Optimizing the Sequence of Therapy for Follicular Lymphoma

Medical oncologist and lymphoma specialist Matthew J. Matasar, MD, is chief of medical oncology at Memorial Sloan Kettering (MSK) Bergen, in Montvale, New Jersey. His research interests focus on elucidating the long-term effects of lymphoma treatments and on evaluating new ways to improve the quality of life for lymphoma survivors.

Can you provide a little background on the epidemiology and characteristics of FL?

Follicular lymphoma is the most common slow-growing B-cell non-Hodgkin lymphoma in the United States. It comprises about 20% of all cases of non-Hodgkin lymphoma diagnoses.¹ It affects men and women equally and the median age at diagnosis is 63 years, but FL can also occur in younger adults and (very rarely) in children.²

While some lymphomas have a very uniform natural history and disease course, FL is not such a malignancy. Patient presentations can vary widely, from localized to advanced disease. For example, FL may be diagnosed incidentally in an asymptomatic patient or a patient may present with bulky disease and significant symptoms.

What is the standard of care for early-stage FL?

Several guidelines can inform clinical decision-making in the management of newly diagnosed FL.^3,4 These guidelines often suggest that treatment be informed by the patient’s underlying disease burden (eg, comorbidities), the presence or lack of symptoms, and the burden of disease.

Can you describe some treatment options for patients with early-stage disease?

Many patients will be diagnosed with a relatively low disease burden, in which case active observation is the most appropriate treatment.⁵ In the United States, the median time from diagnosis to first treatment actually exceeds 3 years. For patients presenting with localized disease who truly have stage 1 disease in an irradiable field, radiation therapy with or without rituximab is a standard of care.

How does first-line therapy influence subsequent lines of therapy?

In initiating care for a patient with newly diagnosed FL, oncologists really should be taking the entire treatment sequence into account. The choices that we make early in the course of illness, when planning that first-line therapy, have clear consequences in terms of subsequent lines of therapy.

The clearest example of that is the use of anthracycline-based chemoimmunotherapy. It is known that patients can typically only receive 1 course of doxorubicin-based treatment due to the cumulative cardiotoxicity of doxorubicin.⁶ Therefore, in choosing to treat a patient with FL with doxorubicin you are closing that door for subsequent lines of treatment. Oncologists must be thoughtful as to when and how to administer doxorubicin to patients with FL.

What are some other first-line therapeutic options?

We certainly have a wide range of effective therapies for FL, including CD20 antibody monotherapy (with rituximab, for example), or chemoimmunotherapy using either rituximab or obinutuzumab combined with one of several chemotherapy backbones including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and bendamustine. There is also lenalidomide, which is typically coadministered with rituximab.

For patients with relapsed FL, there are additional newer treatments; these include agents that target the phosphoinositide 3-kinase (PI3K) pathway as well as the EZH2 inhibitor tazemetostat, a newer medicine that slows tumor growth.

Which biomarkers are available to guide therapy selection for patients with FL?

For newly diagnosed patients, unfortunately, much of the work that could inform and optimize therapy for individual patients is still immature. We cannot yet use genomics or other specific biomarkers to guide first-line therapy successfully. Instead, choice of therapy is often based upon the burden of disease, the tempo of the lymphoma’s progression, and patient preferences. For patients with relapsed FL, the EZH2 inhibitor tazemetostat does show differential activity depending on whether or not the patient’s FL harbor EZH2 mutations.⁷ In some patients, the presence or absence of genomic alterations of the EZH2 gene can inform decision-making regarding the use of tazemetostat.

How difficult is it to select a therapeutic regimen for patients with relapsed disease? Which options are available in this setting?

All of the options that I have previously mentioned — including lenalidomide, PI3K inhibitors, tazemetostat, and chemoimmunotherapy — are very relevant in the management of patients with relapsed FL. Relapsed disease does present a challenge for many patients. It is well recognized that with each subsequent line of therapy, patients’ expectations are diminished in terms of the likelihood of a response to treatment and the response duration that they will be able to enjoy. For this reason, it is essential that oncologists choose subsequent lines of therapy based on these considerations: what agents their patient received in prior lines, the quality and duration of the treatment response, and the individual patient’s comorbidities and personal goals of care.

What are some promising treatments under investigation in FL?

It is a tremendously exciting time for those of us who study novel therapies for FL. In terms of a drug type or class, we are most enthusiastic about agents within the field of immunotherapy. Specifically, we have CAR T-cell therapy with axicabtagene ciloleucel already approved by the US Food and Drug Administration (FDA) and then there are bispecific antibodies such as mosunetuzumab, epcoritamab, and IGM-2323 in clinical development. These bispecific antibodies target both CD20 on lymphoma cells and CD3 on healthy T cells, creating an immune synapse. In ongoing clinical trials, drugs in this class have proven to be highly effective and well tolerated in patients with relapsed FL.