Expert Reviews Recent Approval and New Emerging Treatments in Follicular Lymphoma

In follicular lymphoma (FL), the treatment landscape was recently enriched with another approval, the approval of tazemetostat for 2 indications in this setting. These include the treatment of adult patients with relapsed/refractory disease harboring an EZH2 mutation with at least 2 prior lines of systemic therapy and for the treatment of adults with relapsed/refractory disease who have no satisfactory alternative treatment options.

This approval was based on findings from a phase 2 study (NCT01897571), which evaluated the efficacy and safety of this EZH2 inhibitor as treatment of patients with relapsed/refractory FL who either had an EZH2 mutation or EZH2 wild-type disease. This is an exciting new addition to the treatment landscape, that already has several agents approved for treatment, including the Pi3K inhibitors.

Chimeric antigen receptor (CAR) T-cell therapy has also emerged as an exciting alternative treatment for this patient population. Most recently, a supplemental Biologics License Application for the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta) was supported by data from the ZUMA-5 clinical trial (NCT03105336). CAR T cells have been made available in other treatment landscapes, such as diffuse large B-cell lymphoma and mantle cell lymphoma, and these treatments are still under investigation in clinical trials now for FL.

In an interview with Targeted Oncology, Alan P. Z. Skarbnik, MD, a hematologist/oncologist, Novant Health, discussed the current therapeutic strategies for treating patients with FL. He also highlights the recent advances that look most promising for the treatment of patients with FL, including the recent approval of tazemetostat as treatment of patients with relapsed/refractory FL.

TARGETED ONCOLOGY: What does the current treatment landscape look like for patients with FL across all stages of disease?

Skarbnik: With new options being approved like tazemetostat, approval of even newer agents, such as CAR T-cell therapy for FL, should come in the near future. The whole issue with FL is that it is a highly heterogeneous disease both in biology and presentation, as well as age of patients involved with it and if they have comorbidities or not. The treatment for FL in my opinion should be highly personalized depending on how the patient presents with grade of disease and the biopsy if you do have access for genetic mutation, which is interesting to be done in order to better understand the factors we're trying to target if you're trying to use any kind of targeted therapy. In general terms of FL, for patients who do require treatment, remembering that not all patients require treatment for many years and can be watched on active surveillance until treatment is required. For patients who do require treatment, it's going to depend on stage, age, and grade of the lymphoma, as well as comorbidities. For early-stage disease which is not common, stage I or II, and is about 25% of patients presenting with FL, there is a potential chance for a curative approach, particularly if the lymph nodes that are involved are single side or 2 contiguous sides. In general, treatment with radiation therapy with or without rituximab may be an option, and patients may experience either very prolonged disease-free interval or even be cured potentially.

As a rule of thumb for advanced-stage disease, which is the majority of patient, stage III or stage IV disease is are not curable. The whole intent here is to get the best response possible with each treatment while being as safe as possible, and then having the longest possible response. In that setting, traditionally chemoimmunotherapy has been the treatment of choice for patients who can tolerate that, so bendamustine and rituximab and RCHOP are usually the regimens mostly used in the United States. Bendamustine/rituximab, which is the most widely used therapy regimen for all grade lymphomas in general, certainly is not inferior than the others. There are different side effects for each. There are different goals with each approach. In general, if the patient is presenting a more advanced grade, such as grade III, especially grade A or B. If the patient has bulky disease, I try to give preference to an anthracycline-based regimen, so R-CHOP will be my treatment of choice for patients who have less bulky disease, and lymphoma of grade 1/2, I usually prefer bendamustine-based regimens.

You do have the option of what antibody you're going to use in association with it, and it's going to rituximab or obinutuzumab. After that, you have the option whether you're going to do maintenance therapy for this patient or not with an antibody, and there's a plethora of data published already indicating this for some patients may be beneficial or for some patients, it may not be as beneficial. It depends also on the antibody that's being used, what the counterpart to the antibody in the chemotherapy arm is, so again, you should personalize patient by patient. In general terms, if I'm using the R-CHOP regimen, they tend to give rituximab afterwards as maintenance. Bendamustine is somewhat fashionable to use as maintenance afterwards because it does increase the risk for secondary infections in these patients. It tends to be a little bit more myelotoxic than CHOP long term.

The advantage of using anti-CD20, particularly obinutuzumab, in patients over the age of 65 is seen in the phase 3 trial that led to the approval of this maintenance, where it seems not to be as beneficial as in younger patients. This all comes to play. If you're trying to deviate from chemotherapy agents, then lenalidomide and rituximab, also known as R2, it's certainly a reasonable option for those patients followed by rituximab maintenance after the initial induction of the regimen. Finally, you can use an anti-CD20 antibody alone again, depending on age comorbidities, and what the goal is for this patient. We have a lot of options. That's a great thing.

TARGETED ONCOLOGY: In terms of active surveillance, what patients are eligible? How do you decide when to move to treatment?

Skarbnik: We know how this disease progresses and what the natural history of this disease is, and how to look for it, so the patient may need treatment at some point in time, we're just trying to do it at the right point in time where we're not going to just be buying them side effects, but also we'll be potentially prolonging their lifespan and the disease-free period. For patients who do not present with any symptoms associated with FL, such as those without significant fatigue, night sweats, or weight loss, or whose blood counts are not abnormal in a significant way secondary to the lymphoma traditionally in the bone marrow but don't present bulky disease or don't present multiple sides of disease, they're enlarged, etc, there is no indication that disease is progressing quicker than you would expect otherwise, and this patient certainly can go through active surveillance, knowing that there may be a point in their lifetime where treatment will be required.

Based on presentation, we use the Groupe D’Etude des Lymphomes Folliculaires criteria for prognosis, and then we tend to adapt how often we will follow this patient, depending on how they present as well. Then if at some point in time that changes and the patient presents with criteria that would endorse the use of treatment, certainly we can change very quickly to treat at that time.

TARGETED ONCOLOGY: Could you discuss the data that led to the approval of tazemetostat and how this may impact the treatment landscape for FL?

Skarbnik: Tazemetostat is an EZH2 inhibitor that has recently been approved for patients with FL and at least 2 prior therapies. No phase 3 clinical trials compared [tazemetostat] to other treatments that are available based on response rate and duration of response. EZH2 is a molecule that can be mutated in a percentage of FL, and it can be upregulated in another percentage without the mutation present. However, that's harder to inform because there's no test to establish that, so the clinical trials used tazemetostat for the treatment of patients with both wild-type EZH2 and mutated EZH2.

The rates of response were different in these 2 patient populations. For patients with EZH2-mutant FL, the response rate was about 65%, and the duration of response was close to a year. The rates of complete response are higher with about 12% whereas for patients with EZH2 wild-type, the response rate was about 32% of patients, but there was a much lower rate of complete responses. However, the duration of response was not much different. It was about 13 months, so for those patients who do have a response, the duration of response is similar, whether they are wild-type or mutant, but it's a much higher rate of response in those patients who have EZH2-mutant FL because it's likely the driver of the disease at that point, not just saying that the patients who have wild-type disease even have EZH2 upregulated and then responded because of that. However, that's more uncommon as being the sole driver, the main driver of the disease, so likely that's why we see a lesser degree of response in these patients.

It is an interesting drug. It's oral, so it's fair to say, some patients have nausea or the general side effects that we see with this kind of therapies, but tazemetostat is overall well tolerated. It does, in this time of COVID-19 where we're trying to minimize patient trips to the office and infusion rooms where they have to be exposed to more staff and all the patients that are there, I think that options that are oral and can be taken at home certainly improve the of not only contracting COVID-19 but having a hard turn, like a more harsh course of it. Trying to protect patients from unnecessary exposure is important, so both lenalidomide and tazemetostat are interesting therapies in this sense, and they are fairly effective.

For patients who are EZH2 wild-type, then we have to consider potentially other options, such as Pi3K kinase inhibitors or lenalidomide if they have not been exposed to it before. If they have been exposed to those agents, I don't see a reason why not to try. With tazemetostat, as I said, about one-third of patients do have a response to it, so it's not completely inefficient in this patient population, but certainly, if EZH2 is mutant, I would prefer tazemetostat over Pi3K inhibitors. That's where this therapy falls right now in the paradigm for these patients.

TARGETED ONCOLOGY: Are there any ongoing studies with tazemetostat, maybe looking at it in earlier lines of treatment or in combination with other agents?

Skarbnik: As I said before, tazemetostat is a fairly well tolerated treatment, so that gives potential to combine this treatment with other therapies that are available. That’s usually how treatments come through, so we started as a single agent, and that's well tolerated. We start then bringing it to earlier lines of therapy and see if the agent is adequately combined with other treatment regimens.

There are trials ongoing up tazemetostat plus chemoimmunotherapy for patients with relapsed disease, particularly, and that's very exciting because there seems to be a synergistic effect by adding tazemetostat to chemoimmunotherapy. We know we need more data to understand how this is going work and if it’s safer, so we'll need to wait a little bit until those data are available, but that's certainly very exciting.

TARGETED ONCOLOGY: Beyond tazemetostat, is there other research efforts that are being conducted in the FL space that you think are particularly exciting and you'd like to highlight?

Skarbnik: A couple of research efforts are ongoing in FL. One that is newer is the Pi3K inhibitors. There are currently 3 inhibitors approved for the treatment of FL, including idelalisib (Zydelig), copanlisib (Aliqopa), and duvelisib (Copiktra). One of them is an infusion while the other 2 are oral. They have different side effect profiles, and historically, the issue of Pi3K inhibitors has been the tolerability and adherence to treatment for patients because some of them can certainly cause very significant side effects, particularly gastrointestinal toxicity with inflammatory diarrhea or rash. The second generation of Pi3K inhibitors, duvelisib for instance, which does not only inhibit the delta portion of Pi3K but also gamma, and it does lead to somewhat of a downregulation of the T cell immune meshwork that supports the proliferation of disease. It also prevents some of those immune-related side effects, so it seems to be a little bit better tolerated.

There is umbralisib that is under investigation, and the data so far has shown that this treatment on its own seems to be very well tolerated and the adherence seems to be very positive. Of course, this is cross trial comparison. There is no head to head comparison between the Pi3K inhibitors available, but just based on clinical experience in what we're seeing with the data set that we have so far, that seems to be very interesting. By that sense, by continued adherence to the treatment, there is a potential of continued efficacy of the drug, so we need to wait and see what the final data are going to be on that particular component.

What we're all most excited about is the use of CAR T-cell therapy. CAR T-cell therapy has been used in a number of different lymphomas. It has approvals in diffuse large B-cell lymphoma and mantle cell lymphoma so far. It has also a separate approval for acute lymphoblastic leukemia in patients under the age of 25. Those are different agents. They're different components, but the ZUMA-5 trial used axi-cel in FL patients with 2 or more prior therapies, and that trial had very interesting response rates at an upwards of 80% overall response rates with a fairly significant number of complete remissions. A significant duration of responses beyond 1-year were observed, and the 1-year overall survival for this patient population is about 96%. The median survival has not been reached, so it's still early. We need to wait a little bit longer for the data to mature, and we're waiting for this to be approved.

The advantage of CAR T-cell therapy is that it is a front-loaded treatment, but it's not continuous, so it is costly. That's something that we need to understand how to circumvent because it can certainly put could put a load in the healthcare system and be complicated for a number of patients, particularly patients on Medicare, remembering that most patients with active FL are over the age of 65. Those things need to be taken into consideration, but the response rates are very interesting. It is safe in the sense that we know what the riskiest side effects are, which include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, or ICANS. We know that they happen usually in the first 2 weeks after infusion, so patients tend to be hospitalized for the timeframe, but we know how to treat it and how to deal with it. It's very, very unusual for patients to have long-term side effects from this treatment, but you're buying a significant response and significant control level of disease with that therapy.

CAR T-cell therapy is the wave of the future in the treatment of FL and other kinds of lymphoma.