Follicular Lymphoma: The Environment as the Target

Combined Rituximab and Lenalidomide Treatment for Untreated Patients with Follicular Lymphoma (RELEVANCE)

Celgene Corporation, USA, and GELARC, France

NCT01476787

30 centers throughout the United States

1,000 patients

This is a phase 3, open-label, randomized study to compare efficacy and safety of rituximab plus lenalidomide (CC-5013) versus rituximab plus chemotherapy followed by rituximab. Adult patients with follicular lymphoma (FL) grades 1, 2, or 3a; stage II to IV; and not previously treated with systemic therapy are eligible. Patients must be in need of treatment for symptomatic disease and have an ECOG performance status of 0-2. After full staging, patients are randomized 1:1 between standard therapy and lenalidomide plus rituximab. Standard therapy can be one of the following, selected prior to randomization by the investigator: R-CHOP, R-CVP (both given every 21 days for 8 cycles) or R-bendamustine (every 28 days for 6 cycles). The experimental arm comprises rituximab 375 mg/m² on day one and lenalidomide 20 mg daily on days 2 to 22 of a 28-day cycle, for six cycles.

Patients with an objective response to initial therapy go on to receive maintenance treatment. Those in the standard arm receive maintenance for two years with rituximab alone, while those on the experimental arm have lenalidomide for one year and rituximab for two years. The maintenance dose of lenalidomide is determined by the initial response. Patients with a CR or CR(unconfirmed) [CR(u)] take 10 mg, while those with PR continue to take 20 mg for 3 to 6 cycles until CR/CR(u) is reached, and then they continue to take 10 mg.

The primary endpoints are CR/CR(u) rate and progression-free survival (PFS), with secondary outcome measures such as time to treatment failure, time to next anti-lymphoma treatment, and overall survival. Quality-of-life measurements will also be recorded using EORTC QLQ-C30 questionnaires. The target for recruitment is 1,000 patients, and the aim is to detect a 30 percent improvement in PFS.

The inflammatory microenvironment plays an important role in governing the biologic aggressiveness and clinical course of FL (Farinha P et al. Blood. 2005;106:2169-2174 and Dave SS et al. N Engl J Med. 2004;351:2159-2169). Lenalidomide has been shown to have a range of antilymphoma actions, including modulation of the tumor microenvironment (Ramsay AG et al. Blood. 2009;114:4713-4720). Pre-clinical studies suggest that the addition of lenalidomide may enhance the activity of rituximab (Chang DH et al. Blood. 2006;108:618-621 and Wu L et al. Clin Can Res. 2008;14:4650-4657), and a recent phase 2 study of the combination as firstline treatment for indolent non-Hodgkin lymphoma demonstrated impressive response rates among patients with advanced FL. Of the 39 evaluable, 34 (87%) achieved a CR. Following cycle 6, nearly all FL patients had undetectable t(14;18) by PCR (Samaniego F et al. J Clin Oncol. 2011; 29:(suppl):abs 8030). Comparable molecular CR rates have not been seen with previous rituximab combination regimens, making this an attractive proposition for a new randomized study.

The possibility of using a non-cytotoxic regimen for the initial therapy of advanced FL has great appeal, but until recently the only option for this was to use rituximab alone, which does not appear to have sufficient potency and durability of effect for patients with high-risk disease. If the combination of rituximab and lenalidomide performs as well in the phase 3 study as the pilot, it may provide an important new option for the standard of care. Some questions remain concerning the long-term safety of lenalidomide, particularly regarding the incidence of second primary malignancies in studies of myeloma, so long-term follow-up will be important in this trial, as will careful analysis of the quality-of-life endpoints.