Patients with relapsed or refractory indolent lymphoma lived more than twice as long without disease progression when they received lenalidomide (Revlimid) and rituximab (Rituxan) versus rituximab alone, results of a randomized trial showed.
Treatment with lenalidomide plus rituximab led to a median progression-free survival (PFS) of 39.4 months compared with 14.1 months with rituximab and placebo. Adverse events occurred more often with the addition of lenalidomide, but the side effects were manageable, as reported online in the Journal of Clinical Oncology.
“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 (NHL),” concluded John P. Leonard, MD, of Weill Cornell Medicine and NewYork-Presbyterian Hospital in New York City, and co-authors.
The author of an accompanying editorial said the trial results may eventually support regulatory approval of the lenalidomide-rituximab combination for follicular lymphoma. However, the study did not rule out a continuing role for rituximab monotherapy at relapse, said Paul Barr, MD, of the University of Rochester in New York.
The favorable 2-year overall survival in both groups (93% with lenalidomide, 87% with rituximab alone) “reminds us that these patients can receive additional therapy with subsequent relapses. Therefore, both treatment arms still have a place in the management of follicular lymphoma.”
“With the growing number of available options for patients with indolent lymphoma, tailoring therapy to patient risk or disease biology is the greater needed,” Barr added. “Unfortunately, application of risk stratification algorithms to clinical practice and identifying predictive biomarkers for indolent lymphoma have been difficult.”
Patients with relapsed/refractory indolent NHL (primarily follicular and marginal zone lymphomas) have several treatment options, none of which is considered curative, Leonard and co-authors noted in their introduction. Rituximab monotherapy is an option for patients who previously responded to the drug, and retreatment frequently leads to new responses.
Several previous studies showed that the combination of lenalidomide and rituximab has activity in patients with previously treated indolent NHL, leading to response rates of 65-77%, complete responses in 35-41% of patients, and median PFS of 1 to 2 years, the authors continued. Additionally, the combination proved clinically active in a phase III trial of patients with untreated follicular lymphoma.
Collectively, the evidence provided a rationale for the phase III AUGMENT trial, which compared rituximab plus placebo or lenalidomide in 358 patients with relapsed/refractory indolent NHL enrolled at 97 centers in 15 countries. The trial had a primary endpoint of PFS as determined by an independent review committee (IRC).
The patients had a median age of 63 years, 295 had follicular lymphoma, 63 had marginal zone lymphoma, and 51% had high tumor burden. The majority of patients (56%) had one prior therapy (range 1-12) and 24% of patients had received at least three prior regimens. The authors reported that 117 patients had relapse or disease progression within 2 years of their initial diagnosis.
Final data analysis occurred after a median follow-up of 28.3 months. The 25-month difference in median PFS translated into a 54% reduction in the hazard for disease progression or death in favor of the lenalidomide-rituximab combination (P<0.001). Investigator-assessed PFS was 25.3 months with lenalidomide-rituximab and 14.3 months with rituximab and placebo, representing a 49% reduction in the PFS hazard.
The combination led to an overall response rate of 78% versus 53% for rituximab and placebo by IRC (P<0.001) and complete response rates of 34% versus 18% (P<0.001). Most other IRC-assessed secondary endpoints favored the lenalidomide group, including response duration, event-free survival, time to next lymphoma therapy, time to next chemotherapy, and PFS on next lymphoma treatment. Investigator-assessed outcomes were consistent with the IRC findings.
An analysis of outcomes by lymphoma subtype showed no difference in PFS or preliminary overall survival for patients with marginal zone lymphoma. The comparison yielded a hazard ratio of 1.00, associated with wide confidence intervals (95% CI 0.47-2.13), suggesting the data were uninformative, the authors noted.
In his editorial, Barr acknowledged that the small number of patients with marginal zone lymphoma might have accounted for the lack of difference (numerically they favored rituximab alone). However, he added that “treating physicians need to be aware that treatment efficacy is likely different for the two lymphoma subtypes.”
Overall, adverse events occurred more often with the lenalidomide-rituximab combination, including infections (63% vs 49%), neutropenia (58% vs 23%), and cutaneous reactions (32% vs 12%). Additionally, grade 3/4 neutropenia occurred in 50% of the lenalidomide group and 13% of the placebo arm and grade 3/4 leukopenia in 7% versus 2%.
“Neutropenia was predictable and manageable,” the authors noted in their conclusion. “The modest increase in infections and cutaneous reactions must be considered in light of the significantly greater efficacy of the lenalidomide plus rituximab combination. In fact, more patients in the lenalidomide plus rituximab group completed therapy than those in the placebo plus rituximab group.”
The AUGMENT trial was sponsored by Celgene.
Leonard disclosed relationships with Celgene, Biotest, Sunesis Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Epizyme, Pfizer, Bayer, Genentech, ADC Therapeutics, MEI Pharma, AstraZeneca, Novartis, Merck, Sutter Medical Group, MorphoSys, BeiGene, Nordic Nanovector, United Therapeutics, Karyopharm Therapeutics, Sandoz, and Takeda. Multiple co-authors disclosed relationships with pharmaceutical companies and other commercial interests.
Barr disclosed relationships with Pharmacyclics, AbbVie, Seattle Genetics, Genentech, Celgene, Novartis, Infinity Pharmaceuticals, Janssen, Merck, and TG Therapeutics.