How I Sequence Therapy for Patients With Follicular Lymphoma

As treatment options have expanded for follicular lymphoma, deciding how to sequence therapies for individual patients has grown more challenging. Below, I share how and why I individualize therapy across settings for patients with follicular lymphoma.

First-line Treatment
Patients with follicular lymphoma are most commonly diagnosed after developing lymphadenopathy or other findings, at which point the decision is whether to treat vs watch and wait with careful monitoring. Factors influencing this decision include tumor burden, lymph node size, laboratory abnormalities, risk of organ obstruction, and the presence of symptoms requiring intervention. For most patients with low tumor burden who are asymptomatic, watch and wait with careful monitoring is appropriate. For the subset of patients with low tumor burden who need treatment, I typically recommend 4 doses of single agent rituximab followed by observation. More often, patients have bulky disease, progressive disease, and/or symptoms requiring treatment, in which case we pursue chemoimmunotherapy with bendamustine/rituximab or bendamustine/obinutuzumab. The latter has a slight improvement in progression-free survival (PFS) but no difference in overall survival (OS) and more toxicity. If there are concerns for transformation, then we may use R CHOP.

Maintenance After First-line Treatment
The next decision point is considering whether patients who respond to first-line therapy should receive maintenance treatment with an anti-CD20 antibody. Data indicate that rituximab maintenance has some benefit after an R CHOP–like regimen and potentially after bendamustine/rituximab. We also have data suggesting benefit with obinutuzumab as maintenance vs rituximab maintenance. However, it is important to note that while maintenance treatment with an anti-CD20 antibody seems to improve PFS, it has not been shown to increase median OS after induction chemoimmunotherapy.

I discuss these options with my patients but usually do not recommend maintenance therapy because there is no OS benefit. We tend not to use maintenance after single agent rituximab because data from the RESORT trial indicate that patients can be retreated with rituximab at the time of progression. When patients choose to pursue maintenance, we administer maintenance therapy for 2 years.

Second-line Treatment
In general, patients who experience a first remission longer than 2 years have a more favorable prognosis at relapse vs those with shorter remission. Clinical trials are underway to determine the optimal approach for those experiencing shorter remission, but the available options are similar whether the patient experiences late vs early progression. Rebiopsy at relapse should be considered to assess for transformation, particularly in those who had a shorter first remission, high lactate dehydrogenase, and/or high standardized uptake value (SUV) on a PET scan.

In the second line setting, we can again elect to observe the patient if they are asymptomatic and use single agent rituximab if they have low tumor burden but do have symptoms associated with follicular lymphoma. Chemoimmunotherapy is an option, but we typically use a different combination than their first-line regimen. For example, if a patient had first-line bendamustine based therapy, we might choose CVP or CHOP based therapy in the relapsed setting and vice versa. Obinutuzumab-based therapy can be used for patients with rituximab refractory disease.

Another option is lenalidomide/rituximab, also called R2, which has demonstrated higher rates of overall response and complete response, a longer PFS, and potentially better OS vs single agent rituximab in second- and subsequent-line settings. I would consider lenalidomide/rituximab for many patients, particularly those who are hesitant about chemotherapy and/or who had first-line bendamustine based therapy, in order to avoid the risk of toxicity with second-line R CHOP.

Subsequent-Line Treatment
In the third line setting, we have other options in addition to those discussed earlier. In particular, we can now consider the PI3K inhibitors—copanlisib, duvelisib, idelalisib, and umbralisib—which all have similar efficacy and slightly different administration and safety profiles. We also have tazemetostat, an EZH2 inhibitor with indications in relapsed/refractory follicular lymphoma for those with an EZH2 mutation after ≥2 prior systemic therapies and those with no satisfactory treatment alternatives regardless of EZH2 status. The PI3K inhibitors have a response rate of approximately 50% and a duration of response lasting approximately 1 year or more, whereas tazemetostat has a response rate of 69% in EZH2 mutant and 34% in EZH2-wildtype cohorts, with a duration of response of 10 and 13 months, respectively. Thus, if we have access to EZH2 mutation testing and the patient is found to have an EZH2 mutation, I would sequence tazemetostat before a PI3K inhibitor. Otherwise, my choice of therapy would depend on what the patient received in earlier lines of therapy and I may consider a PI3K in the third-line setting.

Other possibilities include more aggressive chemotherapy, autologous stem cell transplantation, and CAR T cell therapy, which are options particularly for patients who had shorter remissions and more resistant disease. CAR T cell therapies have encouraging short term data but we await long term data on response duration. For most patients, we would sequence PI3K inhibitors before CAR T-cell therapy given the complexity and toxicity associated with the latter, but that will depend on the patient’s preferences.

Your Thoughts?
When would you consider CAR T-cell therapy for your patients with follicular lymphoma? Join the discussion by leaving a comment and answering the polling question.

At the upcoming ASH 2021 annual meeting, join me and my colleagues Brad S. Kahl, MD, and Julie M. Vose, MD, MBA, on Friday, December 10, 2021, at 7:00 PM Eastern time for a live satellite symposium to learn more about managing follicular lymphoma and other B-cell lymphomas. Register here to attend the in-person event or for the live simulcast!