Follicular lymphoma (FL) is a specific type of B-cell lymphoma that accounts for approximately 35% of all non-Hodgkin lymphomas (NHLs).1 Patients can present with lymphadenopathy, splenomegaly, and fatigue.1 Less than 20% of patients present with the classic “B” symptoms such as night sweats, fever, and weight loss.1 Roughly 85% of patients have t(14;18), which leads to a reduction in cell apoptosis via overexpression of the BCL-2 protein.1 This translocation does not completely explain the carcinogenesis found within F, as t(14;18) can be found in individuals without cancer.1

At least 70% of patients have bone marrow involvement,1 though involvement of other organs is uncommon. FL can transform to diffuse large B cell lymphoma (DLBCL) in 10% to 70% of patients over time, with a risk of approximately 2% per year.1 Depending on stage, treatment options include radiation therapy, rituximab (intravenous or subcutaneous), bendamustine, and lenalidomide.1 With advancements in treatment options, namely rituximab, overall survival (OS) has significantly increased, with a 10-year OS as high as 92% in certain age groups.2 

As OS has improved, there has been some concern that patients with FL are at increased risk for development of a secondary primary malignancy (SPM).3 Although this risk may be explained, at least partly, by advancing age alone, systemic therapy and/or radiation therapy have been implicated.3-5 In addition to treatment-related factors, biologic, genetic, and environmental factors also may contribute to emergence of SPMs, making a strong case for routine immunosurveillance.3,4

Risk Factors for SPM Development

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A study conducted by Giri and colleagues using a US Surveillance, Epidemiology and End Results (SEER) registry, the results of which were published in Clinical Lymphoma, Myeloma & Leukemia in 2017, found that, at a median follow-up of 71 months, SPMs developed in 1540 (9.9%) of 15,517 patients with FL.5 The cumulative incidence of SPMs was 11% at 10 years. Increased risks for the development of Hodgkin lymphoma; acute myeloid leukemia; oral cavity and pharynx, stomach, and lung cancers; melanoma; nonepithelial skin cancers; and urinary bladder and renal cancers were all statistically significant (P <.01), with standardized risk ratios ranging between 1.24 to 5.85. Older age (>65 years), male sex, and exposure to radiotherapy predicted a higher propensity for SPMs.

A similar study was conducted by Prusila and colleagues and published in the British Journal of Haematology in 2019. The authors evaluated the risk of secondary hematological malignancy (SHM) and found a 1.1% 5-year risk of SPM in 1028 patients with FL. This risk was higher in patients who had received second-line treatment (1.6%) compared with those who had received first-line therapy (0.5%).6

Prior Malignancy Diagnosis May Be Germane to SPM Development

Presence of a prior malignancy diagnosis (PMD) is another patient-related factor that may contribute to development of a SPM in patients with FL. PMD has been evaluated as a proxy for genetic susceptibility in other malignancies, such as multiple myeloma.3 Currently, there is a significant lack of data assessing the impact of a PMD on the development of SPMs and mortality in patients with FL. Therefore, Dinnessen and colleagues evaluated these factors using a Netherlands-based patient database published their findings in eJHaem in 2020.3

A total of 8028 patients with FL were identified in a nationwide registry. Of these, 483 (6%) had a PMD, and SPM developed in 1106 (14%). Fifty-two percent of patients with a PMH did not receive radiotherapy or chemotherapy. Patients with a PMD were more likely to be female (57% vs 50%; P <.001) and older  (median age 69 years vs 60 years; P =0.005) at FL diagnosis compared with patients without PMD. 

Patients with a PMD also had higher 5-year cumulative incidences of SPMs vs those without a PMD (10.1% vs 5.8%). When analyzed as a binary variable, PMD was associated with an increased incidence of SPMs (subdistribution hazard ratio [SHR], 1.44; 95% CI, 1.15-1.80; P =0.001).