Novel Strategies With BTK Inhibitors Seek to Impact Frontline MCL Treatment Landscape

Brad S. Kahl, MD

The mantle cell lymphoma (MCL) paradigm continues to expand, and efforts are underway to evaluate novel approaches with BTK inhibitors to continue to improve outcomes in both older and younger patient subsets, according to Brad S. Kahl, MD, who added that future research directions could focus on evaluating CAR T-cell therapies in earlier lines of treatment.

In the ongoing phase 3 SHINE trial (NCT01776840), investigators are evaluating the use of the BTK inhibitor ibrutinib (Imbruvica) in combination with bendamustine/rituximab (Rituxan; BR) vs BR alone in the frontline treatment of patients with MCL who are 65 years of age or older and are not candidates for high-dose chemotherapy. Another phase 3 trial (NCT02972840) is examining the efficacy of acalabrutinib (Calquence) plus BR vs placebo plus BR in older patients with previously untreated MCL. Both trials have completed enrollment and data are pending, Kahl said.

For younger patients with MCL, the phase 2 EA4181 (NCT04115631) has been launched to evaluate 3 chemotherapy regimens comprised of bendamustine, rituximab, high-dose cytarabine, and acalabrutinib. The phase 3 TRIANGLE study (NCT02858258) is examining whether the addition of ibrutinib to standard frontline treatment can improve efficacy or even challenge the use of high-dose chemotherapy with autologous stem cell transplantation (ASCT).

In an interview with OncLive®, Kahl, a professor in the Department of Medicine, Oncology Division, at Washington University School of Medicine in St. Louis, discussed personalizing frontline treatment in MCL, clinical trials further examining BTK inhibitors, and research opportunities with CAR T-cell therapy.

OncLive®: What are some currently available options for patients with newly diagnosed MCL? What factors must be considered during initial treatment selection?

Kahl: If we have a patient with newly diagnosed MCL, we must first determine whether the patient requires treatment at the time [we are seeing them]. A small group of patients are candidates for a watch-and-wait strategy. These would be patients with a leukemic non-nodal version of MCL or those with classic MCL who has a low tumor burden and are asymptomatic. It is reasonable to utilize a watch-and-wait strategy [for select patients], as studies have shown there is no harm to those patients.

However, most patients we encounter will need to start treatment soon, so the next decision [we must make is whether] the patient is a candidate for an intensive treatment strategy or whether they are better suited for a non-intensive approach. In general, mainly younger patients are considered for intensive treatment strategies, with an age cutoff of approximately 65 years old. Of course, there is more than just the age that goes into that decision, as some patients in their early 60s may be unhealthy and should not have intensive treatment, and other patients in their late 60s could easily tolerate intensive treatment. There needs to be some individualization in that selection.

Intensive treatment strategies usually involve a high-dose, cytarabine-containing induction strategy. This is followed by ASCT, which is then followed by maintenance rituximab. It is 12 months of very difficult treatment for the patient, and then prolonged maintenance. As such, it is important to choose patients who are appropriate for that pathway. The benefit to this, however, is that patients generally derive longer first remissions…in the 7- to 9-year range on average, with some even extending beyond that. That is the advantage of pursuing an intensive treatment strategy.

If we have an older patient, or someone who is less healthy, then the intensive strategies are not worth all the toxicity incurred during treatment. It has too much detrimental effect on quality of life and outcomes are not as good. For those patients, we try to find non-intensive treatment strategies. The most used strategy in 2021 in the United States is bendamustine plus rituximab, which is a simple approach to administer. It is effective and gets most patients into remission. Moreover, if just bendamustine and rituximab are administered for 6 cycles without any maintenance therapy, the data suggest an average remission length of approximately 3 years.

Data [reported] at the 2021 ASCO Annual Meeting looked at a strategy of 6 cycles of bendamustine plus rituximab, followed by 2 years of maintenance rituximab. This strategy showed an average remission length of more than 5 years, so maintenance rituximab can have a role in MCL. [Maintenance rituximab] has been proven to be beneficial in younger patients after stem cell transplant, as well as after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] chemotherapy. It has not been as conclusively proven to be beneficial after bendamustine and rituximab, although data from the phase 2 E1411 trial [NCT01415752] provide strong evidence for the benefit of maintenance rituximab after bendamustine/rituximab induction.

Having said that, what we do not know is the optimal duration [for this treatment strategy], although some studies have examined up to 3 years. The COVID-19 pandemic has posed additional challenges, as well. Patients who are receiving rituximab do not respond as well to vaccines, therefore, this must be weighed when making treatment decisions. Some patients with MCL have paused their maintenance treatment to increase the likelihood of getting a good vaccine response. Although maintenance rituximab is beneficial in MCL, that must be factored in with the current climate of the pandemic.

What emerging agents possess the potential to further change the frontline paradigm?

Certain emerging agents could influence frontline treatment considerations. Looking specifically at older patients and the standard treatment of bendamustine and rituximab, 2 important phase 3 trials have been completed and looked at the addition of BTK inhibition to this combination. One of the trials [assessed the addition of] ibrutinib, and the other used acalabrutinib. Both trials are fully enrolled, and we are waiting for outcome data to determine whether the BTK inhibition does improve outcomes in the frontline setting. I encourage that people not to do this until we see the results and get a chance to analyze them.

In younger patients, trials are also looking at the incorporation of BTK inhibition. There is the phase 2 EA4181 trial, which tests the addition of acalabrutinib to a standard immunochemotherapy backbone in a randomized fashion. Additionally, the TRIANGLE study, which was done in Europe, adds ibrutinib to standard therapy in younger patients, with R-CHOP and rituximab, dexamethasone, cytarabine, and cisplatin induction, followed by stem cell transplant. Finally, a third arm adds ibrutinib and subtracts the stem cell transplant, as well as examines substituting novel agents for standard therapy. That trial is fully enrolled but there are no results yet. Overall, multiple important studies are fully enrolled [and they] could [all] significantly influence the treatment landscape.

If BTK inhibitors are combined with frontline therapy, will that limit the available options in the relapsed/refractory setting?

The studies that are testing BTK inhibition in the frontline setting give the BTK inhibitor with chemoimmunotherapy, and once the chemoimmunotherapy is done, the patient is to remain on the BTK inhibitor until progression. If a patient progresses, they become BTK inhibitor refractory, and we will have used up a good option in the frontline setting. From what is known about mechanisms of resistance, if a patient were to become resistant to [either] ibrutinib or acalabrutinib, they are going to be resistant to the other agent, as well. Some new BTK inhibitors that are not on covalent binders could still have activity, but they are not FDA approved yet.

Certain CAR T-cell therapies can be offered, or other FDA-approved agents, but that will be the big question when the frontline BTK inhibitor trials are published and presented. Certainly, if [we see] an overall survival [OS] benefit, then it will be an easy decision. However, if there is just a progression-free survival [PFS] benefit without an OS benefit, it will depend on the magnitude of the PFS benefit and the toxicity profile of the novel combination.

Do you anticipate CAR T-cell therapy moving into the frontline setting?

It is possible that CAR T-cell therapy could move into earlier lines of treatment, including frontline, although it is hard to project right now because the data that we have in relapsed MCL is lacking long-term follow-up. It is fair to say that we do not know how good CAR T-cell therapy is in MCL yet. The response rates are high, and patients are doing quite well at 12 months and 18 months, but we do not know how patients are doing at 3 years and 5 years. It is hard to know whether moving CAR T-cell therapy into the frontline [setting] is justified without having a bigger relapsed/refractory experience, so longer follow-up is needed.

Overall, there should be enthusiasm for testing CAR T-cell therapy in earlier lines. Even in the frontline setting, it may become a way to consolidate patients instead of [turning to] stem cell transplantation. It may become the preferred treatment approach for patients with bad biologic disease, like p53-mutated MCL. One can envision some scenarios where it would be beneficial to test CAR T-cell therapy in frontline MCL. We are far from being ready to do that, but I can envision some trials where that would be perfectly appropriate to test.