Tailoring Treatment to the Patient in Follicular Lymphoma

Brad S. Kahl, MD

Options to treat patients with follicular lymphoma have only grown in the past 5 years, allowing for physicians to create an individualized treatment as possible for each patient. However, this growth has come with its own challenges and physicians have to continue to address them throughout treatment.

At the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023), Brad S. Kahl, MD, discussed the changes in the field of follicular lymphoma and how physicians should approach treatment now in his talk, “Treatment of Follicular Lymphoma, What Is the New Order?”. While the frontline setting has not changed as much as the second-line and further setting, having a long-term strategy in mind for patients with disease recurrence is imperative.

Kahl, director of the lymphoma program and professor of medicine in the division of oncology at Washington University Physicians, in St Louis, Missouri, spoke with The SOHO Daily News about the way physicians should look at the treatment paradigm in follicular lymphoma.

The SOHO Daily News: What has been some of the biggest updates in the field of follicular lymphoma in the past 5 years or so?

KAHL: There actually has not been a lot of movement in the frontline [setting of treatment for patients with] follicular lymphoma. Follicular lymphoma is generally considered incurable, or at least hard to cure, although the long-term outcomes for patients are still excellent.¹ In other words, patients can live a long time with their disease and the treatments are very effective at establishing remission, but because the disease tends to recur, you need to have a [long-term treatment] strategy. What am I going to use now vs what am I going to save for later? I’m going to talk about the strategy [in my presentation]. With the first line treatments, the first decision one really needs to make is does the patient require treatment. Some patients do not, because they have no symptoms and have a very low disease burden, therefore, it’s still okay to watch and wait selected patients with follicular lymphoma.

What would be your treatment strategy for patients with a low tumor burden vs a high tumor burden?

For patients who have low tumor burden, but are uncomfortable with watch and wait, single agent rituximab [Rituxan®; Genentech, Biogen] is still a good choice for those patients. It has good activity and excellent tolerability, but the trickier scenarios is what to do with patients who have high tumor burden, symptoms, or both. You have several choices that you could employ in the frontline [setting for these patients]. Probably the most common strategy, in the United States, is to administer a combination of bendamustine HCl [Bendeka®; Teva] and rituximab, so a chemotherapy drug and an immunotherapy drug.² [It’s an active combination], it will put most patients into complete remission and on average, those remissions last in the 5-year range.³

There are other choices that are equally reasonable. The R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, and vincristine sulfate] regimen can be administered to [patients with] high-tumor burden FL,⁴ and some physicians prefer that. There was a study a few years ago called GALLIUM [NCT01332968], where they substituted a monoclonal antibody obinutuzumab [Gazyva®; Genentech] for rituximab, which improved outcomes slightly.⁵ So, some physicians will pick their favorite chemotherapy, whether it’s bendamustine or CHOP, and combine it with obinatuzamab instead of rituximab, which is fine too. All these results are very similar, and then once you finish the induction therapy, which takes about 6 months, you have to make a decision about whether you want to employ maintenance therapy.

What are the latest considerations for maintenance therapy in this space?

Maintenance therapy usually consists of 2 years of either rituximab or obinutuzumab, and studies such as the PRIMA study [NCT00140582] showed good outcomes with the addition of maintenance [therapy].⁶ However, the problem with maintenance [treatment] really hit when the COVID-19 pandemic came. The maintenance anti-CD20 monoclonal antibody makes it hard for your immune system to deal with new pathogens. You’re usually okay dealing with old pathogens because your immune system has a memory. But if you’ve never seen that pathogen before, your immune system is going to have a hard time responding to it. So, our patients getting rituximab maintenance seem to have increased risk for severe COVID or death from COVID, and they didn’t respond well to vaccination either. That created a real dilemma for those of us in practice where we were commonly administering maintenance rituximab, but I found myself kind of changing my mind and no longer recommending it. The risk benefit ratio just didn’t seem to be right anymore for those patients, so now I’m recommending just an induction strategy. I tend to use bendamustine rituximab then no maintenance rituximab, but you’ll get differing opinions on that, but that would be my frontline treatment of choice.⁷

WBC image | Image Credit: © stockdevil - www.stock.adobe.com

Where does treatment in the second- and third-line setting currently stand?

Then when you get into third-line, that’s where things have changed in the past year, because we had the approval of mosenatuzumab-axgb [Lunsumio™; Genentech], which is a bispecific monoclonal antibody.⁸ This [drug] targets CD20 on the malignant B-cells and CD3 on T-cells, and is really designed to bring the patient’s T-cells into proximity to their B-cells and let the T-cells kill the tumor. Mosenatuzumab looks very active [for patients with] relapsed follicular lymphoma with an ORR of around 80% and a CR rate of around 60%.9 With the approval of mosentuzumab in December of 2022,⁸ that would be the third-line treatment that I would recommend going forward.

How has the addition of CAR T-cell therapy impacted treatment options in this patient population?

We now have approval for CAR T-cell products [to treat patients with] relapsed follicular lymphoma. Although, it’s not so obvious which patients to recommend that [treatment] to. [Treatment with CAR T-cell has] very active response rates, over 90% CR rates over 75%.10 [However], we don’t really have long-term follow up to know what proportion of patients are staying in remission at 3 years and 4 years with CAR T-cell therapy. There is [also] some risk for prolonged B-cell depletion and some risk for myelodysplastic syndrome. So, I think about [using] CAR T-cell therapy when I have a young patient with follicular lymphoma, who’s maybe in their 40s or [up to their] 60s, who are getting inadequate responses to conventional therapies, which then I might think the risk benefit ratio of CAR T-cell therapy is appropriate. But if I have an older patient, in their 70s or 80s, and they’re getting good responses to standard therapy, then I would think CAR T-cell therapy would not be the right choice for that kind of a patient.

What message would you like attendees to take away from your presentation at SOHO this year?

There is a lot of individualization that needs to occur when managing [care for patients with] follicular lymphoma, especially when you get into second-, third-, fourth-, and fifth-line treatment. [Those decisions are] going to depend on what the patient had before, how well it worked, and other factors like age and comorbidities. So, it’s hard to give a blueprint, but I’ll just try to give a menu with some guidelines about what criteria you might use when selecting a particular therapy for [later lines] of treatment.

_References:

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_{2. Subramanian J, Cavenagh J, et al. Rituximab in the treatment of follicular lymphoma: the future of biosimilars in the evolving therapeutic landscape. Cancer Manag Res. 2017;9:131-140. doi: 10.2147/CMAR.S120589.}

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_{4. Wang Y, Zhou S, Qi X, et al. Efficacy of front-line immunochemotherapy for follicular lymphoma: a network meta-analysis of randomized controlled trials. Blood Cancer J. 2022;12(1):1. doi:10.1038/s41408-021-00598-x}

_{5. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. N Engl J Med. 2017;377(14):1331-1344. doi:10.1056/NEJMoa1614598}

_{6. Bachy E, Seymour JF, Feugier P, et al. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019;37(31):2815-2824. doi:10.1200/JCO.19.01073}

_{7. Leonard JP, Trneny M, Izutsu K, et al; AUGMENT Trial Investigators. AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma. J Clin Oncol. 2019;37(14):1188-1199. doi:10.1200/JCO.19.00010}

_{8. FDA grants accelerated approval to mosunetuzumab-axgb for relapsed or refractory follicular lymphoma. Press release. December 23, 2022. Accessed: September 1, 2023. https://tinyurl.com/47k93ajj}

_{9. Budde LE, Assouline S, Sehn LH, et al. Single-Agent Mosunetuzumab Shows Durable Complete Responses in Patients With Relapsed or Refractory B-Cell Lymphomas: Phase I Dose-Escalation Study. J Clin Oncol. 2022;40(5):481-491. doi:10.1200/JCO.21.00931}

_{10. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022;28(2):325-332. doi:10.1038/s41591-021-01622-0}