Expert Discusses Developments in Follicular Lymphoma

Lori Ann Leslie, MD

Combination regimens with low toxicity profiles are being explored in follicular lymphoma, as novel agents seem to have low single-agent activity in early lines of treatment, says Lori Ann Leslie, MD.

“The issue with monotherapies, such as ibrutinib (Imbruvica) and venetoclax (Venclexta), is that their activity as single agents is low. Finding combinations with tolerable toxicity profiles remains to be the main challenge,” said Leslie.

Moreover, data presented at the 2017 ASH Annual Meeting revealed studies that have confirmed the benefit of rituximab (Rituxan) in the maintenance setting of follicular lymphoma. Long-term follow-up of the PRIMA trial, for example, showed the benefit of maintenance rituximab versus observation post-upfront chemoimmunotherapy with R-CHOP.

However, in the phase III RELEVANCE study, the combination of rituximab and lenalidomide (Revlimid) followed by maintenance therapy with the same regimen did not improve response or progression-free survival (PFS) versus rituximab and chemotherapy with rituximab maintenance for patients with previously untreated follicular lymphoma.

OncLive: What is the state of the treatment paradigm in follicular lymphoma?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Leslie, lymphoma attending, John Theurer Cancer Center, provided expert insight on the latest developments in the field of follicular lymphoma.Leslie: A 10-year update from the PRIMA study, presented at the 2017 ASH Annual Meeting regarding the role of maintenance rituximab post-chemoimmunotherapy, showed a continued PFS benefit at 10 years. Over half of the patients who received maintenance rituximab versus observation did not require subsequent therapy compared with 35% in the observation arm. There is the use of maintenance rituximab following bendamustine/rituximab (BR) induction therapy. Though there are no clinical trials that are randomized to support this approach, there were some retrospective studies and analyses of prior follicular lymphoma cohorts that suggest a similar PFS benefit.

Can you elaborate on the data presented in the maintenance setting?

There are novel approaches in the upfront setting, but nothing is practice changing. In terms of prognostic models, there were some abstracts looking at the importance of including factors from the tumor microenvironment and host immune system, in addition to our more standard clinical and genetic risk factors used of the tumor itself.The 10-year follow up of PRIMA, the randomized study looking at 2 years of maintenance rituximab versus observation after upfront chemoimmunotherapy, reported a greater than 50% PFS in the maintenance arm versus 35% in the observation arm. Though there was no difference in overall survival (OS), the use of maintenance rituximab made a significant difference in time to next treatment.

The BIONIC study looked at the use of bortezomib (Velcade) [added to BR] in the induction setting with or without the addition of lenalidomide [as continuation treatment] in the maintenance setting. This showed no increase in efficacy. Increased toxicity was seen with the addition of these agents, so it's not an approach that is being further pursued.

Is chemotherapy vital in the management of the disease?

Have the results of the GALLIUM study impacted patients with follicular lymphoma?

The last study that we discussed in the maintenance realm was the MAINTAIN study, which looked at the difference between 2 and 4 years of maintenance rituximab following BR induction therapy. This showed that there was no difference in PFS, but also no difference in toxicity between the 2 approaches. They then did a cross-trial analysis looking at 2 years of maintenance in the MAINTAIN study versus observation after BR. This was compared with a 2003 study in Hodgkin lymphoma, where 2-year maintenance treatment showed a similar PFS benefit versus observation without the OS benefit we had seen in other studies. As it stands now, yes. Induction includes chemotherapy for patients with follicular lymphoma. The RELEVANCE trial looked at the use of lenalidomide plus rituximab versus any chemoimmunotherapy in the upfront setting. We are eagerly awaiting those results; they will likely be reported at an upcoming meeting. The GALLIUM study was presented in 2016 and was recently published in the New England Journal of Medicine. The study is looking at the upfront use of obinutuzumab (Gazyva), a type II anti-CD20 monoclonal antibody, versus rituximab in combination with chemotherapy followed by CD20-antibody maintenance therapy. The study showed a PFS benefit, but also an increased incidence of serious adverse events in the obinutuzumab group.

Can you explain duvelisib’s mechanism of action?

Due to this possible toxicity signal and also a potential cost differential, it hasn't been formally analyzed to my knowledge. It hasn't moved into frontline standard of care, but it is being used as a backbone in ongoing trials of novel approaches in the upfront setting. One trial is examining obinutuzumab plus bendamustine, for example.PI3K is an important target in follicular lymphoma, and duvelisib has shown efficacy in the relapsed/refractory setting. However, it is not without toxicity. Duvelisib and some of the other targeted agents, though effective, have a similar toxicity profile. Some newer agents approved in the relapsed/refractory setting, like copanlisib (Aliqopa), have a similar efficacy without the added toxicity of some of the previous generation PI3K inhibitors.

What has the progress of CAR T-cell therapy been in lymphomas?

Umbralisib is another efficacious and tolerable PI3K-delta inhibitor that soon will be approved for follicular lymphoma. Developing better prognostic indices to predict poor outcomes to upfront chemoimmunotherapy will help us better use risk-adapted approaches to combine novel agents with standard-of-care backbones. Hopefully, we will be able to move towards a chemotherapy-free approach.CAR T-cell therapy is a very exciting field across lymphoma subtypes with recently approved constructs in the diffuse large B-cell lymphoma setting. We have ongoing trials at John Theurer Cancer Center in MCL that have also show promising efficacy in heavily pretreated patients. Indolent lymphomas, including follicular lymphoma, are a great subtype for CAR T-cell therapy.

One of the challenges with aggressive subtypes of lymphoma is that patients get too sick before they are able to receive the infusion of cells. Although the data are limited at this point, we are seeing excellent results in follicular lymphoma. Soon, we will be opening a low-grade lymphoma trial at John Theurer Cancer Center. There are other trials that are available throughout the country. Hopefully, this will move forward as a potentially curative approach in indolent NHL.