In the phase III AUGMENT trial, reported in the Journal of Clinical Oncology, John P. Leonard, MD, of Meyer Cancer Center, Weill Cornell Medicine and NewYork-Presbyterian Hospital, and colleagues found that the addition of lenalidomide to rituximab significantly prolonged progression-free survival in patients with relapsed or refractory indolent lymphoma.¹

Study Details

In the double-blind trial, 358 patients with relapsed or refractory follicular lymphoma (82%) or marginal zone lymphoma (18%) from 97 centers in 15 countries were randomly assigned between February 2014 and January 2017 to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Treatment consisted of lenalidomide (or placebo) at 20 mg daily (10 mg daily for patients with creatinine clearance of 30–59 mL/min) on days 1 to 21 plus rituximab at 375 mg/m² on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2 to 5 every 28 days. Treatment with lenalidomide or placebo continued for 12

Lenalidomide improved [the] efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile....

— John P. Leonard, MD

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cycles (with prophylactic anticoagulation at investigator discretion) or until relapse, progressive disease, withdrawal of consent, or unacceptable toxicity. The primary endpoint was progression-free survival on independent radiology review.

For the lenalidomide/rituximab vs rituximab groups: the median age was 64 vs 62 years; 42% vs 54% were male; the histology was follicular lymphoma grade 1 or 2 in 70% vs 68% and grade 3a in 12% vs 14% and marginal zone lymphoma in 17% vs 18%; 54% vs 48% had high tumor burden on Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria; the Follicular Lymphoma International Prognostic Index score was 0 or 1 in 29% vs 37%, 2 in 31% vs 32%, and 3 to 5 in 39% vs 30%; 43% vs 46% had at least 2 prior systemic regimens (median number = 1, range = 1–12); 85% vs 83% had prior rituximab and 73% vs 72% had a prior rituximab-containing chemotherapy regimen; 31% vs 34% had relapse or disease progression up to 2 years after diagnosis; and 17% vs 14% were refractory to the last regimen received.

Progression-Free Survival

The median follow-up was 28.3 months. The median progression-free survival was 39.4 months with lenalidomide/rituximab vs 14.1 months with rituximab (hazard ratio [HR] = 0.46, P < .001). Lenalidomide plus rituximab was associated with consistent progression-free survival benefits across all prespecified subgroups, except for the relatively small marginal zone lymphoma subgroup (n = 63; HR = 1.00, 95% confidence interval [CI] = 0.47–2.13). Hazard ratios in favor of

lenalidomide/rituximab were 0.40 (95% CI = 0.29–0.56) among patients with follicular lymphoma, 0.47 (95% CI = 0.34–0.66) among patients with prior rituximab treatment, 0.40 (95% CI = 0.27–0.61) among patients with a GELF high tumor burden, and 0.47 (95% CI = 0.31–0.73) among patients who had at least 1 prior systemic regimen.

Response rates on independent review were 78% vs 53% (P < .001), with complete response occurring in 34% vs 18% (P = .001). The median duration of response was 36.6 vs 21.7 months (P = .0015). The median event-free survival was 27.6 vs 13.9 months (HR = 0.51, P < .001). The median time to next antilymphoma treatment was not reached vs 32.2 months (P = .007). Although overall survival data are not mature, Dr. Leonard noted that there was an overall survival benefit in the follicular lymphoma subset of patients. Fewer deaths have been observed in the lenalidomide group (HR = 0.61, 95% CI = 0.33–1.13). Estimated 2-year overall survival was 93% vs 87%.

Adverse Events

The lenalidomide-plus-rituximab group had higher rates of any-grade infections (63% vs 49%) and cutaneous reactions (32% vs 12%). Individual adverse events of any grade that occurred with an incidence ≥ 10% higher in the lenalidomide/rituximab group were neutropenia (58% vs 23%), constipation (26% vs 14%), leukopenia (20% vs 9%), anemia (16% vs 4%), thrombocytopenia (15% vs 4%), and tumor flare (11% vs 1%). Grade 3 or 4 adverse events occurred in 69% vs 32% of patients; higher rates of grade 3 or 4 neutropenia (50% vs 13%) and leukopenia (7% vs 2%) were observed with lenalidomide plus rituximab, with no other grade 3 or 4 adverse event differing by ≥ 5% between groups. Febrile neutropenia occurred in 3% vs 1% of patients, and growth factors were administered to 36% vs 12%. Serious adverse events occurred in 26% vs 14% of patients, with pneumonia being the most common (3% in each group). Deep vein thrombosis occurred in 2% vs 1% of patients. Second primary cancers occurred in 3% vs 6%. Adverse events led to death in two patents in the lenalidomide/rituximab group (arrhythmia and cardiopulmonary failure) and two patients in the rituximab group (general physical health deterioration and pneumonia).

The investigators concluded: “Lenalidomide improved [the] efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile…. The magnitude of efficacy differences between the two treatments is clinically meaningful and suggests that lenalidomide plus rituximab should replace rituximab monotherapy as a standard of care for patients with relapsed or refractory indolent [non-Hodgkin lymphoma].” ■

DISCLOSURE: The study was supported by Celgene. Dr. Leonard is a consultant/advisor with and received institutional research funding from Celgene. For complete disclosures for Dr. Leonard and the other study authors, visit www.jco.ascopubs.org.

REFERENCE

1. Leonard JP, Trneny M, Izutsu K, et al: AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 37:1188-1199, 2019.