Amy Sievers, Ann LaCasce
Follicular lymphoma (FL) represents 20%–30% of all non-Hodgkin lymphomas (NHL) and is the second most common NHL in Western populations after diffuse large B-cell lymphoma (DLBCL) (1). FL comprises about 80% of the indolent NHLs. The term follicular is derived from the tendency of the neoplastic cells to form microscopic nodules. The cell of origin is the follicular center B cell. Eighty-five to 90% of all cases harbor the characteristic cytogenetic translocation t(14;18), resulting in the placement of the anti-apoptotic bcl-2 gene under the control of the immunoglobulin (Ig) heavy-chain promoter on chromosome 14. Follicular lymphoma is considered incurable without stem-cell transplantation, with the exception of localized disease that may be cured with radiotherapy in a subset of patients. Treatment is therefore based on disease control rather than cure, and eventual relapse after treatment is the usual natural history of FL (2).
INCIDENCE
The incidence of follicular lymphoma is approximately 2.2–3.2 per 100,000 in the United States and Western Europe (3). Follicular lymphoma is more common in Caucasians than in people of African or Asian descent and typically affects the middle-aged or elderly with an average age at diagnosis of 60 years. The disease occasionally occurs in children or young adults. FL in children is a distinct clinical entity, presenting with localized disease that is often eradicated with initial therapy. In contrast, adults with FL typically present with advanced stage disease and experience recurrence after standard treatment. Although there are no universally accepted risk factors for the development of FL, herbicides and pesticides have been linked with the disease. Familial cases represent a small proportion of total incidence, and there appears to be a slightly increased risk in relatives of patients with FL.
PRESENTATION
Clinically, patients with FL often present with asymptomatic peripheral lymphadenopathy or have enlarged lymph nodes detected incidentally on imaging studies. Although hilar and mediastinal nodes are frequently involved, large mediastinal masses are uncommon. The spleen and bone marrow are commonly involved by disease, but CNS and organ involvement is uncommon. Infiltration of the bone marrow is present in 60%–80% of patients at time of diagnosis. The majority of patients (70%–80%) will present with advanced stage disease, and up to 25% will have B symptoms or an elevated serum LDH level. Although bone marrow involvement is common and sensitive molecular testing frequently identifies circulating lymphoma cells, cytopenias are uncommon at presentation.
In addition to the classic presentation of FL as described above, there are a few distinct clinical variants. Primary intestinal follicular lymphoma is often found incidentally on endoscopy performed for unrelated indications and most often involves the second portion of the duodenum. Pediatric lymphoma is another variant and has distinct features as noted above. Intrafollicular neoplasia, or in situ FL, refers to follicles with high levels of BCL-2 expression but without other features of FL. This condition has relatively low rates of progression to disseminated FL. Rarely, patients will present with diffuse large B-cell lymphoma (DLBCL) with concurrent, previously undiagnosed FL. Prognosis for these patients with transformation is significantly worse than for de novo DLBCL without underlying FL. Of note, DLBCL with t(14;18) translocation does not necessarily imply transformed FL. Histologic features of coexisting FL, most commonly presenting with involvement of the bone marrow with FL, in addition to DLBCL are required for the diagnosis of transformed FL. Histologic transformation most commonly occurs after a variable period of FL, is a natural feature of the disease rather than a side effect of treatment, and when it occurs, it signals an acceleration in the natural history of disease.
DIAGNOSIS
The diagnosis of FL is typically determined by examination of an involved lymph node, ideally by means of an excisional biopsy of a complete node. Fine needle aspirates are not adequate to fully assess the architecture of the disease and establish the grade of the lymphoma. Bone marrow biopsy is an important component of staging but does not allow for disease grading. FL is one of the few lymphomas where morphologic evaluation alone is often sufficient for diagnosis. Distinguishing FL from reactive follicular hyperplasia or other types of lymphomas may be difficult on occasion. FL most commonly appears as tightly packed nodules of varying size and shape consisting of a mixture of small lymphocytes with cleaved nuclei and large lymphocytes with noncleaved nuclei that efface the normal lymphoid architecture. This is in contrast to a normal lymph node, where follicles are more uniform in appearance and interfollicular elements are more prominent. Additionally, FL nodules typically have lower Ki-67 fractions and decreased numbers of phagocytic cells compared with reactive nodes. FL less commonly involves lymph nodes in a diffuse pattern and involved lymph nodes may have both nodular and diffuse areas of disease involvement. Bone marrow involvement typically appears as paratrabecular lymphoid aggregates.
FL grading is based on the relative frequency of large noncleaved cells in the histologic specimen. Of note, grading of FL is notoriously nonconcordant between pathologists and with sequential readings by the same pathologist. Grading criteria are:
• Grade 1: 0–5 large cells per high power field (follicular small cleaved)
• Grade 2: 6–15 large cells per high power field (follicular mixed)
• Grade 3: >15 large cells per high power field (follicular large cell)
• 3A: small cleaved cells present
• 3B: small cleaved cells absent, solid sheets of large cells present
Grades 1, 2, and 3A are felt to represent a spectrum of disease, whereas the biology of grade 3B is distinct from the other subsets and cells typically lack CD10 and BCL-2 expression. Immunohistochemistry and flow cytometry demonstrate CD19, CD20, CD21, and CD79 positivity. CD10 is positive in up to 90% of cases. CD5, CD43, and CD11c are negative, and CD23 expression is variable although more commonly negative. The neo-plastic cells typically express monoclonal surface immunoglobulin, most commonly IgM or IgG. Cytoplasmic BCL-2 is strongly expressed in most grade 1, 2, and 3A FL, but is less commonly found in grade 3B disease.
Cytogenetic analysis demonstrates a BCL-2 translocation in 85%–90% of cases, typically as the result of a (14;18) translocation between the BCL-2 gene on chromosome 18 and the Ig heavy chain on chromosome 14. This translocation can also be found in up to 30% of cases of de novo DLBCL and occasionally in germinal center B cells in healthy individuals. Translocations between BCL-2 and the kappa light chain on chromosome 2 or lambda light chain on chromosome 22 are less common. All three translocations result in constitutive activity of BCL-2 leading to cellular resistance to apoptosis. BCL-2 translocations may also be identified by FISH and by PCR. The prognostic significance of minimal residual disease following therapy has not been clearly demonstrated. In addition, BCL-6 translocations on chromosome 3 are identifiable in 5%–15% of cases of FL and are more common in grade 3B disease, usually signifying a more aggressive clinical course. BCL-2 and BCL-6 translocations are not mutually exclusive, although FL harboring both mutations is uncommon.
STAGING AND PROGNOSIS
The Ann Arbor staging classification is employed in FL (4, 5):
• Stage 1: Limited to one lymph node region or lymphoid organ, or a single extranodal site (IE).
• Stage II: Limited to two or more lymph node regions on the same side of the diaphragm, or a single extranodal site with associated nodal involvement.
• Stage III: Involvement of lymph node regions or lymphoid organs on both sides of the diaphragm.
• Stage IV: Disseminated involvement of one or more extralymphatic sites, including liver, pleura, CNS, or bone marrow, with or without associated lymph node involvement.
Patients with persistent fevers, drenching night sweats, or a loss of >10% total body weight are considered to have B symptoms. Patients with FL are typically staged with computed tomography (CT) scans of the chest, abdomen, and pelvis as well as a bone marrow biopsy. Additional studies, such as CT scans of the neck, may be indicated based on individual clinical situations. FL is uniformly FDG avid on positron emission tomography (PET), and PET scans may upstage patients with FL compared with CT scan alone. Although a number of recent studies have examined the prognostic role of pretreatment, interim, and end-of-treatment PET scans, no clear guidelines exist on the use of this imaging modality and its use is currently investigational in FL (6, 7).
The best predictors of disease course and outcome are the factors that comprise the Follicular Lymphoma International Prognostic Index (FLIPI) score and disease grade. The FLIPI was developed using a retrospective multivariate analysis of over 4000 patients with follicular lymphoma from 1985 to 1992, before the routine use of rituximab. The prognostic value of the FLIPI has been validated in subsequent clinical trials (8, 9). The FLIPI score is based on the following criteria:
• Age >60
• Ann Arbor stage III of IV
• Hemoglobin <12.0 g/dL
• Involved nodal areas >4
• Serum LDH greater than the upper limit of normal
Five- and 10-year overall survival (OS) rates were determined based on the number of adverse factors present.
• Low risk (0–1 adverse factors): 91% and 71%
• Intermediate risk (2 adverse factors): 78% and 51%
• High risk (≥3 adverse factors): 52% and 36%
The FLIPI2 examined approximately 900 patients receiving therapy from 2003 to 2005 and identified the following criteria as independently prognostic (10):
• Age >60
• Bone marrow involvement
• Hemoglobin <12.0 g/dL
• Largest node >6 cm
• Elevated serum β2 microglobulin
The 3-year progression-free survival (PFS) was 91%, 69%, and 51%, and OS 99%, 96%, and 84% for patients with low (0), intermediate (1–2), and high (3) risk factors, respectively. Of note, only patients who received therapy were included in the analysis and the FLIPI2 prognostic score has not been prospectively validated in clinical trials.
Disease grade is also an important prognostic factor. Grades 1 and 2 disease have a similar clinical course and are treated uniformly. In general, grade 3 disease is more aggressive, though grade 3A disease may behave in a fashion more similar to grades 1 and 2 disease. Grade 3B is felt to represent a distinct entity and behaves more like DLBCL. Pathologic distinction between grades 3A and 3B disease may be difficult even with expert hematopathology consultation.
Finally, emerging data from gene expression profiling studies suggest that the tumor microenvironment and tumor immunology may predict disease behavior. Immune responses enriched with T cells as compared to those with higher percentages of monocytes/macrophages or dendritic cells appear to correlate with more favorable survival and lower rates of transformation to DLBCL (11, 12).
TREATMENT
Given that chemotherapy has not been curative in advanced stage FL and early therapy has not been shown to improve survival, the decision of when to begin treatment and the selection of therapy must balance symptoms from disease and influence of the cancer diagnosis on the patient with both disease- and treatment-related complications. The median survival for FL is in the range of 7–10 years, although extremes on either end occur. Overall survival may be significantly higher since the advent of rituximab. The 15%–20% of patients diagnosed with early-stage disease are potentially curable with local radiotherapy (RT). The mainstay of treatment for the remaining patients is systemic chemotherapy and/or immunotherapy, with a goal of disease control rather than cure. Radioimmunotherapy is another effective approach for some patients. More aggressive and toxic therapies may achieve better initial responses, but do not appear to translate into improved survival. As therapy has become more effective with incorporation of rituximab into combination chemotherapy regimens as well as its use as maintenance therapy, a larger fraction of patients achieve complete remissions and remissions are more durable than the median of 2 years achieved with older treatment regimens. For younger patients with relapsed or refractory disease, stem-cell transplantation may offer the potential for long-term control of the disease, at the expense of higher toxicity.
TREATMENT OF EARLY STAGE DISEASE
Involved field radiotherapy (RT) may cure a subset of patients with nonbulky localized FL. RT leads to a 10-year OS of 60%–80% and median survival of 19 years, with some patients achieving cure (13). Larger doses and larger fields of radiation do not appear to improve outcomes, although randomized trials of radiation field are underway. In general, patients receive total doses of 24–30 Gy with additional boosts of up to 6 Gy for bulky or slowly responsive disease. Despite data supporting the use of RT in this setting, only 27%–34% of patients with limited stage FL receive RT according to multiple large studies (14, 15). Often curative RT is not offered to patients because physicians assume that the disease is widespread. Although localized disease accounts for only 15%–20% of patients, the use of RT offers the potential for cure that may be lost if patients are managed by the watch-and-wait approach. All patients should have the disease staged including scans and bone marrow biopsy. RT may be omitted in a subset of patients due to abdominal disease, or stage II disease that is noncontiguous and/or would require large RT fields. While RT is the recommended therapy for most cases of early stage FL, among patients who are not appropriate candidates for RT based on the location and/or bulk or extent of disease, watchful waiting or systemic therapy may be reasonable options. Both combined chemoimmunotherapy and immunotherapy alone are options for systemic therapy of early stage disease, although data are limited as to efficacy in this setting. There are no clear data to suggest combined systemic and radiotherapy improves outcomes in early stage FL. In addition, a recent study analyzing patterns of care in a large number of patients with stage I FL showed excellent outcomes with a number of treatment approaches including RT, chemoimmunotherapy, or immunotherapy alone with or without RT and observation (16).
Although up to 20% of patients are diagnosed with early stage disease based on standard staging procedures with CT scans and unilateral bone marrow biopsy, a subset of patients will have occult higher stage disease. The studies evaluating the role of RT in localized disease predated the use of PET scans. At present, there are no data to suggest that using more sensitive means of detecting occult disease such as PET scans or peripheral blood or bone marrow assessment by PCR translates into better outcomes.
TREATMENT OF ADVANCED STAGE DISEASE
Multiple randomized clinical trials have demonstrated no advantage to early therapy versus a “watch and wait” strategy in asymptomatic patients with advanced stage follicular lymphoma. Both the Groupe d’Etude des Lymphomes Folliculaires (GELF) and British National Lymphoma Investigation developed criteria to determine when treatment of advanced-stage FL is indicated (17, 18). Extracting from both of these guidelines, primary indications for treatment in advanced stage FL include: (1) symptomatic bulky lymphadenopathy or splenomegaly, (2) compromise of organ function from disease, either directly or through nodal compression, (3) significant B symptoms, (4) significant cytopenias, (5) transformation to a more aggressive NHL, (6) presence of symptomatic effusions or other extranodal disease, or (7) an increase in the pace of disease. However, the GELF criteria are the most frequently invoked criteria for not treating:
• Maximum diameter of disease <7 cm
• Fewer than 3 nodal sites
• No systemic symptoms
• Spleen <16 cm on CT
• No significant effusions
• No risk of local compressive symptoms
• No circulating lymphoma cells
• No marrow compromise (Hgb <10 g/dL, WBC count <1.5 × 109/L, platelet count <100 × 109/L)
Among patients for whom treatment is indicated, there are a number of potential regimens for the initial treatment FL. For patients with a lower burden of disease who are frail or who have significant comorbidities, rituximab monotherapy is an option. The overall response rates range from 50% to 70% with a median time to progression from 13 to 34 months (19, 20). For the majority of patients requiring therapy, chemoimmunotherapy is the treatment of choice. In general, FL is sensitive to either single-agent chemotherapy such as alkylating agents or purine analogs, or combination regimens such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or cyclophosphamide, vincristine, and prednisone (CVP). Overall response rates with rituximab plus chemotherapy are 80%–100%. Multiple randomized studies have demonstrated benefit in PFS with the addition of rituximab in combination with chemotherapy (chemoimmunotherapy) compared to chemotherapy alone. Some of these studies have also shown an OS benefit with the incorporation of rituximab (21, 22). Rituximab in combination with fludarabine has comparable response rates to R-CVP and R-CHOP at the expense of increased toxicity, particularly myelosupression and risk of stem cell damage. More recently the alkylating agent bendamustine, which structurally also has purine analog-like features, has shown promise in terms of both efficacy and tolerability (23). Bendamustine in combination with rituximab is rapidly becoming the standard initial systemic therapy for FL based on preliminary data demonstrating improved complete response (CR) rates and PFS as well as tolerability as compared to R-CHOP (24, 25). OS is similar, though the follow-up is relatively short at this time.
Disease-free intervals can often be prolonged and partial responses (PRs) potentially converted to CRs with the use of maintenance rituximab in both the up-front and relapsed/refractory setting (26). In the PRIMA trial, patients responding to an initial combination regimen were randomized to observation or rituximab every 8 weeks for 2 years (27). Patients in the rituximab group had a 3-year PFS of 75% compared to 57.6% in the observation group. An influence on OS has not yet been demonstrated in the up-front setting. At this time, both maintenance rituximab and retreatment with rituximab at the time of progression remain acceptable options.
Grade 3 FL
Grade 3A follicular lymphoma is typically treated in a manner consistent with grades 1 and 2. Grade 3B disease, however, is often managed as DLBCL with anthracycline-based combination chemotherapy, such as R-CHOP or dose-adjusted EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin). Studies comparing grades 3A and 3B have not been consistent in terms of response to therapy and prognosis. This may, in part, be due to the lack of diagnostic reproducibility. Some studies have demonstrated that patients with grade 3B disease may experience long-term disease control with initial anthracycline-based chemotherapy (28).
Large Cell Transformation
Patients with FL have a risk—from 3% to 7% annually—of transformation to a more aggressive NHL, most commonly DLBCL. Transformation is often heralded by rapidly enlarging masses, the onset of systemic symptoms, and a rapidly rising LDH. Suspicion of aggressive transformation should prompt immediate biopsy and treatment. Patients with transformed disease are treated with regimens appropriate for aggressive lymphoma such as R-CHOP. More intensive regimens, such as dose-adjusted R-EPOCH are currently being studied. The prognosis for previously treated patients with histologic transformation to DLBCL is generally poor with most series showing a median survival <12 months, though patients who are chemotherapy naive at the time of transformation have a more favorable prognosis. A subset of patients treated with R-CHOP may achieve long-term remissions after consolidation with high-dose chemotherapy and autologous stem cell rescue; 5-year disease-free survivals range from 30% to 60% (29). However, the low-grade follicular component may reemerge after therapy. Rarely, transformation is associated with the acquisition of a MYC translocation or overexpression, a “double hit” lymphoma in the case of both MYC and BCL-2 translocations, which is associated with a particularly poor prognosis (30).
Stem-cell Transplantation
The role of high-dose therapy with autologous stem-cell transplant (ASCT) for patients with FL is controversial. Several prospective trials examining ASCT in previously untreated FL have shown improvements in CR rate and PFS without a benefit in overall survival (31, 32). A small randomized study of relapsed FL in the pre-rituximab era showed that stem-cell transplantation demonstrated improved PFS and OS compared to standard chemotherapy (33). In addition, single institution studies have shown 10-year PFS of 30%–50%. A plateau in PFS after 10 years has been identified in some very mature studies, possibly suggesting that ASCT may be curative in approximately a quarter of patients (34). Earlier studies reported up to 10%–20% transplant-related mortality (TRM) with ASCT, though in the modern era TRM of 4%–5% is more usual. In the era of total body irradiation-containing preparatory regimens, the risk of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was greater than 10% in some series. Chemotherapy-only conditioning regimens appear to have a substantially lower risk. In general, ASCT is reserved for patients with aggressive histology transformations or for patients with chemosensitive relapsed or refractory disease and good performance status. The role of maintenance rituximab following ASCT has not been clearly defined but it is widely used.
Allogeneic transplantation, primarily through a graft-versus-lymphoma immune response, offers the best chance of cure in FL. Because of the substantial risk of TRM (up to 30%–40% at 1 year in older studies) and the risk of chronic GHVD, allogeneic SCT has generally been reserved for patients with good performance status whose disease is chemotherapy resistant or has an extremely poor prognosis, such as patients who have relapsed after ASCT. Outcomes are better, however, among patients without transformed disease and who have received fewer previous lines of therapy. Although the risk of toxicity is high, rates of long-term disease-free survival with allogeneic transplant exceed 60% in some series (35, 36). TRM is lower with reduced-intensity conditioning regimens or T-cell-depleted transplants, but the optimal conditioning regimen has not been defined.
Radioimmunotherapy
Radioimmunotherapy (RIT) is another effective therapy in FL. Currently two radiolabeled anti-CD20 monoclonal antibodies are approved by the FDA: Yttrium-90 ibritumomab tiuxetan (Zevalin) and Iodine-131 tositumomab (Bexxar). These agents have not been compared directly in randomized clinical trials. RIT is typically employed in the relapsed/refractory setting, with the majority of patients responding, including those who have received prior rituximab. In addition, responses are often more durable than those obtained from previous treatments. RIT as initial treatment is highly active, though it has not been compared directly to rituximab alone. In addition, consolidation after chemotherapy prolongs progression-free survival, but again this strategy has not been compared to chemoimmunotherapy or to maintenance rituximab (37). In addition, RIT is also being added to conditioning regimens before both autologous and allogeneic transplantation (38). Thus far the toxicities of RIT have been acceptable, with hematologic effects occurring for approximately 4–8 weeks after therapy due to the radiation effects on the bone marrow. This effect on the marrow has been associated with a small risk of prolonged cytopenias and myelodysplastic syndrome. Though published reports claim no permanent marrow damage from RIT, clinical experience suggests that marrow tolerance to subsequent courses of chemotherapy is compromised by RIT.
Refractory or Relapsed Disease
Patients with primary progressive disease or patients who fail to achieve a PR—defined as 50% reduction in the burden of disease—with initial treatment are considered to have refractory disease. In managing patients who display primary refractory or relapsed disease in the setting of a rising serum LDH, disproportionate growth in one area, new development of extranodal disease, or new “B” symptoms, obtaining a repeat biopsy to exclude transformation to DLBCL is indicated. Therapeutic options for patients with relapsed FL are dictated by treatment goals. Additionally, indications for treatment or relapsed/refractory disease are similar to indications for initial treatment. Treatment options include watchful waiting, monotherapy with immunotherapy, combined chemoimmunotherapy, RIT, clinical trials, and stem-cell transplantation. For patients with refractory disease or short durations of remission who respond to subsequent therapy and are appropriate candidates, stem-cell transplantation may be considered. A number of novel agents such as lenalidomide and bortezomib are active and numerous other drugs are in clinical trials, including novel antibodies, antibody drug conjugates, and Bruton’s tyrosine kinase (BTK) and BCL-2 inhibitors (39–41).
Monitoring
There are no consensus guidelines on monitoring of FL and the frequency of imaging is highly controversial given the potential risk from radiation exposure related to serial scans. A reasonable approach is clinical examination and laboratory tests including CBC, comprehensive metabolic profile, LDH, and possibly β2-microglobulin every 3–6 months for the first year after diagnosis or after treatment, and then every 6–12 months thereafter. Relapses are almost always detected by the patient. Imaging is generally performed at time of diagnosis and before initiation of treatment, and then following the completion of treatment. Surveillance imaging is left to the discretion of the treating physician and patient. As noted previously, a proper biopsy is a key component of the initial diagnosis and should be considered at recurrence, particularly if clinical, laboratory, or radiographic findings suggest transformation.
SUMMARY
FL is the most common subtype of indolent lymphoma. A subset of patients with localized disease may achieve long-term disease control with radiotherapy. FL is not usually cured with chemotherapy or chemoimmunotherapy alone. Stem-cell transplant is potentially curative in selected younger and good performance status patients with relapsed or refractory disease. The mainstay of treatment for advanced-stage disease is combination chemoimmunotherapy, often followed by maintenance immunotherapy. There are numerous options for systemic treatment. OS is 13–15 years for most patients, although patients with transformation to more aggressive histologies have a poorer prognosis.
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