Initial Therapy for Asymptomatic Follicular Lymphoma: Start With Watch and Wait or Rituximab

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For patients with indolent follicular lymphoma, generally take a conservative approach to treatment unless the patient is symptomatic, advised John P. Leonard, MD, Executive Vice-Chair of Weill Department of Medicine at Weill-Cornell Medicine/NewYork-Presbyterian, New York.1 “Prognostic scores are helpful but don’t really define the need for therapy or the specific type of therapy,” Dr. Leonard said at the virtual 2020 Chemotherapy Foundation ­Symposium.1

John P. Leonard, MD

John P. Leonard, MD

For example, the Follicular Lymphoma International Prognostic Index (FLIPI) may argue for more intensive therapy according to the presence or absence of risk factors, “but FLIPI itself won’t necessarily help you decide which therapy to use,” Dr. Leonard explained. The M7 FLIPI is a refinement of FLIPI that incorporates molecular features to help categorize patients as higher risk or not, but this tool is not typically used in practice yet, he noted.

General Framework

Dr. Leonard finds the Groupe d’Etude des Lymphomes Folliculaire (GELF) criteria more useful in deciding which patients to treat.2 Patients with a high tumor bulk (defined by one of five criteria [ie, tumor > 7 cm, three nodes in three distinct areas > 3 cm, symptomatic splenic enlargement, organ compression, ascites or pleural effusion]), the presence of systemic symptoms, and abnormally high serum lactate dehydrogenase or beta-2 microglobulin levels suggest the need for treatment.

Considerations are similar in selecting therapy for patients with follicular lymphoma at diagnosis and at relapse. They include indications for therapy, bulk of disease, comorbidities, toxicity concerns, interest in and availability of clinical trials, risk of transformation, and grade. “Typically, I treat grades 1, 2, and 3A similarly,” Dr. Leonard shared.

“Our general framework for localized disease is that radiation or watch and wait is typically recommended; for symptomatic advanced-stage disease, options are rituximab alone, rituximab/chemotherapy, ­obinutuzumab/chemotherapy, or possibly no chemotherapy with a lenalidomide/rituximab–based approach,” Dr. Leonard told listeners.

“Our treatments will improve progression-free survival, but the impact on overall survival with more intensive therapy is unclear,” he stated. “I’ve had patients relapse 20 years later or a few days later. The concept of cure is complex, even in the limited-stage disease setting,” he said.

“I’ve had patients relapse 20 years later or a few days later. The concept of cure is complex.”
— John P. Leonard, MD

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A recent trial compared involved-field radiation therapy plus rituximab added to cyclophosphamide/vincristine/prednisolone (CVP) vs involved-field radiation therapy alone in 150 patients with limited stage I and II follicular lymphoma.3 At a median follow-up of 9.6 years, the 10-year progression-free survival was 59% vs 41%, respectively. However, the 10-year overall survival rate was similar, 87% and 95%, ­respectively.

“Patients like this can have a long remission, and if they have a relapse in 5 or 10 years or longer, they will need additional therapy. Because long-term survival is similar, the decision is complicated. You could perform radiation therapy or watch and wait. My approach is that watch and wait is acceptable, particularly if there is no suspicion of disease elsewhere or, alternatively, a low chance of needing therapy soon, such as resected low-volume disease or older age,” Dr. Leonard continued. “Radiation therapy is most commonly used, however, and dependent on location and size.”

“In general, we have not yet adapted combined-modality therapy [as initial treatment], because we are not sure of the relative value of systemic treatment early vs later at relapse,” he noted.

“Do not overemphasize the concept of ‘cure’ vs ‘functional cure,’ given the favorable long-term prognosis for follicular lymphoma. Most patients [with follicular lymphoma] won’t die of their disease,” Dr. Leonard told listeners.

Advanced-Stage Disease

A study in advanced-stage, low tumor burden, asymptomatic follicular lymphoma compared rituximab vs watch-and-wait.4 The study did not show an overall survival benefit for rituximab but concluded that rituximab could be a treatment option for this group of patients.

Dr. Leonard said that for patients with advanced-stage follicular lymphoma with a low tumor burden, he favors a watch-and-wait approach, “at least for enough time to allow assessment of the pace of disease over time.” If the patient desires therapy but has few symptoms, Dr. Leonard may treat with four cycles of rituximab with no maintenance therapy. For patients who prefer a longer remission and are willing to have greater efficacy, even if there is more toxicity, chemotherapy or emerging combinations such as lenalidomide/rituximab are options. “The latter choice is made by a minority of patients,” he added.

Bendamustine/rituximab vs cyclophosphamide/doxorubicin/vincristine/prednisone/rituximab (R-CHOP) was compared in a randomized, open-label trial of 549 patients with indolent or mantle cell lymphoma.5 The study found that the bendamustine arm achieved significantly longer progression-free survival compared with R-CHOP: 69.5 months vs 31.2 months, respectively (P < .0001), and it was better tolerated with fewer toxicities. The study concluded that bendamustine plus rituximab was a preferred first-line option, in part due to better ­tolerability.

Maintenance rituximab after R-CHOP or R-CVP induction therapy improved progression-free survival in patients with follicular lymphoma and a high tumor burden in the PRIMA phase III study, but there was no difference with or without maintenance rituximab in 10-year overall survival.6 The authors stated that more than half of the patients receiving rituximab maintenance therapy were progression-free, with no requirement for treatment beyond 10 years.

“One option is to reserve single-agent rituximab at disease progression,” Dr. Leonard said.

In the GALLIUM study, obinutuzumab plus chemotherapy was compared with rituximab plus chemotherapy and as maintenance therapy in the first line treatment of 1,202 patients with previously untreated advanced follicular lymphoma.7 A modest progression-free survival advantage was observed with obinutuzumab vs rituximab, but there was no difference in overall survival. High-grade adverse events were also more common with obinutuzumab.

“Obinutuzumab is now an option. In this study, it didn’t matter what type of chemotherapy was used—CHOP, CVP, or bendamustine,” Dr. ­Leonard pointed out. “Some people favor bendamustine/rituximab over bendamustine/obinutuzumab in relation to infection profile.”

Another option is the combination of lenalidomide/rituximab, based on the international, phase III trial called RELEVANCE; it compared this combination vs chemotherapy/rituximab in 1,030 patients with advanced untreated follicular lymphoma.8 Efficacy was similar, but the toxicity profile was different in the two treatment arms. The trade-off with lenalidomide vs chemotherapy is less neutropenia and fewer infections but more rash, fatigue, and gastrointestinal side effects.

“For high tumor burden follicular lymphoma, I tend to use bendamustine/rituximab. This combination has less toxicity and similar efficacy compared with R-CHOP. Maintenance rituximab is of limited value, but I offer it in some cases. The combination of lenalidomide and rituximab also is of value but is not superior. Obinutuzumab is of limited value, and a survival advantage is not clear,” he said.

“Minimize surveillance in asymptomatic patients and encourage ‘return to normalcy’ as much as possible.”
— John P. Leonard, MD

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“I tend not to do frequent surveillance imaging scans  because most patients won’t recur within the next 5 years. Don’t go crazy looking for disease progression in patients feeling well because most disease progression is symptomatic,” Dr. Leonard advised.

Follow-up should be tailored to the risk of relapse, based on the extent of prior disease, complete response to partial response to initial therapy, and the potential for transformation. Initially, periodic history, physical exams, and lab tests are advised every 4 to 6 months, with longer intervals becoming more appropriate over time. “Minimize surveillance in asymptomatic patients and encourage ‘return to normalcy’ as much as possible,” Dr. Leonard recommended.

Dr. Leonard posed the following key questions regarding the initial management of follicular ­lymphoma:

  • What will it take to dislodge watch and wait? Trials showing a survival benefit, clear quality-of-life benefit, evidence of “cure”?
  • How will we define “cure”? Some “cured” patients relapse 15 years later. Perhaps “functional cure” should be the goal.
  • How can we better characterize and choose individual quality-of-life targeted therapy?
  • Can we move to risk-adapted treatment for induction, consolidation, and maintenance (based on molecular features, more sophisticated ­imaging)?

DISCLOSURE: Dr. Leonard has served as a consultant or advisor to AbbVie, ADC Therapeutics, Akcea, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Epizyme, Genentech/Roche, Genmab, Gilead Sciences, Incyte, Karyopharm Therapeutics, MEI Pharma, Merck, Miltenyi, Morphosys, Nordic Nanovector, Regeneron, Sandoz, and Sutro; has received institutional research funding from the Alliance for Clinical Trials in Oncology, Celgene, Epizyme, Janssen Oncology, the National Cancer Institute, Pfizer, and Takeda; and has been reimbursed for travel, accommodations, or other expenses by BeiGene.


1. Leonard J: How to pick front-line therapy for low-grade lymphoma. 2020 Chemotherapy Foundation Symposium. Presented November 4, 2020.

2. Nastoupil L, Sinha R, Hirschey A, et al: Considerations in the management of follicular lymphoma. Community Oncol 9:S53-S60, 2012.

3. MacManus M, Fisher R, Roos D, et al: Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol 36:2918-2925, 2018.

4. Ardeshna KM, Qian W, Smith P, et al: Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: An open-label randomised phase 3 trial. Lancet Oncol 15:424-435, 2014.

5. Rummel MJ, Niederle N, Maschmeyer G, et al: Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle cell lymphomas. Lancet 381:1203-1210, 2013.

6. Salles GA, Seymour JF, Feugier P, et al: Long-term follow-up of the PRIMA study. 2017 ASH Annual Meeting and Exposition. Abstract 486.

7. Marcus R, Davies A, Ando K, et al: Obinutuzumab for first-line treatment of follicular lymphoma. N Engl J Med 377:1331-1344, 2017.

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