Treatment Options for Relapsed Follicular Lymphoma


Christopher Flowers, MD: For patients who relapse early after one of those chemoimmunotherapy regimens—bendamustine/rituximab or R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] being the most commonly used ones in the United States—those are patients who have very poor expected overall survival and progression-free survival.

In a landmark paper that was led by Carla Casulo, MD, from the National LymphoCare Study, we saw that patients who received R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen and then relapsed within 2 years of their primary therapy had a very poor expected overall survival of approximately 50% or less at 5 years. For those particular patients, we need to think about newer approaches.

There is a chemoimmunotherapy compared with targeted therapy approach being explored in a randomized trial for patients with an early relapse. That is a US intergroup trial looking at the combination of bendamustine/obinutuzumab for those who had R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] as their frontline regimen, or obinutuzumab/CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] for those who had bendamustine as their first-line chemoimmunotherapy regimen. That is 1 arm of the trial. Lenalidomide/obinutuzumab is the second arm of the trial, and a PI3-kinase inhibitor, umbralisib, and obinutuzumab is a third arm in the trial. That really should be the preferred approach for this poor-risk patient population.

For those patients who are unable or unwilling to go on a clinical trial, the kinds of regimens that we might think about in the relapsed setting as approved regimens are bendamustine/obinutuzumab, which this patient got in this particular situation; or lenalidomide and rituximab, which is now approved based on the AUGMENT trial in the relapsed and refractory setting; or other forms of chemoimmunotherapy.

For those patients who are young enough and healthy enough, autologous stem cell transplantation should be considered after that. Those typically would be patients under the age of 70 who are fit and well enough to undergo an autologous stem cell transplantation.

There are also more clinical trials exploring CAR [chimeric antigen receptor] T cells in this setting for patients who have an early relapse.

While this patient experienced an early relapse of follicular lymphoma, which again, happens in about 20% of individuals, the majority of patients will experience a later relapse, something longer than 2 years after initial therapy. For those patients, there are numerous approaches available.

Occasionally, single-agent rituximab can be used in that setting to control disease and help prevent a subsequent relapse. In addition, lenalidomide/rituximab is now approved in that setting. Bendamustine/obinutuzumab is another option, and any other first-line chemoimmunotherapy regimens that weren’t used in the first-line setting are also potential options for use in the second line for a relapse.

For patients who experience a second relapse after that first, early relapse, there are a number of other agents, including those that I just mentioned, that would be options. And additionally, the PI3-kinase inhibitors, by themselves, are approved in this setting.

Transcript edited for clarity.

Case:A 77-Year-Old Man With Follicular Lymphoma

Initial Presentation

  • A 77-year-old man complains of a 4-month history of occasional fevers, decreased appetite, and an unintentional 7-lbs. weight loss
  • PMH: unremarkable
  • PE: palpable left axillary lymph nodes ~ 4 cm; spleen palpable 4.5 cm below costal margin

Clinical Work-up

  • Labs: ANC 1.5 x 109/L, WBC 10.6 x 109/L, 42% lymphocytes, Hb 10.1 g/dL, plt 100 x 109/L, LDH 325 U/L, B2M 3.3 µg/mL; HBV negative
  • Follicular lymphoma grade 2
  • Bone marrow biopsy showed lymphoid aggregates, 35% 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


  • He was treated with R-CHOP for 6 cycles; continued rituximab maintenance 375 mg/m3; achieved partial response
  • 6 months later he complained of increasing frequency of fevers
    • Repeat PET/CT revealed progression of disease
    • He was started on bendamustine + obinutuzumab for 6 cycles and continued maintenance obinutuzumab
    • Repeat lymph node biopsy grade 2 follicular lymphoma
  • 8 months later he complained of increased weight loss
    • He was started on idelalisib 150 mg PO BID
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