Pathophysiology of Follicular Lymphoma and Frontline Therapy

Shared insight on the indolent nature of follicular lymphoma and frontline therapy options for this disease.


Bijal D. Shah, MD, MS: Let’s talk a little about follicular lymphoma. When I think about follicular lymphoma, I think of it as being one of the more common B-cell lymphomas we’re going to see. I believe it’s the second most common B-cell lymphoma in the United States, I think around 20,000 cases a year, somewhere thereabouts. Most of my patients with follicular lymphoma I have to say are diagnosed by accident. They end up in the emergency department for one reason or another. Sometimes, I believe there’s like a CT [computed tomography] scanner that you just walk through, at least that’s the way it feels. They get a CT scan, and the next thing you know there’s a lymph node that we can’t explain or a constellation of lymph nodes that leads to a biopsy that leads to this diagnosis of follicular lymphoma.

Most of my patients thankfully come to me without symptoms, though B symptoms we certainly can see in this condition. Typically, fevers, night sweats, weight loss. Less often do I see leukemic disease, massively enlarged spleen. Thus, it allows us to do something that’s unique, which is watchful waiting in a subset of these patients, particularly those who have low-grade follicular lymphoma. And I think that histological grading has really helped us define the low risk from the higher risk, with the grade 1 and 2s more often, not uniformly, but more often being ones that we can observe. Caron, how do you think about follicular lymphoma as being distinct and different from some of the other lymphomas that we’ve seen?

Caron A. Jacobson, MD, MPH: Yes. It is a slow-growing lymphoma, as you had mentioned, and many patients can be watched for years before they need their first therapy. But the one thing about follicular lymphoma, of course, is that it is really incurable outside of an allogeneic stem cell transplant. Although we’re hopeful that other immunotherapies will change that in the future. But people live with this disease for generally 20 to 30 years at a time, and sometimes they need therapy. Therapy is often very effective at causing the lymphoma to go into remission, but given enough time it’s bound to relapse, and patients will need subsequent therapies. Thus, while it has generally a very long natural history and because most people are 68 or 70 and older when they’re diagnosed, it’s a disease they’ll die with, not necessarily a disease they’ll die from. But it is important to note that with each relapse, the median response duration to the next line of therapy and progression-free survival actually decrease quite a bit. By the time you get to the third line, the median overall survival for those patients is about 5 years. Hence, there’s still an unmet need in follicular lymphoma, especially for the multiply relapsed patients.

Bijal D. Shah, MD, MS: Good points. Ian, how do you use that information to guide what you do when you see a patient with newly diagnosed follicular lymphoma? We talked about watchful waiting. Is there a group where you’re going to say, “No, no, you need chemotherapy,” or are there other alternatives?

Ian W. Flinn, MD, PhD: Occasionally there are patients who walk in and they’re quite sick when they’re diagnosed, and they need immediate chemotherapy. But the vast majority of patients who are diagnosed these days, you can, as Caron pointed out, watch and wait for a couple of years. But when the decision is made that you do need therapy, there are several reasonable choices. There are now a couple of clinical, randomized phase 3 trials that show that bendamustine, rituximab [BR] is superior to R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], at least in terms of progression-free survival. But also, I like to use bendamustine, rituximab instead of R-CHOP to keep R-CHOP around for later in case there’s a transformation to a more aggressive point. And there are other choices beyond chemoimmunotherapy. We know from the RELEVANCE trial that basically the R2 regimen, lenalidomide and rituximab, is equivalent to chemoimmunotherapy in that frontline setting, albeit it with its own unique set of adverse effects, and duration of therapy is a little bit longer than you might use with chemoimmunotherapy. Thus, there are a few choices, but I generally hold on to R-CHOP for patients who I’m worried that they’ve transformed.

Bijal D. Shah, MD, MS: One of the interesting things that came out of the BRIGHT study that you led actually, was the use of Rituxan maintenance after BR. Is that something you feel comfortable doing in your patients with follicular lymphoma?

Ian W. Flinn, MD, PhD: I do feel comfortable doing it, but I don’t generally do it or I generally do not use rituximab maintenance because, for the most part, that’s shown us an improvement in progression-free survival, but we’ve not seen an improvement in overall survival. Hence, despite 10 years of all these trials with a promise that ultimately, we were going to get an improvement in overall survival, we’ve never seen that. Thus, I generally don’t do it. Right now I really don’t do it because of COVID-19 and the risk of increased mortality if you’ve been on rituximab maintenance. That was a long-winded answer to your very short question.

Bijal D. Shah, MD, MS: It’s a good answer. Brian, can you briefly discuss other options? Are there patients where, for example, you want to use single-agent Rituxan? Are there patients where you’re doing that? Are there other things, maybe even agents that we think about in the relapsed setting, that you’re pushing forward?

Brian T. Hill, MD, PhD: Yes. I would just follow up on the prior point, that the reason we, I think, use maintenance a little more in mantle cell lymphoma is there is an overall survival advantage, and I think many of us feel comfortable despite the COVID-19 risk. But I also agree in follicular, there’s never been an overall survival advantage, so I think we’ve really cut back on it after frontline treatment. But to answer your question about frontline alternatives, I think the 3 big ones would be R-CHOP, BR, or R2. There are patients who are older and frailer, and they have maybe just some mild symptoms, and are not really good chemotherapy candidates. And there are good prospective data that show just treating with 4 weekly doses of rituximab can be quite beneficial and very well tolerated and so simple to do. Beyond that, I think then you’re starting to get into the novel agents, which aren’t really approved in the frontline setting.

Bijal D. Shah, MD, MS: That’s a perfect segue back to pirtobrutinib. If I recall, pirtobrutinib did enroll patients with follicular lymphoma. What was your sense, Michael, from the pirtobrutinib data?

Michael Wang, MD: In the first presentation in 2020, there were about 5 patients, about a 50% response rate. I really think the BTK [Bruton tyrosine kinase] inhibitors are active in follicular lymphoma, and other BTK inhibitors have shown in clinical trial to be effective. I think pirtobrutinib will have activity in follicular lymphoma, it probably will be in a combination setting with a monoclonal antibody, or with another agent such as venetoclax and copanlisib. How to use it will have to come from clinical trials. I’m sure this is coming.

Bijal D. Shah, MD, MS: Absolutely.

Transcript edited for clarity.

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