Personalized, Chemo-Free Regimens Emerging in Follicular Lymphoma

Kieron Dunleavy, MD

While there is no standard of care for patients with follicular lymphoma, there are a handful of systemic treatment options in the armamentarium with others emerging in clinical trials, explained Kieron Dunleavy, MD.

One regimen that has been added to the paradigm includes the chemotherapy-free combination of lenalidomide (Revlimid) and rituximab (Rituxan; R²) in patients with previously treated follicular lymphoma and marginal zone lymphoma. The regimen was approved by the FDA in May 2019, based on data from the phase III AUGMENT trial, in which the R²  regimen reduced the risk of disease progression or death by 54% versus rituximab alone in patients with relapsed/refractory indolent non-Hodgkin lymphoma.¹ 

Additionally, the phase III RELEVANCE trial explored the combination in previously untreated patients with advanced follicular lymphoma. Results showed that the best overall response rate (ORR) was 84% for R²  and 89% for those who received rituximab/chemotherapy.²  PFS was also similar between the arms.

As the second-most common form of non-Hodgkin lymphoma, follicular lymphoma can be treated with a variety of regimens, but patients can also be monitored before active treatment is necessary, Dunleavy added.

“Over the past few years, there have been a lot of advances in the therapeutics of [follicular lymphoma], both in the treatment of patients who are newly diagnosed with follicular lymphoma as well as for patients who have relapsed or refractory disease,” said Dunleavy. “There are a lot of new agent approaches available in the upfront setting, but we still watch and wait a significant proportion of patients with follicular lymphoma.”

In an interview during the 2019 OncLive State of the Science Summit on Hematologic Malignancies, Dunleavy, a professor of medicine, director of the Lymphoma Program, and co-director of the Microbial Oncology Program in the Division of Hematology and Oncology at the George Washington University Cancer Center, discussed emerging treatment options and when to use the watch-and-wait approach in follicular lymphoma.

OncLive: What is the current state of follicular lymphoma treatment?

Dunleavy: For patients with advanced disease who are symptomatic, we typically apply systemic therapy. There is a lot of controversy about what therapy to use. Over the past 1.5 years, there have been several studies that have looked at different upfront therapies and compared them. The RELEVANCE trial, for example, added lenalidomide to rituximab in a regimen called R² compared with rituximab and chemotherapy in untreated patients with advanced follicular lymphoma.

At the end of the day, there were over 1000 patients on that study, and the two arms were equivalent in terms of survival. However, there was a very different range of toxicities depending on whether you got R² or R-CHOP because lenalidomide has a very different toxicity profile compared with chemotherapy.

[The GALLIUM] study compared rituximab plus chemotherapy versus obinutuzumab (Gazyva) with chemotherapy. That study showed a PFS benefit for patients who received obinutuzumab, but the overall survival was similar between arms. In terms of the toxicity profile, the obinutuzumab arm was more toxic than the rituximab arm.

There are a lot of new agents in follicular lymphoma that are being tested principally in the relapsed/refractory setting. There is a lot of excitement about PI3K inhibitors. There are now a number of them that have been investigated and have good activity as single agents.

BTK inhibitors are another class of agents that are being tested. There are many other drugs in development as well, including polatuzumab vedotin (Polivy), which is an anti-CD79b agent. Additionally, anti-CD19 CAR T-cell therapy is an interesting strategy in follicular lymphoma. It's still early, but there are some interesting results so far. We'll just have to wait and see what the long-term outcome of that approach is.

What systemic regimens do you typically use in clinical practice?

When we institute systemic therapy, there are many choices in follicular lymphoma and there are no standards regarding what approach you should use. Single-agent rituximab is sometimes a reasonable treatment. For patients with more aggressive disease, we generally think of combining a CD20-directed monoclonal antibody with chemotherapy. There are different regimens, such as bendamustine/rituximab, R-CHOP, and R². The choice to use one of those depends on a number of different factors. For patients with very aggressive disease, and if I think there may be any transformation present, I would tend to use a more aggressive regimen such as R-CHOP. If that's not the case, there are other reasonable regimens to consider. It depends on the clinical picture.

Could you elaborate on the data that have been reported with PI3K and BTK inhibitors?

There are a number of PI3K inhibitors that have been tested in follicular lymphoma. All of these PI3K inhibitors work in slightly different ways and have different toxicity profiles. We are seeing good activity as a single agent in the relapsed/refractory setting and, when we look at the activity of these agents, we need to consider toxicity, as well. As we see more trials with PI3K inhibitors, we are seeing different types of toxicities, depending on how they work.

BTK inhibitors are somewhat effective in follicular lymphoma, but they have not been hugely effective so far. They can be combined with other agents or classes of drugs, and we may see synergistic activity [then]. There are lots of ongoing trials at the moment that are looking at interesting combinations in follicular lymphoma.

What other targets are being explored in this disease?

There are a number of interesting targets in follicular lymphoma; one of the most important ones is BCL-2. There are trials that have been published using BCL-2 inhibitors in follicular lymphoma with some overall good activity. There are a number of other targets that are interesting in follicular lymphoma, including BTK, PI3K, CD47, and CD79b. The question is, “Which patients are going to benefit from which strategies?” A lot of work is being done to investigate this to ultimately personalize treatment for follicular lymphoma.

Has there been research on identifying different patient subgroups within follicular lymphoma?

[Subsets of patients are] in the process of emerging. Compared with diffuse large B-cell lymphoma, we don't understand the genomics of follicular lymphoma or the genetic importance of thinking about what agents are best to use in this disease. However, we are gradually moving closer to that point.

How do you assess patients to determine whether they are eligible to hold off on treatment?

When I watch and wait patients, I typically see them back after a certain number of months, usually 6 months, to see how they're doing. Usually, these patients are asymptomatic. I repeat their imaging 6 months after their initial diagnosis to see if there has been any progression over 6 months or if things have stayed completely stable. Generally, if they have stayed very stable and if a patient continues to be asymptomatic, then I continue the watch-and-wait approach. If there has been progression of disease, or if somebody has become asymptomatic in that time period, I would start thinking about instituting some kind of therapy.

In your experience, how long can patients can be watched without active treatment?

There is a whole spectrum. Patients can be [observed] for decades, or sometimes for just a few months. It can it can be anywhere between a short period of time, to a few months, to several years.

References

1. Leonard JP, Trněný M, Izutsu K, et al. AUGMENT: a phase III randomized study of lenalidomide plus rituximab (R2) vs rituximab/placebo in patients with relapsed/refractory Indolent non-Hodgkin lymphoma. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 445.
2. Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus chemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36 (suppl; abstr 7500). doi: 10.1200/JCO.2018.36.15_suppl.7500.