Calling Attention to Treatment Considerations in MCL

Lori A. Leslie, MD

Adapting treatment selection for patients with mantle cell lymphoma (MCL) in the frontline, maintenance, and relapsed/refractory settings is critical in such a heterogenous disease, explained Lori A. Leslie, MD, who added that novel modalities such as BTK inhibitors and CAR T-cell therapy offer a wealth of new opportunities for these patients.

“MCL is very heterogenous type of lymphoma,” said Leslie. “It has a lot of the features of an aggressive lymphoma such as diffuse large B-cell lymphoma (DLBCL), but it also has a lot of the difficult-to-treat features seen in indolent lymphomas.”

In an interview with OncLive, Leslie, a lymphoma attending at John Theurer Cancer Center (JTCC), Hackensack Meridian Health, discussed the current treatment landscape in MCL, factors to consider when selecting between BTK inhibitors, and other treatment options on the horizon.

OncLive: What does the current frontline treatment landscape look like in MCL?

Leslie: There are many different up-front treatment options for patients with MCL. [Treatment selection largely] depends on the patient’s age and fitness, as well as characteristics of their disease. Two things we look for that are predictive of a more aggressive disease course are high Ki-67 proliferative rate of over 30% and an abnormality in the p53 tumor suppressor gene. In general, when abnormal, a TP53 mutation predicts for a more aggressive course of MCL.

For the standard[-risk] patients without a TP53 abnormality, we don’t typically “watch-and-wait” outside of a relatively rare, indolent subgroup of patients where that method may be appropriate. Instead, we treat the patient.

The first question is, “Is this patient fit to consider an autologous stem cell transplantation (ASCT) or dose-intensive chemotherapy?” Typically, patients will receive dose-intensive chemotherapy. Depending on the regimen, like hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin hydrochloride, and dexamethasone] for example, we don’t necessarily have to do a transplant for consolidation. Other high-dose regimens include dihydroxyacetone phosphate or the Nordic regimen, typically followed by consolidative ASCT. After transplant or high-dose chemotherapy, we consider maintenance rituximab (Rituxan) in the frontline setting as it has been associated with a survival benefit.

For patients with high-risk MCL, such as those with a TP53 abnormality, there is no established standard of care. In those patients, we typically consider clinical trials. There are some approaches looking at combining targeted therapy such as BTK inhibitors with chemotherapy to try to eradicate those more resistant clones. However, clinical trials are key in that high-risk patient group.

For patients who are not candidates for intensive chemotherapy, there are some less intensive chemotherapy options we consider, including R-BAC [rituximab, cytarabine, and bendamustine], bendamustine/rituximab, and VR-CAP [bortezomib (Velcade), rituximab, cyclophosphamide, doxorubicin, and prednisone]. We also consider maintenance rituximab after those options.

What treatment options are available to patients with relapsed/refractory disease?

Relapsed/refractory MCL is a rapidly evolving field with many new targets and novel therapies, including cellular therapy which is entering our armamentarium. Typically, the most important choice when someone comes in with relapsed/refractory MCL is what they received as frontline therapy and how long they were in remission.

If I had a patient who received chemoimmunotherapy and ASCT and enjoyed a 10-year remission, that patient is different than someone who received chemoimmunotherapy and is relapsing while they are on maintenance rituximab.

For patients with a higher risk of relapse or really any [risk of] relapse, the standard of care is usually targeted therapies, including BTK inhibitors. There are emerging data looking at venetoclax (Venclexta) in this group of patients. Lenalidomide (Revlimid) with rituximab is another potential option. Bortezomib-based therapies are also used here but fall a little further down the preference list now that we have BTK inhibitors.

In patients with multiple relapses, anti-CD19 CAR T-cell therapy is most exciting. There have been recent data looking at CD19-directed CAR T-cell therapy in patients with relapsed MCL who are resistant or refractory to BTK inhibitors showing a very high overall response rate (ORR). About two-thirds of patients are achieving complete responses (CRs) that appear durable. As more data emerge, hopefully that will become another standard option that is available outside of clinical trials for our patients with relapsed disease.

What is the role of maintenance therapy in the frontline and relapsed/refractory settings?

In the frontline setting, if a patient has had chemotherapy and transplant, it’s standard to consider maintenance rituximab therapy. The most common schedule is to give it every 2 months for 3 years, or for 2 years in certain situations. Rituximab is continued until a patient progresses or [develops] some toxicity with the therapy. Though, it is typically well tolerated.

There is a suggestion of overall survival benefit in some studies, as well as progression-free survival benefit [with maintenance rituximab]. Typically, we recommend maintenance therapy unless there is a reason not to give it after frontline therapy.

In the relapsed/refractory setting, it really depends on what the patient’s treatment is. BTK inhibitors are generally indefinite therapies, so there is not a maintenance-type approach [in that situation]. Patients will stay on BTK inhibitors until they progress or develop an unacceptable toxicity. Looking toward time-limited therapy, maybe we could add a BCL-2 inhibitor with venetoclax in MCL like we are doing in chronic lymphocytic leukemia (CLL).

What additional considerations need to be taken into account when treating an older or unfit patient with MCL?

Patients with MCL who are older or unfit have a unique need. A lot of what I do first is talk to the patient about what their expectations are. Typically, significantly older patients are not candidates for intensive frontline therapy or ASCT. In those patients, less intensive chemotherapy with maintenance rituximab [is preferred].

There are some emerging data about using BTK inhibitors in the frontline setting as induction with abbreviated chemotherapy afterward. That regimen is being evaluated more so in young patients to minimize the amount of chemotherapy used. This could potentially be used as a frontline regimen in older or unfit patients who can’t tolerate the previous standard of care.

BTK inhibitors have had a significant impact in the treatment of patients with MCL. How are you currently selecting between the available BTK inhibitors in the relapsed/refractory space?

BTK inhibitors have rapidly impacted the treatment of patients with relapsed/refractory MCL in the past 5 years or so. There are an increasing number of BTK inhibitors that are approved in the space with more on the way. Currently, FDA-approved options include ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). These are all drugs that have minimal comparative data with each other.

Without direct comparison, the toxicity profiles seem to differ slightly across B-cell malignancies, including CLL, Waldenström macroglobulinemia, and MCL. The newer BTK inhibitors have a potentially lower risk of cardiac or bleeding toxicities. Though, that has not been shown in a head-to-head comparison in MCL, it may be a reason to select acalabrutinib or zanubrutinib [over ibrutinib].

Dosing also differs. Ibrutinib is once daily, acalabrutinib is twice daily, and zanubrutinib can be dosed once or twice daily. Sometimes that is a factor when deciding between these agents.

Additionally, something about zanubrutinib that is different from acalabrutinib is the ability to take proton pump inhibitors. Sometimes those drug-drug interactions help select which BTK inhibitor to use.

Importantly, the cost can be quite different from agent to agent. Sometimes we will select 1 BTK inhibitor and the copay, despite whatever copay assistance is given, ends up being too high. In those cases, we may opt for another BTK inhibitor. Obviously, we don’t want [cost] to drive our treatment choices. However, sometimes cost is prohibitive for the patient.

How might CAR T-cell therapy impact the treatment landscape? What does the future look like with that treatment modality?

CAR T-cell therapy has changed the landscape of lymphoma treatment over the past few years. Specifically, CD19-directed CAR T-cell therapy is in the late stages of investigation across B-cell malignancies. It is approved in DLBCL and has been extensively studied in other lymphomas, including MCL.

The ZUMA-2 study looking at anti-CD19 CAR T cells was presented at the 2019 ASH Annual Meeting and then published in the New England Journal of Medicine. We participated in that study at JTCC and treated a number of patients. Of note, the patients on that study were very high risk. About one-third of patients had pleomorphic or blastoid-variant MCL, which is a challenging and aggressive type of MCL. All patients had to have been exposed to ibrutinib, but 88% of patients were primary refractory to BTK inhibitor therapy or initially responded and then relapsed while on ibrutinib. That is a really difficult-to-treat patient population.

Despite that, the ORR was high, at over 90%. Additionally, 67% of patients achieved a CR. According to the latest dataset, 80% of those patients who had a response were still in a response at around 1 year. It seems that those responses are durable.

Although there can be infusion-related toxicities that can be serious with cytokine release syndrome and neurotoxicity, it is a one-time cell infusion. Then patients are off therapy. Most of these patients have received several lines of treatment, and indefinite BTK inhibitor therapy. To go from that to having a one-time infusion and hopefully never needing treatment again is remarkable.

What are some remaining challenges or unanswered questions in MCL?

We need to continue working on how to identify those patients who are high risk from the beginning. Of course, we know that elevated Ki-67 and TP53 abnormalities are clinically prognostic, but outside of that, we need to know how to identify patients who would perhaps benefit from more targeted therapy plus chemotherapy early on.

Using minimal residual disease (MRD) is becoming increasingly important and increasingly available. A patient who has intensive therapy and is in CR but has detectable MRD may be someone who could benefit from consolidation, CAR T-cell therapy, or some other consolidative immunotherapy to try to eradicate the few cells that will eventually lead to relapse.

Are there any emerging agents on the horizon that look promising?

Another agent that is interesting and being developed for MCL is the ROR1 inhibitor cirmtuzumab. That is being studied in combination with ibrutinib in CLL and MCL. Some preliminary data were presented at the 2020 ASCO Virtual Scientific Program showing that the combination was well tolerated and led to a high ORR.

ROR1 is different than anything else we’re targeting in MCL. That is an appealing, well-tolerated agent that has a novel mechanism of action. Perhaps we can add cirmtuzumab to BTK inhibitors or other therapies to try to improve upon treatment for patients with relapsed/refractory MCL or potentially those with newly diagnosed disease.