<p>The treatment of high-risk mantle cell lymphoma (MCL) in both the frontline and relapsed settings is evolving as more treatments become available. Emerging combination therapies that are being evaluated in patients with high-risk MCL include various combinations of BTK inhibitor therapy, anti–BCL-2 therapy, immunotherapy, chemoimmunotherapy, and CAR T-cell therapy.</p>

Even when you use the combination of pirtobrutinib and venetoclax, the best duration of remission is often not long enough to get patients with high-risk MCL to treatment consolidation. In addition, we are not really able to treat refractory disease in a meaningful way.

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One idea is that combining therapies such as lenalidomide and acalabrutinib will stimulate immunity, so that, if a patient’s MCL progresses, we can use CAR T-cell therapy in an immune-hot environment. I am a part of a group assessing the combination of lenalidomide and acalabrutinib with rituximab. Similar to what is being done in the early phase 1 Window-3 trial, which is combining acalabrutinib plus rituximab followed by CAR T-cell therapy, we want to find a way to stimulate the immune system before we deliver the CAR T-cell therapy so that we can transform the treatment of patients with high-risk MCL. This is because we now have patients in whom quadruplet therapy with a BTK inhibitor fails to provide any meaningful response. So, I think that trying to find better ways to intervene in patients with ultra high-risk MCL is incredibly important.

I think that the status of chemotherapy-free doublet therapy has been put into question because the phase 3 ECHO trial indicated that adding acalabrutinib to the combination of bendamustine plus rituximab (BR) improves progression-free survival (PFS) and trended toward an improvement in overall survival. The phase 2/3 ENRICH trial randomized patients receiving rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) or BR followed by maintenance rituximab to receive either ibrutinib with rituximab (IR) or R-chemotherapy, which was R-CHOP or BR, each with maintenance rituximab. Of the patients who received R-chemotherapy, approximately 73% received BR and approximately 27% received R-CHOP. In terms of PFS, IR outperformed R-CHOP but was comparable to BR. So, there are no clear data to suggest that a chemotherapy-free doublet therapy could beat BR, although another trial, the phase 3 MANGROVE study, is currently evaluating zanubrutinib in combination with rituximab vs BR.

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We are now moving far beyond doublet therapies into triplets. A phase 1b trial evaluating the combination of acalabrutinib, venetoclax, and rituximab had a 100% overall response rate, but some patients who were unvaccinated died of COVID-19. The international phase 2 TrAVeRse trial is now evaluating this combination in more patients with treatment-naïve MCL. Finally, a small phase 2 trial from Weill Cornell Medicine is evaluating the addition of acalabrutinib and lenalidomide to rituximab or obinutuzumab. The overall response rate with acalabrutinib, lenalidomide, and rituximab was 100%, and the complete response rate was 83% after 12 induction cycles.

There is a lot of interest in understanding more about high-risk factors in the frontline setting so that we can better predict a patient’s clinical course. The selection of first-line treatment is very important, particularly now that the combination of acalabrutinib, bendamustine, and rituximab is US Food and Drug Administration (FDA) approved for patients with previously untreated MCL who are ineligible for a transplant. There are also ongoing clinical trials evaluating CAR T-cell therapy in the frontline setting.

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It is important to recognize that some patients will develop resistance within the first 3 to 4 months of initiating therapy with a BTK inhibitor. These patients typically do not have a durable response to subsequent lines of therapy either, and their median PFS, even with anti–BCL-2 therapies or pirtobrutinib, is typically no longer than 10 months.

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It is unclear what role CAR T-cell therapies will play in the first-line setting. Ongoing clinical trials, such as the large, randomized, phase 2 CARMAN study in Germany, are evaluating CAR T-cell therapy vs other therapies in this setting.