Regimens Emerging Beyond Chemo in Follicular Lymphoma

Caroline Seymour

Celeste Bello, MD

Celeste Bello, MD

Novel treatment regimens are showing potential in patients with follicular lymphoma, especially those without a chemotherapeutic backbone, explained Celeste Bello, MD, a hematologist/oncologist at Moffitt Cancer Center.

Results from the phase III RELEVANCE trial demonstrated similar efficacy between the combination of rituximab (Rituxan) and lenalidomide (Revlimid; R2) and rituximab and chemotherapy in patients with untreated follicular lymphoma.1 Data presented at the 2018 ASCO Annual Meeting showed that at a follow-up of 120 weeks, R2 induced a complete remission (CR) rate of 48% versus 53% with rituximab/chemotherapy (P = .13).

The objective response rates were 84% and 89% with the R2 and rituximab/chemotherapy regimens, respectively. The 3-year duration of response rates were 77% and 74%, respectively, making the R2 regimen a viable and more tolerable nonchemotherapeutic frontline approach for patients.

In addition to the RELEVANCE trial, data were presented for duvelisib, a novel inhibitor of the PI3Kδ and PI3Kγ pathways. In April 2018, the FDA granted a priority review to the drug for the treatment of patients with relapsed/refractory follicular lymphoma.

In an interview during the 2018 OncLive® State of the Science SummitTM on Hematologic Malignancies, Bello discussed the latest advances in the treatment of patients with follicular lymphoma.

OncLive: What were some of the updates you covered in your presentation on follicular lymphoma?

Bello: I gave updates on some of the newer treatment options that are available. Two of the drugs were presented at the 2018 ASCO Annual Meeting. One was duvelisib, which is a newer PI3K inhibitor. We also saw the preliminary results of the RELEVANCE trial, which looked at the combination of lenalidomide and rituximab in the upfront setting.

Can you explain the design and findings of the RELEVANCE trial?

It enrolled over 1000 patients who were previously untreated with low-grade follicular lymphoma and randomized them to lenalidomide and rituximab or investigator’s choice of chemotherapy––either CHOP and rituximab (R-CHOP), bendamustine and rituximab (BR), or CVP and rituximab. After [approximately] 6 months of treatment, if patients obtained either a CR or a partial remission, they were put on a maintenance treatment for 1 or 1.5 years depending on what line of treatment they were on.

At the 2018 ASCO Annual Meeting, preliminary data were presented and showed that there was no difference between lenalidomide/rituximab and chemotherapy. The take-home message was that it’s a nonchemotherapy regimen that had just as good a response as a chemotherapy regimen. We always have to be cautious, because if you jump onboard too early [you may] find out that there are some problems later on. It will be really interesting to see the long-term data, which will probably be [presented] at either the 2019 ASCO Annual Meeting or the 2019 ASH Annual Meeting.

What do physicians think about the results? Were they hoping to see superiority with R2?

I don’t think most people know about the data just yet because it's fairly new, so I don't think there are feelings either way just yet. The people who were aware of the study are very excited about it because it's a nonchemotherapy option. Patients with follicular lymphoma live a long time; it's managed like a chronic illness. It’s a great option if you can give them a nonchemotherapy option with very little adverse events and no hair loss, nausea, or vomiting.

That's kind of [where] most of the field is going in low-grade lymphoma. We know that people can do well without treatment for a long time, so when you do treat them you don't want to make them worse than how they were to start with. There is a lot of excitement about these low-intensity treatments. It's not curative, but no one expected that.

Has chemotherapy been a standard regimen?

Compared with other cancers, [patients with follicular lymphoma] are not really symptomatic. We just observe them unless they have some issues that you're worried about, such as organ damage or low blood counts [in their] white cells, red cells, or platelets. The thought is: if they are OK, leave them alone as long as possible. When they do need treatment, chemotherapy is the recommended therapy combined with rituximab.

How has duvelisib entered the field?

Duvelisib is extremely new and it’s not yet FDA approved. The pharmaceutical company [Verastem] submitted an application [to the FDA] earlier in 2018. The data in follicular lymphoma were not that overwhelming; it did show responses in patients who had received several prior lines of treatment. I can't say I'm really excited about the duvelisib data, but it's nice to have another option out there. I know they are already working on combination studies with duvelisib and rituximab, and I believe duvelisib and venetoclax (Venclexta). It's all promising.

Can you discuss to the data with copanlisib (Aliqopa)?

The efficacy was very similar to the other PI3K inhibitors, such as idelalisib (Zydelig) and to some extent, duvelisib. The only difference is the administration. It's given intravenously instead of orally. Because of that difference the side effect profile is different. There were certain toxicities that were less with copanlisib versus idelalisib and duvelisib.

What other trials are ongoing?

At Moffitt Cancer Center, we are evaluating chimeric antigen receptor (CAR) T-cell therapy in patients who have progressed despite multiple lines of treatment or who have very aggressive types [of follicular lymphoma] who aren't responding to chemotherapy. The data on that are going to be exciting. It's going to be nice to have that added to the repertoire of treatments.

We've heard about CAR T-cell therapy in other lymphomas, so it must be exciting to see it enter the field of follicular lymphoma.

Yes. It's definitely not for everybody, but there are people who really need it. It's going to be nice to have some data on it.

Is biomarker research being done in the field?

We have lagged behind with biomarkers in follicular lymphoma, probably because the disease is such a chronic illness that there is not any urgency. Recently, there were some data on a new molecular profile called the m7-FLIPI. That looked at genetic markers that would predict poor response to chemotherapy and short survival. It really showed some good results, but it's experimental. The weighted test for those markers is still experimental. It's not something that you can get at any routine lab. It's out there now, and it's becoming more available.

Molecular profiling and personalized [medicine] are what everybody is looking for now. We know that [follicular lymphoma] is a heterogeneous disease. One patient [with follicular lymphoma may not have the same type] as another. We don't know what to do with that information yet, but it is going in the right direction.

What are the biggest challenges in follicular lymphoma?

The biggest challenge is that we don't have a cure for it. Despite all these treatments and genetic markers, we still can't cure it. Our end goal is always to cure. About 2% to 3% of these low-grade follicular lymphomas will mutate to a more aggressive type per year. When that happens, patients have a bad prognosis. That is a group of patients we need to work on a better treatment for than just high-dose chemotherapy and stem cell transplant.
Fowler NH, Morschhauser F, Feugier P, et al. RELEVANCE: Phase III randomized study of lenalidomide plus rituximab (R2) versus hemotherapy plus rituximab, followed by rituximab maintenance, in patients with previously untreated follicular lymphoma. J Clin Oncol. 2018;36(suppl; abstr 7500).
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