The State of the Targeted Therapy Landscape for Mantle Cell Lymphoma

Cyrus M. Kahn, MD

Updates over the past 5-10 years brought Bruton’s tyrosine kinase (BTK) inhibitors and chimeric antigen receptor (CAR) T-cell therapy into the mantle cell lymphoma (MCL) treatment landscape. According to Cyrus M. Khan, MD, these therapies were a great improvement for relapsed/refractory disease, but more is needed in the frontline setting.

The FDA-approved BTK inhibitors for relapsed/refractory MCL include ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). In the clinical trials that supported the approval of these agents, objective response rates (ORRs) range from 59% to 81%.^1-3 The CAR T-cell agent, brexucabtagene autoleucel (brexu-cel; Tecartus), is also FDA approved to treated relapsed/refractory MCL. In the ZUMA-2 study (NCT02601313) which supported the approval, the brexu-cel achieved a 93% ORR.⁴

New therapies are needed in the case of relapse on a BTK inhibitors, and for frontline MCL, and elderly patients. Moreover, oncologists treating patients in the community setting may have to consider therapies that are not yet approved but being offered in clinical trials to best treat the aggressive form of lymphoma.

“I think more vigilance is required to treat patients with mantle cell lymphoma. Once the disease becomes problematic, it becomes very difficult to treat. From the get-go, I think they need to have the mantle cell patients seen by an experienced center to see whether the patient would qualify for a more aggressive therapy upfront in a clinical trial, and whether they need an autologous transplant. Remember that CAR T-cell therapies are available to them in the second-line setting,” said Kahn, hematologist in the hematologist, Division of Hematology and Cellular Therapy at West Penn Hospital of Allegheny Health Network.

In an interview with Targeted Oncology™, Khan, discussed novel strategies for the treatment of MCL and needs for the future.

TARGETED ONCOLOGY: How has the treatment landscape for MCL evolved over the past 5-10 years?

Khan: With mantle cell lymphoma, I think it's changed quite a bit in the second- and third-line settings. We had BTK inhibitors come out about 7 years ago or so for mantle cell lymphoma in the relapsed setting. That was a big advance. And now the second has been CAR T-cell therapy in the relapsed setting. That has been a major advance and patients are living longer.

It's unfortunate that mantle cell lymphoma is an aggressive lymphoma, for the most part, and we can't cure it. We must deal with a 2-pronged problem for a long time. As far as frontline treatments, the landscape hasn't changed much. I think we still use aggressive chemotherapy than we take the patients to an autologous transplant for consolidation in the hopes that we would induce a deep remission for a long time. But the major change has been how we treat relapsed/refractory mantle cell lymphoma.

Which class of agents has been the most impactful, in your opinion?

The first class would be BTK inhibitors in general, whether that's ibrutinib, acalabrutinib or zanubrutinib. All 3 are approved in relapsed/refractory mantle cell lymphoma. BTK inhibitors were a great advance in the field. The second major one has been CAR T-cell therapy. I think the data is very exciting, even for patients who relapsed after BTK inhibitor. We really were running up choices, but now that's really expanded the portfolio of treatments that we have available in the relapsed/refractory setting.

Is there any ongoing clinical trial in MCL that have the potential to change the standard of care?

I think we have a bunch of trials in the frontline setting, combining newer targeted therapies like venetoclax, with the BTK inhibitors and the new monoclonal antibodies, that look very exciting. This is especially true for trials that include older patients. Those patients can't really tolerate all these chemotherapeutic options, so it's nice to have something available for them. For example, we have a trial open at our center, which is for older patients. It's randomization between bendamustine/rituximab [Rituxan] versus zanubrutinib/rituximab. Investigators are trying to see whether we can get away with simply using a novel agent to prevent a lot of toxicity for older patients.

Also, there are various CAR T-cell therapy studies. The dual head CAR Ts are being trialed, and NK cell-therapy for mantle cell lymphoma in the relapsed setting. We're also looking at a newer BTK inhibitor, pirtobrutinib [LOXO-305], because some patients might progress on the current generation of BTK inhibitors due to certain mutations. There are a lot of exciting things are happening.

What are some of the unmet needs in the MCL landscape?

With younger patients, it’s easier to treat. They're robust, they don't have a lot of comorbidities, good functioning liver and kidney. We can throw pretty much the kitchen sink at them as far as the chemotherapy is concerned. We can get those younger patients into remission or take them to an auto transplant. But cure is elusive for those patients too.

In older patients, if we treat them with conventional therapy, most of the patients relapse within 3 years. We need to make a lot of advances in frontline treatment for those patients, including treatment with novel agents. For those patients, once it becomes relapsed/refractory, it becomes very difficult to treat them. There's also been using bispecific T-cell engager therapy also in those patients. I think that might also add into the whole paradigm of treatments in the future.

There are other trials looking at minimal residual disease [MRD] in mantle cell lymphoma. What we're trying to answer is whether everybody would benefit from a frontline autologous transplant or whether there are certain categories that might not benefit from it. I think a major question that still is out there are whether patients need cytarabine in the frontline setting or not in combination. The data from the bendamustine/rituximab in inducing MRD negativity also looks pretty good. There are a lot of unanswered questions, and a lot of research is going into that too.

What advice do you have for community oncologists who are treating patients with MCL?

I think more vigilance is required to treat patients with mantle cell lymphoma. Once the disease becomes problematic, it becomes very difficult to treat. From the get-go, I think they need to have the mantle cell patients seen by an experienced center to see whether the patient would qualify for a more aggressive therapy upfront in a clinical trial, and whether they need an autologous transplant. Remember that CAR T-cell therapies are available to them in the second-line setting.

_REFERENCES:

_{1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369(6):507-516.}

_{2. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. News release. FDA. November 14, 2019. Accessed September 16, 2022. https://bit.ly/3U9HYf7}

_{3. FDA grants accelerated approval to acalabrutinib for mantle cell lymphoma. News release. FDA. October 31, 2017. Accessed September 16, 2022. https://bit.ly/3Sa9maV}

_{4. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. News release. FDA. July 24, 2020. Accessed September 16, 2022. https://bit.ly/3eKzLxy}