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Supplements Targeting the PI3K Pathway in Follicular Lymphoma

Follicular Lymphoma: A Review of Mechanisms, Risk Factors, and Unmet Needs

Follicular lymphoma (FL) is an indolent, B-cell lymphoproliferative disorder that accounts for about 20% of all cases of non-Hodgkin lymphoma (NHL).1,2 Although findings from most studies point to a declining incidence of FL over the past several decades, certain subpopulations of patients may be at higher risk. In particular, there is a linear relationship between increasing age and risk,3 and unlike other NHL subtypes, FL occurs more commonly in women than men.1,3 Nevertheless, because of its low incidence, FL is considered an orphan disease in much of the world.2

Despite having a relatively favorable prognosis in the majority of cases,3 FL is associated with considerable clinical heterogeneity and molecular and morphologic diversity.1 Correspondingly, older age2,4 and more advanced stage at the time of diagnosis2 are associated with increased mortality rates. The hallmark tranlocation t(14;18), which is identified in 75% to 90% of cases,1,5 leads to overexpression of BCL2, an anti-apoptotic protein that promotes cell survival. On its own, BCL2, however, is not considered to be sufficient for lymphomagenesis.5-7

Because of the heterogeneous disease course of FL, decisions to initiate treatment for patients with the disorder are usually individualized and may be based on the patient’s performance status and individual characteristics.8 Watchful waiting is commonly employed in frontline settings for individuals with asymptomatic, low tumor-burden FL,8 whereas chemoimmunotherapy, usually with the addition of rituximab, is generally preferred when treatment is initiated.9-11 From a historical perspective, the introduction of rituximab to the treatment armamentarium for FL has significantly improved clinical outcomes,12-14 with median survival in the chemotherapy era approaching 20 years and median progression-free survival (PFS) greater than 7 years.12 Unfortunately, however, about 20% of patients with FL experience disease progression within the first 2 years of first-line therapy, which, in turn, is associated with poor survival.10,12 Additionally, it has been found through long-term follow-up that about 60% to 70% of patients will experience a relapse despite initial response to therapy.8 Histologic transformation to a more aggressive lymphoma occurs in about 2% to 3% of cases per year and is associated with poor survival.5

Beyond the clinical implications, progressed FL has consequences for healthcare costs and impact on patients’ quality of life. In one study, the 12-month cumulative costs associated with FL were approximately 3.5 times higher for patients with progressive disease than for individuals without progressive disease ($30,890 vs $8704), which was driven in large part by the use of rituximab-containing combination chemotherapy regimens. Patients with progressive FL had more total outpatient visits and laboratory procedures, as well as more frequent chemotherapy visits per month, than individuals with non-progressive disease.2 Although decrements in quality of life outcomes have been reported for patients with FL, relapsed disease is associated with a more profound impact on quality of life, increased anxiety and depression, and greater loss of work productivity.2

Recent advances in the understanding of FL biology and pathogenesis have identified several somatic mutations and host immune factors thought to drive oncogenic signaling pathways that may be targetable with novel therapeutic approaches.8 This article reviews the pathogenesis, prognosis, state of treatment, and unmet needs of patients with FL.

Etiology and Pathogenesis

The family of NHL subtypes comprises about 90% of malignant lymphomas, with significant etiologic variation among NHL subtypes and differences in clinical presentation and course.1

Genetic susceptibility and environmental factors have been shown to play a role in the etiology of FL, although the exact role of each and the extent of their influence on each other have yet to be elucidated.1 Because some degree of genetic instability is integral for normal lymphocyte differentiation, progenitor B cells are particularly susceptible to acquiring chromosomal translocations and other oncogenic mutations.

Genome-wide association studies are helping to elucidate the role of genetic diversity in the etiology of various NHL subtypes, including FL, and to identify susceptibility variants in human leukocyte antigen (HLA) class 1 and 2 regions that may predispose lymphocytes to acquiring hallmark translocations. One study that used SNP2HLA as a reference reported that homozygosity in HLA class 2 loci—but not in any HLA class 1 loci—were associated with increased risk of FL.15 Because HLA class 1 and 2 molecules have distinct functions within the immune system, these data provide at least suggestive evidence that differing immune pathways are relevant for initiation and progression among the separate NHL subtypes.15 Perhaps related, single-nucleotide variants (SNVs) in the coding region for CXCR5, a receptor involved in B-cell migration and activation, are more strongly associated with risk for FL than other NHL subtypes.8 For instance, alterations in CXCR5 may alter host immune functions, potentially influencing FL initiation and progression.6,16 SNVs have also been identified in the HLA region, and 5 have been identified in non-HLA loci that are near genes coding for BCL2, offering evidence that SNVs may contribute toward predisposition for acquisition of t(14;18).5,6,17

A complex series of pathways are suspected to perpetuate FL precursor cells to pathogenesis, including epigenetic dysregulation, increased stimulation of survival pathways, and immune evasion.5 Disruption of histone‑modifying enzymes occurs through genetic lesions, which permit FL precursors to undertake rapid transcriptional and phenotypic alterations during the differentiation process and enhance various survival pathways.5 Aberrant DNA methylation is recognized as an additional mode of epigenetic dysregulation in FL pathogenesis.5 In the context of cells already resistant to apoptosis due to BCL2 overexpression, such epigenetic dysregulation serves to perpetuate proliferation programs and genetic instability.5 Under normal conditions, BCL signaling drives formation and maintenance of the germinal center, whereas it must be downregulated to permit B cells to exit the germinal center and progress toward terminal differentiation. Constitutive expression of BCL locks B cells in a germinal center-derived phenotype, while also making the arrested B cell susceptible to DNA damage.5 In turn, “chronic active” B-cell receptor signaling affects activation of a variety of additional pathways, including NF-κΒ, MAPK, and PI3K-AKT, that directly or indirectly promote cell survival.5 Finally, the skewing of T-cell composition within the FL microenvironment toward an immunosuppressive phenotype drives tumor growth by activation of B-cell receptors through paracrine secretion of protumor cytokines and by fostering escape from immune surveillance.5


NHL is more common in developed countries; it is recognized as the 10th most common malignancy worldwide while ranking seventh in the developed world.1 In a review of data from the National Cancer Data Base, which accounts for approximately 70% of newly diagnosed cancer cases in the United States and Puerto Rico, 596,476 cases of NHL were diagnosed between 1998 and 2011, of which 17.1% were FL.18 Rates appear to vary according to geographic region. One study reporting on trends in the United States, United Kingdom, France, Italy, the Netherlands, Australia, and Japan found an incidence ranging from 2.1 per 100,000 in France to 4.3 per 100,000 in the United States.2 Other studies have found that FL accounts for a lesser proportion of all NHL cases in eastern countries than in the United States.18

Most evidence points to a trend in declining incidence of FL. Although results from a 2006 study reporting on surveillance, epidemiology and end results data for the period 1974 to 1992 demonstrated a modest increase in the numbers of follicular lymphoma cases,1 findings from a 2016 study suggest declining incidence of follicular lymphoma from 2001 through 2012.3 The authors of the latter study reported an estimated incidence of 3.4 per 100,000 population (from 2011 to 2012), or about 13,960 new cases per year in the United States.3 The contrast in incidence in different time periods is similar to data for overall lymphoma incidence rates, which increased steadily during the 1970s and 1980s before leveling off and eventually declining throughout the 1990s.3 One potential contributing factor in incidence trends for FL may be a decline in smoking rates since 2001; a positive association between smoking history and risk of FL has been noted in some studies.3 It has been suggested that tobacco use may induce the t(14;18) translocation, which is found in 70% to 95% of tumor tissue in patients with FL.1,5

Notwithstanding overall trends, certain subpopulations continue to be disproportionately affected by FL. An increasing incidence of FL in individuals from age 30 to 70 years was observed in a large-scale analysis of data from the North American Association of Central Cancer Registries.3 Additionally, in contrast to other NHL subtypes, FL is more common in women than men.1,3 Geographic differences do not appear to account for the sex difference; a higher 10-year prevalence of FL among women (26.2/100,000) than among men (24.1/100,000) was reported in a study from the United Kingdom.2 Specific risk factors for FL, including autoimmune conditions such as Sjögren syndrome, which is more common in women, may be a factor in a slight preponderance in women (incidence rate ratio, 1.18).3 Other suspected risk factors have been recognized, including smoking history in women and environmental exposure to benzene or solvents.3

Risk Factors

Although family history of NHL, recreational sun exposure, hay fever, and allergies are associated with increased risk across most, if not all, NHL subtypes, there is significant heterogeneity in the risks associated with each subtype.19 As may be expected, the greatest differences in associated risks are between B-cell and T-cell lymphomas, although there is also significant heterogeneity in risk factors within the family of B-cell lymphomas.20 Moreover, a cluster analysis of risk factors demonstrated that groupings of NHL subtypes share common risks: peripheral T-cell lymphoma and mycosis fungoides/Sézary syndrome; marginal zone lymphoma and Burkitt lymphoma; and diffuse large B-cell lymphoma, FL, chronic lymphocytic leukemia/small lymphocytic leukemia, mantle cell lymphoma, and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia—and within the last group, certain shared risk factors further differentiate FL and mantle cell lymphoma from the others.19

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