Emerging Agents and Regimens in the Management of Follicular Lymphomas

Follicular lymphoma (FL) is one of the most common subtypes of indolent non-Hodgkin lymphoma (NHL). Although FL is considered incurable with currently available therapy, the introduction of monoclonal antibodies has improved clinical outcomes for this group of patients. Ongoing research focuses on assisting practicing oncologists with selecting the proper therapeutic options for specific clinical scenarios. This article presents some of the most recent and novel approaches for treatment of FL, with regimens involving rituximab (Rituxan), bendamustine (Treanda), lenalidomide (Revlimid), and bortezomib (Velcade).

Rituximab Maintenance
This past January, the US Food and Drug Administration approved rituximab for maintenance therapy in patients with previously untreated FL who achieved a response to rituximab in combination with chemotherapy.¹ Updated results from the PRIMA (Primary Rituximab and Maintenance) trial (Table 1) showed sustained benefits from rituximab maintenance therapy in patients with FL who had high tumor burden (n = 1193). In the observational arm, 60.3% of patients achieved 3-year progression- free survival (PFS) compared with 78.6% of patients in the maintenance arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.44-0.68).^2,3 Similar to what was observed in rituximab maintenance clinical trials in the relapsed/refractory setting, improvements in PFS did not translate into improvement in overall survival (OS).^2,3

For asymptomatic patients with nonbulky FL, many clinicians believe watchful waiting is superior to chemotherapy. As research on less toxic and effective therapies such as rituximab continues to emerge, clinicians are questioning the watchful waiting approach. For example, Ardeshna and colleagues reported results of a clinical trial comparing ri tuximab induction therapy followed by rituximab maintenance versus observation for nonbulky FL grades 1-3a (Table 1). Preliminary results are encouraging, with patients in the rituximab arm achieving a significant delay in the need to initiate new therapy compared with those in the watchful waiting arm (P <.001; 95% CI, 0.13-0.29).⁴ Im prove ments in more clinically relevant end points, such as PFS and OS, have not yet been observed.

The benefit of rituximab maintenance in FL patients was further evaluated by Vidal and associates in a meta-analysis of clinical trials comparing rituximab maintenance with observation in previously untreated or relapsed/refractory FL. Results showed increased OS in the rituximab maintenance arm for relapsed/ refractory FL (HR, 0.75; 95% CI, 0.57- 0.91) but no significant change in OS for previously untreated patients (HR, 0.83; 95% CI, 0.56-1.23).⁵ In the absence of a clear benefit in OS, clinicians must carefully weigh the benefits and risk for individual patients of starting rituximab maintenance in the firstline or relapsed/refractory setting.

Rituximab in Combination with Lenalidomide
Several trials have evaluated the combination of rituximab and lenalidomide in FL patients. Ahmadi and colleagues treated rituximab-resistant relapsed/refractory indolent or mantle cell lymphoma patients with rituximab, lenalidomide, and dexamethasone (Table 2). Preliminary results showed an overall response rate (ORR) of 60% for the subset of 18 patients with FL, and 78% of all patients were progression-free at 12 months.⁶ Another study evaluated the ability of lenalidomide to overcome the negative impact of low affinity FCGR3 genotype on rituximab activity. Early analysis suggests that patients with the higher affinity FCGR3 genotype (158V/V) appear to have significantly increased ORR and PFS compared with patients with the low-affinity FCGR3 allele (158F) when treated with rituximab monotherapy.⁷ Dutia and colleagues formally evaluated whether lenalidomide could improve rituximab activity in FL patients with FCGR3-158V/F or FCGR3-158F/F genotypes.

Patients with relapsed/refractory indolent lymphoma were treated with a combination of rituximab and lenalidomide. FcγRIIIA genotype was determined in DNA isolated from peripheral blood cells by polymerase chain reaction amplification followed by allele-specific restriction enzyme digestion. Preliminary results suggest an impressive ORR of 100% and median PFS of 14.85 months for patients with the FCGR3-158V/F polymorphism and 8.31 months for patients with the FCGR3-158F/F polymorphism. The subsets of patients with other polymorphisms of the FCGR3 genotype were too small for researchers to draw any preliminary conclusions. Enrollment into the study continues, and final results might support using lenalidomide in combination with rituximab to treat relapsed/refractory lymphomas.⁸

Rituximab and lenalidomide were also tested in the first-line setting by Fowler and colleagues in a single-arm study that enrolled 30 patients with previously untreated NHL, including 17 patients with FL (Table 2).⁹ The ORR was 86%; 79% of all patients and 94% of FL patients achieved a complete response (CR). Grade 3/4 adverse events consisted primarily of rash (6 patients), neutropenia (7 patients), and myalgia (4 patients). Other grade 3/4 adverse events included neuropathy, infection, fatigue, and thrombosis, each of which affected 1 patient. After a median follow-up period of 14.1 months, only 1 patient progressed. Based on these results, planned accrual was increased to 110 patients.

Rituximab in Combination with Bortezomib
Bortezomib plus rituximab has shown activity in FL patients. Pre clinical data suggest rituximab and bortezomib interact biologically. Coiffier and associates presented the results of a phase 3 clinical trial evaluating the efficacy of bortezomib in combination with rituximab. 10 Re lapsed rituximab-naïve or -sensitive FL patients were randomized to single-agent rituximab or the combination regimen. Preliminary results indicated that the doublet of rituximab and bortezomib resulted in a higher ORR than rituximab alone (63% vs 49%, respectively; P = .039). Patients receiving the combination were also more likely to experience CR than patients in the monotherapy arm (25% vs 18%, respectively; P = .035) and also demonstrated prolonged PFS (398 days vs 334 days, respectively; P <.001). At the time the data were presented, median OS had not been reached in either group. These findings suggest that bortezomib is potentially an active agent for patients with FL. Ongoing studies are seeking to better define the role of bortezomib in treating FL and to find ways to minimize the treatment-related toxicities observed when using this agent.

Rituximab in Combination with Bendamustine
The treatment of previously untreated FL continues to change. The incorporation of various chemotherapy agents focuses on improving clinical outcome and minimizing drug-related toxicities. A recent phase 3 clinical trial compared rituximab combined with a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus bendamustine for patients with grade 1/2 FL who required systemic chemo therapy (n = 549). Although the ORR was similar between the 2 treatment arms, the CR rate was higher in the group of patients receiving rituximab plus bendamustine than in the group of patients treated with rituximab-CHOP (40% vs 30%, respectively; P = .0323). In addition, median PFS was longer for patients treated with rituximab plus bendamustine than for those patients receiving rituximab-CHOP (54.8 vs 34.8 mo, respectively; P = .0002). Although these preliminary results are interesting, it is important to stress that only patients with grade 1/2 FL were included in this study. Sym ptomatic patients with grade 3a FL should be treated with rituximab- CHOP therapy.¹¹

Conclusion
Results of recently completed and ongoing clinical studies are encouraging and suggest that several novel agents are someday likely to have a place in the management of untreated relapsed/refractory FL patients. The largest “obstacle” facing clinicians and re searchers today is determining the best way to streamline evaluations of the large number of effective therapies and establishing the optimal use and sequencing of these agents. Overcoming these hurdles promises to improve the quantity and quality of life for FL patients today and in future generations.

References

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