Examining Treatment Approaches in Relapsed/Refractory Mantle Cell Lymphoma

Tycel Phillips, MD

With no standard of care in the second-line setting for patients with mantle cell lymphoma (MCL) currently available, choosing the best treatment option for this patient population is a challenge for experts.

Some of the available options for patients with MCL include ibrutinib (Imbruvica), acalabrutinib (Calquence), zanubrutinib (Brukinsa), and Bruton tyrosine kinase (BTK) inhibitors. Despite the number of treatments available, low overall response rates are demonstrated and responses to treatment typically only last between 5-10 years.

At the National Comprehensive Cancer Network (NCCN) 2022 Annual Congress: Hematologic Malignancies, Tycel Phillips, MD, presented on each of the effective treatment options available for patients with MCL. He gave detailed descriptions on the safety profiles that have been seen with each option and explained which patients would benefit the most each option.

“It's an exciting time for patients with mantle cell lymphoma but I still think we have a lot of work to do. Hopefully, the future remains as bright as we're all assuming it to be with a lot of these newer treatments that are hitting the market. As we better understand exactly why some of these drugs are not working, we can better find ways to circumvent the cancer's resistance pattern,” stated Phillips, clinical associate professor, the Division of Hematology and Oncology, the Rogel Cancer Center, Michigan Medicine, University of Michigan Health, in an interview with Targeted Oncology^TM.

In the interview, Phillips discussed the many treatment options available and those that are being examined for patients with MCL in the second-line setting.

Targeted Oncology: Can you discuss the session you were a part of at NCCN this year?

Phillips: At the most recent NCCN meeting in New York, my topic of discussion was on the treatments in relapsed/refractory mantle cell lymphoma. I separated things into 2 broad categories: Late relapses and early relapses and what options we have for patients based on when they relapse from disease. As a general preference, I think some research has shown that as long as patients have initial remission that lasts at least 24 months, that does set them on a slightly different trajectory compared with those who relapse within 24 months of initial therapy.

How has the treatment landscape for MCL changed over the past few years?

Before the advent of BTK inhibitors, we had agents such as lenalidomide [Revlimid], bortezomib [Velcade], in Europe they had another third agent called temsirolimus [Torisel]. The needle shifted with the approval of the BTK inhibitors, which initially started with ibrutinib. The original paper from Michael Wong, MD, indicated progression-free survival of the group was around 13.9 months, which at that point was substantial in that patient population, and an overall response rate of around 60%. That shifted how we went about things. After, Simon Rule, MD, combined several ibrutinib studies indicating that the BTK inhibitor was far more effective in the second-line, and in the third-line setting. With patients who got a complete remission with ibrutinib in the second-line setting, the duration of response was almost 5 years. From that, it cemented that we should be using this agent in the second-line setting in an effort to get the longest remission possible for most of our patients.

Thereafter, we had second generation BTK inhibitors, acalabrutinib and zanbrutinib which have come onto the market. A lot of those have come onto the market specifically due to some of the toxicities that we know exist with ibrutinib in the hope that these drugs have more fidelity to the BTK receptor and less off target impact. We may see less side effects and we will have in patients come off of ibrutinib [due to] bleeding, atrial fibrillation, arthralgias, myalgias, which are muscle and bone pain, and joint aches and pains, infection, and some of the newer cardiovascular risks that we see like hypertension and ventricular arrhythmias.

It does appear that some of these side effects may be a class effect and not specifically related to ibrutinib. All in all, it does still appear that all these drugs are very efficacious. You have some different side effects between acalabrutinib, zanbrutinib, etc., but with more time, we will truly get a sense of the side effect profile of those drugs.

What combination therapies are available for patients with MCL?

With the approval of the BTK inhibitors, there have been several studies looking at combinations that are trying to see what we can [do to] better improve the overall response rate and duration of response. That has been a bit of a disappointment overall and a lot of studies haven't shifted and moved the needle substantially. More recently, we had a study that came out of Australia by Constantine S. Tam, MD, that looked at ibrutinib and venetoclax [Venclexta], which showed an improvement in a complete remission rate, not so much of an improvement of the overall response rate. That has spurred a phase 3 study called SYMPATICO [NCT03112174] that is currently ongoing. We're waiting for a readout that is looking at ibrutinib plus venetoclax vs ibrutinib of inpatients relapsed/refractory mantle cell lymphoma. I will say as of right now, that's probably our best chance to have an effective combination regimen in the second-line setting and beyond.

Other than that, studies looking at ibrutinib and lenalidomide have not played out so much. They've tried to combine BTK inhibitors and PI3 kinase inhibitors, but the toxicity was prohibitive with that. As of right now, I think SYMPATICO is our biggest leap forward when we talk about combinations with BTK inhibitors. There are a few other studies that are looking at the targeting of ROR1, whether these be zilovertamab or zilovertamab vedotin, zilovertamab being a naked antibody and zilovertamab vedotin being the drug antibody conjugate. These are being combined with ibrutinib in the second-line setting, but those studies are much earlier than where we are with the ibrutinib and venetoclax combination.

What CAR T-cell therapies can be used in the treatment of MCL?

With BTK inhibitors, the good part is the long duration of response. The bad thing is that when patients fail BTK inhibitors, we don't really know the rationale or reason why these patients are not responding because it's very different from what we see in a chronic lymphocytic leukemia patient population. We didn't really have any effective drugs, until brexucabtagene autoleucel got an approval. With that CAR T product, it showed that we had a marked improvement in overall response rate for patients who have failed BTK inhibitors. It appeared to be agnostic to some of the very poor-risk factors that we typically associate, whether it be the blast pleomorphic variant, highly proliferative cancers, or those who harbor p53 mutation.

That has become approved for the second- or third-line. For most patients it is a third-line treatment given the time it takes to get insurance approval from vein, meaning from CAR T-cell collection to the current product that takes probably about 4-6 weeks in most situations. Ideally, patients will already be on something for a second-line treatment or would have filled a second-line therapy.

The downside with CAR T has been some of the side effects. We have cytokine release syndrome which occurs in the majority of patients. It is manageable, but it has to be managed in a hospital setting, which has limited the integration of CAR T outside of academic sites. The other side effect is high cancer neurotoxicity. The study reported that grade 3 or above occurred in 30% of patients, which is a high and a significant impact. None of these side effects are not manageable, but ideally, they're easier manageable in a hospital setting. As I mentioned, it makes it harder to have these integrated into community settings, which may not have ready access to a hospital that manages these patients because they can take days to get these symptoms to resolve.

What options excite you most for the future of this space?

One is the non-covalent inhibitor pirtobrutinib [LOXO- 305] which functions a little bit differently from the other drugs we talked about as it doesn't permanently bind to the BTK receptor. The exciting part about this is it did show efficacy in a post-BTK setting. Patients who failed 1 of the 3 covalent BTK inhibitors still had about a 50% response rate, which, outside of CAR T, we hadn't seen that with any other agent. With the study itself, the duration of response is still premature, so we don't know how durable the responses are, but we are getting some responses. The toxicity profile thus far appears very favorable compared with what we saw with the covalent drugs, so that is an option.

The other thing I think is circulating are the bispecific antibodies. They function similarly to how CAR T cells work. They sort of utilize the patient's own T cells to fight off the cancer, except the difference between this and CAR T is that these are more of an off the shelf product. We don't need to have manufacturing; we don't necessarily have to go through the rigmarole with insurance approval and all the stuff that delays CAR T. The biggest takeaway from these drugs is that the side effect profile appears to be a bit better than CAR T. [There is] hope that these drugs may be able to go into the community setting and have a wider impact because of the number of patients that can get these treatments outside of academic centers vs what we see with CAR T.

I think in the next year or so we will hopefully have bigger studies with these bispecific antibodies. Hopefully we'll have some indications and get some experience with these in the community centers and will allow these drugs to actually help some of these patients who can get access to CAR T, or who are poor candidates for CAR T due to concerns of some of the side effects.

What unmet needs still exist in this space.

The early relapse patients still do very poorly even with all the treatments and with the BTK inhibitors. There is a very short response, especially for those who have p53 mutations or have aggressive morphology. Even with CAR T products we haven't hit a plateau. If you look at CAR T for diffuse large B-cell lymphoma, there's a plateau whereas if patients are in remission after a certain point, their cancers won't typically come back. We have not seen that with mantle cell lymphoma. As time goes on, these patients are still relapsing continuously, and we haven't hit that plateau yet. The question of whether that will happen is up for debate.

In that situation, we still need more treatments in the post-CAR T setting. We need more treatments for patients with very high-risk features. If we are ever going to approach the lifespan of patients that have chronic lymphocytic leukemia, until we can get something that's curative, we need more treatments in general that knock off resistance. We don't know why certain drugs stopped working, so increasing our knowledge base into why these drugs are working will help us better derive other treatments that may rescue these patients. From our end, a lot to do with understanding more about cancer, and then obviously, sequencing more of these treatments to help extend the lives of our patients.

What is important to know about the current MCL landscape?

It's an exciting time for patients with mantle cell lymphoma but I still think we have a lot of work to do. Hopefully, the future remains as bright as we're all assuming it to be with a lot of these newer treatments that are hitting the market. As we better understand exactly why some of these drugs are not working, we can better find ways to circumvent the cancer's resistance pattern.