Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10

Background: Previous trials from the Swiss Group for Clinical Cancer Research (SAKK) and the Nordic Lymphoma Group (NLG) showed that therapy with single-agent rituximab can produce long-term remissions in a sizeable subset of follicular lymphoma (FL) patients, with overall survival not inferior to chemo-immunotherapy, providing the rationale for the development of chemotherapy-free treatment strategies. Promising results have also been reported with the combination of rituximab and lenalidomide. The SAKK 35/10 phase-2 study was developed and conducted by the SAKK in cooperation with the NLG to compare the activity of rituximab plus lenalidomide versus single-agent rituximab in the first-line FL therapy.

Methods: Patients with histologically confirmed untreated FL, grade 1, 2, 3a and in need of systemic therapy, were randomized either to rituximab monotherapy (R) (8 infusions of 375mg/m2 at day 1 of weeks 1, 2, 3, 4, and repeated at day 1 of weeks 12, 13, 14 and 15) or to rituximab (given at the same schedule) in combination with lenalidomide (RL) (lenalidomide given orally, 15 mg daily, starting 14 days before the first rituximab administration and continuously until 14 days after the last). The primary endpoint was the complete response (CR/CRu) assessed at week 23, defined according to the NCI standardized criteria (Cheson et al 1999). The study sample size was calculated to allow the detection of a 20% increase of the CR/CRu rate with RL over R, with 90% power and a type I error of 0.10. The 2 arms were compared using a one-sided Z-test with unpooled variance for proportions. Trial treatment was discontinued in patients who at week 10 did not achieve at least a minimal response, defined as reduction of more than 25% in the sum of product of tumor diameters (SPD), and rescue chemotherapy was given at the discretion of the treating physician.

Results: In total, 154 patients were randomized; 77 (40 women and 37 men; median age 63yrs, range 29-85; 52% with stage IV and 47% with poor-risk FLIPI score) were allocated to arm R and 77 (42 women and 35 men; median age 61yrs, range 26-80; 48% with stage IV and 47% with poor-risk FLIPI score) to arm RL. Treatment was discontinued by 21 (28%) patients in arm R, in 16 due to lack of response at week 10 and in 1 due to toxicity, and by 19 (25%) patients in arm RL, in 3 due to lack of response at week 10 and in 13 due to toxicity. Adverse events of any grade were reported in 91% of patients in arm R and 100% in arm RL and adverse events of grade ≥3 were more common in arm RL than in arm R (51% vs 18% of patients). Grade 3-4 neutropenia was observed in 5% of patients in arm R and 19% in arm RL. The primary endpoint analysis (using the response assessment from the local investigators, reviewed by the study chairs) showed a significantly higher CR/CRu rate in patients treated with RL in comparison with those receiving R. This difference was observed both in the intent-to-treat (CR/CRu rate, 36% vs. 25%, respectively; p=0.056) and the per-protocol population (CR/CRu rate, 42% vs. 28%, respectively; p=0.049).

Conclusions: The addition of lenalidomide to rituximab results in a significantly better CR/CRu at the cost of an expected increased toxicity. Further follow-up is needed to ascertain whether the response improvement will translate into prolonged time to next treatment and superior progression-free and overall survival rates.