Future Directions and Unmet Needs in the Treatment of R/R FL


Looking ahead, Loretta Nastoupil, MD, reviews the future direction and unmet needs in the management of relapsed/refractory follicular lymphoma (R/R FL).

Loretta Nastoupil, MD: I often wonder if there is an unmet need in follicular lymphoma, given the vast majority of patients will do very well despite having or expecting recurrence of their disease, with the projected natural history or life expectancy to be 20-plus years. There are a couple of strategies to consider. It would be great if we could cure this disease and spare patients from having subsequent therapies. Understanding the biology of follicular lymphoma may shed light on strategies that might lead to full eradication of the disease, where we would then not need to counsel patients and manage expectations regarding the potential for recurrence. This would also lend itself well to exploration in the low tumor burden setting where there’s tremendous anxiety among patients and even clinicians about watchful waiting among patients who are newly diagnosed.

It’s early, but because an EZH2 [mutation] is an early event in the lymphomagenesis, and the toxicity profile of tazemetostat appears to be quite favorable, there are strategies that could be employed looking at combinations with tazemetostat, even in low tumor burden untreated follicular lymphoma. If that would alter the natural history of this disease, that would be a tremendous improvement.

If we’re unable to accomplish that, the next setting where we have the greatest unmet need is in the fourth-line or later space. I mentioned a number of agents that have been approved in the third-line space, which generally result in a median PFS [progression-free survival] of about 10 to 11 months. Despite that, many patients will be looking at fourth or later lines of treatment. There is still a need for an effective therapy that could potentially result in significant improvement in disease control in those later lines of therapy. That would require an effective strategy that is not toxic and can be administered in older patients, oftentimes with comorbidities and potentially even cytopenias as a result of prior therapy. There’s an unmet need for active well-tolerated treatments in the fourth-line or later space. There’s active drug development underway that may provide additional options for patients.

To summarize, this is a 75-year-old woman with high tumor burden, high-risk FLIPI [Follicular Lymphoma International Prognostic Index] advanced-stage follicular lymphoma who received common management strategies in the modern era, such as bendamustine, rituximab followed by R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], and still experiences a recurrence of her disease. She has an EZH2 mutation that was picked up at diagnosis and is thought to be present throughout the course of her disease. One of the newest therapies approved for follicular lymphoma, tazemetostat, was started in the third-line space.

Because we have a number of good options for patients with follicular lymphoma, another unmet need is figuring out how we sequence therapy in the modern era and how frequently to pursue molecular profiling. Are there strategies that might result in exceptional responses where a one-time therapy could be expected to be the last therapy? These are all aspirations that we continue to strive to address. The good news for patients and providers is there are great treatment options for relapsed follicular lymphoma. The treatment landscape continues to expand, and selecting your therapy based off of either an EZH2 mutation or the toxicity profile suggests that we have better and new options for patients in 2021.

This transcript has been edited for clarity.

Case: A 75-Year-Old Woman With Relapsed/Refractory Follicular Lymphoma

Initial presentation

  • A 75-year-old woman complains of a 3-month history of fatigue, occasional fevers, decreased appetite, fatigue, and a 12-lb weight loss
  • PMH: Medically-controlled hypertension, osteoporosis, hypercholesterolemia managed with diet and exercise
  • PE: palpable bilateral axillary and left cervical lymph nodes, ~ 3 cm in both axillae and 2 cm in the cervical nodes; spleen palpable 4 cm below left costal margin

Clinical workup

  • Labs: ANC 1.6 x 109/L, WBC 11.4 x 109/L, 43% lymphocytes, Hb 9.8 g/dL, plt 98 x 109/L, LDH 325 U/L, B2M 3.7 µg/mL; HBV negative
  • Excisional biopsy of the axillary lymph node on IHC showed CD 20+, CD 3+, CD5+, CD 10+, BCL2+; follicular lymphoma grade 2
  • Bone marrow biopsy showed paratrabecular lymphoid aggregates, 42% involvement
  • Cytogenetics: t(14;18) (q32;q21)
  • Molecular testing: EZH2m+
  • PET/CT showed bilateral axillary, left cervical, and mediastinal lymphadenopathy (3.3 cm, 3.1, cm and 4.6 cm respectively)
  • Ann Arbor Stage IV; ECOG 1


  • She was treated with bendamustine and rituximab for 6 cycles, achieved partial response and continued rituximab maintenance
  • 24 months later she complained of ULQ discomfort, loss of appetite, fevers new onset itching; she was currently taking antibiotics for her 2nd bacterial infection in the past 6 months
    • Repeat PET/CT revealed progression of disease
    • She was started on R-CHOP for 6 cycles and continued on rituximab maintenance
    • Repeat lymph node biopsy grade 2 follicular lymphoma
  • 12 months later she complained of continued weight loss, increased itching and worsening fatigue; recurrent infections continued
    • She was started on tazemetostat 800 mg BID
Related Videos
Video 10 - "RCC: Informing Treatment Decisions with Clinical Trial Data"
Video 9 - "KEYNOTE-564: Adjuvant Pembrolizumab in Renal Cell Carcinoma"
Video 8 - "Clinical Pearls for Optimal Management of mHSPC"
Video 7 - "Multidisciplinary Approach in mHSPC Management "
Video 6 - "Treatment Considerations in High Disease Burden and Comorbidities"
Video 5 - "Pivotal Trials in mHSPC"
Video 4 - "ARASENS Trial- Darolutamide in mHSPC"
Video 3 - "Treatment Intensification in Metastatic Prostate Cancer"
Video 2 - "Treatment Options for mHSPC"
Video 1 - "Initial Impression and Risk Assessment"