Relapsed/Refractory FL: Third-Line and Beyond Treatment Options


Treatment options available for patients with relapsed/refractory follicular lymphoma in later-line settings and factors that impact the selection of a PI3K inhibitor over other types of therapies.

John P. Leonard, MD: There are a number of choices for patients like this 1 in third-line therapy. If we practice long enough and have patients who have had follicular lymphoma long enough, there are many people who will go on to receive third-, fourth-, and even later-line therapy over the course of their disease, depending on their individual situation.

Some of the same options that we discussed earlier would be things to at least consider depending on the patient’s prior therapy. Giving the patient bendamustine-based therapy or CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone]–based therapy would be reasonable. Again, you have rituximab and obinutuzumab. These would come up among our choices. We would also think about lenalidomide if the patient hadn’t received this class of treatment in the past. Sometimes retreatment is used. 

In patients with more resistant disease, the PI3 kinase inhibitors are choices that show value for a number of patients. We have data that suggest they can be helpful in patients with disease that’s resistant to rituximab, to chemotherapy.

The first of these that was approved was idelalisib, which is an oral focused on the PI3K-delta isoform. We also have copanlisib and duvelisib approved in this setting. These would also be possibilities for this particular case.

Perhaps one chose idelalisib in this situation because it’s been around the longest. But the other choices would also be reasonable. It’s notable that idelalisib and duvelisib are oral agents, whereas copanlisib is given intravenously on a weekly schedule with some breaks. So the route of administration is different. Because of the PI3 kinase selectivity, the toxicity profile is a bit different.

But in particular, the oral route of administration is something that many patients appreciate with idelalisib as well as duvelisib among these choices. Copanlisib might be a better choice for patients who have issues with compliance or for whom in-office treatment with an infusion might be preferred. These are all very reasonable treatments to consider.

I will also add that there are other chemotherapy drugs. A stem cell transplant could be used in certain patients. This is not as likely to be employed in older patients, but an autologous stem cell transplant is still an important treatment modality for patients with recurrent follicular lymphoma. We also have tazemetostat, an EZH2 inhibitor, approved for patients with recurrent follicular lymphoma as well in certain situations, particularly more effective if they have an EZH2 mutation.

There are a number of choices. Certainly, idelalisib would have been a reasonable choice, as was selected in this patient case, but there are a number of others that could have been chosen as well.

Transcript edited for clarity.

 Case: A 72-Year-Old Woman With Follicular Lymphoma

Initial Presentation 

  • A 71-year-old woman complains of a 5-month history of occasional fevers, decreased appetite, fatigue, and an unintentional 7-lbs. weight loss
  • PMH: unremarkable 
  • PE: palpable left axillary lymph nodes ~ 4 cm and bilateral cervical lymph nodes ~ 3 cm; spleen palpable 4.5 cm below costal margin 

Clinical Work-Up 

  • Labs: ANC 1.5 x 109/L, WBC 11.8 x 109/L, 42% lymphocytes, Hb 9.6 g/dL, plt 100 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, 45% involvement 
  • Molecular genetics: t(14;18) (q32;q21) 
  • PET/CT showed enlargement of left axillary, mediastinal, and bilateral para-aortic lymphadenopathy (4.2 cm, 5.3 cm, 3.6 cm, and 3.5 cm respectively) 
  • Ann Arbor Stage IV; ECOG 0 


  • She was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m3; achieved partial response 
  • 6 months later, she complained of increasing frequency of fevers and chills 
  • Repeat PET/CT revealed progression of disease 
  • She was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance on obinutuzumab 
  • Repeat lymph node biopsy grade 2 follicular lymphoma 
  • 12 months later, she complained of increased weight loss and fatigue 
  • She was started on idelalisib 150 mg PO BID and achieved partial response 
  • She experienced grade 2 diarrhea, which was successfully managed 
Related Videos