Evolving Role of CAR T-Cell Therapy in Mantle Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has been a facet of emerging treatment for a number of hematologic malignancies in recent years, including mantle cell lymphoma (MCL). While use of CAR T-cell therapy has been predominantly used for multiply relapsed/refractory MCL, there has been interest in moving this strategy to earlier lines of treatment.

Ahead, Brian Hill, MD, director of the Lymphoid Malignancies Program and staff physician in the Cleveland Clinic Taussig Cancer Institute, discusses the use of CAR T-cell therapy in earlier lines of treatment for mantle cell lymphoma and considers other emerging modalities in this setting.

Targeted Oncology™: Is there a potential role for CAR T-cell therapy in earlier lines of treatment for mantle cell lymphoma?

Brian Hill, MD: A lot has been discussed about CAR T-cell therapy for B-cell lymphomas as well as ALL [acute lymphocytic leukemia] and myeloma. In the case of mantle cell lymphoma, the registration trial that led to FDA approval of CAR T-cell therapy for relapsed/refractory mantle cell lymphoma enrolled patients who had all essentially been previously treated with an oral BTK [Bruton tyrosine kinase] inhibitor. As a result, most of the patients who’ve received CAR T-cell therapy for MCL are in the third line or later lines of therapy. But there is interest in using CAR T-cell therapy in earlier lines, for instance, in second-line therapy for mantle cell lymphoma. There is a cohort of patients who have been treated in this way as part of the ZUMA-2 study, which is the registrational trial. This is an additional cohort of brexucabtagene autoleucel for mantle cell lymphoma. We haven’t seen any published data from this, but there is interest in testing the use of CAR T-cell therapy before BTK inhibitors.

Targeted Oncology™: Are there any clinical trials with emerging CAR T-cell therapies you’d like to highlight?

Brian Hill, MD: In addition to brexucabtagene autoleucel, there are studies using other CAR T-cell products, including tisagenlecleucel and lisocabtagene maraleucel, which are FDA approved for large B-cell lymphoma. There are emerging data on the safety and efficacy of those CAR T-cell products for mantle cell lymphoma, but as of late 2022, we still don’t have FDA approval for those CAR T-cell therapies for mantle cell lymphoma.

Targeted Oncology™: What might the potential role of pirtobrutinib be in the mantle cell lymphoma treatment landscape?

Brian Hill, MD: The covalent BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, are all very effective oral agents for the treatment of mantle cell lymphoma and other B-cell malignancies, including CLL [chronic lymphocytic leukemia] and others. They all have a similar mechanism of action in that they bind to the BTK protein at the same site. Pirtobrutinib is a new generation of oral BTK inhibitor, which is the noncovalent inhibitor of BTK. It binds not in a covalent fashion, but through the hydrophobic pocket of BTK and inhibits its signal transduction. Pirtobrutinib is very effective in mantle cell lymphoma, and we’ve seen in recent phase 2 data presented at national meetings that it’s very well tolerated with low rates, or almost nonexistent rates, of atrial fibrillation and other arrhythmias. It is not associated with bleeding the way the covalent BTK inhibitors can be. Importantly, pirtobrutinib has demonstrated clinical efficacy, not only in patients who are naive to BTK inhibitors, but also in patients who’ve been exposed to or treated with the traditional covalent BTK inhibitors. So going forward, there’s a lot of enthusiasm about this agent for mantle cell lymphoma, and we look forward to having greater access to this outside of clinical trials, hopefully through an approval in the not-too-distant future.

Targeted Oncology™: Is there a role for combination therapies in the treatment of mantle cell lymphoma? Are there any combination therapies in development that you’d like to highlight?

Brian Hill, MD: Given the clinical activity of the covalent BTK inhibitors in mantle cell lymphoma, there has been interest in building upon those agents as a backbone therapy. We know that the oral BCL2 inhibitor venetoclax is very effective in certain hematologic malignancies, including CLL. As a single agent, it has modest activity in mantle cell lymphoma, but some short-lived responses. There is a significant amount of evidence preclinically of a synergistic antitumor effect with the combination of BTK inhibition with the BCL2 inhibitor venetoclax. And so, the SYMPATICO trial is testing the combination of ibrutinib with venetoclax in previously treated relapsed/refractory mantle cell lymphoma. This study may lead to a regulatory approval of that combination, and we need to wait until we see more mature data. But having higher response rates and deeper remissions than ibrutinib alone is something we would look forward to seeing.

Targeted Oncology™: As these new treatment options emerge, how do you foresee therapies being sequenced in mantle cell lymphoma?

Brian Hill, MD: The sequencing of treatment in mantle cell lymphoma is continuously evolving. The standard frontline treatment in the United States remains chemotherapy for most patients. A typical regimen might be bendamustine, rituximab, sometimes with high dose cytarabine, and we can talk a l bit later about whether consolidation with autologous stem cell transplant is needed. But after some induction therapy, typically patients are maintained on treatment with rituximab as a single agent. And maintenance treatment has been shown to extend the duration of response, progression-free survival, and in some cases, even overall survival. Unlike with other more indolent non-Hodgkin lymphomas, maintenance treatment is a very important part of treatment for MCL. In terms of sequencing, for second line therapy, the covalent BTK inhibitors are probably the most commonly used second-line regimen. But as we talked about, there is interest in trying CAR T-cell therapy before that use of BTK inhibitors. And if you do that, for patients who may not have durable remissions, an open question remains what the efficacy of the BTK inhibitors may be in that setting. Similarly, as we get the newer BTK inhibitor pirtobrutinib more widely available, we know that it works after failure of covalent BTK inhibitors. How exactly that plays into the sequencing algorithm of treatment of mantle cell is something that will likely evolve in the coming years.

Targeted Oncology™: In addition to the agents previously mentioned, are there any other drug classes or therapies you’d like to highlight?

Brian Hill, MD: In terms of ROR1, this is a receptor on the surface of CLL cells and mantle cell lymphoma cells. ROR1 has been targeted in various fashions by monoclonal antibodies as well as antibody-drug conjugates, and now bispecific T-cell engagers. The preliminary data suggest that this is a worthy target in mantle cell lymphoma, and we look forward to having more mature data of the bispecific T-cell engagers targeting ROR1 for mantle cell lymphoma. Similarly, the use of the oral EZH2 inhibitor tazemetostat has been tested in various B-cell non-Hodgkin lymphomas. The agent is well tolerated and approved for relapsed/refractory follicular lymphoma. As of now, there have been a limited number of patients with mantle cell lymphoma treated with tazemetostat, and we look forward to more data emerging to get a better sense of the efficacy of this agent in MCL.

Targeted Oncology™: Do you have any clinical pearls you’d like to share for community physicians who are treating patients with mantle cell lymphoma?

Brian Hill, MD: For community oncologists who are treating mantle cell lymphoma, it’s important to get a sense of the risk level at the time of diagnosis. Not all patients with MCL are created equally, and there’s a subset of patients who can present in a very indolent fashion, with lymphocytosis that may be diagnosed or noted incidentally and mistaken for, or present more like a typical patient with CLL. These patients with so-called leukemic non-nodal mantle cell lymphoma can safely be monitored with active surveillance and a watch-and-wait approach rather than immediate treatment in many cases. On the other side of things, there are some patients with mantle cell lymphoma who present with very aggressive disease, typically characterized by a blastoid morphology on IHC, or immunohistochemistry, staining of lymph node biopsies. Blastoid variant mantle cell is typically very difficult to treat. It’s often characterized by a 17p deletion. And we know that 17p deletion or TP53 mutation confers a very high risk of treatment failure in blastoid as well as classical mantle cell lymphoma. I would encourage community oncologists to make sure that when they see a patient with newly diagnosed mantle cell lymphoma, make sure the pathology is reviewed at an expert center or a referral center that can do testing for TP53 mutation or 17p deletion. Those patients typically respond poorly to chemoimmunotherapy and should probably be transitioned to targeted or more novel agents such as cellular therapy earlier in the course of therapy.

Targeted Oncology™: How do you see the field of mantle cell lymphoma management evolving over the next 5 to 10 years? Are there ongoing challenges or unmet needs within this particular patient population?

Brian Hill, MD: The field of mantle cell lymphoma treatment is evolving more and more toward targeted therapies, cellular therapies, and newer agents, and away from chemotherapy. Right now, it is still common to perform autologous stem cell transplant, if possible, in younger, fitter patients under the age of 65, or a fit patient under the age of 70. Autologous stem cell transplant does require travel to a referral center and is associated with toxicity, prolonged hospitalization, potential late morbidity, and even secondary malignancies. At the most recent American Society of Hematology [ASH] meeting, there was a large phase 3 trial called the TRIANGLE study from the Nordic Consortium in Europe, which tested whether introduction of ibrutinib to induction therapy and maintenance treatment afterward might obviate the need for autologous stem cell transplant. And the results were provocative. They suggested that substituting ibrutinib during induction and maintenance therapy can achieve similar or even better outcomes than autologous stem cell transplant. There were some caveats to the study, including the lack of rituximab maintenance treatment in all of the control patients. Only about half of the patients received maintenance therapy, and this may have confounded the results of the study. But it seems to be that we’re moving in the direction of earlier lines of targeted agent and maybe less reliance on autologous stem cell transplant.

The other thing that’s likely to become more integrated in a practice in the years to come is the testing of minimal residual disease [MRD] in the blood after induction therapy. There’s a large cooperative group trial ongoing to test whether or not autologous stem cell transplant is needed in patients who achieve an MRD undetectable state after induction therapy, as most patients do. I would say, these kind of issues about use of targeted agents, MRD-guided therapy, and possible omission of autologous stem cell transplant are all likely to evolve in the coming years for the management of mantle cell lymphoma.