Optimal Treatment Selection Needed in Advanced Follicular Lymphoma

Benjamin Heyman, MD

The influx of alternative treatment options in the frontline and maintenance settings of advanced-stage, high-tumor burden follicular lymphoma has raised questions concerning the optimal therapy to prevent early relapse for patients, said Benjamin Heyman, MD.

"In follicular lymphoma, the vast majority of patients respond well to initial treatment. They can have long, durable remissions with many having near-normal life expectancies," said Heyman. "The question is trying to identify which patients are at risk for early progression with high-risk disease and [optimizing] therapies to prevent those early relapses."

In an interview during the 2020 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Heyman, a hematologist and assistant clinical professor of medicine at University of California, San Diego, discussed frontline and maintenance therapy options, novel targeted approaches, and the expanding role of minimal residual disease (MRD) in patients with follicular lymphoma.

OncLive: Should obinutuzumab (Gazyva) be used in all-comers in the frontline setting?

Heyman: The GALLIUM study demonstrated that patients who received chemoimmunotherapy with obinutuzumab (Gazyva) had an improved 3-year progression-free survival (PFS) compared with rituximab (Rituxan)-based chemoimmunotherapy; however, that benefit does come with increased toxicity.

A more recent analysis showed that patients treated with obinutuzumab-based regimens had a reduction in disease progression within 24 months versus rituximab-based chemoimmunotherapy. Those who have disease progression within 24 months of induction therapy have particularly poor outcomes.

In practice, I reserve obinutuzumab-based therapy for patients at high-risk for early progression, including those with higher grade, more advanced, and more aggressive disease. There is a particular toxicity concern with obinutuzumab in combination with bendamustine. As such, the combination [should be considered] for younger, fitter patients.

What are some alternative options in the frontline setting?

Chemoimmunotherapy regimens that include rituximab should also be considered a standard of care.

We have recent data showing that the combination of rituximab and lenalidomide (Revlimid; R²) is noninferior to rituximab chemoimmunotherapy. R² is a great option for patients with advanced-stage, high-tumor burden follicular lymphoma.

What factors do you consider when determining treatment for patients?

[Ultimately], it is patient preference and how aggressive the disease is behaving. R² is considered a chemotherapy-free regimen, but it is an 18-month-long therapy versus a 6-month treatment with bendamustine/rituximab or obinutuzumab.

Also, [it is important to discuss] whether patients want to take an oral or intravenous medication. The data with R² showed that patients have a decreased risk of infection and cytopenia; however, lenalidomide has increased cutaneous adverse events (AEs). It is about balancing the duration of therapy and the potential AEs that can come with it.

Is there role for active surveillance in follicular lymphoma, or do all patients require treatment at diagnosis?

The standard of care for patients with advanced-stage, high-tumor burden follicular lymphoma depends on whether or not they need treatment. We use the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria to determine that.

We know that follicular lymphoma is incurable. Giving patients chemotherapy when they do not meet the GELF criteria does not necessarily prolong their survival, and it leads to unnecessary [AEs].

The watch-and-wait approach is considered a standard of care until patients meet certain requirements: including symptoms, cytopenias, 3 enlarged lymph nodes >3 cm, and 1 enlarged lymph node >7 cm. These criteria would [indicate] high-tumor burden disease.

Should maintenance therapy with rituximab be utilized?

In my practice, I don't typically recommend [rituximab as maintenance therapy]. The 10-year updated data from the PRIMA study demonstrated, once again, that there is a PFS benefit with rituximab maintenance. About 50% of patients treated with rituximab were progression free compared with 35% of patients who had observation. It also demonstrated that there was an improvement in time to next chemotherapy treatment. Patients in the observation arm had about 9 years to next treatment, while this number was not reached in the rituximab arm.

While there was no overall survival (OS) benefit with rituximab maintenance, there are a few select situations where I still think about utilizing it in the maintenance setting.

For example, I would use it in a patient who does not necessarily have a complete response (CR) after induction chemotherapy. I am potentially concerned about early relapse in those patients, so giving rituximab may get them to a CR.

Also, I'll consider rituximab maintenance if I have an elderly patient who I am not sure can tolerate chemoimmunotherapy for a second time upon relapse. Maintaining remission for as long as possible may be important for those patients; therefore, the increased toxicity is worth it.

Similarly, remaining in remission may be particularly important for some patients. Maintenance rituximab may be a personal choice for patients, even though they have to come into the hospital every 2 months for 2 years and will potentially have an increase in AEs.

What options are available in the third-line setting? Is it feasible for patients to tolerate PI3K inhibitors?

In the third-line setting, patients are typically refractory to rituximab and potentially chemotherapy. Switching to a targeted approach, such as a PI3K inhibitor, is an attractive option that essentially shows response rates of 55% to 60%, irrespective of refractory status.

Whether or not they can tolerate PI3K inhibitors is patient dependent. A young, fit patient who has aggressive disease may still be able to tolerate it; however, many times patients in the third-line setting are elderly.

The AEs [associated with] PI3K inhibitors can be pretty significant, and can include hepatotoxicity, colitis, pneumonitis, and increased risk of infections, such as pneumocystis jiroveci pneumonia and cytomegalovirus. All of those can be serious. Even an infusion of copanlisib (Aliqopa) can cause hypertension and hyperglycemia.

As an alternative, lenalidomide or rituximab is great option in the second- and third-line settings if a patient has not previously received them.

We know that autologous stem cell transplant has a survival benefit as patients get further into the relapsed/refractory setting. Additionally, CAR T-cell therapy is being explored in patients with relapsed disease.

Where could venetoclax (Venclexta) fit best in the follicular lymphoma treatment paradigm?

A phase I study of single-agent venetoclax came out fairly recently and showed promise using a higher dose than what is typically used in chronic lymphocytic leukemia. In that study, using venetoclax at >800 mg showed an overall response rate of 44% and a durable CR rate of about 14%.

One would think that, as a BCL-2 inhibitor, venetoclax would be an attractive option for a disease that is somewhat dependent on BCL-2 overexpression. However, the exploratory analysis showed that BCL-2 expression was not dependent on response to venetoclax.

Venetoclax will play a role in follicular lymphoma whether it is as a single agent or as combination therapy. Looking at venetoclax plus a CD20-directed antibody and potentially other combinations hold promise.

How is MRD currently being used in follicular lymphoma? Why is achieving MRD-negative status important?

MRD has been explored a lot within B-cell lymphoid malignancies. Follicular lymphoma is an attractive disease to study MRD in because of t(14;18). We can use either polymerase chain reaction or flow cytometry to measure MRD.

In follicular lymphoma, the current status of MRD is investigational. We know from several trials that patients who achieve MRD negativity after the end of induction therapy or during maintenance therapy have significantly improved PFS compared with patients who [have MRD-positive disease]. This was initially demonstrated in prior studies. More recently, the GALLIUM study showed that patients with MRD-negative disease had significantly prolonged PFS irrespective of their prior treatment with rituximab or obinutuzumab compared with patients with MRD-positive disease.

How can we use MRD in follicular lymphoma? Can we use an MRD-adapted or -consolidated therapy to improve outcomes in this space? We know from the FIT trial—which used radioimmunotherapy in patients with MRD-positive disease at the end of induction chemoimmunotherapy—that if you give ibritumomab tiuxetan (Zevalin) to patients with MRD-positive disease, their PFS increases 4-fold [when they achieve MRD negativity].

Moving this approach [up in treatment] and [further understanding] who will benefit from consolidation or maintenance therapy is a way forward in follicular lymphoma that is being actively explored.

What is your take-home message?

Currently, we have the M7-Follicular Lymphoma International Prognostic Index (FLIPI) score, which can determine which patients are high-risk and are likely to relapse within 5 years of chemoimmunotherapy. Unfortunately, M7-FLIPI has not been easily utilized in clinical practice.

Looking at clinical, molecular, and genetic markers to help identify patients who are at high-risk for early progression can help to [optimize] which consolidation or novel treatment [is likely to] improve outcomes for those patients with advanced-stage, high-tumor burden follicular lymphoma. That is where [the field] is headed.