Expert Discusses Emerging Agents and the Future of Follicular Lymphoma

John P. Leonard, MD

Indolent lymphoma accounts for approximately 30% of patients with non-Hodgkin lymphoma (NHL). When it comes to treating the most common type, follicular lymphoma, oncologists must carefully consider treatments, says John P. Leonard, MD, medical oncology, at Weill Cornell Medicine and NewYorkPresbyterian Hospital.

“When patients relapse after initial therapy, the key factors in choosing a treatment include the time from first therapy, the time to reoccurrence, how sick they are, their age, and what they need in terms of symptom relief at that time,” says Leonard.

Standard treatment options include single-agent rituximab (Rituxan) and chemotherapy with rituximab. However, a number of new approaches for indolent lymphoma and more are on the horizon, Leonard says.

OncLive: What upcoming treatment options for indolent lymphoma do you see the most potential for?

In an interview with OncLive, Leonard discusses the potential for lenalidomide (Revlimid), idelalisib (Zydelig), and ibrutinib (Imbruvica) in follicular lymphoma, possible combination therapies, and challenges that remain in the treatment of the disease. Leonard: There has been some recent data with lenalidomide, which is active in follicular lymphoma both alone and combination with rituximab. There is also idelalisib, a PI3 kinase inhibitor that is FDA approved for refractory follicular lymphoma, and the BTK inhibitor ibrutinib is also active and approved in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma.

What role do you see lenalidomide having for the treatment of follicular lymphoma?

There is also the novel approach of venetoclax, which is in clinical trials for follicular lymphoma. In addition, radioimmunotherapy, which has been around for a period of time, and autologous stem cell transplant, which is appropriate for some patients, are other options. We recently published a paper in the Journal of Clinical Oncology¹ that looked at rituximab relapse in follicular lymphoma. The overall response rate with single-agent lenalidomide was approximately 45% and the response duration was about 1 year. When you add rituximab to that, the response rate went up to 75%, and durability was about 2 years.

What is the safety profile of lenalidomide?

Can you discuss the potential for ibrutinib and idelalisib in follicular lymphoma?

There is an ongoing randomized study known as the AUGMENT trial (NCT01938001), which is looking at single-agent rituximab versus rituximab plus lenalidomide in recurrent indolent follicular lymphoma and other indolent subtypes. This will help us really determine what the role of lenalidomide is versus single-agent rituximab. Lenalidomide is generally well tolerated. Patients can have some fatigue, occasional rash, and occasional thrombosis. People are usually familiar with dealing with these symptoms in myeloma and other places where lenalidomide is approved. Most of these patients tolerate it well, can function and go to work, and have an overall good quality of life while on treatment. Idelalisib was FDA approved in rituximab-refractory indolent lymphoma, including follicular lymphoma, in a study of 125 patients who had 4 prior regimens. The overall response rate was around 54% and durability was about 1 year. The main side effects to watch for with this agent are liver enzyme abnormality and colitis.

Are there additional trials you are interested in?

What are the biggest challenges that remain in the treatment of follicular lymphoma?

Ibrutinib, which is approved in CLL and mantle cell lymphoma seemingly has a lower response rate, but is active in follicular lymphoma. The toxicity profile is very similar to what people are familiar with in CLL and mantle cell lymphoma. There are a number of trials looking at standard therapy with a new drug, such as bendamustine-rituximab with idelalisib, ibrutinib, or a BCL-2 inhibitor, such as venetoclax. There are also studies looking at novel anti-CD20 antibodies. Those are all moving through the system. We need to determine if they are better with regard to overall survival or are just better with regard to progression-free survival, if at all. Also, what are the effects on quality of life? If you are making people live longer, then you need to also try to improve their quality of life. Accurately measuring that is important. One thing to keep in mind is that transformation can occur into an aggressive subtype. We suspect this because of high standardized uptake value on a PET scan or high lactate dehydrogenase, so we should do a biopsy to look for transformation.

Recent data have shown that in patients with follicular lymphoma who progress within 2 years of initial therapy, which is about 20%, have an unfavorable median overall survival of about 5 years. Therefore, that 2-year mark is becoming important. Patients that take longer than 2 years to progress have more sensitive disease; these patients are more likely to die not of their disease, but with their disease. They have a lot of options. However, that 20% of patients who progress in 2 years from their initial therapy are people who we need to think about more carefully, because they are not going to do as well long-term. We need to be able to identify those early progressers.

1. Leonard JP, Jung SH, Johnson J, et al. Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015;33(31):3635-3640.