Follicular lymphoma (FL), the second most common type of lymphoma in the U.S., accounts for about 35% of all non-Hodgkin lymphoma cases. A recent update on the diagnosis and management of FL discusses the diagnosis, prognosis, and treatment options for early and advanced-stage disease and relapsed FL.

While 85% of FL patients have t(14;18) chromosomal translocation of human follicular lymphoma that leads to overexpression of BCL-2 protein, a compound that inhibits apoptosis, this translocation can be found in healthy individuals as well as those with diffuse large B-cell lymphoma.

The World Health Organization has classified FL (Grade I to IIIb) based on the number of centroblasts (enlarged activated B-cells). Nonetheless, between 10% and 70% of patients with FL undergo histologic transformation to diffuse large B-cell lymphoma at a rate of 2% per year.

The preferred initial treatment for limited-stage FL is radiation therapy, although <10% of cases are diagnosed while in stage I/II. Radiation therapy is associated with a 60% to 80% overall survival (OS) rate, resulting in a median survival of about 19 years. Radiation therapy with chemotherapy +/- rituximab may improve overall progression-free survival (PFS), but not OS compared with radiation therapy alone. Although not the norm, select patients may undergo “watchful waiting,” as over 60% of these patients still did not require treatment at 7 years. Despite these recommendations, radiation therapy is not as widely used in early stage disease, and patients are often treated instead with chemoimmunotherapy or rituximab monotherapy. 

Even patients with advanced disease, the stage at which most persons are diagnosed, do not require treatment unless they have symptomatic nodal disease, impaired organ function, along with B symptoms (i.e., fever, night sweats, weight loss) or if they have symptomatic extranodal involvement or cytopenias. 

Rituximab is not recommended in asymptomatic patients. If it is used, rituximab remains as effective at progression as if a patient had undergone 2 years of maintenance therapy. For the symptomatic patient with advanced disease, rituximab added to chemotherapy is associated with improved response rates, time to progression, and OS. Bendamustine-rituximab has been shown to have similar efficacy as R-CHOP. 

However, neither regimen improves OS. While bendamustine-rituximab may produce longer PFS, it is often not well tolerated in older adults. Bendamustine has also been combined with obinutuzumab, but this regimen is associated with toxicity and no improvement in OS. Rituximab monotherapy in patients with indolent disease has been linked to a twofold increase in event-free survival. Maintenance therapy with CHOP-R or CVP-R is still considered standard compared with bendamustine regimens. 

When rituximab was combined with lenalidomide in previously untreated patients, all patients were alive at 5 years. Radioimmunotherapy +/- conventional chemotherapy has been studied, but combination radiotherapy with CHOP offers no advantage over CHOP-plus-rituximab regimens. 

Autologous stem cell-transplantation is associated with increased secondary malignancies, which negate any benefit initially seen with this therapy. 

Unfortunately, indolent disease progresses to a higher grade histologic subtype, such as diffuse large B-cell lymphoma, and disease is more severe if patients who had been treated with bendamustine-rituximab progress within 24 months of initiating therapy. CHOP-like chemotherapy has been found to induce a complete remission in patients with more aggressive histology, especially when this is their first treatment. Consolidation with autologous stem-cell transplant after R-CHOP improves 5-year OS compared with chemoimmunotherapy alone (55% vs. 40%); however, treating with CHOP alone in treatment-naïve patients leads to a better outcome than combination therapy with autologous stem-cell transplants.

Options to treat patients with relapsed FL include rituximab alone or in combination with chemotherapy, radioimmunothrapy, and stem-cell transplantation. The role of rituximab monotherapy is unclear. Obinutuzumab, an anti-CD20 monoclonal antibody, combined with chemotherapy has response rates in the 90th percentile. CHOP-R followed by maintenance rituximab in rituximab- and anthracycline-naïve patients was associated with improved PFS. Rituximab has also been combined with fludarabine/cyclophosphamide/mitoxantrone and bendamustine in relapsed FL for improved response rates. 

Bendamustine with obinutuzumab followed by obinutuzumab maintenance therapy is more effective than bendamustine alone. The combination of lenalidomide plus rituximab is associated with increased PFS compared with rituximab therapy alone. Although anti-CD20 radioimmunotherapy can delay time to progression by up to 4 years, it is not widely used. FL is responsive to low-dose radiation therapy. Stem-cell transplant, either autologous or allogeneic, is controversial in relapse FL but may be a viable option in younger patients with more resistant disease. 

Newer approaches include the use of immunomodulatory agents such as the immunostimulants, IL2, and CPGs; active immunization using idiotype protein as the antigen; kinase inhibitors; CD19 CART (chimeric antigen receptor T) cells; and anti-CD47 antibodies.

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