Weighing Treatment Options in Newly Diagnosed Follicular Lymphoma

John P. Leonard, MD

John P. Leonard, MD

Deciding between a watch-and-wait approach and systemic therapy in patients with newly diagnosed follicular lymphoma (FL) should be carefully assessed based on specific disease characteristics, with follow-up tailored toward patients’ risk of relapse, according to John P. Leonard, MD.¹

“We know that patients who are asymptomatic with low tumor burden can be observed without detriment to their long-term overall survival,” Leonard, professor of medicine at Weill Cornell Medical College of Cornell University in New York, New York, said to an audience at the37th AnnualCFS.

Leonard reviewed the Groupe D’Etude des Lymphomes Folliculaires and the British National Lymphoma Investigation criteria for identifying patients who need treatment.^2,3According to the criteria, patients with bulky disease, many sites of disease, high LDH [lactic acid dehydrogenase], and presence of symptoms are those that should be considered for therapy.

After staging evaluation, patients can typically be classified into 1 of 3 groups for treatment consideration: those with localized disease, advanced indolent disease but with minimal or no symptoms, and advanced disease with symptoms.

Limited-Stage Disease

Leonard said that existing data suggest that for patients with stage I FL, there is about a 70% chance they will not relapse or need treatment over the next 10 or 15 years. Therefore, a watch-and-wait approach or radiotherapy without systemic therapy are both acceptable options at this stage of the disease.

In a multicenter, randomized controlled trial of 150 patients with stage I/II low-grade FL, patients were randomized to involved-field radiotherapy (IFRT) or IFRT with systemic therapy of cyclophosphamide, vincristine, and prednisone (CVP) or rituximab (Rituxan) plus CVP. Progression-free survival (PFS) was improved with the addition of systemic therapy, with 10-year rates of 59% versus 41% with IFRT alone (HR, 0.57; 95% CI, 0.34-0.95;P= .033). Despite these results, overall survival (OS) was similar between the 2 arms (P= .40).⁴

Currently available data for patients in this setting are not enough to suggest value for early versus later therapy, Leonard said. “I do not typically use combined modality treatment for these patients,” he said. “For patients with limited-stage FL, I think it is still reasonable to watch and wait.”

Advanced-Stage FL With Low-Tumor Burden

Patients with advanced-stage disease may also be treated by a watch-and-wait approach, but single-agent rituximab can result in longer remissions. Both of these approaches are favorable over chemoimmunotherapy or other emerging combinations in terms of toxic effects, and should be considered for FL at this stage, said Leonard.

Patients in this category may “have some mild indications for therapy. [For them], 4 doses of rituximab can give us about an 80% response rate, and about half of those will be complete responses.”

Based on data in 49 patients with low—tumor burden FL, the median PFS with 4 weekly doses of rituximab was 23.5 months (95% CI, 13.6-36.7), and 15% of the study population were still progression free more than 7 years following treatment without needing any other therapy.⁵

“This is a reasonable choice for patients who have modest indications for therapy,” Leonard said. He went on to explain that although OS was not affected significantly by therapy, these results indicate that early therapy with rituximab may give the patient more time before needing subsequent therapy.

Symptomatic and Advanced Disease

In the final group of patients with advanced disease, Leonard said induction with bendamustine plus rituximab (BR) is just as good, if not better than, treatment with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) with respect to PFS and tolerability.

In 274 patients with stage III/IV indolent lymphoma, patients with FL treated with BR had improved PFS versus those receiving R-CHOP (HR, 0.61; 95% CI, 0.42-0.87;P= .0072). Additionally, patients in the BR group had fewer toxic effects than those in the R-CHOP group, with serious adverse events (AEs) occurring in 19% and 29%, respectively.⁶

“Overall survival with either of these treatments is the same, so either of these regimens are reasonable choices,” Leonard said. “I tend to use BR for these patients.” However, in patients for whom there is a concern for occult transformation, he suggested considering R-CHOP.

Other options for patients in this setting may include the use of anti-CD20 agents, such as obinutuzumab (Gazyva), or immunomodulatory drugs like lenalidomide (Revlimid).

The open-label, randomized phase III GALLIUM trial tested the use of obinutuzumab versus rituximab with chemotherapy of CHOP, CVP, or bendamustine followed by maintenance therapy. Results showed PFS was improved significantly, with 3-year rates of 80.0% versus 73.3%, respectively (HR, 0.66; 95% CI, 0.51-0.85;P= .001), but grade ≥3 AEs were more frequent with obinutzumab (74.6% vs 67.8%), as were serious AEs (46.1% vs 39.9%). OS results were similar between the 2 arms (P= .21).⁷

Based on these data, Leonard said obinutuzumab has been adopted, but either agent can be used in the frontline setting. “With obinutuzumab, there are more toxicities and you don’t have the subcutaneous [formulation as with rituximab] that patients like,” Leonard said.

The multicenter, international phase III RELEVANCE trial comparing lenalidomide plus rituximab (R2) versus investigator’s choice of chemotherapy failed to meet its coprimary end points but showed that R2 produced similar efficacy as the control with different toxicities. The rate of confirmed or unconfirmed complete response at 120 weeks was 48% (95% CI, 44%-53%) with R2 and 53% (95% CI, 49%-57%) with standard therapy (P= .13), and 3-year PFS rates were 77% (95% CI, 72%-80%) and 78% (95% CI, 74%-82%), respectively. Rates of grade 4 neutropenia (50% vs 32%), febrile neutropenia across all grades (7% vs 2%), and grade 3/4 infections (4% vs 2%) were higher in the control arm; however, rates of grade ≥3 rash (7% vs 1%) were higher in the R2 arm.

“One could argue that this is a reasonable regimen to consider for some patients, particularly those who don’t mind oral therapy,” Leonard said. “There is [more incidence of rash], but less cytopenias and febrile neutropenia,” making it a reasonable option for some patients.

Leonard concluded by highlighting the need to move toward a more “risk-adapted” approach to therapy, with a greater emphasis on the role of prognostic score, tumor and patient profiling, imaging, and other modalities.

“There are several important questions, [such as] what will it take to dislodge the watch-and-wait approach as a standard therapy option. I think that is an important research question.”

References

1. Leonard JP. Follicular lymphoma: current treatment options for newly diagnosed patients. Presented at:37th AnnualCFS, hosted by Physicians’ Education Resource, LLC; November 6-8, 2019; New York, New York.
2. 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 def Lymphomes de l’Adulte.J Clin Oncol. 1997;15(3):1110-1117. doi: 10.1200/JCO.1997.15.3.1110.
3. 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.
4. 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.
5. 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.
6. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mentle-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.
7. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma.N Engl J Med. 2017;377(14):1331-1344. doi: 10.1056/NEJMoa1614598.
8. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma.N Engl J Med. 2018;379(10):934-947. doi: 10.1056/NEJMoa1805104.