Precision Medicine Shapes the Future of Follicular Lymphoma Management

Carla Casulo, MD

The management of patients with relapsed or refractory follicular lymphoma (FL) is evolving as novel therapies inch their way toward FDA approval and into clinical practice. The 2 kinds of agents stirring excitement in the FL paradigm are targeted therapies and the hope of chimeric antigen receptor (CAR) T-cell therapies.

Tazemetostat (Tazverik), a first-in-class small molecule EZH2 inhibitor, is the most recently approved agent in the FL landscape. The FDA granted it accelerated approval in June 2020 for the treatment of adult patients with relapsed or refractory FL whose tumors harbor EZH2 mutations, as detected by an FDA-approved test, and who have received at least 2 prior lines of systemic therapy, and for the treatment of adult patients with relapsed or refractory FL who have no satisfactory alternative treatment options. With this approval, tazemetostat joined several other FDA-approved targeted agents for relapsed/refractory FL, including duvelisib (Copiktra), umbralisib (Ukoniq), and copanlisib (Aliqopa).

In addition to what is FDA approved, the FDA is considering a Biologics License Application for axicabtagene ciloleucel (axi-cel; Yescarta) for the treatment of patients with relapsed or refractory FL, which, if approved, will be the first CAR T-cell therapy approved for the treatment of relapsed or refractory FL.

In an interview with Targeted Oncology, Carla Casulo, MD, associate professor, Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, discussed the modern management of patients with relapsed/refractory FL. She also explained how ongoing research may shape the future of the field.

TARGETED ONCOLOGY: What treatment options are currently available to treat patients with relapsed/refractory FL?

Casulo: There are many different treatment options for patients with relapsed FL. They include standard cytotoxic chemotherapy such as CHOP or bendamustine with either obinutuzumab or rituximab. They also include some novel targeted agents such as lenalidomide or the PI3-kinase inhibitor class, of which there are 4 drugs currently approved.

TARGETED ONCOLOGY: What challenges do oncologists face when treating these patients?

Casulo: The challenges in treating patients with relapsed FL surround the fact that there's no clear way to distinguish who will do poorly after their treatment, and there's no biomarkers of response to treatment. Right now, with all the different treatments that we have, we might treat someone based on when they recurred. If they recurred, then you might consider treating those patients more aggressively. And if there's a patient that's a little older, you might want to treat them a little more gently. For patients that have standard relapsed/refractory FL, given the plethora of options, there's no clear way to say this treatment will be more efficacious in that patient because we don't have biomarkers or predictors of response to those treatments, and I think that that's a huge unmet need right now.

TARGETED ONCOLOGY: What key points can you mention about the management of relapsed/refractory FL?

Casulo: My key points focus on the at-risk population that has relapsed FL. We did research looking at patients that have early disease recurrence, which is one of the most vulnerable populations in FL because they have poor outcomes when you compare to patients who relapse within 2 years of their treatment. If you compare that to patients who did not relapse within that period of time, they have very favorable outcomes, so you want to try to focus your clinical trial options and novel therapies on the group of patients that have early relapse disease.

TARGETED ONCOLOGY: Can you provide detail on how recurrence impacts outcome for these patients and what can be done about recurrence?

Casulo: There are several different factors that help us predict risk in FL. At the time of diagnosis, you have the FLIPI and FLIPI2 scores, and those are prognostic markers that help you understand who with FL will have better or worse outcomes. We're now refining those prognostic factors a little bit better with the incorporation of molecular data so there are certain mutations in genes that modify gene expression and those are epigenetic markers. When you combine that with clinical factors, you can now have a better ability to refine prognosis in patients at the time of their diagnosis, and that's called the m7-FLIPI. So, that's a third way that we can prognosticate patients.

There are also emerging data looking at the incorporation of PET, and total metabolic tumor volume into the frontline diagnostic space in order to, again, try to refine who was FL will do better or worse. Ultimately, that's going to help with treating patients, based on risk because currently we base treatment for patients on how much disease they have but not necessarily on how at risk they are. That's something that will continue to evolve in the next few years, hopefully.

TARGETED ONCOLOGY: Is there any ongoing research around this topic?

Casulo: Research right now is revolving largely around novel therapies. There are dozens of new treatments that are being studied for several different molecular targets. There are small molecule targeted inhibitors of various intracellular pathways. For example, the B-cell receptor has several downstream targets and that's where the PI3-kinase inhibitors come into play. There are also BTK inhibitors and other anti-CD20 monoclonal antibodies that are being studied.

The other thing that's being looked at is combinations of various novel treatments. What goes with what in order to minimize toxicity but improve response rates and duration of response is another important area that's being studied. There was a large, randomized study looking at frontline therapy for patients with follicular lymphoma randomizing patients to R2, which is lenalidomide and rituximab versus chemotherapy, and that study was meant to try to establish a non-inferiority of this regimen versus standard chemotherapy. We found that they're not dramatically different. There was a slight improvement in outcomes with 1 versus the other, but, in general, that's not changing the standard practice too much. So, what’s being looked at right now are new treatments at the time of diagnosis, new treatments either alone or in combination with other agents at the time of relapse. Then, the area that I'm focused on is trying to specifically identify who will benefit most from what treatments to home in and offer a precision approach to patients.

TARGETED ONCOLOGY: Where do you envision this field heading in the next decade?

Casulo: Ithink that the FL field will be more precise, and that's based on some of what's currently going on, which is at the moment research based. As I mentioned, the m7-FLIPI and other gene expression profiling will hopefully be moved towards the more practical setting for clinicians so that we can learn who needs what treatment based on what we know about their biology and other things, not just tumor burden or disease stage or things like that. I think that that will help refine things a little bit better. I see the field going in that direction and I think that we may find that treating patients with less toxic drugs is better than treating them with numerous drugs that have overlapping mechanisms of action and can cause toxicity, because patients with FL can live up to 20 years, which is remarkable. We have to be very nuanced in order to not limit survival for these patients but also offer them the best chance at reaching those 20 years or more.