Emerging Approaches Seek to Expand the Relapsed/Refractory Follicular Lymphoma Treatment Arsenal

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Lori A. Leslie discusses several key studies evaluating emerging approaches in the relapsed/refractory follicular lymphoma paradigm.

Lori A. Leslie, MD

The treatment landscape of relapsed/refractory follicular lymphoma continues to expand with novel approaches, including targeted agents, combination regimens, and CAR T-cell products, according to Lori A. Leslie, MD, who added that as more data emerge on these approaches, more life-prolonging options could soon become available.

“Depending on what the patient received in the frontline setting, options [in this setting] include bendamustine/rituximab versus rituximab, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), which is a good choice there,” said Leslie. “Obinutuzumab (Gazyva) can be the CD20 antibody of choice. There is also clinical trial participation.”

Other agents generating excitement in this setting include tazemetostat (Tazverik), according to Leslie. This agent was approved by the FDA in June 2020, for use in patients with relapsed/refractory disease whose tumors are EZH2 mutated and who have received at least 2 prior systemic therapies, as well as those with relapsed/refractory disease who have no satisfactory alternative treatment options.

The regulatory decision was based on data from 2 open-label, single-arm cohorts of the multicenter Study E7438-G000-101 (NCT01897571) trial, which showed that the agent elicited an objective response rate (ORR) of 69% per independent review committee in patients with EZH2-mutant disease (95% CI, 53%-82%). In those with EZH2 wild-type disease, the ORR was 34% (95% CI, 22%-48%).

“Hopefully, CAR T-cell therapy will also be available soon as a potential standard-of-care option for patients with relapsed/refractory disease,” added Leslie. “It’s a very complex landscape but in an exciting way because [with all of this research], we are becoming increasingly hopeful for our patients with this disease.”

In an interview with OncLive, Leslie, a lymphoma attending at John Theurer Cancer Center (JTCC), Hackensack Meridian Health, highlighted several key studies evaluating emerging approaches in the relapsed/refractory follicular lymphoma paradigm.

OncLive: Could you start off by providing a brief snapshot of the current treatment landscape of follicular lymphoma?

Leslie: Follicular lymphoma is a very heterogeneous type of B-cell non-Hodgkin lymphoma, with varied clinical courses. In the frontline setting, the main factors that inform treatment are the patient's age, comorbidities, and how aggressive their disease appears. However, we don't have great predictive and prognostic factors for choosing those patients in the up-front setting if they're at risk for poor outcomes. Those patients typically progress within 2 years on up-front chemoimmunotherapy.

In general, approaches include CD20 monoclonal antibody monotherapy with rituximab (Rituxan) and chemoimmunotherapy. Some common regimens include bendamustine/R-CHOP, the type II CD20 monoclonal antibody obinutuzumab in combination with chemotherapy.

There's always the discussion of whether to give patients who respond to chemoimmunotherapy a maintenance CD20 antibody, such as rituximab or obinutuzumab, as another choice. It’s getting increasingly complicated [to navigate among the available options], not only in the frontline setting, but also in the relapsed/refractory setting.

Once you get to the relapsed/refractory setting, key components of the patient's case include prior treatment and the time they were in remission from their prior treatment. Those factors dictate the choice of second-line therapy. If someone received rituximab monotherapy, you could consider retreatment in a rare group of patients versus rituximab plus lenalidomide, or R2. Recent data from the AUGMENT study evaluating R2 versus rituximab alone [were released and showed that] patients did [better] with R2.

How do you determine which patients should undergo active surveillance rather than immediate treatment?

Some patients with follicular lymphoma are candidates for the watch-and-wait approach; it’s typically those who are asymptomatic and who are diagnosed incidentally. We use several different criteria [to determine which patients qualify for this approach]. I believe the most commonly used criteria are the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria.

You should start treatment if we're worried that patients may develop symptoms soon or are actually symptomatic from the disease. Some of those factors can include cytopenias from the disease, where it’s pushing out the patient’s normal ability to make red cells or platelets. This can include a leukemic phase; bulky disease, which is usually greater than 10 cm of 1 lesion or 3 areas greater than 3 cm; and effusions. Depending on the degree of symptoms or the clinical picture, if it is suggestive that symptoms are soon to develop, that's really what triggers us to treat versus use the watch-and wait approach.

That being said, some patients don't have a clear trigger; maybe they have fatigue or some of these other hard-to-define B-type symptoms thatyou can see from lymphomasthat do require treatment, but do not necessarily meet the strict GELF criteria. We have many criteria that help us guide who to treat and who to watch and wait, but there is still a lot of variability within that and a discussion between the provider and the patient is necessary.

Shifting back to the treatment of patients with relapsed/refractory disease, tazemetostat recently received regulatory approval for those whose tumors harbor EZH2 mutations. Could you speak to the data that led to that decision? What is the significance of this approval?

Tazemetostat is an oral EZH2 inhibitor. I believe the first [designation for this agent] was in epithelioid sarcoma as an orphan drug at the beginning of 2020. On June 18, 2020, tazemetostat was approved for use in patients with in relapsed/refractory follicular lymphoma.

Although there is activity with this agent in both EZH2 mutant and EZH2 wild-type follicular lymphoma, the label is for patients with relapsed/refractory follicular lymphoma with an EZH2 mutation or those with relapsed/refractory follicular lymphoma who have no other appropriate options. As such, there's a little bit of wiggle room in terms of the actual label based on the data that led to the approval.

The results came from a multicenter phase 2 study looked at [the use of this agent in] 99 patients. One cohort consisted of patients with EZH2-mutant relapsed/refractory follicular lymphoma, and the other cohort consisted of patients with EZH2 wild-type disease. The dosing for tazemetostat is 800 mg twice daily until either disease progression or unacceptable toxicity. In terms of the primary end point of the trial, the ORR in those with EZH2-mutant disease was higher, at 69% with 12% of patients achieving a complete remission (CR). Activity with the agent was also observed in those with EZH2 wild-type disease; in this cohort, the ORR was 34%, with a CR rate of 4%.

The duration of response (DOR) data are a little premature at this time point, but it is somewhere between 11 to 13 months right now, but the toxicity profile of the agent was very favorable. In this group of patients with relapsed/refractory follicular lymphoma, compared with other agents we are familiar with such as the oral PI3K inhibitors, tazemetostat had a well-tolerated toxicity profile. Some fatigue, nausea, and upper respiratory tract infections were reported, but most of these effects were grade 1 or 2, with very low rates of grade 3 to 4 toxicity.

It’s a great option to have available for a subset of our patients, but it’s also an exciting option to have [for potential use in future]combinations, as we continue to develop the drug in follicular and other EZH2-abnormal lymphomas.

Do you feel that with this approval, testing for EZH2 mutations in these patients is becoming more of a standard practice?

This incidence of the EZH2 mutation is reported to [be present in] 20% to 30% [of] overall follicular lymphomas. However, I don’t think this mutation was being looked for too much prior to this targetable drug.

Now, Hackensack Meridian Health and several other research centers are doing next-generation sequencing and molecular testing on all lymphomas in the up-front setting but also at the time of each relapse so that we can understand molecularly how these patients evolve as they relapse. We also want to determine [how we might be able to] target [this mutation] to prevent relapse in the future. With the approval of tazemetostat, there is also a companion diagnostic test that was approved to allow for relative ease of EZH2 testing in the community setting.

What are the future directions for research with tazemetostat? Are any novel combinations with this agent already under exploration?

An ongoing study is assessing the R2 regimen in combination with tazemetostat. The initial phase 1b portion is examining R2 plus EZH2 inhibition and then that will likely expand into a phase 3 trial assessing R2 plus or minus EZH2 inhibition. This trial is being done is in patients who have received at least 1 prior line of therapy; however, the prior line can be just rituximab monotherapy.

In many of our relapsed/refractory follicular lymphoma studies, to be considered relapsed, a patient must have had exposure to a prior CD20 antibody as well as an alkylating agent.

Although this is a relapsed/refractory setting, it's a patient population that could potentially only be exposed to a CD20 antibody and a chemotherapy-free approach early on. In the landscape of follicular lymphoma, this is very appealing. This study is open at my institution and several others and I'm very excited to see how this pans out for our patients with this disease.

Could you expand on the data that have been reported with R2 in the relapsed/refractory setting?

The phase 3 AUGMENT trial is examining R2 in [patients with] relapsed/refractory follicular lymphoma, which has been very exciting. Specifically, patients with indolent lymphomas, including follicular and marginal zone lymphoma (MZL) [have been enrolled]. Participants were randomized to receive either rituximab monotherapy or R2 for 1 year of treatment. It wasn't surprising to me that ORR, progression-free survival (PFS), and DOR were [prolonged] with R2 versus rituximab alone.

However, when examining some of the more distant outcomes, which is PFS2, so PFS to the subsequent line of therapy, time to next treatment and even overall survival in the follicular lymphoma cohort all favored R2. As such, it makes me wonder whether introducing an immunomodulatory agent earlier in the course of the disease is going to be a very important strategy moving forward. As those data further mature, I'm very interested to see how those patients do later on and how these other combinations with R2 are going to pan out.

Are any other exciting approaches in the pipeline?

The most exciting upcoming treatment in follicular lymphoma is CD19-targeted CAR T-cell therapy. Data from the ZUMA-5 trial were presented during the 2020 ASCO Virtual Scientific Program. In this trial, investigators assessed [axicabtagene ciloleucel (axi-cel; Yescarta)] in patients with indolent lymphoma. Results were mostly focused on the follicular lymphoma cohort of that study.

The initial 9-month data were presented; 80 of the patients had follicular lymphoma and 16 patients had MZL. With a median follow-up was 15.3 months, the ORR in the whole cohort of relapsed/refractory indolent lymphomas was 93% with the majority of patients, or 80%, achieving a CR.

Looking at the follicular lymphoma cohort specifically, the ORR was 95%, with 81% of patients achieving a CR. [ORRs were] was slightly lower in the 16 patients who had MZL, at 81%, with 75% achieving a CR. I'm very interested to see how this will pan out with more follow-up. Hopefully, there will be another presentation later this year with updated data from that trial. I'm hopeful that these data will lead to an FDA approval for patients with relapsed/refractory follicular lymphoma, and potentially in the future, MZL. I believe that has the potential to dramatically change the treatment landscape for relapsed/refractory disease.


FDA granted accelerated approval to tazemetostat for follicular lymphoma. News release. FDA. June 18, 2020. Accessed August 28, 2020. bit.ly/310qcSe.

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