Optimal first-line therapy and the role of postremission/maintenance therapy are evolving challenges in the management of follicular lymphoma. The impact of recent studies on these issues was explored at a session on clinical management of common lymphomas during the recent 14th Annual International Congress on Hematologic Malignancies in Whistler, British Columbia, Canada.

Optimal First-line Therapy: New Standard Emerging?

R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, prednisone) is standard first-line therapy for follicular (indolent) lymphoma in most countries, but this regimen has not been proven to be the best treatment, said session moderator Andrew Zelenetz, MD.  Dr. Zelenetz is Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York.

Michael Williams, MD, the Byrd S. Leavell Professor of Medicine and Pathology at the University of Virginia in Charlottesville, discussed his approach to follicular lymphoma. The discussion of first-line therapy centered on a potentially practice-changing study presented at the Annual Meeting of the American Society of Hematology in December 2009. That study, presented by Matthias J. Rummel, MD, on behalf of the German Study Group on Indolent Lymphoma (StiL), found that first-line therapy with bendamustine (Treanda) plus rituximab was superior to CHOP plus rituximab (CHOP-R) in follicular lymphoma. Not only was bendamustine/rituximab better tolerated than CHOP-R, but it also clearly resulted in a significantly superior progression-free survival (PFS).

The study included 549 patients who were symptomatic with a large tumor burden and had a protocol-specified indication for therapy in line with criteria recommended by GELF (Groupe d'Etude des Lymphomes Folliculaires). Significantly lower rates of grade 3 and 4 hematologic toxicity (including leukocytopenia and neutropenia) occurred with bendamustine/rituximab vs CHOP-R (P < .0001). The incidence of nonhematologic toxicities was also much lower in the group receiving the experimental treatment.

Overall response rates were similar in the two arms. Complete response rates were 39.6% for the experimental arm vs 30% for CHOP-R, translating to a significantly better PFS-a median of 54.9 vs 34.8 months, respectively (P = .00012).

"This study raises the important question of how influential these findings should be. In our discussion of follicular lymphoma at the meeting in Whistler, this trial came up over and over again," Dr. Zelenetz said. He added, "A confirmatory study is ongoing in the United States, Canada, and Australia. Nonetheless, anecdotal evidence suggests that this regimen is being adopted for selected patients."

Postremission Therapy

Another controversial topic explored by Dr. Williams was the role of postremission therapy in follicular lymphoma. Dr. Zelenetz said that currently three options are available for maintenance therapy in follicular lymphoma once remission has been achieved: observation; consolidation with radioimmunotherapy; or maintenance rituximab (see Table 1).

Speakers at the Whistler meeting also discussed the benefit of maintenance therapy with rituximab in follicular lymphoma. Although rituximab maintenance therapy is often given to patients who respond to first-line rituximab-containing regimens, randomized controlled trials have not reported any overall survival benefit.

Two separate randomized controlled trials in relapsed/refractory patients with follicular lymphoma have shown that maintenance rituximab significantly prolonged PFS. In one study, following R-CHOP, patients were randomized to receive either maintenance rituximab or no treatment.¹ In the second trial, following R-FMC (rituximab, fludarabine, mitoxantrone, cyclophosphamide), patients were also randomized to maintenance rituximab vs no treatment.²

A recent meta-analysis of randomized trials suggested an overall survival advantage for maintenance rituximab in previously treated relapsed/refractory follicular lymphoma.³ However, the meta-analysis was difficult to interpret, Dr. Zelenetz said, because the induction therapy prior to maintenance therapy varied and included different regimens.

"Unfortunately, no trial has directly addressed the role of maintenance rituximab as remission therapy after front-line chemotherapy," he stated.

With the two randomized controlled trials mentioned above as background, results of the Primary Rituximab and Maintenance (PRIMA) trial are eagerly awaited, Dr. Zelenetz continued. In this European trial, maintenance rituximab was given following three different rituximab-containing regimens: FMC-R, CVP (cyclophosphamide, vincristine, prednisone)-R, and CHOP-R.

"PRIMA explores the question of whether there is a benefit in patients who respond to first-line rituximab-containing regimens," Dr. Zelenetz explained. "Although the primary endpoint of PFS is of interest, an impact on overall survival would be practice-changing."

The final results of PRIMA will be presented at the ASCO Annual Meeting this June.

Radioimmunotherapy

Radioimmunotherapy is the only FDA-approved postremission therapy for follicular lymphoma. An international, randomized phase III trial showed that consolidation therapy with yttrium-90-ibritumomab tiuxetan (Zevalin) after first remission prolonged PFS by 2 years compared with no consolidation therapy in patients with advanced follicular lymphoma.⁴

Dr. Zelenetz said that as both single-agent rituximab and radioimmunotherapy can be used at relapse, the compelling use of postremission therapy will occur if either strategy provides an overall survival advantage.

Another twist in this evolving story is whether radioimmunotherapy can replace rituximab as upfront therapy. A separate trial called SWOG 0016 will evaluate radioimmunotherapy after CHOP vs rituximab upfront. This study is a direct comparison of R-CHOP vs CHOP followed by radioimmunotherapy (with tositumomab and iodine I-131 [Bexxar]). Results of this trial are anticipated in late 2010, according to lead investigator Oliver Press, MD.

For additional information on rituximab immunotherapy, watch for abstract 8088 at the 2010 ASCO Annual Meeting. For more on radioimmunotherapy in FL, see pages 1, 10, and 17 in this issue.

References

1. van Oers MH, Klasa R, Marcus RE, et al: Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: Results of a prospective randomized phase 3 intergroup trial. Blood 108:3295-3301, 2006.

2. Forstpointner R, Unterhalt M, Dreyling M, et al: Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 108:4003-4008, 2006.

3. Vidal L, Gafter-Gvili A, Leibovici L, et al: Rituximab maintenance for the treatment of patients with follicular lymphoma: Systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 101:248-255, 2009.

4. Morschhausser F, Radford J, Van Hoof A, et al: Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 26:5156-5164, 2008.