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Updated data show that lenalidomide plus rituximab provides an acceptable, long-term, chemotherapy-free alternative to rituximab plus chemotherapy in patients with advanced untreated follicular lymphoma (FL).

The randomized, phase III RELEVANCE trial compared an immunomodulatory regimen, rituximab plus lenalidomide, with the current standard of care, rituximab plus chemotherapy (mostly bendamustine or CHOP), in 1,030 previously untreated patients with advanced FL who were in need of treatment according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. In 2018, the of the data found that, after 3 years, both treatment groups showed good outcomes, and a median had not yet been reached for either progression-free survival (PFS) or overall survival (OS). Superiority was not shown for either regimen.

A continues to demonstrate comparable, durable efficacy and safety for rituximab plus lenalidomide versus rituximab plus chemotherapy, and provides an acceptable chemotherapy-free alternative.

In the following interview, Gilles Salles, MD, chief of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York City, discusses the long-term results and the significance for FL patients.

What does this article add to the literature?

Salles: When we define patients with advanced FL we consider patients who need therapeutic intervention. The standard of care for years has been a combination of cytotoxic agents plus rituximab, given that this demonstrates improvement in overall survival over chemotherapy alone. The main chemotherapy regimens are , , or bendamustine, which has a preferable toxicity profile. Some patients who may eventually receive rituximab as a single agent were considered unfit for these combinations.

Lenalidomide and rituximab in the first-line setting showed a high response rate in a phase II study, with an initial favorable outcome that subsequently was maintained. The challenge is whether the same regimen would show similar benefit of duration of disease control and OS. This new analysis adds an additional 3 years of follow-up to the initial phase III study and confirms those results.

What are the highlights of the study?

After a median follow-up of 72 months, we essentially confirm the response data, showing no significant difference in overall response rate. Overall response after progression was 61% with lenalidomide plus rituximab and 59% with rituximab plus chemotherapy, and PFS was 60% versus 59%. The two regimens were similar in time of response and prolongation of efficacy.

We tend to say FL is incurable with modern management, yet we found that 60% of patients did not progress at 6 years after initiating therapy.

The initial assumption was that lenalidomide-rituximab would be better than rituximab-chemotherapy. We failed to demonstrate that, but the statistical design was not aimed to show that. Even with this consideration, I personally feel safe offering patients lenalidomide plus rituximab in terms of efficacy. Also, there were no new safety signals.

What is the significance of the nearly 90% estimated 6-year survival rate?

Salles: With different tools over the past two decades, we are improving survival in FL. This probability of survival is extremely encouraging for patients. An important message for patients is that with adequate management of FL, they have a significant chance of being alive at 6 years. This reflects the efficacy of first-line regimens; 60% of patients may not need to start a second-line regimen before many years.

Why is it important to develop a chemotherapy-free regimen for FL patients?

Salles: We have learned much about the biology of FL, including accumulating evidence about how mutations modify the microenvironment and allow tumor cells to escape response. We have not yet found therapeutic tools to target molecular defects at the origin of the tumor. But I believe there is a good rationale for immune-based therapy.

FL patients survive for years, and may be exposed to recurrence. Therefore, keeping chemotherapy for a later intervention is important. We can use different therapies for different times of the disease. Starting with a chemotherapy-free regimen is a good strategy to develop.

Does lenalidomide plus rituximab change the natural history of FL?

Salles: Advanced FL is not curable, but in RELEVANCE we found that 60% of patients have not progressed after 6 years. The study found that 10-year OS estimates were approximately 80% in both study arms, comparing maintenance therapy with rituximab after induction of response with chemotherapy plus rituximab in comparison with no maintenance therapy. At 10 years about 50% of patients had not progressed, and likely a significant proportion were cured. We may have changed the natural history of the disease with immune-based therapy.

It will be interesting to use ct [circulating tumor] DNA to see why there is no detectable disease years after treatment. We may be able to build new interventions, perhaps using other combinations with anti-CD-20 drugs, or take a combination approach with the new generation of bispecific antibodies, to continue to move the field forward.

What is your bottom-line message for practicing oncologists?

Salles: Lenalidomide plus rituximab is an option for advanced FL patients and should be offered as an alternative to classic chemotherapy. Discuss the pros and cons of therapeutic options with your patients, including the duration of treatment and side effects profile. Also note we need to use low-dose aspirin as prophylaxis with this regimen.

Read the study here.