expert roundtables

Chemotherapy‐Free Treatment Options in Relapsed Mantle Cell Lymphoma

by Christopher Flowers, MD, MS; Anita Kumar, MD; and John P. Leonard, MD

Overview

There is great hope that chemotherapy-free strategies may become the mainstay of frontline mantle cell lymphoma (MCL) treatment over the next decade. Today, chemotherapy-free regimens are already preferred for most patients with MCL in the relapsed setting. Bruton tyrosine kinase (BTK)–based therapy is most commonly used, while lenalidomide-based treatment is another option.

Q:

What is the current role of chemotherapy-free treatment in patients with relapsed/refractory MCL?

Anita Kumar, MD

Regional Care Network Medical Site Director
Basking Ridge, NJ
Assistant Attending
Department of Medicine, Lymphoma Service
Memorial Sloan Kettering Cancer Center
New York, NY

“In the relapsed setting, chemotherapy-free treatment strategies are now preferred for nearly all patients with MCL, particularly those with TP53 mutation.”

Anita Kumar, MD

The MCL treatment landscape has changed in recent years with the introduction of novel targeted therapies. In the relapsed setting, chemotherapy-free treatment strategies are now preferred for nearly all patients with MCL, particularly those with TP53 mutation. Data from the Nordic Lymphoma Group suggest that these patients are not well served by intensive immunochemotherapy in the frontline and relapsed settings. Eskelund et al examined the prognostic value of genetic aberrations in diagnostic bone marrow specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 studies. The authors concluded that those with TP53 mutations appear to have a phenotypically distinct and highly aggressive form of MCL, with poor or no response to regimens that include cytarabine, rituximab, and autologous stem cell transplantation. 

In general, we would favor novel therapeutic approaches for patients with MCL in the relapsed setting. BTK inhibition has emerged as a standard treatment approach for relapsed MCL. Many clinical trials are actively studying BTK inhibition in combination with other biologically targeted agents, such as BCL2 inhibitors, PI3K inhibitors, and CDK4/6 inhibitors. These combinations may increase the depth and durability of response in the relapsed setting. Patients with relapsed/refractory MCL and TP53 mutation can have responses to BTK inhibition; however, the depth and duration of response are quite limited. In addition to combinatorial approaches, there are also emerging novel immunotherapies, such as chimeric antigen receptor (CAR) T cells or bispecific antibody therapies, that may be associated with more durable responses, even in the highest-risk patients with MCL. 

Christopher Flowers, MD, MS

Chair, Department of Lymphoma/Myeloma
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, TX

“BTK inhibitors have become the most commonly used and most appropriate second-line therapy in the relapsed setting for patients with MCL.”

Christopher Flowers, MD, MS

We have moved into a new era of chemotherapy-free approaches to the treatment of patients with MCL who relapse or become refractory to treatment. In the past, we would have thought of giving chemotherapy for induction and then chemotherapy again in relapse, but that is no longer the case in most instances. Thus, we really have moved to a chemotherapy-free era in the relapsed setting. BTK inhibitors have become the most commonly used and most appropriate second-line therapy in the relapsed setting for patients with MCL. These include the first-generation BTK inhibitor ibrutinib, as well as the second-generation BTK inhibitors acalabrutinib and zanubrutinib. Other options, including bortezomib, lenalidomide, and other small molecules, are used less frequently. Chemotherapy is still a potential option for this patient population, but nonchemotherapy approaches are now being used with increased frequency for MCL in the relapsed setting. CAR T-cell therapy and other novel approaches are currently under evaluation and may be available in the near future, but these are still investigational approaches as of now. The US Food and Drug Administration and the European Medicines Agency have not yet approved these treatments for MCL.

John P. Leonard, MD

The Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Professor of Medicine
Executive Vice-Chairman, Department of Medicine
Senior Associate Dean for Innovation and Initiatives
Weill Cornell Medicine
Attending Physician, NewYork-Presbyterian Hospital
New York, NY

“We have to consider whether the patient is better served by a chemotherapy-free approach that may be long-term or a chemotherapy-based approach that has a finite treatment duration.

John P. Leonard, MD

Chemotherapy-free approaches may have a role in some upfront settings as well as in relapsed settings. Whether these approaches are better than chemotherapy in terms of response rates and toxicities, and better for certain patients, is the focus of ongoing investigation. We now have several BTK inhibitors approved for the treatment of patients with MCL. At this point, I do not believe that we have strong evidence that the BTK inhibitors differ meaningfully in efficacy in the treatment of MCL. Although there are theoretical reasons for potential differences that we might see in efficacy, these are not well established. The toxicity profiles are a bit variable in some ways, and that may influence how specific BTK inhibitors are chosen for a specific individual patient.

Another consideration is that, at this point, chemotherapy-free approaches are primarily BTK inhibitor based or lenalidomide based, and some of the important questions relate to risk-benefit considerations and trade-offs at the patient level. For example, how is quality of life impacted in those receiving these regimens on a chronic basis? We have to consider whether the patient is better served by a chemotherapy-free approach that may be long-term or a chemotherapy-based approach that has a finite treatment duration. With respect to the investigational agents and combinations, these are considered most frequently for patients with multiple relapses, but there are no firm guidelines that would steer us toward any specific trial at this time.

References

Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903-1910. 

Jain P, Wang M. Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management. Am J Hematol. 2019;94(6):710-725.

Ladha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its management: where are we now? Exp Hematol Oncol. 2019;8:2. 

Paydas S. Management of adverse effects/toxicity of ibrutinib. Crit Rev Oncol Hematol. 2019;136:56-63.

Rule S. The modern approach to mantle cell lymphoma. Hematol Oncol. 2019;37 suppl 1:66-69. 

Wang M, Rule S, Zinzani PL, et al. Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma. Leukemia. 2019;33(11):2762-2766.

More in Mantle Cell Lymphoma

Thumb

Mantle Cell Lymphoma

Exploring the Potential Use of Chimeric Antigen Receptor T-Cell Therapy to Treat Mantle Cell Lymphoma

Patient Care Perspectives by Brad Kahl, MD

Preliminary reports suggest that chimeric antigen receptor (CAR) T-cell therapy may be a useful option for the treatment of patients with relapsed ...READ MORE

Thumb

Mantle Cell Lymphoma

Management of Toxicities in Patients Being Treated for Mantle Cell Lymphoma

Patient Care Perspectives by Thomas J. Kipps, MD, PhD

Consideration of patient characteristics and the toxicity profiles of individual agents provides a rational approach to managing treatment-related ...READ MORE

Thumb

Mantle Cell Lymphoma

Potential Role of BCL-2 Inhibition in the Treatment of Mantle Cell Lymphoma

Clinical Topic Updates by Brad Kahl, MD

BCL-2 inhibition may represent a promising strategy for overcoming resistance to conventional therapies in patients with mantle cell lymphoma (MCL).READ MORE

More In Oncology

MDS & AML

Emerging Immuno Myeloid Therapies In Mds And Aml

Expert Roundtables by Andrew M. Brunner, MD; Courtney D. DiNardo, MD, MSCE; and Rami S. Komrokji, MD

MDS & AML

Improving Response Durability In High Risk Mds And Aml

Expert Roundtables by Andrew M. Brunner, MD; Courtney D. DiNardo, MD, MSCE; and Rami S. Komrokji, MD

MDS & AML

Integrating Genomics Into The Classification And Management Of Mds

Expert Roundtables by Andrew M. Brunner, MD; Courtney D. DiNardo, MD, MSCE; and Rami S. Komrokji, MD