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Treating MCL
How I Treat Patients With Mantle Cell Lymphoma

Released: November 12, 2021

Expiration: November 11, 2022

Brad S. Kahl
Brad S. Kahl, MD
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Treatment Considerations for Newly Diagnosed Mantle Cell Lymphoma
When we see a patient in the clinic with a new diagnosis of mantle cell lymphoma (MCL), we consider a number of things, including the disease burden on imaging and ascertaining whether the patient is symptomatic or not. As a part of diagnosis for MCL, patients should have a biopsy to assess if the disease has typical MCL morphology or if it is a blastoid variant. In addition, a Ki-67 stain can help provide a sense for how proliferative the disease is—highly proliferative disease tends to be harder to manage than less proliferative disease—and the TP53 mutational status can have a significant influence over the likelihood of responding well to immunochemotherapy. 

We then integrate all of this information for each patient to help determine if the patient needs immediate treatment or if a watch-and-wait strategy is recommended. In my experience, approximately 10% to 15% of patients with newly diagnosed MCL do not need to start treatment immediately. MCL largely remains an incurable disease, so it is necessary to devise a long‑term management strategy for patients. Part of the management strategy may be periods of time when no treatment is needed, and that is perfectly acceptable as a strategy.

Patients with a variant of MCL called “leukemic nonnodal MCL,” which presents more like chronic lymphocytic leukemia, are candidates for the observation approach. This variant is characterized by splenomegaly, high white blood cell counts, and minimal lymphadenopathy. Many of these patients will be asymptomatic and can often be started on just a strategy of close observation. However, if a patient with this variant has symptoms from splenomegaly or significant cytopenias, the patient may need to start treatment immediately. Patients with conventional MCL may also have a low tumor burden and be asymptomatic at diagnosis (eg, if the disease were incidentally diagnosed due to a small lymph node in the neck), and these patients can be safely observed from the time of diagnosis.

For patients who are eligible for a watch-and-wait approach, the length of the observation period will vary: A patient may be able to go on observation for 6-12 months whereas another may remain on observation for 24 months or longer. I have placed some of my patients on observation as long as 5 years without the need for treatment. Although we can recommend this strategy of observation for a minority of our patients with MCL, most will require immediate treatment at the time of diagnosis.

For patients with MCL who need to start treatment at the time of diagnosis, we assess the patient’s age, level of fitness, and presence or absence of comorbidities to determine whether the patient is a good candidate for intensive first-line therapy, because intensive therapy generates longer remissions. Patients who are not good candidates for intensive treatment include those who are older (in their 70s or 80s) with preexisting health issues. Currently, the most commonly used treatment for these patients is bendamustine/rituximab (BR), which is very well tolerated in MCL. Recent data from the phase II ECOG-ACRIN E1411 trial presented at ASCO 2021 showed that treatment with BR induction followed by rituximab maintenance for 2 years resulted in a median progression-free survival in the 5 to 6‑year range. These data suggest that BR with rituximab maintenance is an effective regimen for patients with MCL.

In my own practice, I usually recommend BR for 6 cycles and then 2 years of maintenance rituximab for patients who are best suited for nonintensive therapy. The optimal duration of rituximab maintenance therapy is not clearly defined in this setting: Some studies have used 2 years of maintenance rituximab, other studies have used 3 years, and others have investigated indefinite maintenance rituximab. Until there are more data, I am comfortable recommending 2 years of rituximab maintenance for my patients.

It is also important to note some new studies that could change practice. We might see data at ASH 2021 from the phase III SHINE study, which enrolled patients aged 65 years or older with newly diagnosed MCL for treatment with BR and rituximab maintenance plus either the BTK inhibitor ibrutinib or placebo. For patients randomized to the ibrutinib-containing treatment arm, patients receive ibrutinib during induction and during rituximab maintenance for 2 years, and then the ibrutinib continues indefinitely until disease progression or intolerance. If the SHINE study is positive, it could change clinical practice and this regimen could become a new standard of care as treating physicians may want to incorporate BTK inhibitors into frontline treatment.

For patients who are younger, fit, and candidates for more intensive treatment, we typically recommend a combination immunochemotherapy that includes high‑dose cytarabine and rituximab followed by autologous stem cell transplantation. These more intensive treatment regimens are a significant commitment on the part of the patient—treatment is intensive and generally requires 1 year to go through all of the treatment components, and then patients will get to the point where they start to “feel good” again. Typically, these intensive therapies result in remission that can last for 7-9 years on average, with a proportion of patients remaining in remission for more than 10 years. So, even though it is an intensive therapy that may be difficult in terms of adverse events, there is hope for a payoff in the long run with a long first remission.

There are several important studies that are underway looking at incorporating novel agents into the frontline setting with these more intensive treatment approaches, and some trials are also exploring if some of the more intense chemotherapeutic agents can be removed so that the treatment is not so difficult to tolerate. Other trials are investigating whether use of measurable residual disease status can guide decisions on whether transplant can be avoided. Since intensive therapy for MCL can be quite difficult to tolerate, the idea of removing some of the agents in the treatment regimens while maintaining good outcomes is intriguing and we hope to see the results of these studies in the near future.

Treatment Considerations for Relapsed/Refractory MCL
In the relapsed setting, the first‑line treatment of choice is usually a BTK inhibitor. There are currently 3 FDA-approved BTK inhibitors—ibrutinib, acalabrutinib, and zanubrutinib—for patients with MCL who have received 1 or more previous therapies. They all work very well in relapsed MCL with high response rates and good tolerability profiles. However, the length of remission for patients receiving BTK inhibitors tends to last for approximately 1.5-2.0 years, on average. Currently, there are studies assessing combination approaches with a BTK inhibitor plus another agent to try to improve upon the durability of the response to these agents. For example, we have seen some interesting data from studies combining BTK inhibitors with a BCL2 inhibitor, like the preliminary results from the phase III SYMPATICO trial assessing ibrutinib plus venetoclax vs ibrutinib plus placebo for patients with MCL (NCT03112174).

Other reasonable treatment options for relapsed MCL include lenalidomide/rituximab and bortezomib with or without rituximab. Finally, I sometimes consider treatment with venetoclax for some patients with relapsed MCL, although it is not approved by the FDA for patients with MCL. In my experience, when venetoclax is used as a single agent in this setting, the response rates are approximately 70% to 80%, but the duration of response tends to be short.

It will also be interesting to see how some of the bispecific monoclonal antibodies and the antibody–drug conjugates pan out in this space because we need more treatment options for our patients with relapsed MCL.

CAR T-Cell Therapy
Hopefully, CAR T‑cell therapy will be a major breakthrough in MCL. The FDA recently approved brexucabtagene autoleucel, a CAR T-cell therapy directed against CD19, for relapsed/refractory MCL based on data from the ZUMA-2 trial. The objective response rate in the intention-to-treat population in ZUMA-2 at a median 17.5-month follow-up was 92%, and 67% of the patients achieved a complete response with good durability at 12 months. However, we need longer follow-up and a bigger patient experience to know what the longer-term efficacy is with this agent. As with all CAR T-cell therapy, brexucabtagene autoleucel is associated with the risk for cytokine-release syndrome and neurologic toxicity, so treatment with this agent is not without some risk. However, relapsed MCL has historically been a difficult disease to manage, and therefore, we can accept a certain amount of toxicity for an agent with good efficacy, particularly for those with potential for long-term response. I am excited about CAR T‑cell therapy for patients with MCL and I am hopeful that the data will hold up with time. As we develop additional CAR T‑cell products, I hope that we will continue to find ways to improve even more upon the response rate, duration of response, and safety profile.

Your Thoughts?
What questions do you have on managing patients with MCL?

Do you want to learn more about optimizing the care of patients with MCL? Sign up here to attend the live symposium or simulcast webinar, “A Class in Session: Understanding Current and Future Therapeutic Advances Across B-Cell Lymphomas” on Friday, December 10, 2021, at 7:00 PM Eastern time with me and my colleagues, John P. Leonard, MD, and Julie M. Vose, MD, MBA, when we will discuss the available evidence, key ongoing clinical issues, and new data in various B-cell lymphomas.

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