Therapeutic approaches

Because of the often-indolent clinical course and the lack of symptoms in some patients with follicular lymphoma, watchful waiting remains a standard of care during the initial encounter and for patients with slow asymptomatic relapsing disease. When therapy is required, numerous options may be used in varying sequences with an OS equivalence at 5 to 10 years.[9,21-23] Rituximab can be given alone or in combination with various chemotherapy options.[23-25] Rituximab can also be combined with the immunomodulating-agent lenalidomide to avoid the short- and long-term toxicities of cytotoxic agents.[26-28] Obinutuzumab is a completely humanized anti–CD20 monoclonal antibody that can be given alone or with combination chemotherapy. It may be especially useful for patients who develop severe allergic reactions to rituximab due to human antimouse antibodies.[29] CD19-directed chimeric antigen receptor T cells may be used in patients who have disease progression after two or more prior lines of therapy.[30] Mosunetuzumab, a bispecific CD20-directed CD3 T-cell engager, may also be used in this setting.[31] Consolidation therapy for relapsed disease after reinduction therapy using autologous stem cell transplant (SCT) or allogeneic SCT can be considered.[32]

Outside the context of clinical trials, the use of measurable residual disease (MRD) testing has not been shown to be predictive in directing therapy for patients with follicular lymphoma. In retrospective analyses of two randomized prospective trials, while MRD negativity was prognostic of outcome, maintenance rituximab or obinutuzumab prolonged PFS the most among patients with MRD-negative disease.[33,34][Level of evidence C2] Stopping maintenance rituximab or obinutuzumab was not indicated in patients with MRD-negative disease, negating any possible change in therapy based on that status.

Follicular lymphoma in situ and primary follicular lymphoma of the duodenum are particularly indolent variants that rarely progress or require therapy.[35,36] A so-called pediatric-type nodal follicular lymphoma has indolent behavior and rarely recurs; adult patients with this histological variant have disease characterized by a lack of BCL2 rearrangement in conjunction with a Ki-67 proliferation index greater than 30% and a localized stage I presentation.[37]

Patients with indolent lymphoma may experience a relapse with a more aggressive histology. If the clinical pattern of relapse suggests that the disease is behaving in a more aggressive manner, a biopsy can be performed, if feasible.[38] If disease conversion to a more aggressive histology is confirmed, therapy must change to a regimen applicable to that histological type.[39] Rapid growth or discordant growth between various disease sites may indicate a histological conversion.[38]

In a prospective nonrandomized study, at a median follow-up of 6.8 years, 379 of 2,652 patients (14%) subsequently transformed to a more aggressive histology after an initial diagnosis of follicular lymphoma.[40][Level of evidence C3] The median OS after subsequent transformation was 5 years. However, among 47 patients with evidence of transformation in conjunction with follicular lymphoma at the time of initial diagnosis, the OS was no worse than that of the nontransformed patients (5-year OS rate, 88%; 95% CI, 74%–95%).

Grade 3b follicular lymphoma is managed similarly to DLBCL. For more information, see Aggressive B-Cell Non-Hodgkin Lymphoma Treatment.