies to chemotherapy. Is this a patient who would benefit from chemotherapy, and, if so, which type? What did they have in prior lines of therapy, and how did they do? We want to recommend chemotherapy only when we believe that it is going to help the patient. So, again, individualization should be based upon patient and disease characteristics. 

And it is important to remember that some of these patients may relapse very late. Over the years, we have performed allogeneic stem cell transplantation (SCT) primarily in younger patients, and many of these individuals relapse many years, or even decades, later despite the chemoimmunotherapy. I recently had a patient who relapsed after chemoimmunotherapy and autologous SCT, and he developed a secondary site in the testicle 20 years later. These tumors sometimes demonstrate very odd and unpredictable behaviors.

Individualized care for patients with MCL must occur at every step of disease management, including initial treatment. For younger patients with classic MCL, we still favor an induction followed by an autologous SCT consolidation at the first remission. For older patients and those with high-risk MCL, we need to improve our approach to first-line treatment.

At relapse, a variety of considerations are critical when individualizing therapy. We have so many newer agents that are approved by the US Food and Drug Administration for relapsed MCL, and there is a myriad of combinations that we could explore in clinical trials, so the appropriate sequencing of these agents becomes a challenge. When using BTK inhibitor therapy in patients with relapsed MCL, there may be implications for the next line of therapy that I think we need to better understand.

We also should consider the toxicities of the second-line therapies. Acalabrutinib has shown noninferiority with ibrutinib, and it has a very different cardiovascular profile, with lower rates of atrial fibrillation. Sometimes in MCL, we even rely on the toxicity data from trials involving other types of lymphomas, and, in randomized studies, we have seen somewhat better safety profiles for the next-generation BTK inhibitors than for ibrutinib. For example, a recent study showed improved response rates and lower toxicity in patients with R/R MCL who were treated with zanubrutinib. We are starting to transition to next-generation BTK inhibitors as longer follow-up data become available. So, regarding the choice of a BTK inhibitor, I think that the more long-term data we see that support preserved outcomes with next-generation agents, the more the safety improvements of the next generation are coming into play.

I would echo the importance of engaging the patient so that you can understand their preferences, their fitness levels, and their comorbidities. This is critical in the absence of a clear standard of care for patients with R/R MCL. I agree that there is no single best approach.

BTK inhibitors are increasingly becoming a “go-to” treatment option in the second line. Still, there are some circumstances where we might think about the paradigm a little differently, and we might be planning for chimeric antigen receptor (CAR) T-cell therapy, especially in very high-risk patients. The duration of remission after frontline therapy has become a powerful prognostic factor in patients with follicular lymphoma, and we see similar data in individuals with MCL. Shorter time to progression of disease after first-line therapy is predictive of worse overall survival. Patients with primary refractory MCL or a very short duration of remission after initial chemoimmunotherapy tend to have shorter durations of remission with BTK inhibitor therapy as well.

In recognizing high-risk patients, we know that there is some overlap between the response characteristics and the high-risk disease features, including TP53 mutations, high Ki-67 proliferative index, and blastic or pleomorphic morphologies. Thus, in patients with high-risk MCL who are starting second-line therapy with BTK inhibitors, we may not want to rely on BTK inhibitors alone. I would recommend referring these individuals for a consultation at a specialized center that can deliver CAR T-cell therapy. It can be challenging to prepare very high-risk patients for CAR T-cell therapy, but I think that it is important to consider early CAR T-cell therapy in such individuals.