Sequencing Therapies in Relapsed/Refractory Mantle Cell Lymphoma

Craig A. Portell, MD

At the 2024 Society of Hematologic Oncology (SOHO) Annual Meeting, Craig A. Portell, MD, presented findings on sequencing therapies in relapsed/refractory mantle cell lymphoma (MCL). With increasing resistance to Bruton tyrosine kinase (BTK) inhibitors, Portell discussed the challenges in determining the optimal treatment approach for patients after initial therapy failure.

He emphasized the evolving role of chimeric antigen receptor (CAR) T-cell therapy, noncovalent BTK inhibitors, and emerging therapies like bispecific antibodies in managing this patient population.

A key focus of the session was on patients with p53 mutations. These patients often show poor responses to standard therapies. He also addressed ongoing clinical trials, including a study comparing the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) to covalent BTK inhibitors in the second-line setting, which could help guide future treatment decisions.

As new data continues to emerge, Portell, associate professor of medicine at University of Virginia, highlighted the importance of identifying and managing patients who may not respond to traditional therapies.

This session aimed to provide oncology professionals with valuable insights on how to navigate the complex landscape of relapsed/refractory MCL and improve patient outcomes.

In an interview with Targeted Oncology^TM, Portell explained the takeaways from his session on sequencing therapies in relapsed/refractory MCL.

Microscopic, photorealistic image of lymphoma cells - Generated with Adobe Firefly

Targeted Oncology: What did you discuss at the 2024 SOHO Annual Meeting?

Portell: I [talked] about sequencing therapies in relapsed mantle cell lymphoma. [We are] starting first with patients, whether they have been exposed to BTK inhibitors or not, and how that may impact the decision making, and then, after exposure to BTK inhibitors, how to fit CAR T-cell therapy in vs a noncovalent BTK inhibitor, and [we will] talk about some special scenarios, particularly with p53-mutated relapse disease.

What is the current standard of care for patients with relapsed/refractory MCL?

As we are seeing more relapsed disease after first-line covalent BTK inhibitor, it is often probably a CAR T-cell therapy, but most patients will have not seen a covalent BTK inhibitor in the first-line relapsed setting. I think covalent BTK inhibitors are the standard of care for that patient population.

How have sequencing therapies changed the landscape of MCL treatment?

It has become more complicated as we have learned more about BTK inhibitor resistance, making it difficult to know what to do afterwards. The CAR T-cell space has been helpful, and we are hopeful to see some interesting data with bispecific antibodies and other new therapies, including covalent BTK inhibitors and venetoclax [Venclexta]. These are all therapies that can be challenging to sequence, and sometimes it really depends on the individual patient.

Could you discuss the mechanisms of action and clinical efficacy of each available BTK inhibitor and how they differ from each other?

Ibrutinib [Imbruvica], being the first-generation BTK inhibitor, differs from the second-generation BTK inhibitors, acalabrutinib and zanubrutinib, although they all work essentially the same way. They bind to the ATP pocket of the BTK protein and prevent it from functioning. The main differences between them lie in their adverse event profiles. Ibrutinib, as a first-generation BTK inhibitor, tends to have more "dirty" kinase inhibition, which leads to a higher incidence of serious [adverse] effects, including cardiovascular and bleeding events. In contrast, both acalabrutinib [Calquence] and zanubrutinib [Brukinsa] have fewer of these issues. However, acalabrutinib is associated with more headaches, which typically improve over time, while zanubrutinib may cause slightly more hypertension, which can develop over time. So, while all 3 drugs work similarly, their adverse event profiles differ slightly.

Can you just discuss any key clinical trials that are ongoing in this space?

I think one of the major clinical trials pending in our space is a study that is randomizing patients in the second-line setting to receive a noncovalent BTK inhibitor called pirtobrutinib vs an investigator's choice of a covalent BTK inhibitor. The goal is to see if the noncovalent BTK inhibitor will be more effective than the covalent BTK inhibitors we currently use in the second-generation space. More importantly, if a patient fails a noncovalent BTK inhibitor, can we still use the covalent BTK inhibitors to salvage those patients? Currently, we think we can salvage a patient failing a covalent BTK inhibitor with a noncovalent BTK inhibitor, but we do not know if the reverse is true. This study should help answer that question.

How have sequencing therapies impacted long-term outcomes for patients with MCL?

Adding more therapies to the landscape has helped. We still have some very significant challenges with mantle cell lymphoma, particularly thepatients [with p53 mutations]. They tend to not really respond as well to a lot of our standard therapies. How to address those particular patients, I think, is the next step in our clinical paradigm with MCL.

What are the future directions of research in MCL?

I think really understanding which patients will do well with our standard therapies is important, and for those patients, maybe we should just continue with our standard treatments since we know they will do well. However, there are some patients we identify who do not do well, and it is hard to predict that they will not respond to our standard therapies. Understanding how to predict a poor response and then acting on it is really the next step. We do know that p53 mutations may play a significant role. There are some data suggesting that patients with this mutation may not do as well, but as we conduct more testing in this space, we will be able to determine if that is truly the case. For now, early data suggests that, so we may need to focus on that patient population.

Are there any emerging therapies or combinations that you believe she will promise?

One of the most emerging therapies, particularly for patients [with p53 mutations], is a combination of zanubrutinib, venetoclax, and obinutuzumab [Gazvya], called BOVen, which is being developed by the Memorial Sloan Kettering [Cancer Center] group, at least in the first-line setting. It seems to have a good response rate, but how it will translate overall is still unclear, as it is in an early-phase, single-arm phase 2 study. It is also uncertain how long those patients will stay in remission, so follow-up data from this study will be helpful. There are other novel ways of attacking mantle cell lymphoma, focusing on epigenetic and genetic mechanisms associated with the disease, which may be promising in the future. However, these are still in early-phase studies, so how they will be incorporated remains to be seen.

What are the current challenges and limitations in this space?

So again, I think it is the patients [with p53 mutations], the ones that do not really respond to covalent BTK inhibitors. Those tend to be the patients who have rapid progression and are hard to get to CAR T-cell therapy because their disease is progressing so quickly. It is difficult to collect the T cells and wait for them to be manufactured. It is also a challenge to determine how to sequence their treatments.

What are the key takeaways for a community oncologist?

[We will be] really going through the pathways of when a patient would relapse in various scenarios. So, hopefully that will be informative and give some suggestions about how to manage patients in certain scenarios after progression with various different disease characteristics.