First-line Therapy Options in ND Follicular Lymphoma


Loretta Nastoupil, MD, discusses first-line therapy options for patients with newly diagnosed follicular lymphoma (ND FL).

Loretta Nastoupil, MD: In the modern era, there is still a role for watch and wait for patients with newly diagnosed follicular lymphoma who have low tumor burden. We generally define that based off of the GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria, which takes into account size and location of lymph nodes; whether or not there might any impending organ compromise as a result of size and location of those nodes; cytopenias, such as absolute neutrophil count, hemoglobin and platelets; symptomatic splenomegaly, usually defined as 16 cm or larger and often resulting in fatigue and weight loss; effusion, such as pleural effusion or ascites; and elevation in LDH [lactate dehydrogenase] or beta-2 microglobulin.

At times, patients are uncomfortable with the notion of having cancer and not receiving therapy at initial diagnosis. It’s important to have a careful discussion as to why it may be feasible to observe them. It’s important to explain that we’re not watching and waiting until they have significant risk to their health, we’re just watching and waiting until 1 of these characteristics emerges, because at that point, the [adverse] effects of therapy might be justifiable and less risk than the disease. Once patients have 1 of the GELF criteria, treatment is indicated. There are a number of treatment options for patients. We take into consideration patient-specific characteristics, such as age, comorbidities, their functional status, and our assessment as to whether they will tolerate intensive therapy.

In the United States, the most common treatment strategy includes chemotherapy plus a CD20 antibody, with bendamustine being one of the more frequent chemotherapy partners based on the perception and reports of a more favorable safety profile in comparison to an anthracycline-based approach in particular. In my opinion, it is reasonable to withhold the anthracycline until there are clinical or pathologic features to suggest transformed disease. Outcomes in the past were quite poor for patients with transformed disease when CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone] was more commonly administered for frontline follicular lymphoma. As we’ve utilized more bendamustine or nonchemotherapy approaches for the front line and reserved anthracycline for the instance of transformation, we have seen those outcomes improve.

In this case, this patient had a number of features that designated her to have high tumor burden and in need of therapy. She received one of the more common frontline approaches: a bendamustine-based therapy. The question of whether to tack on maintenance has been debated for years. If we observe the 10 years of follow-up of the PRIMA study, we observe a significant improvement in the first progression-free survival interval of about 10 years vs 4 years among patients who did not receive maintenance rituximab. The limitation of the PRIMA study is that most of those patients, about 74%, had CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]. Bendamustine was not utilized in the PRIMA study. In the StiL study, which compared bendamustine, rituximab vs R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], there was no maintenance utilized. There’s still debate as to whether to pursue maintenance rituximab following bendamustine and rituximab.

Unfortunately, the GALLIUM study did not address this. All patients who had 6 cycles of chemoimmunotherapy induction went on to receive 2 years of CD20 maintenance therapy, whether they were on the rituximab or obinutuzumab arm. The argument against maintenance is that we have yet to see an impact in overall survival despite these dramatic differences in the first progression-free interval, which highlights that this is a disease where the vast majority of patients will experience a relapse, and sequential therapy will overcome those dramatic differences with their first-line approach.

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
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