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Rituximab plus lenalidomide as effective as standard of care for follicular lymphoma
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Treatment-naive patients with advanced follicular lymphoma who received a combination of rituximab plus lenalidomide appeared to have similar outcomes as patients treated with rituximab and chemotherapy, according to findings from the phase 3 RELEVANCE clinical trial.
The combination of rituximab (Rituxan; Genentech, Biogen) and chemotherapy led to increased incidence of high-grade neutropenia and febrile neutropenia, whereas the combination of rituximab and lenalidomide (Revlimid, Celgene) led to greater incidence of high-grade cutaneous reactions.
“These study results represent a landmark in this disease setting,” Franck Morschhauser, MD, PhD, professor of hematology at University of Lille in France, told HemOnc Today. “Results from the RELEVANCE trial showed that the chemotherapy-free immunomodulatory regimen is a credible first-line option for patients with follicular lymphoma needing treatment.”
The combination of rituximab and chemotherapy followed by maintenance rituximab has been the standard of care for the treatment of advanced follicular lymphoma.
“Although chemoimmunotherapy is generally a highly active first-line therapy, most patients will experience relapse, in part due to defective antitumor immune responses in follicular lymphoma,” Morschhauser said.
Previous phase 2 clinical trials have shown treatment-naive patients with advanced follicular lymphoma had high response rates to a regimen of rituximab plus lenalidomide.
“Lenalidomide is an immunomodulatory agent that has shown complementary mechanisms when combined with rituximab, as well as clinical activity with a tolerable safety profile in multiple studies of patients with B-cell malignancies,” Morschhauser said.
Morschhauser and colleagues randomly assigned 1,030 patients (median age, 59 years; 49% high risk) from 137 clinical centers around the world in a 1:1 ratio to receive rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517), followed by rituximab maintenance therapy.
Patients in the rituximab-lenalidomide group received 20 mg lenalidomide daily on days 2 through 22 of every 28-day cycle for six cycles, followed by 10 mg a day for 12 cycles if in complete response, or 20 mg per day for three to six cycles if in partial response. They received 375 mg/m2 rituximab on days 1, 8, 15 and 22 of the first cycle and on day 1 of cycles two through six. Patients who responded continued to receive maintenance rituximab every 8 weeks for 12 cycles.
Patients assigned the rituximab-chemotherapy group received investigator’s choice of three regimens — rituximab plus CHOP (72%); rituximab plus bendamustine (23%); or rituximab, cyclophosphamide, vincristine and prednisone (5%) — followed by 12 cycles of maintenance rituximab every 8 weeks.
Confirmed or unconfirmed complete response at 120 weeks and PFS served as coprimary endpoints.
Researchers measured tumor response according to 1999 International Working Group criteria.
Median follow-up was 37.9 months.
An independent review committee determined confirmed or unconfirmed response rates at 120 weeks of 48% (95% CI, 44-53) in the rituximab-lenalidomide group compared with 53% (95% CI, 49-57) in the rituximab-chemotherapy group, which did not represent a significant difference.
Investigator-assessed rates also were comparable, at 55% (95% CI, 51-60) in the rituximab-lenalidomide group compared with 58% (95% CI, 53-62) in the rituximab-chemotherapy group.
Best overall response rates included 84% (95% CI, 81-87) in the rituximab-lenalidomide group compared with 89% (95% CI, 86-91) in the rituximab-chemotherapy group per the independent review committee, and 86% (95% CI, 83-89) in the rituximab-lenalidomide group compared with 92% (95% CI, 89-94) in the rituximab-chemotherapy group per the investigator assessment.
Interim 3-year PFS rates were 77% in the rituximab-lenalidomide group and 78% in the rituximab-chemotherapy group. Risk for progression or death did not differ between the groups in the independent review committee assessment (HR = 1.1; 95% CI, 0.85-1.43) or investigator assessment (HR = 0.94; 95% CI, 0.73-1.22).
Overall, 99.8% of the rituximab-lenalidomide group and 99% of the rituximab-chemotherapy group experienced at least one adverse event. Adverse events of any grade that appeared less frequent in the rituximab-lenalidomide group included anemia (66% vs. 89%), fatigue (23% vs. 29%), nausea (20% vs. 42%), vomiting (7% vs. 19%), peripheral neuropathy (7% vs. 16%), leukopenia (4% vs. 10%), febrile neutropenia (2% vs. 7%) and alopecia (1% vs. 9%).
Adverse events of any grade that were more common with rituximab-lenalidomide
included cutaneous reactions (43% vs. 24%), diarrhea (37% vs. 19%), rash (29% vs. 8%), abdominal pain (15% vs. 9%), myalgia (14% vs. 6%), muscle spasms (13% vs. 4%) and tumor flare reaction (6% vs. < 1%).
The proportion of patients who experienced grade 3 to grade 4 adverse events appeared similar between the two groups (rituximab-lenalidomide, 65% vs. rituximab-chemotherapy, 68%).
However, researchers noted more patients in the rituximab-chemotherapy group experienced grade 3 to grade 4 neutropenia (50% vs. 32%).
Short follow-up for time-to-event endpoints, including OS, is the study’s biggest limitation, according to Morschhauser.
“Longer follow-up with more mature survival data and continued safety monitoring are needed to fully assess long-term outcomes and possible differences between treatment arms,” he said.
“Additional analyses will be conducted to evaluate possible biomarkers and the immune-based mechanisms of action of lenalidomide plus rituximab in patients, as well as potential differences between arms for other exploratory endpoints (eg, quality of life),” he added. – by Melinda Stevens
For more information:
Franck Morschhauser, MD, PhD, can be reached at University of Lille, CHU Lille, EA 7365, GRITA– Groupe de Recherche sur les formes Injectables et les Technologies Associees, F-59000, Lille, France; email: franck.morschhauser@chru-lille.fr.
Disclosures: Morchhauser reports nonfinancial support from Celgene during the conduct of the study and fees from Bristol-Myers Squibb, Celgene, Gilead, Janssen and Roche for work outside of the study. Please see the study for all other authors’ relevant financial disclosures.
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