: 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?

: 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.

: 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.

: 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 

-mutant and patients who are wild-type and have no other options. Then, of course, there are always clinical trials.

: 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?

: 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.

: 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.

: 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.

: 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 

 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.

: 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] 

-mutant relapsed/refractory follicular lymphoma, the other 

 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 

 mutation was higher at 69%, with 12% of patients achieving a complete remission. Also, activity in 

 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.

: That agent was just recently approved. Again the approval was for patients with 

-mutant disease or patients who don’t have other effective therapies. There was higher activity in the patients with 

-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 

-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 

. So certainly the rates of response were different in these 2 populations. For patients with 

 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 

 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 

 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?

: 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.

: 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.

: 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.

: 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.

Articles

Experts provide their perspectives on the evolving treatment landscape for patients with follicular lymphoma.

Expert Perspectives in the Evolving Treatment Landscape for Follicular Lymphoma

Although the majority of patients with follicular lymphoma (FL) have a life expectancy similar to that of the general population, predicting which patients will relapse and finding therapies that provide durable responses in the relapsed or refractory (R/R) setting remains an ongoing challenge, according to oncologists specializing in hematologic malignancies who participated in a recent 

workshop held on July 29, 2020, led by John Pagel, MD, PhD, of the Swedish Cancer Institute in Seattle.

FL is the second-most-common subtype of non-Hodgkin lymphoma (NHL) and accounts for 20% to 25% of new diagnoses in Western countries.

 The age-adjusted rates of new cases and deaths were 2.7 and 0.5 per 100,000 individuals per year, respectively, based on data from the Surveillance, Epidemiology, and End Results (SEER) program from 2013 to 2017.

 FL tends to be more common in older adults, with a median age of 60 to 65 years at diagnosis.

 The overall survival (OS) has increased since the 1990s, with a 5-year relative survival of 89% based on data from the SEER 18 registry spanning 2010 to 2016.

The World Health Organization grading system categorizes FL based on cytologic features.

 Pagel noted that patients with grades 3A and 3B FL often have more aggressive disease and may require a different management strategy than do patients with grade 1 or 2 FL. Grades 1 and 2 FL have a similar Ki67 index (<20%) and phenotypic and cytogenic features but differ in the number of centroblasts per high-powered field (0-5 and 6-15 centroblasts for grades 1 and 2 FL, respectively).

 Grades 3A and 3B FL have a Ki67 index greater than 20% and more than 15 centroblasts per high-powered field, but 3A FL is characterized by centrocytes with expression of CD10 and BCL2 and translocation of 

 in about 75% of cases, whereas grade 3B FL is characterized by diffuse areas of centroblasts and usually a lack of 

 translocation or lack of expression of CD10 and BCL2.

Prognostic Scores and Predicting Risk for Relapse

The Follicular Lymphoma International Prognostic Index (FLI- PI) was published in 2004 and is based on results from an international cooperative study that analyzed 4167 cases of FL diagnosed initially between 1985 and 1992.

 Based on the study team’s retrospective analyses, the FLIPI model was built based on age at diagnosis, Ann Arbor stage, hemoglobin level, number of nodal areas involved, and serum lactate dehydrogenase level.

 Classification of patients as low (0-1 factor), intermediate (2 factors), or high risk (3 or more factors) predicted OS at 5 and 10 years.

 The FLIPI index has also been shown to predict OS in the chemoimmunotherapy era, with hazard ratios (HRs) for OS of 2.37 and 6.17 in the intermediate- and high-risk groups, respectively, compared with the low-risk group in an analysis of 2192 patients enrolled in the National LymphoCare Study (NCT00097565).

However, the FLIPI index may have limited clinical utility because the initial cohort may not reflect the current course of the disease and because the index was based on a retrospective analysis of archive data. To improve on this predictive model, investigators prospectively collected data of 942 patients from 2003 to 2005 to build the FLIPI2 index, a model that includes age, body mass index, hemoglobin level, greatest diameter of the largest involved node, and serum β

 The 3-year progression-free survival 2 (PFS) was 91%, 69%, and 51% in the patients classified as low (0 factors), intermediate (1-2 risk factors), and high risk (3-5 risk factors), respectively, by the model.

The PRIMA-prognostic index scoring system was recently introduced to simplify the prognostic scoring system and included bone marrow involvement and β

 -microglobulin level. In the 2 prospective PRIMA trial cohort of patients treated with chemoimmunotherapy, the 5-year PFS was 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively.

Introduced in the late 2010s was the m7-FLIPI score, calculated as the sum of predictor values weighted by Lasso coefficients of the FLIPI index score, Eastern Cooperative Oncology Group performance status, and nonsilent mutations in 

EZH2, ARID1A, EP300, FOXO1, MEF2B, CREBBP

 genes. In the training cohort of 151 patients with FL, high- and low-risk groups identified by the m7-FLIPI score had 5-year failure-free survivals of 38.29% and 77.21%, respectively. The m7-FLIPI also outperformed a prognostic model that included only gene mutation status, as well as the FLIPI-2 index.

However, results of a recent study did not show a difference in time to treatment failure or OS between m7-FLIPI high- and low-risk groups in patients with FL who received rituximab with or without interferon alfa-2a.

Although Peter Martin, MD, of Weill Cornell Medicine in New York, New York, said that he calculates FLIPI scores for his patients, the scores do not directly affect his management decisions. “It’s the sort of thing you report and then move on with life. You manage the person according to the way that you think that person needs to be managed,” said Martin.

Unmet Needs in POD24 and Aggressive Disease

Despite the good survival outcomes in most cases of FL, progression of disease within 24 months of diagnosis (commonly known as POD24) occurred in 19% of patients with stage II to IV FL who received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and was associated with poorer OS from a risk-defining event at 2 and 5 years compared with patients who did not have POD24 (68% vs 97% at 2 years; 50% vs 90% at 5 years).

 Additionally, Mitchell R. Smith, MD, PhD, of George Washington Cancer Center and George Washington University in Washington, DC, said that the ability to predict the approximately 20% of patients who relapse with aggressive disease remains an unmet need and that analyzing samples collected at initial diagnosis to identify predictors of relapse should be a priority moving forward.

The panelists also discussed the role of PET-CT scans at initial diagnosis for predicting which patients are most likely to relapse with aggressive disease or have disease transformation. Alan Skarbnik, MD, of Novant Health Care Institute in Charlotte, North Carolina, said that he performs a biopsy of the “hottest spot” identified by PET-CT scan and performs repeat biopsies in patients with POD24 to obtain additional in- formation about disease behavior, as he pointed out that these patients also have an increased risk for disease transformation.

Nathan Fowler, MD, of The University of Texas MD Ander- son Cancer Center in Houston, added that he performs PET-CT scans on all his patients at initial diagnosis to establish a baseline, identify extranodal disease, and possibly upstage some patients. “If you’re thinking about radiation or limited-stage radiation, the PET sometimes will move you away from that when you find the sites of distal disease,” he said.

Approximately 10% to 30% of patients with FL present with stage I or II disease,

 and radiation therapy yields 10-year OS rates of 60% to 80% and a median OS of about 19 years.

 With advanced disease, Pagel pointed out that treatment, although not a cure, can be instrumental in prolonging survival. Front- line regimens generally involve chemoimmunotherapy combinations, although nonchemotherapy approaches used in the R/R setting have recently been introduced in this setting and may provide a less toxic option for select patients.

Two phase 3 trials have introduced bendamustine as a more tolerable and efficacious chemotherapy component than R-CHOP or rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP). The phase 3 StiL trial (NCT00991211) showed superior PFS and fewer toxic events with rituximab- bendamustine than with R-CHOP in patients with previously untreated stage III or IV indolent NHL or mantle cell lymphoma.

 Similarly, the phase 3 BRIGHT trial (NCT00877006) showed a higher PFS rate at 5 years with rituximab-bendamustine than with R-CHOP or R-CVP in patients with indolent NHL or mantle cell lymphoma.

During the workshop, Pagel noted that the newer anti-CD20 antibody obinutuzumab provides an option besides rituximab for anti-CD20 therapy, although the superiority of one agent over the other is unclear. The phase 3 GALLIUM trial (NCT01332968) showed superior PFS with obinutuzumab plus chemotherapy than with rituximab plus chemotherapy (estimated rate at 3 years, 80.0% vs 73.3%, respectively) in the intention-to-treat population of patients with FL, although OS was not different and the rates of grade 3 or higher adverse events (AEs) and of severe AEs were higher in the obinutuzumab arm.

 A subsequent analysis showed that the obinutuzumab arm had a lower cumulative incidence rate of progressive disease or death due to progressive disease at 24 months, corresponding to a 46% average HR-based reduction in risk for a POD24 event.

Another analysis of data from the GALLIUM trial showed that obinutuzumab was consistently associated with superior investigator- and independent review committee (IRC)–assessed PFS across the different chemotherapy backbones (CHOP, CVP, or bendamustine) at a median follow-up of 41 months (although the chemotherapy regimens were not randomized).

Although lenalidomide plus rituximab (R2) is commonly considered in the R/R setting, data from the phase 3 RELEVANCE trial (NCT01476787) suggest that the regimen also has efficacy in the frontline setting. In the trial, PFS and OS were similar between R2 and rituximab plus chemotherapy in patients with previously untreated FL.

“This has been well described as the most positive negative study,” said Pagel. “I like thinking of it that way because there are patients who are certainly going to benefit from [R2], even in the frontline [setting].”

The synergistic effects of lenalidomide and rituximab and superior efficacy of obinutuzumab over rituximab prompted investigators to evaluate the therapeutic benefits of combining obinutuzumab with lenalidomide. Results of a single-center phase 2 trial (NCT02871219) showed an overall response rate (ORR) of 98% and an estimated 2-year PFS of 96% at a median follow-up of 22 months in patients with previously untreated stage II to IV FL with a high tumor burden, although Fowler said in the workshop that he would not consider obinutuzumab- lenalidomide to be a standard-of-care option in the frontline setting yet.

During the workshop, Kieron Dunleavy, MD, of the Microbial Oncology Program at the George Washington Cancer Center, said that he discusses treatment options with his patients for “an hour and a half” and considers age, findings on PET, and toxicity profile when choosing a regimen. For a younger patient, he said that he is more inclined to treat them, even if they are asymptomatic, than adopt a watch-and-wait approach, and he emphasized the importance of further research on the prognostic significance of gene expression profiling and immune response gene signatures in the current era of therapies.

“There were some studies that showed that the immune response signature wasn’t important, but those studies are pretty historic now in terms of the treatments that we use,” Dunleavy said. “Hopefully it can inform us on who we should be treating and who we shouldn’t.”

The experts also discussed the use of maintenance therapy after frontline treatment was also discussed in the workshop. Results of the phase 3 PRIMA trial (NCT00140582) showed that, compared with observation, 2 years of maintenance rituximab significantly improved PFS and increased rates of conversion from partial to complete or unconfirmed complete response (CR) in patients with FL who had achieved a CR or partial response to induction immunochemotherapy; however, OS was not improved.

Pagel cautioned that careful selection of patients for maintenance therapy is warranted because of the potential for AEs over time. Lori A. Leslie, MD, of the John Theurer Cancer Center/Hackensack Meridian Health in New Jersey, said that she opts for maintenance therapy after rituximab-

chemotherapy (for younger patients) or rituximab-bendamustine (for older patients) as long as the patient is responding to treatment. However, Kami Maddocks, MD, of The James Cancer Hospital at The Ohio State University in Columbus, said that she typically reserves maintenance therapy for patients who are not in complete remission after induction therapy because it has minimal benefit and potential risk for infectious toxicity over time in older patients who have achieved a CR.

Nilanjan Ghosh, MD, of the Levine Cancer Institute in Charlotte, North Carolina, said that he considers single-agent rituximab for patients with low-volume disease, and Martin added that single-agent rituximab may help avoid the need for chemotherapy in some patients with low tumor burden. “If it doesn’t get you everything you wished for, you can still move on from there to chemotherapy or R2, which is now approved in that setting, or to clinical trials,” explained Martin.

In the workshop, Pagel noted that the increasingly shorter remission periods following second and higher lines of therapy high- light the unmet need for therapies with durable responses in the R/R setting. Retrospective data from the observational National LymphoCare Study (NCT00097565) showed that the median PFS in patients with FL was 7 years following frontline therapy and decreased incrementally to 1.50, 0.83, 0.69, and 0.68 years following second-, third-, fourth-, and fifth-line therapy, respectively.

R2 is a common choice for second-line therapy based on results from the phase 3 AUGMENT trial (NCT01938001), which showed a higher IRC-assessed median PFS (39 months vs 14 months), ORR (78% vs 53%), and CR rate (CRR; 34% vs 18%) with R2 than with rituximab plus placebo in patients with R/R FL or marginal zone lymphoma.

 The overall rate of grade 3 or 4 AEs was higher with R2 (69% vs 32%) and was primarily driven by higher rates of grade 3 or 4 neutropenia (50% vs 13%) and leukopenia (7% vs 2%).

For patients with FL that is R/R to rituximab, obinutuzumab plus bendamustine followed by maintenance obinutuzumab was approved by the FDA in February 2016

 based in part on results from the phase 3 GADOLIN trial (NCT01059630). In the trial, bendamustine-obinutuzumab followed by maintenance obinutuzumab in nonprogressing patients led to significantly longer PFS (not reached vs 15 months with bendamustine monotherapy) in patients with rituximab-refractory indolent NHL.

 An updated analysis showed that the obinutuzumab-bendamustine group had a longer median PFS (26 months vs 14 months) and fewer mortalities (52 patients [25.5%] vs 73 patients [35.0%]) after a median follow-up of 32 months.

During the workshop, the panelists said that their choice of therapy in the R/R setting depends on patient age and comorbidities, treatment that the patient received in the first-line setting, and timing of relapse. Jonah Shulman, MD, of the Icahn School of Medicine at Mount Sinai in New York, New York, said that he often considers a rituximab-chemotherapy approach 

for patients who relapse within 2 years after single-agent rituximab, although he said that he has been increasingly giving R2 to patients who are older or may not tolerate chemotherapy. Bita Fakhri, MD, MPH, of the University of California, San Francisco Medical Center, added that transformation may be a concern for patients with early relapse and said that she usually gives obinutuzumab or obinutuzumab-CHOP followed by maintenance obinutuzumab (if the transformation occurred while on maintenance rituximab) or R2 (if the patient received bendamustine-rituximab in the first-line setting).

Several of the panelists said that they do not frequently perform autologous stem cell transplants for FL, although Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, said that he considers it for younger patients with POD24 who “burn through” multiple regimens quickly and have a good match for stem cell transplant. Similarly, Smith said that he considers transplant only for a young patient who was refractory to or had a short first remission with chemoimmunotherapy.

Therapies targeting PI3K have also been of interest in the R/R setting based on the important role of the p110δ isoform of PI3K in B-cell and T-cell development, B-cell receptor signaling, and the decreased B-cell number and function observed in mouse embryonic knockout of p110δ.

Idelalisib is a PI3K inhibitor that targets the p110δ isoform with greater selectivity than the α, β, or γ isoforms,

 and a phase 2 trial (NCT02044822) of idelalisib showed an ORR of 57%, median PFS of 11 months, and median OS of 20 months in patients with R/R indolent B-cell NHL who were previously treated with rituximab and an alkylating agent. Diarrhea and/ or colitis was the most common grade 3 or higher AE, occur- ring in 16% of patients, and AEs led to discontinuation of idelalisib in 25 of 125 patients enrolled.

Results of a phase 2 trial of copanlisib (NCT01660451), which primarily targets p110α and δ isoforms,

showed that patients with FL who had received prior rituximab and alkylating agents had an ORR and CRR of 59% and 14%, respectively, and a median duration of response of 12 months.

 However, dose delays were required for 74% of patients, and 91% of these were due to AEs such as transient hyperglycemia, transient hypertension, and neutropenia.

 The most common treatment-emergent AEs reported in an updated analysis included transient hyperglycemia (50%), diarrhea (35%), transient hypertension (30%), neutropenia (29%), pyrexia (27%), and fatigue (26%).

A phase 2 trial of duvelisib (NCT01882803), which targets the p110δ and γ isoforms, showed that the IRC-assessed ORR was 42% (although this included only 1 CR) in patients with FL who were refractory to rituximab and chemotherapy or radioimmunotherapy, and the median PFS was 9.5 months.

 However, several grade 3 or higher AEs were reported, including neutropenia (25%), diarrhea (15%), anemia (15%), and thrombocytopenia (12%).

Newer-generation PI3K inhibitors are being developed with the goal of reducing toxicities associated with the current agents. Umbralisib, a dual inhibitor of PI3Kδ and CK1ε, is currently be- ing studied in the phase 2b UNITY-NHL trial (NCT02793583) and is awaiting accelerated approval by the FDA. ME-401, an inhibitor of PI3Kδ, received FDA fast track designation and is currently being studied in the phase 2 TIDAL trial (NCT03768505), which is evaluating intermittent dosing to reduce immune-related toxicities associated with continuous daily dosing of PI3K inhibitors.

 Results of a phase 1b study (NCT03985189) showed an ORR of 78% in R/R FL with low (< 10%) rates of grade 3 AEs of special interest related to ME-401 exposure in patients dosed on an intermittent schedule.

Ghosh said that in his experience, umbralisib seems to be associated with less liver toxicity and colitis than are idelalisib and duvelisib, and an umbralisib regimen has not required treatment interruptions or discontinuations in most patients. “We’ve had some dose reductions, but [it is] overall much better tolerated than what I would have expected with so many other PI3 kinase inhibitors,” said Ghosh.

Similarly, Dunleavy said that the current PI3K inhibitors would not be his first choice for third-line therapy, but he would like to be able to identify patients with tumor biology that is likely to respond to PI3K inhibition. Dunleavy concluded that the high heterogeneity of FL, particularly after multiple lines of therapy, makes selection of therapy difficult in the R/R setting.

EZH2 is an enzymatic subunit that catalyzes methylation of Lys27 of histone H3, which represses genes involved in cell cycle checkpoints and differentiation.

 mutations are present in approximately 15% to 20% of FLs, and most of these are point mutations that result in substitution of tyrosine 641 within the histone methyltransferase domain, leading to a gain-of-function effect.

 Expression of the mutant allele synergizes with deregulation of BCL2, which accelerates the development of lymphomas and provides a rationale for

Tazemetostat is an EZH2 inhibitor that received accelerated approval from the FDA on June 18, 2020, for patients with R/R FL harboring an 

 mutation who have received 2 or more prior systemic therapies or who have no satisfactory alternative treatment options.

The FDA also approved the cobas EZH2 Mutation Test (Roche Molecular Systems) as a companion diagnostic test for tazemetostat on the same day.

The approval was based in part on results from a phase 2, open-label, multicenter study (NCT01897571) of tazemetostat in patients with R/R FL after 2 or more standard prior systemic therapies, including at least 1 anti–CD20-based regimen; the results of those harboring an 

 wild-type were analyzed separately. Tazemetostat was generally well tolerated, with 7 grade 3 or higher AEs (3 cases of thrombocytopenia, 2 cases of anemia, and 1 case each of fatigue and asthenia) reported among 99 patients. The investigator- and IRC-assessed ORRs in the 

-mutated cohort were 78% and 69%, respectively, and only 1 case of IRC-assessed progressive disease was reported. Responses were also observed in the 

 wild-type cohort, with investigator- and IRC-assessed ORRs of 33% and 35%, respectively, and IRC-assessed evidence of tumor reduction in 71%. IRC- assessed duration of response was similar between the 

 mutant and wild-type cohorts (11 months and 13 months, respectively), and the IRC-assessed median PFS values were 14 and 11 months for the 

 mutant and wild-type cohorts, respectively.

During the workshop, the faculty members said that although their personal experience with tazemetostat was limited, the data appear promising. “I’ve never personally used it, but I think the trial is interesting, especially in patients with an 

 mutation, and [it] is going to encourage us to check for the mutation,” said Fakhri.

Smith added that although the efficacy data with tazemetostat do not appear to be better numerically than with PI3K inhibitors in the 

wild-type setting, the low toxicity of tazemetostat may encourage physicians to select it over a PI3K inhibitor. “People are going to be much more comfortable giving this than starting a PI3 kinase [inhibitor] and worrying about monitoring liver function tests and what happens if the patient has diarrhea,” said Smith. “While I’m not convinced [tazemetostat is] better than those efficacy-wise, in terms of toxicity, I think this might replace [PI3K inhibitors] when you get down to that later-line therapy.”

Leslie added that the low toxicity profile of tazemetostat may make it favorable for combination therapy with other agents. One example of a trial evaluating combination therapy is a recently opened phase 1b/3 trial (NCT04224493) whose investigators plan to add either tazemetostat or placebo to R2 treatment in patients with R/R FL, then compare the results.

Panelists were somewhat divided on whether they would consider tazemetostat in patients with wild-type or unknown EZH2 status. Shulman said that he would consider tazemetostat in the third-line setting for patients with 

-mutated FL but would likely use it further down the line in patients with 

 wild-type disease. In contrast, Skarbnik said that he may consider tazemetostat over a PI3K inhibitor if the patient prefers a lower toxicity profile, and he pointed out that the dose interruptions often required with PI3K inhibitors may increase risk for progression. Nevertheless, the panelists stated that community oncologists may choose tazemetostat without diagnostic testing because of its low toxicity and ease of use; its role in that setting remains to be determined.

According to Pagel, key advantages of bispecific antibodies, which target 2 or more antigens simultaneously to exert 

antitumor effects, include their ability to be given off the shelf and their adaptability in dosing. Mosunetuzumab and REGN1979 are bispecific antibodies that target CD3 (on the surface of T cells) and CD20 (on the surface of tumor cells), and they are in early-stage trials for indolent NHL.

The results of an ongoing phase 1/1b study of mosunetuzumab (GO29781; NCT02500407) showed an ORR and a CRR of 64% and 42%, respectively, in efficacy-evaluable patients with indolent NHL.

 Although CRs appeared durable and Pagel noted an exceptional response in a patient who had received 8 prior lines of therapy, he added that longer follow-up is needed.

The results of a phase 1 study of REGN1979 (NCT02651662) in patients with R/R B-cell NHL showed an ORR of 93% and CRR of 71% among the 14 patients with grade 1 to 3a FL.

 Pagel noted that cytokine release syndrome (CRS) may be a concern with REGN1979, with all-grade CRS reported in 55 of 96 patients and grade 3 CRS reported in 7 patients.

Maddocks and Brody added that although more data are needed on bispecific antibodies, they may be used more widely than chimeric antigen receptor (CAR) T-cell therapy because of their greater tolerability and availability.

CAR T-cell therapy has also shown promising activity in R/R FL. An interim analysis of the phase 2 ZUMA-5 trial (NCT03105336), which is evaluating axicabtagene ciloleucel in patients with advanced-stage indolent NHL, showed an ORR of 95% and CRR of 80% in the subgroup with FL at a median follow-up of 11.5 months. However, 83% of patients experienced grade 3 or higher AEs, including CRS in 11% and neurologic events in 19%.

At the conclusion of the workshop, the faculty members pointed out the promising trends in shifting toward nonchemotherapy options for FL and said that further research in effective therapeutic combinations with low toxicity will be important moving forward. “It’s exciting to see that there are potentially curative therapies other than [allogeneic] transplantation out there,” said Ghosh.

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Although the majority of patients with follicular lymphoma have a life expectancy similar to that of the general population, predicting which patients will relapse and finding therapies that provide durable responses in the relapsed or refractory setting remains an ongoing challenge.

Current and Emerging Treatments in Follicular Lymphoma | Supplements and Featured Publications

Expert Perspectives in the Evolving Treatment Landscape for Follicular Lymphoma

Current and Emerging Treatments in Follicular Lymphoma

Dr. Maddocks on the Role of Tazemetostat in EZH2-Mutant Follicular Lymphoma

Dr. Leslie on Phase 1b Trial of Tazemetostat Plus Lenalidomide/Rituximab in Follicular Lymphoma

Dr. Skarbnik on Active Surveillance in Follicular Lymphoma

Dr. Burke on Tazemetostat’s Mechanism of Action in EZH2-Mutated Follicular Lymphoma

Dr. Maddocks on Treatment Considerations in Follicular Lymphoma