Second-Line Treatment for Relapsed Follicular Lymphoma


Recommendations for appropriately assessing patients with follicular lymphoma with disease progression after frontline treatment and options to consider as second-line therapy.

John P. Leonard, MD: There are a number of agents available at the time of first relapse, and many of them are also available at subsequent relapses. The key prognostic information comes from the time to progression after the first therapy. Those patients who progress within 2 years have a particularly less favorable prognosis than those patients who progress after chemoimmunotherapy after 2 years.

The duration of the first response, particularly after chemoimmunotherapy, is quite important in looking at long-term outcomes. I would generally look at a patient and look at their duration of response to their up-front therapy as a key factor in determining what I do next. If a patient progresses early, within that 2-year time frame, I’m particularly concerned. In fact, about half of those patients have transformation at the time of progression. That’s a patient who I might be more prone to rebiopsy or at least get a PET [positron emission tomography] scan to look for the presence of transformation.

If transformation is there, a more aggressive approach is with anthracyclines, if not already given, or perhaps an autotransplant. Those would be things I would think about.


The majority of patients will progress later—after 2 years from their initial therapy. Those are patients who have a relatively favorable prognosis. There are a number of options for these patients, depending on what they had before. One could often give single-agent rituximab if they had a long remission. We know that lenalidomide-rituximab can be useful and is associated with a PFS [progression-free survival] benefit and a higher response rate when combined with rituximab as second-line therapy in rituximab-relapsed patients.

Other options include chemoimmunotherapy again. If the patient had CHOP up front, you could use bendamustine-based therapy at relapse, or vice versa. If the patient had bendamustine up front, you could consider CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, prednisone] or other combination chemotherapies in the relapsed setting.

The use of obinutuzumab vs rituximab is another important distinction. Based on the time to progression and if the patient has more resistant disease, I might be more prone to use obinutuzumab in the more resistant disease setting, and rituximab in the more relapsed setting.

But all of these really figure into the decision as to what I would choose as second-line therapy. 

Obviously, the indications for therapy include, is the patient at risk for transformation? Do they need treatment at all in the relapsed setting? All these factors figure into what we would choose in the relapsed setting for patients with follicular lymphoma.

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 
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