Expert Perspectives in the Evolving Treatment Landscape for Follicular Lymphoma

John M. Burke, MD

OncLive: Could you discuss the current treatment paradigm for follicular lymphoma? What options are available for patients in both the front-line and relapse/refractory settings?

Burke: We know that the majority of patients will take many years to relapse, and those patients have an excellent prognosis with a median survival approaching that of patients who don’t have follicular lymphoma. The unfortunate patients tend to relapse more quickly. We know that those who relapse within a couple of years of their treatment tend to have less favorable prognosis with median survival on the order of 4 to 5 years. The options for relapsed patients include additional chemoimmunotherapy, maybe the same, or maybe different from what they received before the combination of lenalidomide and rituximab. Then, PI3 kinase inhibitors (which has the 3 options within that category) are available for treatment of follicular lymphoma. Then, just recently, we had a fourth tool in the arsenal added, with tazemetostat, which is has a novel mechanism—it’s an EZH2 inhibitor. That’s a new mechanism that we have available to us for relapsed follicular lymphoma. I should also add radioimmunotherapy has been an option for these patients for many years, as well, and still remains an option.

Lori A. Leslie, MD

Leslie: Follicular lymphoma is a very heterogeneous type, B-cell non-Hodgkin lymphoma, with very clinical courses. I think in the frontline setting, the main factors that decide treatment are a patient’s age, comorbidities, clinical situation of how they’re presenting, [and] how aggressive the disease appears. But we honestly don’t have great predictive and prognostic factors for choosing those patients in the upfront setting who are at risk for poor outcomes, so those patients are typically those who progress within 2 years of their up-front chemotherapy. In general, treatments include CD20 monoclonal antibody monotherapy with rituximab. Chemoimmunotherapy—some common regimens are bendamustine plus rituximab, R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), vincristine sulfate, and prednisone], obinutuzumab, [and] the type 2 CD20 monoclonal antibody in combination with chemotherapy is also something used in the front line. Then there’s always the discussion [with] patients who respond to chemoimmunotherapy whether or not you give a maintenance CD20 antibody, whether that’s rituximab or obinutuzumab as another choice. It’s getting increasingly complicated not only in the frontline setting but also the relapsed/refractory setting.

Kami J. Maddocks, MD

Maddocks: Once they do require treatment, some patients are able to be treated with single-agent antibody therapy with rituximab. Some patients need combination treatment. Treatment options that are available at that time include combination chemoimmunotherapy, bendamustine in combination with rituximab, CHOP chemotherapy in combination rituximab, [and] sometimes CVP [cyclophosphamide, vincristine, and prednisone] chemotherapy in combination with rituximab is still used. Bendamustine can also be combined with anti-CD20 monoclonal antibody obinutuzumab, and so can CHOP in the frontline setting. These continue to be options at relapse. [Although] not FDA approved, rituximab in combination with lenalidomide up front has been studied and [is shown] to have efficacy in that setting, and that is also an option for patients who you may not feel chemotherapy is appropriate for. In the relapsed setting, these options [may] be used. Also, lenalidomide is approved and an option for second and later lines of therapy. There [are also] PI3 kinase inhibitors. There are 3 approved PI3 kinase inhibitors—duvelisib, copanlisib, and idelalisib—that are used most often in the third-line or later setting. This summer we saw the approval of tazemetostat, which is an EZH2 inhibitor approved for both the patients who are EZH2-mutant and patients who are wild-type and have no other options. Then, of course, there are always clinical trials.

Alan Skarbnik, MD

Skarbnik: The treatment in follicular lymphoma in my opinion should be highly personalized, depending on how the patient presents [and] what grade the person has. In terms of biopsy, if you could have access for genetic mutation tests, that is interesting to be done to better understand what are the attackers we’re trying to target if we were to use any targeted therapy. But in general terms of patients with follicular lymphoma who do require treatment and remembering that not all patients require treatment, they may expect an observation for many years until treatment is required. But for patients who do require treatment, it’s going to depend on stage, age, and grade of the lymphoma, as well as comorbidities.

What patients are eligible for the watch-and-wait approach versus when you would decide to initiate therapy?

Burke: First of all, there’s the stage. There’s the low tumor burden versus high tumor burden distinction for those with advanced stage. Then there’s the risk stratification of scoring systems such as the FLIPI score, which has prognostic implications. There’s the FLIPI score. There’s the FLIPI2 score. There’s the m7-FLIPI score. The m7-FLIPI score incorporates results of a gene sequencing analysis to understand what mutations the cancer cells have.

Leslie: An indolent B-cell non-Hodgkin lymphoma, follicular lymphoma in general, is the most common type of B-cell non-Hodgkin lymphoma. Some patients are candidates for watch and wait. So typically, those patients have been asymptomatic. [They received a diagnosis] incidentally, and there are several different criteria. I think the most commonly used criteria are the GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria. Looking at symptoms that trigger [whether] this patient should start treatment, we worry they’re either going to develop symptoms soon or are actually symptomatic from the disease. So those factors are cytopenias from your follicular lymphoma where it looks like it was [limiting the bone marrow's ability] to make red cells or platelets. We can include a leukemic phase of follicular lymphoma, LP [lymphocyte-predominant] disease, which is usually greater than 10 cm of 1 lesion or 3 areas greater than 3 cm, effusions. Basically, depending on the degree of symptoms or the clinical picture suggesting symptoms are soon to develop—that’s really what triggers a treatment versus watch and wait.

Maddocks: Frequently, somebody who [receives a diagnosis of] follicular lymphoma and you’re going to watch and wait is [a patient] who has a lower tumor burden, either not with very large lymph nodes or not very many lymph nodes involved. It’s going to be an asymptomatic patient, so they don’t have symptoms of their disease. They’ll have a relatively normal blood count, so it’s not making them anemic; [they don't have] thrombocytopenia or other problems that you have to address with treatment.

Skarbnik: We know that patients may need treatment at some point. We’re just trying to [treat] at the right time where we are not just avoiding adverse effects but also potentially prolonging their life span and disease-free period. So patients who do not present with any symptoms associated with [it], mainly don’t present with significant fatigue, night sweats, weight loss, or blood counts that are not abnormal in the significant way secondary to the lymphoma, lymphoma neutropenia of the bone marrow, or don’t present bulky disease, or don’t present multiple sites of disease that are enlarged. The GELF criteria include 3 cm on 3 sides, about an inch in size on 3 different sides. There’s no indication that it is progressing quicker than we would expect otherwise; these patients can certainly go through active surveillance, knowing at a point in their lives, treatment will be required. For base presentation, we use the FLIPI [Follicular Lymphoma International Prognostic Index] criteria for prognosis. Then adapt to how often to follow these patients, depending on how they present as well. At some point in time, if that changes and patients present with criteria that would endorse the use of treatment, then simply we can change very quickly at a time.

Could you discuss the recent approval of tazemetostat and the data that led to that approval?

Burke: The drug appeared to be more active in the patients who have a mutated EZH2 component of their follicular lymphoma. The toxicities of the drug were relatively modest. Grade 3 and 4 toxicities were very rare. The toxicities that were notable [were] anemia, some other cytopenias were seen, fatigue, and asthenia was reported, some upper respiratory tract infections were reported. It was a well-tolerated treatment. It takes a little bit longer to work than most conventional [chemotherapy] drugs. The median time to response was almost 4 months, so it’s not quite as quick as a chemotherapy regimen in terms of shrinking tumors, and most responses are partial. It’s a new option for patients, and again, a lot of it comes down to the patient selection because it has those 2 different indications that it got the label for.

Leslie: Tazemetostat is an EZH2 inhibitor, an oral agent. The first approval, I believe, was in epithelioid sarcoma as an orphan drug, beginning of 2020. And then more recently, just on June 18 of this year, it was approved in relapsed/refractory follicular lymphoma. There's a multi-center phase 2 study that looked at 99 patients; 1 cohort of [patients with] EZH2-mutant relapsed/refractory follicular lymphoma, the other EZH2 wild-type. Dosing is 800 mg twice daily of tazemetostat until either progression or unacceptable toxicity. Then primary end points. Overall response rate in those with EZH2 mutation was higher at 69%, with 12% of patients achieving a complete remission. Also, activity in EZH2 wild type, overall response rate of 34% as a single agent with 4% complete remission. One thing that caught my eye about this study was that the duration of response rate is a little bit premature at this point, but it’s somewhere right now in the 11- to 13-month range, but the toxicity profile was very favorable. So, I think, in this group of [patients with] relapsed/refractory follicular lymphoma, compared with what we’re familiar with for some of the other oral agents, in particular the oral PI3 kinase inhibitors, there was a well-tolerated toxicity profile in my opinion for tazemetostat.

Maddocks: That agent was just recently approved. Again the approval was for patients with EZH2-mutant disease or patients who don’t have other effective therapies. There was higher activity in the patients with EZH2-mutant disease and those who were wild-type, but there were still responses, although [the results were more than] double that in the patients who were EZH2-mutant. This is [an] oral therapy, so it’s brought another oral therapy available to patients in this setting. All these therapies have toxicities, but [it] seemed some of the toxicities that we see with some other available oral therapies...seem to maybe be better tolerated than that. So it’s an option that could be used potentially earlier than some of the other options that are a little bit better tolerated.

Skarbnik: Tazemetostat is a drug that’s an EZH2 inhibitor that was previously approved for epithelioid sarcoma and has been recently approved for follicular lymphoma with at least 2 prior therapies. The clinical trials are based on phase 2 data, so [there are] no phase 3 data to really compare with other treatments that are available. It is based on response rate and duration of response. The clinical trials used tazemetostat for treatment of patients with both wild-type EZH2 and mutated EZH2. So certainly the rates of response were different in these 2 populations. For patients with EZH2 mutant disease, it was about 65% response rate and the duration of response was close to a year. For patients with complete response, the response was higher, 12%. Whereas in patients with EZH2 wild-type, it was about 32% of patients who presented any kind of response, overall response rate, but much lower rate in their response of complete remissions or complete responses. However, the duration of response was not much different. It was about 13 months. For those patients who do present a response, the duration of response is similar whether they’re wild-type or mutant, but it is a much higher rate of response in those patients who have EZH2 mutant disease because it’s likely the driver of the disease at that point.

Are there any other novel drugs or combinations in the pipeline that appear promising? For example, chimeric antigen receptor (CAR) T-cell therapies?

Burke: There are exciting things in development for follicular lymphoma. Just to name a couple, and I’m probably forgetting many, but CAR T-cell therapy really looks promising and effective in follicular lymphoma, but that certainly has no insignificant toxicities. Bispecific antibodies appear to be having good activity against follicular lymphoma in clinical trials, and I know that additional development is ongoing with those. There’s some exciting new molecules and drugs being developed to improve outcomes even more.

Leslie: I think the most exciting upcoming treatment for follicular lymphoma is CD19 CAR T-cell therapy. Just at ASCO [American Society of Clinical Oncology Virtual Scientific Program] this year the ZUMA-5 [NCT03105336] data [were presented], which looked at CD19 CAR T in patients with indolent lymphoma, mostly focusing on the follicular lymphoma cohort of that study. The data presented were the initial 9 months [of] data, so patients had at least 9 months of follow-up. Most, 80, had follicular lymphoma. It did include 16 patients with marginal zone lymphoma and, again, a median 15.3 months of follow-up. The overall response rate in the whole cohort of relapse/refractory indolent lymphomas was 93%, with the majority of patients, 80%, achieving a complete remission. Then looking at the follicular lymphoma cohort overall response, 95%, with 81% achieving complete response [but] slightly lower in the 16 patients that had marginal zone with a response rate of 81% and 75% complete response.

Maddocks: CAR T cells do appear promising for follicular lymphoma. There may be a specific group of follicular patients that may benefit most from this therapy. There are newer bispecific antibodies that have been studied in relapse lymphomas in general and that have included follicular lymphoma. These appear, although earlier in the study, promising, [with] less toxicity and just [an] easier administration access for patients. So I do look to this to be something that will probably be an exciting option for us in follicular lymphoma. There are some other antibody-drug conjugates, maybe we have a little bit more data in large cell, but certainly these are approved in Hodgkin [lympho- ma], other proliferative diseases, and our potential thing that will be available in follicular [lymphoma] in the future. Tafasitamab is a single-agent CD19 antibody that was just approved in large cell in combination with lenalidomide, and certainly that will probably be evaluated further in follicular lymphoma.

Skarbnik: What we’re all most excited about is the use of CAR T-cell therapy in follicular lymphoma. So CAR T-cell therapy has been used in a number of different lymphomas. It has approval in diffuse B-cell lymphoma and mantle cell lymphoma. It has also separate approval for patients with lymphoblastic leukemia, for patients under 25. Those are different agents there, different components. The ZUMA-5 study used the axi-cel in follicular lymphoma patients with at least 2 prior therapies and had very interesting response rates, upwards of 80% overall response, with very noticable complete remissions and duration of response. It’s beyond 1 year. The 1-year overall survival in these populations, about 96%. The median survival has not been reached. The PFS [progression-free survival] has not been reached, so it’s very early. We need to wait a little bit longer for the data to mature, and certainly we are waiting for these data to be approved.