Follicular Lymphoma

Background

• Follicular lymphoma is an indolent lymphoproliferative disorder of follicular center B cells that may be asymptomatic, or present with diffuse lymphadenopathy, bone marrow involvement, and/or splenomegaly.
• Follicular lymphoma is the second most common lymphoma in the United States and western Europe, accounting for 22%-35% of non-Hodgkin lymphoma cases and 70% of indolent lymphoma cases. The median age of diagnosis is 65 years.
• Variants of follicular lymphoma include follicular lymphoma in situ, pediatric-type follicular lymphoma, and primary follicular lymphoma of the duodenum.
• Given the indolent nature of follicular lymphoma, and the existence of excellent treatments, prognosis is generally favorable with a reported 10 year overall survival of approximately 80%.
• Adverse prognostic factors include older age, advanced disease stage, higher number of sites of nodal involvement, lower hemoglobin level, and elevated lactate dehydrogenase level. There is approximately 2% risk per year of histologic transformation to a more aggressive diffuse large B-cell lymphoma, which is associated with a poor prognosis.

Evaluation

• Suspect follicular lymphoma in patients presenting with lymphadenopathy (often asymptomatic), cytopenias, and/or splenomegaly.
• Diagnosis is confirmed based on immunophenotyping of surgical specimen/excisional lymph node biopsy. The typical immunophenotype of follicular lymphoma is:
  • CD10-positive (may rarely be CD10-negative)
  • BCL2-positive (may rarely be BCL2-negative)
  • BCL6-positive
  • CD19-positive
  • CD20-positive
  • CD23-positive or negative
  • monoclonal immunoglobulin-positive
  • CD5-negative
  • cyclin D1-negative
• Consider assessment of grade of follicular lymphoma by determining number of centroblasts counted per high power field. Grades 1, 2, and 3A are considered indolent disease and grade 3B is considered an aggressive lymphoma.
• Obtain the following studies to further evaluate stage of disease, risk stratification, and prognostic markers (Strong recommendation):
  • Blood tests including complete blood count, comprehensive metabolic panel, and other chemistries
  • Cytogenetic and molecular analysis; the majority of patients with follicular lymphoma have the t(14;18) translocation
  • Imaging with positron emission tomography-computed tomography (PET-CT) scan for staging.
  • Bone marrow biopsy with aspirate if radiotherapy is indicated for stage I-II disease or to assess unexplained cytopenias.

Management

• Management strategies are based on many factors, including presence of indications for treatment, disease grade and stage of disease, and risk stratification.
• Consider enrollment in a clinical trial (Weak recommendation). See clinicaltrials.gov for list of trials for patients with follicular lymphoma.
• For management of patients with early stage disease (stage I and contiguous stage II [can be captured within single radiation field]):
  • First-line involved-site radiation therapy (ISRT) is the preferred treatment for clinical stage I or contiguous stage II disease (Weak recommendation).
  • Consider ISRT with rituximab or obinutuzumab with or without chemotherapy (Weak recommendation).
  • In patients with high tumor bulk or if ISRT is not feasible, consider anti-CD20 monoclonal antibody with chemotherapy in those with treatment indication, or observation in those without a treatment indication (Weak recommendation).
  • Appropriate follow-up is required to determine need for additional therapy.
    • Consider maintenance therapy or observation (Weak recommendation) and offer surveillance and monitoring for disease progression (Strong recommendation) for patients with a complete or partial response to therapy.
    • If there is no response, assess for indications for treatment and if present, consider treating as advanced stage disease (Weak recommendation).
• For management of patient with advanced stage disease (noncontiguous stage II or stage III/IV):
  • Initial treatment of noncontiguous stage II disease:
    • If the patient presents with high tumor burden and cannot tolerate ISRT, consider anti-CD20 monoclonal antibody with or without chemotherapy (Weak recommendation).
    • Consider observation when the toxicity of ISRT is expected to outweigh the clinical benefit and there is no indication for treatment (Weak recommendation)
    • If a single field radiation can be safely given, then ISRT alone is the favored approach. However, it is reasonable to add anti-CD20 monoclonal antibody therapy in some cases.
  • For stage III/IV disease:
    • If the patient does not have any indications for treatment , offer initial observation (Strong recommendation).
    • If the patient has indications for treatment, consider obtaining PET-CT scan to assess for histologic transformation (Weak recommendation) followed by one of following:
      • First-line treatment with chemoimmunotherapy (Strong recommendation).
      • Radiation therapy for palliation of locally symptomatic disease in appropriate patients (Weak recommendation).
    • The use of rituximab monotherapy in asymptomatic advanced stage follicular lymphoma is an area of controversy. It could be considered as a possible strategy if high value is placed on delaying future treatment. In patients displaying high risk features for progression or poor outcome, the benefits of treatment would likely outweigh the risks even in the absence of symptoms. The Groupe d’Etude des Lymphomes Folliculaire (GELF) criteria is widely used to identify these patients.
    • Subsequent management is based on follow-up evaluation.
      • For patients achieving a complete or partial response, consider observation or maintenance or consolidation therapy (Weak recommendation).
      • For patients without a response, consider second-line therapy options (Weak recommendation).
• For management of a patient with relapsed disease:
  • Consider repeat biopsy and PET-CT scan to rule out transformation into aggressive lymphoma (Weak recommendation).
  • Consider observation for an asymptomatic patient with low tumor burden (Weak recommendation).
  • For a patient with indications for treatment, choice of therapy may depend on duration of response to prior therapy and disease stage at time of relapse.
    • Regimens used for first-line therapy are typically not repeated, especially in early relapses (for example < 12-24 months).
    • Consider treatment with (Weak recommendation):
      • second-line regimens, including preferred options of anti-CD20 monoclonal antibody with chemotherapy or lenalidomide plus rituximab
      • autologous hematopoietic stem cell transplantation in select younger patients with early relapse
      • radiation therapy for palliation of locally symptomatic disease (Weak recommendation)
      • alternative options for older adults or frail patients (Weak recommendation)
  • For subsequent treatment, consider maintenance therapy with rituximab (Weak recommendation) or obinutuzumab (Weak recommendation), and/or consolidation with hematopoietic stem cell transplant (Weak recommendation).
  • For third-line therapy and beyond, consider the following options (Weak recommendation):
    • second-line regimens that have not yet been used
    • phosphatidylinositol-3-kinase (PI3K) inhibitors
    • chimeric antigen receptor T cell (CAR T-cell) therapy in select cases (Weak recommendation)
    • mosunetuzumab (Weak recommendation)
    • hematopoietic stem cell transplant in some populations (Weak recommendation)
• Complications may be disease or treatment-related, and may include tumor lysis syndrome and recurrent infections.
• After treatment, surveillance is essential and includes clinical evaluation at regular intervals to determine presence of recurrent disease or histological transformation.