Treatment Challenges Beyond the Second-line in R/R FL


Loretta Nastoupil, MD, describes the challenges of selecting treatment beyond the second-line.

Loretta Nastoupil, MD: We have observed over many years that the remission durations get significantly shorter as we get into the third-line or later space. It’s also important to recognize that many of these patients are diagnosed with follicular lymphoma in their early to mid-60s. When we observe them in the third-line or later space, they’re often in their mid- to late 70s. That leads to additional considerations regarding patient characteristics, comorbidities, age, their preference between oral vs IV [intravenous] therapy, and number of office visits, which has been of significant concern in the COVID-19 era. We recognize that many of these patients will experience multiple recurrences. They may not need therapy at each relapse, so we still will practice watchful waiting. I usually follow similarly to the frontline setting to observe for GELF [Groupe d’Etude des Lymphomes Folliculaires] criteria. If they fit the criteria, the [adverse] effects of therapy can be justifiable.

I’m always on the lookout for signs of transformed disease because about 20% to 30% of patients with follicular lymphoma will experience a transformation event over the course of their disease. Even though the outcomes are improving, transformed disease still drives many of the poor outcomes we see among patients with follicular lymphoma. In the absence of transformed disease in patients who are in need of therapy in that third-line or later space, your treatment options include PI3 kinase inhibitors, lenalidomide and rituximab, tazemetostat, and most recently, axicabtagene ciloleucel. I weigh the efficacy with the safety profile to choose among these various options. I take into consideration whether a patient might prefer an oral vs an IV therapy.

Tazemetostat provides one of the most favorable toxicity profiles and lends itself well, particularly as a monotherapy to dosing with patients who have potentially significant comorbidities or are on the frailer side. If patients have not had lenalidomide in the third-line or later space, I will consider this option as well, given the favorable efficacy that’s been reported in the AUGMENT and MAGNIFY trials. Even though it’s a targeted therapy, some of the limitations of lenalidomide are the chemotherapy-like [adverse] effects, such as fatigue, nausea, constipation, arthralgias, myalgias, and then the less frequent risk factors, such as DVT [deep vein thrombosis]. With lenalidomide-based approaches, I commonly experience cytopenias, including neutropenia, that often warrant dose adjustment and potential growth factors.

The PI3 kinase inhibitors are clearly effective strategies for at least half of patients. The toxicity profiles may impact my treatment selection of one over another. The IV formulation of copanlisib provides an option for patients who cannot tolerate oral therapies, though the transient hypertension and hyperglycemia may not lend itself well to patients who have poorly controlled diabetes or hypertension. What also can emerge over the course of a patient’s disease history is that they may lose CD20 expression due to repeated exposure to CD20-based therapies. Targeted therapy that does not rely on partnering with CD20 antibodies can be very attractive in the third-line or later space where we start to see the CD20-negative diseases emerge. Things like tazemetostat or a PI3 kinase inhibitor are more attractive than lenalidomide monotherapy, which has not performed well. I will reserve axicabtagene ciloleucel for patients who have high-risk features, such as POD24 [progression of disease within 24 months], or clinical concern for transformed disease.

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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