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Research Perspectives: Chemotherapy-Free Initial Therapy for Older Patients With Mantle Cell Lymphoma

by Brad Kahl, MD; John P. Leonard, MD; and John M. Pagel, MD, PhD

Overview

Less intense treatment regimens may be important frontline options for older patients with mantle cell lymphoma (MCL). Investigational chemotherapy-free induction regimens for MCL have shown promise, although further study is needed.

Q:

Has there been any news on the development of chemotherapy-free frontline regimens for older/unfit patients?

Brad Kahl, MD

Professor of Medicine, Division of Oncology
Washington University School of Medicine
Director, Lymphoma Program
Alvin J. Siteman Cancer Center
Saint Louis, MO

“Data on chemotherapy-free initial treatment for MCL are limited right now, but what we do have look promising." 

Brad Kahl, MD

There are lower-intensity regimens such as bendamustine and rituximab that are well tolerated in older patients; however, the options for chemotherapy-free initial treatment in MCL are relatively few. Looking to clinical trials, probably the most impressive data that have been published to date would be with lenalidomide-rituximab, which Dr Leonard could likely elaborate on, since his center was the lead site for that trial. It was a phase 2 study in patients who were not candidates for transplantation, and the response rates were good. What was most impressive to me was the durability of the responses, with the majority of patients still holding their remissions after 3 and 4 years.

There are also some impressive early data for Bruton tyrosine kinase (BTK) inhibitors used in the frontline setting. BTK inhibition is generally well tolerated, and, although complete responses are infrequent, the pairing of a BTK inhibitor with rituximab seems to deepen the responses somewhat. The toxicity profile of ibrutinib-based therapy in elderly patients includes cases of new-onset atrial fibrillation, so it is important to remember that chemotherapy free is not toxicity free. Having said that, we now have second-generation BTK inhibitors such as acalabrutinib and zanubrutinib that are likely to be tested in frontline chemotherapy-free settings. And, presumably, these agents will be better tolerated than ibrutinib-based regimens. Thus, data on chemotherapy-free initial treatment for MCL are limited right now, but what we do have look promising.

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

“For these older patients who are not transplant candidates, bendamustine plus rituximab is a standard treatment that is fairly well tolerated by most.”

John P. Leonard, MD

We recently updated our data on frontline lenalidomide-rituximab in MCL, and approximately 60% of patients were still in remission after a median follow-up of approximately 7 years. This was a smaller study, but this regimen worked better than we thought it would. Thus, 7 years later, we still have some patients on this same therapy that we use pretty much indefinitely in those with relapsed/refractory MCL. For these older patients who are not transplant candidates, bendamustine plus rituximab is a standard treatment that is fairly well tolerated by most. Favorable 5-year progression-free survival rates were reported in the BRIGHT study.

Our experience with these novel oral agents (eg, BTK inhibitors, lenalidomide) comes from the relapsed and refractory MCL setting, where we use these agents indefinitely until progression. And so, there are a number of questions that arise with frontline combination therapy, including questions regarding the duration of treatment (eg, would it be indefinite?). Additionally, we do not yet know whether these combinations are better than chemoimmunotherapy, and the toxicities of novel agent combinations may be challenging for some older patients. Each treatment approach comes with its own questions, including how long to use it and how it compares with other treatments. All things considered, I think that the quality-of-life aspect is critical, and that is something that is difficult to compare across studies.

John M. Pagel, MD, PhD

Chief of Hematologic Malignancies
Center for Blood Disorders and Stem Cell Transplantation

Swedish Cancer Institute

Seattle, WA


“It is important to remember that maintaining quality of life is an important goal in this patient population.”

John M. Pagel, MD, PhD

One of the factors that we remain mindful of when considering older patients with MCL is that fitness is often more of a decision driver than biologic age. I think that most people are able and fit enough to tolerate some amount of a chemoimmunotherapy regimen such as bendamustine and rituximab, although bendamustine might be given at a lower dose and in a reduced number of cycles in those who are less fit.

It is also important to remember that maintaining quality of life is an important goal in this patient population. We are generally palliating these patients, not pursuing autologous stem cell transplantation. We are looking to keep them happy and healthy for as long as possible. Many of these patients do very well with more conservative approaches in frontline settings, including those with more indolent, non-nodal MCL. Our goal with these individuals is to provide significant survival outcomes so that they can continue to enjoy very safe, healthy, and active lifestyles. 

References

Flinn IW, van der Jagt R, Kahl B, et al. First-Line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019;37(12):984-991. doi:10.1200/JCO.18.00605

Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. doi:10.1186/s13045-020-00914-1

Jain P, Lee HJ, Steiner RE, et al. Frontline treatment with ibrutinib with rituximab (IR) combination is highly effective in elderly (≥65 years) patients with mantle cell lymphoma (MCL) - results from a phase II trial. Blood. 2019;134(suppl 1):3988. doi:10.1182/blood-2019-125800

Ruan J. Approach to the initial treatment of older patients with mantle cell lymphoma. Hematol Oncol Clin North Am. 2020;34(5):871-885. doi:10.1016/j.hoc.2020.06.005

Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132(19):2016-2025. doi:10.1182/blood-2018-07-859769

Ruan J, Martin P, Shah B, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835-1844. doi:10.1056/NEJMoa1505237

Yamshon S, Martin P, Shah B, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma (MCL): 7-year analysis from a multi-center phase II study [abstract 704]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

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