First-Line Treatment Options for Follicular Lymphoma


A key opinion leader explains the first-line treatment options for follicular lymphoma and the challenges of treating patients with early disease progression.

Perry Cook, MD: Let’s review this case. What were our options as primary therapy? Did we make the right choice? Rituximab and bendamustine is a category 1A recommendation in the NCCN [National Comprehensive Cancer Network] guidelines. It appears to be superior in the SEAL study to rituximab and CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or rituximab and CVP [cyclophosphamide, vincristine, prednisone]. Those would be alternative regimens that would have been acceptable as first-line therapy, but there is a general consensus that rituximab and bendamustine is the optimal first-line therapy. Unfortunately, despite choosing the best therapy, we didn’t get the result that we wanted. The response was deep at the beginning, but it wasn’t sustained, and progression occurred within the 24-month window. This patient is identified as one with a guarded prognosis going forward.

What are the treatment options for patients who progress early? What would you consider? I think the general consensus for people who progress early is something other than chemoimmunotherapy is probably the best option. What options are there? An IMiD [immunomodulatory imide drug]in combination with a CD20 agent is an option, in combination with either rituximab or obinutuzumab, would be a reasonable next step. In addition, the PI3 kinase inhibitors are approved, but they require 2 prior lines of therapy. This patient doesn’t qualify yet for a PI3 kinase inhibitor. He was evaluated in terms of his molecular profile and found to be EZH2 wild type. That’s an interesting finding, because patients who are EZH2 wild type are considered appropriate for EZH2-directed therapy, even in the second line, if other therapies are considered too burdensome or too difficult to provide. We could make that argument here because he lives at a great distance. Tazemetostat is a therapy that doesn’t require close surveillance with very frequent blood testing. That would be a consideration for him, and we’ll go into some detail later about the consideration of tazemetostat. For many patients, the next option would be a CD20 drug with an IMiD. Patients who have an EZH2 mutation have a somewhat higher response rate, almost double the response rate, as EZH2-wild type patients, but the duration of response modestly favors the EZH2-wild type patients. That’s a paradox we don’t entirely understand.

What are the challenges of treating patients like this? The challenges are that we have to break out of our comfortable shell of treating with chemoimmunotherapy; we have to do something different. How do you make the decision to treat? I think, in general, it’s based on what our previous experience has been, and what the literature tells us. In this case, the overwhelming reality is that the patient did relatively poorly on initial chemoimmunotherapy, and so there’s an urgency to offer an alternative therapy. The 2 alternative therapies available to this patient at this point, are an IMiD, CD20-based regimen, that’s approved in the second line, or since he is EZH2 wild type, we could also offer tazemetostat.

Tazemetostat is a drug that works by a completely different mechanism of action than traditional chemoimmunotherapy. Eighty percent of patients with follicular lymphoma, and a similar percentage of those who progress within the first 24 months, are EZH2 wild type, so this is a viable option for our patient. It’s an option that would arguably be much less burdensome on him, living at a distance from the treatment center. It would not involve infusions of rituximab, it would simply involve swallowing pills at home and checking his blood counts, which could presumably be achieved closer to his home at an outpatient laboratory, with the results shared with the treating oncologist. These are the 2 primary options for this patient. The third option would be a radioisotope. Radioisotope would require coming to the center, of course, and would require frequent blood counts afterward, which could be done in the community. But this patient had significant bone marrow involvement at the start, and radioisotope is not recommended for patients who have more than 20% bone marrow involvement with follicular lymphoma. That hasn’t been reviewed at the time of relapse in this patient. If we were thinking in that direction, another bone marrow would be necessary to determine his extent of bone marrow involvement. At this point, I would leave you with these 3 options: IMiD with a CD20, tazemetostat since he is wild type, or ibritumomab tiuxetan if his bone marrow involvement is modest or absent at the time of relapse.

This transcript has been edited for clarity.

Case: A 76-Year-Old Man With Relapsed/Refractory Follicular Lymphoma

Initial presentation

  • A 76-year-old man complains of a 4-month history of bloating, fevers, and unintended weight loss of 9 lbs
  • PMH: Medically-controlled hypertension, brittle diabetes, CABG 10 years prior
  • SH: Lives by himself 2.5 hours from the clinic; only daughter lives out of state
  • PE: palpable right axillary lymph nodes, ~ 3 cm and bilateral cervical lymph nodes, ~ 2 cm; spleen palpable 4.5 cm below left costal margin

Clinical workup

  • Labs: ANC 1.6 x 109/L, WBC 11.4 x 109/L, 45% lymphocytes, Hb 9.5 g/dL, plt 96 x 109/L, LDH 426 U/L, B2M 3.4 µg/mL; HBV negative
  • GFR 59 ml/min
  • 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: EZH2 wild type
  • PET/CT showed right axillary, bilateral cervical, and mediastinal lymphadenopathy (3.3 cm, 3.4, cm and 2.6 cm, and 3.2 respectively)
  • Ann Arbor Stage IV; ECOG 1


  • He was treated with bendamustine and rituximab for 6 cycles, achieved complete response and continued on rituximab maintenance
    • Side effects included grade 3 diarrhea with BR
  • 16 months later he complained of fevers and chills with increasing frequency
    • Repeat PET/CT revealed progression of disease
    • He received R-CHOP for 6 cycles and continued on rituximab maintenance
  • 11 months later he had worsening fatigue and increased weight loss and work up revealed progressive disease
    • He was started on tazemetostat 800 mg BID
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