Chemotherapy-Free Approaches in Follicular and Mantle Cell Lymphomas

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As chemotherapy and chemoimmunotherapy regimens reach their maximal impact in follicular lymphoma and mantle cell lymphoma, clinicians are turning to chemotherapy-free approaches to achieve better control, less toxicity, and (hopefully) a cure. During the ASCO20 Virtual Education Program, Sonali M. Smith, MD, FASCO, Elwood V. Jensen Professor in Medicine, Interim Chief of Hematology/Oncology, and Director of the Lymphoma Program at the University of Chicago, discussed the recent “flurry of developments” in noncytotoxic regimens, including U.S. Food and Drug Administration (FDA) approvals and new compendia listings.1

Treatment-Naive Follicular Lymphoma

According to Dr. Smith, follicular and mantle cell lymphomas share the unfavorable distinction of being incurable, but follicular lymphoma can often be managed for decades. At some point, however, the majority of patients will require therapy, and their course is subsequently marked by a number of relapses and remissions.

“It’s quite clear there are excellent outcomes, and lenalidomide plus rituximab has been listed as another option for patients in the front-line setting [for follicular lymphoma].”
— Sonali M. Smith, MD, FASCO

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Nevertheless, there are chemotherapy-free options available at the earliest stage of treatment. Published in 2018, the RELEVANCE trial, a head-to-head, randomized, phase III comparison of chemoimmunotherapy against lenalidomide plus rituximab, showed no difference between the two study arms.2

“Although this was technically a negative study, in that the chemotherapy-free arm did not show superiority, it’s quite clear there are excellent outcomes, and lenalidomide plus rituximab has been listed as another option for patients in the front-line setting,” said Dr. Smith.

Building on this approach, investigators conducted a single-arm, phase II study of lenalidomide plus the type II monoclonal antibody obinutuzumab in place of rituximab, in patients with previously untreated, advanced-stage follicular lymphoma.3 With a median follow-up of 25 months, the 2-year progression-free estimate was 96%, with a 92% complete response rate.

“Clearly, the follow-up is quite short, and we need more mature evaluation as well as a comparison against other standard-of-care options, but these results are certainly encouraging,” said Dr. Smith.

Relapsed or Refractory Follicular Lymphoma

In the setting of relapsed or refractory follicular lymphoma, the FDA has approved three classes of agents: PI3K inhibitors, immunomodulatory agents, and an EZH2 inhibitor.

PI3K Inhibitors: There are currently three FDA-approved PI3K inhibitors: idelalisib4 (delta inhibitor); copanlisib5 (alpha-delta inhibitor); and duvelisib6 (gamma-delta inhibitor). The trials that led to approvals of these agents all focused on an area of unmet need: patients with highly relapsed or refractory follicular lymphoma, many of whom had double-refractory disease.

These patients were also significantly resistant to therapy and refractory to their most recent regimens. Many had been diagnosed within the past few years, suggesting a pace of disease that is significantly quicker than that of the typical patient with follicular lymphoma, Dr. Smith commented. Nevertheless, the overall response rate to these agents was between 40% and 60%, with a median duration of response between 10 and 14 months.

“Whether or not ibrutinib/venetoclax could be a backbone for other chemotherapy-free approaches or not [in mantle cell lymphoma] is being tested prospectively.”
— Sonali M. Smith, MD, FASCO

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Although the toxicity is a limitation for combination therapy for some of these agents, said Dr. Smith, there are ongoing trials with both copanlisib and duvelisib in combinations.

Immunomodulatory Agents: AUGMENT, a randomized phase III trial of lenalidomide and rituximab vs placebo and rituximab in the relapsed setting of follicular lymphoma, led to approval of the first immunomodulatory agent. Of note, said Dr. Smith, all patients had rituximab-sensitive disease.

The progression-free survival for lenalidomide and rituximab was 39.4 months vs 14 months for placebo and rituximab.7 Although there was no statistically significant difference in overall survival, a trend was observed over time, she added, and more follow-up will be helpful.

“Many of us have used rituximab monotherapy in the relapsed setting, and this is one of the first prospective data sets in a randomized setting to show these outcomes,” stated Dr. Smith.

EZH2 Inhibitor: Tazemetostat, a first-in-class oral inhibitor of EZH2 with antitumor activity, was recently approved based on data from a phase II trial in relapsed or refractory follicular lymphoma in a population stratified by mutation status.8 Patients with a mutated EZH2 phenotype had a response rate of 69%, a complete response rate of 13%, a duration of response of 10.9 months, and a median progression-free survival of 13.8 months.

Although these results are better than those in the wild-type group, noted Dr. Smith, there were also responses in the latter.

Treatment-Naive Mantle Cell Lymphoma

As Dr. Smith explained, clinicians stratify patients with mantle cell lymphoma by whether they are fit or unfit. Historically, patients who are young and healthy have received intensive chemotherapy induction, followed by an autologous stem cell transplant with or without maintenance rituximab. Patients who are unfit, on the other hand, are typically given chemoimmunotherapy with or without maintenance rituximab.

“A major question is whether or not the intensive approach we have for our fit patients with mantle cell lymphoma is truly required or is there an opportunity for us to use less-intensive treatments, including chemotherapy-free regimens,” asked Dr. Smith.

A small, phase II, multicenter study of lenalidomide and rituximab focused on 38 patients (median age, 65) with mostly a good performance status (one-third had high-risk disease based on the Mantle Cell Lymphoma International Prognostic Index). The investigators demonstrated an overall response rate of 87%, with a complete response rate of 61%.9

“With a median follow-up of 64 months, the median progression-free survival and the duration of response have not yet been reached, provocatively raising the point as to whether or not a chemo-free approach could be fruitful in fit patients or whether or not it could be expanded to patients with treatment-naive mantle cell lymphoma,” Dr. Smith commented.

Other chemotherapy-free approaches have attempted to build on the lenalidomide/rituximab combination with agents that are already approved in the relapsed or refractory setting, including acalabrutinib, venetoclax, and ibrutinib. As Dr. Smith reported, a phase II study of ibrutinib and rituximab recently showed that minimal residual disease (MRD) negativity was feasible in the front-line setting with this combination. However, approximately 50% of patients needed a dose reduction of ibrutinib for treatment-related toxicity.

Relapsed or Refractory Mantle Cell Lymphoma

For relapsed or refractory mantle cell lymphoma, most chemotherapy-free approaches build upon BTK inhibition with ibrutinib. This agent was approved by the FDA in this setting and has yielded an overall response rate of 68%, a “modest” complete response rate of 21%, and a duration of response of 17.5 months.

The first approach, said Dr. Smith, is to add an anti-CD20 monoclonal antibody such as rituximab. A phase II trial of ibrutinib and rituximab showed an improvement in complete response rate (58%) and median progression-free survival (43 months).10

According to Dr. Smith, the combination of ibrutinib and venetoclax has also demonstrated “encouraging activity.” Despite half of patients having a TP53 deletion or mutation, and nearly half being refractory to their most recent regimen, continuous dosing of ibrutinib and venetoclax in this setting showed a high overall response rate, including a 67% complete response rate and a very high MRD-negativity rate.11

“Whether or not ibrutinib/venetoclax could be a backbone for other chemotherapy-free approaches or not is being tested prospectively,” said Dr. Smith. “Comparative trials will also be helpful to determine whether or not this should be the standard approach for patients who have relapsed and refractory mantle cell lymphoma.”

Finally, a new-generation BTK inhibitor, zanubrutinib, was recently approved for use in this setting. The data on which this approval is based come from a phase II study showing an overall response rate of 84%, a complete response rate of 69%, and a duration of response of 19.5 months.12 The toxicity profile of zanubrutinib monotherapy also appears to be favorable, according to Dr. Smith.

Chemotherapy-Free, Not Toxicity-Free

Despite the encouraging activity of these noncytotoxic regimens, Dr. Smith emphasized there are also unique toxicities. Chemotherapy-free does not necessarily equate to toxicity-free, she noted.

“In my mind, a chemotherapy-free approach must meet a certain bar: It must provide high-quality remission, durable response without indefinite treatment, improvement in the duration and quality of life, and reduction in both short- and long-term toxicities. And, hopefully, it moves us closer to a cure where chemotherapy has failed,” Dr. Smith concluded. 

DISCLOSURE: Dr. Smith has served as a consultant or advisor to AbbVie/Genentech, Bayer, Celgene, Janssen Oncology, Kite Pharma, Seattle Genetics, and TG Therapeutics; has received research funding from Acerta Pharma/AstraZeneca, Celgene, Forty Seven, Novartis, Pharmacyclics/Janssen, Portola Pharmaceuticals, and TG Therapeutics; and has held other relationships with Karyopharm Therapeutics.


1. Smith SM: Chemotherapy-free approaches in follicular lymphoma and mantle cell lymphoma. ASCO20 Virtual Education Program.

2. Morschhauser F, Fowler NH, Feugier P, et al: Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med 379:934-947, 2018.

3. Morschhauser F, Le Gouill S, Feugier P, et al: Obinutuzumab combined with lenalidomide for relapsed or refractory follicular B-cell lymphoma (GALEN): A multicentre, single-arm, phase II study. Lancet Haematol 6:e429-e437, 2019.

4. Salles G, Schuster SJ, de Vos S, et al: Efficacy and safety of idelalisib in patients with relapsed, rituximab- and alkylating agent-refractory follicular lymphoma: A subgroup analysis of a phase II study. Haematologica 102:e156-e159, 2017.

5. Dreyling M, Morschhauser F, Bouabdallah K, et al: Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol 28:2169-2178, 2017.

6. Flinn IW, Miller CB, Ardeshna KM, et al: DYNAMO: A phase II study of duvelisib (IPI-145) in patients with refractory indolent non-Hodgkin lymphoma. J Clin Oncol 37:912-922, 2019.

7. Leonard JP, Trneny M, Izutsu K, et al: AUGMENT: A phase III study of lenalidomide plus rituximab vs placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 37:1188-1199, 2019.

8. Hoy SM: Tazemetostat: First approval. Drugs 80:513-521, 2020.

9. Ruan J, Martin P, Christos P, et al: Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood 132:2016-2025, 2018.

10. Jain P, Romaguera J, Srour SA, et al: Four-year follow-up of a single arm, phase II clinical trial of ibrutinib with rituximab in patients with relapsed/refractory mantle cell lymphoma. Br J Haematol 182:404-411, 2018.

11. Tam CS, Anderson MA, Pott C, et al: Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med 378:1211-1223, 2018.

12. Yang H, Xiang B, Song Y, et al: Zanubrutinib monotherapy for patients with relapsed or refractory non-germinal center diffuse large B-cell lymphoma: Results from a phase II, single-arm, multicenter, study. Presented at the ASCO Virtual Scientific Program. Abstract e20051.