Frontline Treatment for Newly Diagnosed Follicular Lymphoma

Christopher Flowers, MD: For newly diagnosed patients with follicular lymphoma, there are a number of factors that need to be taken into account when making a decision about initial therapy. One of the major classes of therapy to consider is single-agent rituximab. This is an option for those patients who fall into the low tumor burden group, or do not typically meet GELF [Groupe d'Etude des Lymphomes Folliculaires] criteria for treatment.

Those factors that are considered by the GELF criteria include having a single lymph node that is bigger than 7 cm, having 3 or more lymph nodes larger than 3 cm, having evidence of B symptoms, having a large spleen, having a high white blood cell count, or having fusions in the pleural space or peritoneal space.

For those patients who fall into the category of having no GELF criteria with advanced stage follicular lymphoma, the use of single-agent rituximab may be appropriate. Observation may also be appropriate for some of those patients as well. Observation has been the standard approach that we use for those patient populations, because there has never been a randomized controlled trial that has shown that overall survival was improved by early intervention in patients with follicular lymphoma.

For patients who fall into the other category, of high tumor burden by those GELF criteria, the considerations should include a chemoimmunotherapy, for which there are a variety of regimens. Those include rituximab plus CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone] chemotherapy; rituximab plus CVP [cyclophosphamide, vincristine, and prednisone] chemotherapy; rituximab plus bendamustine; or alternatively, another monoclonal anti-CD20 antibody, obinutuzumab, plus CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]; obinutuzumab plus CVP [cyclophosphamide, vincristine, and prednisone]; or obinutuzumab plus bendamustine/rituximab. There now have been randomized controlled trials that have shown that bendamustine plus rituximab has improvements in progression-free survival over R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], and another trial showed that those 2 are equivalent.

Because the toxicity of bendamustine is less, in general, than R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], bendamustine/rituximab has more commonly become a standard frontline regimen for patients with follicular lymphoma. Given that there is no hair loss associated with that regimen, there’s less risk of anthracycline toxicity associated with that, including cardiovascular disease. The other alternative that is now available is the use of lenalidomide plus rituximab. There now have been randomized controlled trials, notably the RELEVANCE trial, that looked at lenalidomide plus rituximab versus rituximab chemotherapy with each of those chemotherapy regimens that I just mentioned.

That randomized controlled trial has become known as the single most positive, negative trial. The intent of the trial was just to show superiority of lenalidomide/rituximab over rituximab chemotherapy. The trial failed at achieving its primary end point—to show benefit in complete response rate at 30 months with a benefit over rituximab and chemotherapy—but those 2 forms of approaches are relatively similar in terms of their progression-free survival. Lenalidomide plus rituximab has a different adverse effect profile compared to chemotherapy. Not the same chemotherapy-related toxicities that are commonly seen with R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone] and bendamustine/rituximab.

There is now potentially the availability of a chemotherapy-free regimen in the frontline setting for follicular lymphoma.

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
  
  

Treatment

• 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