Choosing the Optimal Frontline Approach for Low-Grade Follicular Lymphoma

John P. Leonard, MD

Frontline treatment decisions for patients with follicular lymphoma can be guided by a general framework, according to John P. Leonard, MD, who added that the choice of therapy is often based on the consideration of several factors such as indications of therapy, bulk of disease, comorbidities, and toxicity, among others.¹

In a presentation during the 38th Annual CFS® virtual conference, Leonard, a senior associate dean for Innovation and Initiatives, executive vice chairman of the Department of Medicine, and The Richard T. Silver Distinguished professor of Hematology and Medical Oncology at Weill Cornell Medicine, noted that several treatment options are available for patients at varying stages of disease.

For example, localized disease can be treated with either a watch-and-wait approach or radiotherapy, while a watch-and-wait approach or rituximab (Rituxan) can be used for advanced indolent disease. For patients with advanced disease who are symptomatic, treatment typically consists of either rituximab plus chemotherapy, obinutuzumab (Gazyva) plus chemotherapy, or a chemotherapy-free regimen.²

Several tools can be used to help choose the right treatment for the right patient, according to Leonard. For example, the Follicular Lymphoma International Prognostic index (FLIPI) can be used as a prognostic tool for patients with newly diagnosed follicular lymphoma, although Leonard cautioned against selecting a frontline treatment based on FLIPI alone.

“Some might argue that a more intensive approach might be a little bit better in a higher-risk patient, but patients who have high-risk disease could still be watched or treated less aggressively in some cases. On the other hand, some might argue that low-risk patients could have long remission with more intensive therapy,” explained Leonard. “However, generally speaking, FLIPI in and of itself is not going to decide what therapy you’re going to use or how you’re going to approach [treatment]…Prognostic scores are helpful but not really defining of the need for therapy in and of themselves.”

Other factors that help to determine which patients with follicular lymphoma are in need of treatment include high tumor bulk, presence of systemic symptoms, rapid disease progression in the preceding 3 months, life-threatening organ involvement, renal or liver infiltration, and bone lesions, among others, as specified by both the Groupe d’Etude des Lymphomes Folliculaires and British National Lymphoma Investigation criteria.^3,4

Initial Treatments for Limited-Stage Disease

For limited-stage follicular lymphoma, if a patient shows signs of metastatic disease or they have a low possibility of requiring immediate therapy, as can be seen in some older patients or those with resected low-volume disease, a watch-and-wait approach can be acceptable, according to Leonard. Radiation could be another option for this patient population, depending on the size and location of their tumors.

One study published in the Journal of Clinical Oncology in 2018 examined the efficacy of systemic therapy following involved-field radiotherapy (IFRT) in patients with stage I or II low-grade follicular lymphoma.⁵ In the study, patients were randomized to receive IFRT alone (arm A) or in combination with cyclophosphamide, vincristine, and prednisolone (CVP; arm B). From 2006, rituximab was added to arm B.

After a median follow-up of 9.6 years, the progression-free survival (PFS) was found to be superior in arm B (HR, 0.57; 95% CI, 0.34-0.95; P -.033). Additionally, the 10-year PFS rate was 59% in arm B versus 41% in arm A. Overall survival (OS) rates were similar in both arms, according to Leonard; the OS rates were 95% versus 87% in arm B and arm A, respectively.

“What we do, whether it’s more or less intensive, will improve PFS,” said Leonard. “Adding chemotherapy to radiation therapy will improve PFS. However, the concept of OS impact is still unclear. We don’t have any clear evidence that OS is improved by using more intensive therapy in [patients with] limited-stage disease.”

Combined modality therapies have not generally been used in patients with limited-stage disease, as the value of this approach in early- versus later-lines of treatment remains unclear in the case of relapse, according to Leonard. Efforts are being dedicated to determining whether a short course of rituximab will be beneficial compared with an early chemotherapy-based combined modality regimen. Leonard also emphasized that the concept of a cure within this setting is a bit complicated.

“While we talk about cure in these patients based on long-term, 10- or 20-year remissions, I’ve had patients relapse 20 years later,” Leonard said. “We have to be honest that the concept of curing these patients is complex because they can have long remissions and still recur a few decades later.”

Approaches for Advanced Follicular Lymphoma With Low Tumor Burden

A watch-and-wait strategy is encouraged for patients who have advanced disease with a low tumor burden, according to Leonard. “[This approach provides] some time to allow a patient to understand their disease and for me to get a sense of pace over time,” noted Leonard. Single-agent rituximab can serve as another option if one wants to do without maintenance therapy and experience minimal adverse effects (AEs).

Rituximab monotherapy has been shown to result in a median PFS of 23.5 months (95% CI, 13.6-36.37) with an OS rate of 91.7% in patients with advanced stage, low-tumor-burden disease.⁶ “Single-agent rituximab is a reasonable option for patients with some symptoms or minimal disease indications for therapy,” Leonard explained.

In the RESORT study, patients with previously untreated low-tumor burden disease were given 4 doses of rituximab. Patients who responded to treatment were randomized to either re-treatment with rituximab or maintenance rituximab.⁷ At a median follow-up of 4.5 years, results showed an estimated median time to treatment failure of 3.9 years in patients who were re-treated with rituximab compared with 4.3 years in those who were given maintenance rituximab.

Chemoimmunotherapy or other emerging combinations, such as lenalidomide (Revlimid) plus rituximab, could also be an approach for patients who prefer a longer remission although this is associated with some toxicity. “You can always give [the patient] a more intensive combination regimen if the patient prefers a longer remission,” noted Leonard. However, I don’t know that [this approach] results in an OS benefit, so that’s something I tend to [use] less commonly in this group of patients.”

Strategies for Advanced Follicular Lymphoma With High Tumor Burden

In patients with advanced disease who have a high tumor burden, the most common treatment approach is the combination of bendamustine plus rituximab (BR). Results from a prospective, multicenter, open-label noninferiority trial showed that the doublet was noninferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Specifically, a longer median PFS was observed with BR versus R-CHOP, at 69.5 months (95% CI, 26.1–not reached) versus 31.2 months (95% CI, 15.2-65.7), respectively (HR, 0.58; 95% CI, 0.44-0.74; P <.0001).⁸ BR was also found to have more favorable tolerability versus R-CHOP. However, if there is concern for occult transformation, R-CHOP is recommended, according to Leonard.

Additionally, results from the PRIMA study, showed that maintenance rituximab following R-CHOP/rituximab plus CVP leads to an improvement in PFS, but not OS, added Leonard.⁹ Long-term follow-up results from the trial showed that at 10 years, 51% of patients on the rituximab maintenance arm were estimated to be free of progressive disease (HR, 0.61; 95% CI, 0.52-0.73; P <.0001). However, the OS survival estimates proved to be identical in each arm, at 80% (HR, 1.04; 95% CI, 0.77-1.40; P =.795).

Other approaches, such as lenalidomide plus rituximab and single-agent obinutuzumab, have been shown to have only limited clinical value within this patient population, according to Leonard. However, they can still be utilized, when appropriate.

“I tend not to use lenalidomide and rituximab up front, but if a patient prefers that toxicity profile, it’s certainly a reasonable choice,” concluded Leonard. “Obinutuzumab is also reasonable based on PFS, but the OS or quality of life [benefit is unclear].”

References

1. How to pick frontline therapy in low-grade lymphoma. Presented at: 38th Annual CFS; November 4-6, 2020; Virtual. Accessed November 4, 2020.
2. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055-2063. doi:10.1182/blood-2016-06-721902.
3. Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 1997;15(3):1110-1117. doi:10.1200/JCO.1997.15.3.1110
4. Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362(9383):516-522. doi:10.1016/s0140-6736(03)14110-4
5. 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. 2018;36(29):2918-2925. doi:10.1200/JCO.2018.77.9892
6. Colombat P, Brousse N, Salles G, et al. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol. 2012;23(9):2380-2385. doi:10.1093/annonc/mds177
7. Kahl BS, Hong F, Williams Me, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol. 2014;32(28):3096-102. doi:10.1200/JCO.2014.56.5853
8. 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: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. doi:10.1016/S0140-6736(12)61763-2
9. Salles GA, Seymour JF, Feugier P, et al. Blood. 2017;130(suppl 1):486. doi:10.1182/blood.V130.Suppl1_1.486.486