Follicular Lymphoma Management Overview

Updated: Sep 06, 2018
  • Author: Lauren C Pinter-Brown, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Management Overview

Practice Essentials

Of the approximately 74,680 cases of non-Hodgkin lymphoma (NHL) expected to be diagnosed in 2018 in the United States, [1] approximately 20% are likely to be follicular lymphomas. [2] No sex preponderance is seen for follicular lymphomas, but the incidence increases with age and varies across racial groups. See the image below.

Follicular lymphoma, low-power view. Note the nodu Follicular lymphoma, low-power view. Note the nodular pattern reminiscent of germinal centers. Photograph courtesy of Aamir Ehsan, MD.

Signs and symptoms

Follicular lymphoma is a type of non-Hodgkin lymphoma that most commonly presents as a painless, slowly progressive adenopathy. Systemic symptoms, such as fever, drenching night sweats, or weight loss in excess of 10% of ideal body weight, or asthenia, are infrequent at presentation but can be observed in later stages of the disease.

Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can also be observed in the later stages of the disease. Lymphocytosis, reflecting blood involvement, may also be present.

Despite the fact that most follicular lymphomas are advanced at the time of diagnosis, many patients may not require treatment for prolonged periods of time, and the median survival of patients with follicular lymphomas has historically been approximately 8-10 years. [2] Literature since the rituximab era has shown a further increase in overall survival. [3, 4]

Diagnosis

During the physical evaluation, all lymph node areas and the reticuloendothelial system should be examined. Involved nodes typically are nontender, firm, and rubbery in consistency. The throat, liver, and spleen should also be examined. Splenomegaly is present in approximately 50% of patients at presentation, and hepatosplenomegaly may occur.

A complete blood cell count (CBC) with differential should be obtained, including examination of the peripheral blood smear if the differential is abnormal. A chemistry panel and lactate dehydrogenase (LDH) level should be obtained.

A computed tomography (CT) scan of the chest, abdomen, and pelvis can determine whether abdominal or pelvic adenopathy is present. Positron emission tomography (PET) scanning may also be useful in certain clinical settings, such as localized disease or when transformed disease is suspected. [5]

Biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy (or, if that is not possible, a core biopsy) of an involved node. If the disease is extranodal, a surgical biopsy sample should be obtained from the involved organ.

Because the chromosomal t(14;18) translocation is found in the majority of patients with follicular lymphoma, bone marrow aspiration and chromosome analysis can also help establish the diagnosis.

Staging and grading

Most patients with follicular lymphoma present at an advanced stage, and most patients have bone marrow involvement at diagnosis. Staging is as follows:

  • Stage I – One involved lymph node or lymph node area
  • Stage II – Two or more involved lymph nodes or lymph node areas on the same side of diaphragm
  • Stage III – Involved lymph node or lymph node areas on both sides of diaphragm
  • Stage IV – Disseminated disease, such as bone marrow, liver, or central nervous system involvement

Follicular lymphoma is further categorized into grades according to the number of centroblasts per high-power field (hpf), as follows:

  • Grade 1 – 0-5 centroblasts per hpf
  • Grade 2 – 6-15 centroblasts per hpf
  • Grade 3 – >15 centroblasts per hpf

Grade 3 disease is subdivided into grade 3A, in which centrocytes are present, [6] and grade 3B, in which folllicles composed of centrocytes are present. Clinically, grade 3B follicular lymphoma is treated like diffuse large B-cell lymphoma.

Management

Treatment varies based on the stage of the disease. Early-stage, localized disease may be treated with radiation therapy or excision in certain cases. Observation is recommended for patients with advanced disease until they develop systemic symptoms or disease that threatens organ function.

Multiagent chemotherapy in combination with rituximab is the most common first-line treatment strategy for follicular lymphoma. Combination chemotherapy regimens vary and include the following:

  • Rituximab, cyclophosphamide, vincristine, prednisone (R-CVP) [7]

  • Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) [8]

  • CHOP immediately followed by tositumomab/iodine-131 radioimmunotherapy (CHOP-RIT) [9]

  • Bendamustine plus rituximab [10]

  • Rituximab plus lenalidomide [11] (non-chemotherapeutic regimen)

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Etiology and Pathophysiology

Viruses and chemicals

Viruses have been implicated as etiologic factors for lymphomas, including the Epstein-Barr virus (EBV), human T-cell lymphotropic virus (HTLV) type I, and the herpesvirus associated with Kaposi sarcoma (ie, human herpesvirus [HHV]-8 ). Hepatitis B and C viruses are also associated with risk for lymphoma. Nevertheless, these viruses have been linked mostly to diffuse or high-grade lymphomas.

Chemicals, such as defoliants (eg, Agent Orange) and hair dyes, have been associated with lymphoma.

Immunodeficiency states

Congenital immunodeficiencies have been associated with lymphoma. Acquired immunodeficiencies may include infection with the human immunodeficiency virus (HIV). Most lymphomas associated with HIV are intermediate-grade or high-grade lymphomas.

Patients who have been on immunosuppressant drugs after organ transplantation may develop lymphoma. Most of these lymphomas are diffuse or high-grade lymphomas.

Autoimmune diseases and the treatments for them (eg, methotrexate) that may allow lymphomagenesis are known to be associated with an increased risk of lymphoma. [12]

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Epidemiology

Non-Hodgkin lymphoma (NHL) is the fifth most frequently diagnosed malignancy in the United States. The American Cancer Society estimates that 74,680 cases of non-Hodgkin lymphoma will be diagnosed in 2018. [1] Follicular lymphomas constitute approximately 20% of NHLs. [2] No sex preponderance is seen.

In general, age-adjusted incidence rates of NHL are higher in more developed countries. The incidence of follicular lymphomas increases with age; these conditions are extremely rare in children, though the World Health Organization has delineated a pediatric variant. The median age at diagnosis is 60-65 years. The age-adjusted incidence rates of NHL varied from 3.7-14 cases per 100,000 person years from 1983-1987 in different countries.

Variations in racial incidence are found throughout the world. The incidence of follicular lymphomas is low in China and Japan, but people of Ashkenazi Jewish ancestry have a higher incidence of lymphoma. In the United States, the incidence is 2-3 times higher in white individuals than in black persons. [13]

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Clinical Evaluation

Follicular lymphoma most commonly presents as a painless, slowly progressive adenopathy. Some patients have waxing and waning adenopathy.

Systemic symptoms, such as fever, drenching night sweats, and/or weight loss in excess of 10% of ideal body weight, are infrequent at presentation but can be observed in later stages of the disease. Transformation to an intermediate-grade or high-grade lymphoma should be considered when a patient develops systemic symptoms or rapid enlargement of a lymph node.

Symptoms related to bone marrow dysfunction, such as anemia, leukopenia, or thrombocytopenia, are rare at presentation but can also be observed in the later stages of the disease.

During the physical evaluation, all lymph node areas and the reticuloendothelial system should be examined, including the pre- and post-auricular, submandibular, cervical, supraclavicular, axillary, epitrochlear, inguinal, and popliteal areas. Involved nodes typically are nontender, firm, and rubbery in consistency.

In addition, the throat should be examined for involvement of the oropharyngeal lymphoid tissue (ie, Waldeyer ring), and particular attention should be given to the abdominal examination (eg, liver and spleen), as splenomegaly is present in approximately 50% of patients at presentation and hepatosplenomegaly may occur.

Most lymphomas originate from lymph node tissue and can frequently involve other organs. Lymphomas can involve any organ, including the skin and GI tract, and they can cause detrimental effects by organ invasion and by obstruction of anatomic structures by a tumoral mass. [14, 15] For example, ureteral obstruction by enlarged lymph nodes can lead to renal failure. 

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Staging

Most patients with follicular lymphoma present at an advanced stage, and most patients have bone marrow involvement at diagnosis. Staging is as follows:

  • Stage I - One involved lymph node or lymph node area
  • Stage II - Two or more involved lymph nodes or lymph node areas on the same side of diaphragm
  • Stage III - Involved lymph node or lymph node areas on both sides of diaphragm
  • Stage IV - Disseminated disease, such as bone marrow, liver, or central nervous system (CNS) involvement

See also Pathologic classification systems under Histologic Findings and Follicular Lymphoma (Non-Hodgkin Lymphoma) Staging

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Differential Diagnosis

Autoimmune disorders and chronic infections as well as the following conditions should be evaluated as part of the differential diagnosis of follicular lymphomas:

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Routine Laboratory Tests

A complete blood cell count (CBC) and differential should be obtained, along with examination of the peripheral blood smear if the differential is abnormal. Frequently, abnormal lymphocytes can be identified in the blood smear, reflecting involvement of the blood

Blood chemistries, including lactate dehydrogenase (LDH) levels, uric acid levels, liver function tests, and creatinine measurements should be assessed. LDH is an indicator of tumor load, and an elevated level is a negative prognostic factor.

Hyperuricemia may be observed upon presentation or during therapy. Allopurinol should be considered in patients with hyperuricemia and before treatment to prevent uric acid nephropathy.

Increased creatinine levels can be observed in patients with renal obstruction caused by lymphadenopathy, and increased alkaline phosphatase and bilirubin measurements can be observed in patients with biliary obstruction due to lymphadenopathy or involvement of the liver.

If treatment with rituximab is being considered, serology for hepatitis B (ie, hepatitis B surface antigen, core antibody, and surface antibody) and hepatitis C should be obtained.

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CT and PET Scanning

CT scans of the chest, abdomen, and pelvis should be performed to determine whether adenopathy is present. CT scans allow visualization of the kidneys, ureters, and the hepatobiliary system. In some cases, those organs are affected by obstruction due to lymphadenopathy or by parenchymal involvement with lymphoma.

Positron emission tomography (PET) scanning complements standard radiologic testing, but only a minority of patients will be diagnosed with a higher stage of disease. This imaging modality can distinguish between viable tumor and fibrosis in patients with residual lymphadenopathy after therapy, but because the majority of follicular lymphoma cases are not curable, such a finding may not change management. [5] This is in contrast to Hodgkin lymphoma and intermediate-grade lymphoma, in which a positive PET scan might prompt salvage chemotherapy or radiation because the treatment goal in those diseases is cure.

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Biopsies

The role of the surgeon is to obtain an excisional biopsy adequate to establish the diagnosis. The surgeon should be instructed about the proper handling of the specimen and the special tests that may be required. A discussion of these issues with the pathologist before the biopsy is performed is often helpful.

Pathologic diagnosis from biopsy specimen

Biopsy is essential to establish a diagnosis of lymphoma. Obtain an excisional biopsy of an involved node. Note that a needle aspiration is not adequate for the initial diagnosis of lymphoma. [16] If the disease is extranodal, a surgical biopsy sample should be obtained from the involved organ. If an excisional or incisional biopsy cannot be obtained because of location, a core biopsy may be acceptable.

Posterior iliac crest bone marrow aspiration and biopsies

Although a diagnosis of follicular lymphoma can be established based on histologic findings from lymph nodes and involvement of the bone marrow can be diagnosed using morphologic criteria, cytogenetic analysis of bone marrow cells should be performed because the t(14;18) translocation is found in the majority of patients with follicular lymphoma and can help establish the diagnosis. Fluorescence in situ hybridization (FISH) testing for a t(14;18) chromosome translocation may also be useful.

Acquired nonrandom chromosomal translocations

The most common acquired nonrandom chromosomal translocation in patients with follicular lymphomas is the t(14;18) translocation, which is found in more than 80% of cases. [17] This chromosomal translocation brings the bcl2 proto-oncogene under the transcriptional influence of the immunoglobulin heavy-chain gene, leading to the overexpression of a functionally normal bcl-2 protein. Overexpression of the bcl-2 protein, a protein of the mitochondrial membrane, confers a survival advantage to the cancer cells by inhibiting programmed cell death (apoptosis). Although the exact mechanism of action of bcl-2 is unclear, its interaction with other homologues is felt to determine the likelihood of a cell undergoing apoptosis.

The detection of the t(14;18) product by polymerase chain reaction (PCR) is used frequently in the diagnosis and follow-up of patients with follicular lymphomas. Nevertheless, this translocation has been detected in healthy patients and in patients with other types of tumors.

 

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Histologic Findings

The most common diagnostic pitfall is to confuse follicular lymphomas with other types of lymphomas. The diagnosis of lymphomas is complex, and tissue biopsies should be reviewed by pathologists with experience in interpreting lymph node biopsies and other diagnostic material.

Follicular lymphomas exhibit a follicular or nodular pattern of growth reminiscent of germinal centers. This follicular pattern of growth contrasts with diffuse lymphomas, which usually are intermediate or high-grade neoplasms (see the following images).

Follicular lymphoma, low-power view. Note the nodu Follicular lymphoma, low-power view. Note the nodular pattern reminiscent of germinal centers. Photograph courtesy of Aamir Ehsan, MD.
Diffuse lymphoma. Note the absence of the nodular Diffuse lymphoma. Note the absence of the nodular pattern observed in follicular lymphomas. Photograph courtesy of Aamir Ehsan, MD.

Pathologic classification systems

Several pathologic classification systems have been used since the late 1960s, including the Rappaport, Lukes-Collins, Kiel, Working Formulation, Revised European-American Classification of Lymphoid Neoplasms (REAL), and World Health Organization (WHO). Early classification systems relied solely on the architecture and cytologic appearance of lymph nodes. As more sophisticated tests became available, immunophenotypic, cytogenetic, and molecular criteria were incorporated in the diagnosis of lymphomas. REAL was based on the premise that a classification should attempt to define disease entities using all available information, including morphology characteristics and immunophenotypic, genetic, and clinical features.

More recently, the WHO classification of lymphoid neoplasms adopted the REAL classification and proposed several changes, such as the following [18, 19, 20] :

  • The WHO classification changed the nomenclature from follicle center cell lymphoma to follicular lymphoma.

  • The WHO classification calls for grading of the follicular lymphoma from grades 1-3 based on the number of centroblasts per high-power field (hpf) and recognizes the importance of reporting on the presence of diffuse areas.

  • The WHO classification recognizes two variants of follicular lymphomas: cutaneous follicle center cell lymphoma and diffuse follicle center lymphoma. Nodal follicular lymphoma, according to the WHO classification, is staged as grade 1 (0-5 centroblasts per hpf), grade 2 (6-15 centroblasts per hpf), and grade 3 (>15 centroblasts). Variants include cutaneous follicle center cell lymphoma and diffuse follicle center cell lymphoma.

  • WHO classification further classifies grade 3 into grades 3A and 3B. [6] Grade 3A has centrocytes present whereas grade 3B has follicles composed of centroblasts. Clinically, grade 3B follicular lymphoma is treated like diffuse large B cell lymphoma.

Importantly, progression to diffuse large-cell lymphoma occurs in 10-50% of patients depending on the duration of disease presence. Transformation to diffuse large-cell lymphoma frequently is associated with rapid progression of the disease, including increasing adenopathy, development of systemic symptoms, and infiltration of extranodal sites.

Progression to large-cell lymphoma can be a poor prognostic factor. Many patients who experience transformation succumb to the disease, especially those who have received many lines of previous therapy. See the following image.

A patient with follicular lymphoma who was diagnos A patient with follicular lymphoma who was diagnosed 6 years earlier presents to his hematologist's office because of rapidly growing lymphadenopathy and onset of fever, severe night sweats, and weight loss. In the past, he had been treated with chlorambucil and prednisone when his submandibular lymph nodes became large enough to make him uncomfortable. This treatment had worked well, and he has not required any treatment recently. A biopsy of an involved lymph node is obtained. The diagnosis is transformation to diffuse non-Hodgkin lymphoma.

Xerri et al have demonstrated that high levels of MUM1 positivity are associated with shorter progression-free survival, based on analysis of the patient samples from the PRIMA study and correlating the patient outcomes. [21] Another study of 46 cases of follicular lymphoma was also able to correlate high levels of MUM1 expression with high-grade subtype and poorer outcome because of the propensity for transformation. [22]

The 2008 WHO classification includes three new variants: pediatric follicular lymphoma, “in situ” follicular lymphoma and primary intestinal follicular lymphoma. Pediatric follicular lymphoma is rare and accounts for 1-2% of all lymphomas. In the pediatric population, follicular lymphoma has a distinct biological behavior with common sites of involvement including cervical lymph node and tonsils. [23] Less likely sites of disease include testis, gastrointestinal tract, salivary duct, kidney and skin. They have high frequency of grade 3 and negativity for BCL2 expression and t(14;18). They usually respond well to treatment. “In situ” follicular lymphoma is thought to involve BCL2-positive tumor follicles in reactive lymphoid follicular hyperplasia. In a long term follow-up of “in situ” follicular lymphoma, only one out of 21 patients progressed to overt FL. [24] Finally, primary intestinal follicular lymphoma is a frequent site of extranodal FL especially duodenum. It can be found frequently in the second part of the duodenum as polyps and is survival appears to be excellent even without treatment. The majority of gastrointestinal follicular lymphoma are low grade (grade 1 or 2). However, 85% of the duodenal lymphomas can spread to jejunum and ileum. [23]

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Management Overview

Most patients with follicular lymphoma do not require hospitalization during the early stages of the disease. However, patients with bulky disease at the time of treatment should be followed closely for tumor lysis syndrome. Allopurinol should be considered in these patients.

Physicians who have training and/or experience in antineoplastic agents should be the ones to order the following:

  • Alkylating agents (eg, bendamustinechlorambucil, cyclophosphamide): These agents inhibit cell growth and proliferation. [25]
  • Antimetabolites (eg, fludarabine): These agents interfere with metabolic pathways necessary for the survival of target cells.
  • Anthracyclines (eg, doxorubicin, mitoxantrone): These drugs inhibit DNA synthesis.
  • Vinca alkaloids (eg, vincristine): These drugs inhibit cell growth and proliferation at the mitotic phase of the cell cycle.
  • Corticosteroids (eg, prednisone): These agents have anti-inflammatory effects in many organ system disorders. Corticosteroids are also lympholytic and modify the body's immune responses to diverse stimuli.
  • Monoclonal antibodies (eg, rituximab, obinutuzumabtositumomab and iodine-131, ibritumomab tiuxetan): These agents bind to target cells and recruit immune-effector functions to mediate target-cell lysis. [26, 25]
  • PI3K Inhibitors (eg, idelalisib, copanlisib): These agents inhibit key cell-signaling pathways, inducing apoptosis and inhibiting proliferation of premalignant B cells

For more information, see Follicular Lymphoma (Non-Hodgkin Lymphoma) Treatment Protocols

Patient education

Patients should be educated regarding the signs and symptoms of progression of the disease, including new systemic symptoms, new lymphadenopathy, or rapidly enlarging lymphadenopathy.

Similar to patients with chronic lymphocytic leukemia, patients with follicular lymphoma also are more prone to infections and should be instructed to contact their physician early if they develop signs or symptoms of infection.  Administration of rituximab may lead to hypogammaglobulinemia.

For patient education information, see Leukemia & Lymphoma.

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Radiotherapy - Localized Disease

The rare patient who presents with localized disease should be treated with radiation therapy with curative intent; approximately half of these patients will be cured with radiation alone.

Despite guidelines that recommend radiation therapy for stage I follicular lymphoma, other treatment approaches have been used successfully. In a large study of patients with stage I follicular lymphoma, Friedberg et al found that treatment approaches such as rituximab/chemotherapy and systemic therapy plus radiation resulted in similar excellent outcomes. [27] Unfortunately, fewer than 10% of patients with follicular lymphoma present with localized disease. 

A retrospective analysis of 120 treatment-naïve, low-tumor-burden patients with follicular lymphoma among more than 1000 patients enrolled in a population-based French registry underwent a watchful waiting strategy. [28] The median time to treatment in this group was 55 months. Their outcome was comparable to 242 patients with similar features receiving frontline rituximab-based therapy. Therefore, low-tumor-burden patients with follicular lymphoma can be managed with a watch-and-wait approach. 

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Observation - Asymptomatic Advanced Disease

The treatment for advanced stage disease is considered palliative, because most follicular lymphomas are disseminated and incurable at the time of diagnosis. Many experts recommend observation until the patient develops systemic symptoms, such as fever, weight loss, or bulky lymphadenopathy, because early therapy has not been shown to impact overall survival. [29] Patients in whom treatment is deferred should be followed closely for complications such as ureteral or biliary obstruction. No universally accepted first-line treatment strategy exists for stage III/IV follicular lymphoma.

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Single-Agent Therapy

Single-agent therapy has been an option for patients with symptomatic disease. [20] Single agents tend to have lower response rates and provide a shorter duration of disease control than do combination chemotherapy regimens. Nonetheless, they are appropriate for selected patients because they may be simpler to administer, induce less toxicity, and palliate symptoms.

Chlorambucil

Chlorambucil is an oral alkylating agent that is often reserved for elderly patients with a poor performance status or those who wish to defer intravenous therapy. Few patients will have a complete response, and there is no impact on overall survival.

Fludarabine

Single-agent fludarabine must be administered intravenously; this agent causes a significant degree of myelosuppression and immunosuppression, and there is also some concern that therapy with fludarabine may impair the ability to collect hematopoietic stem cells for an autologous stem cell transplantation. Fludarabine is associated with higher response rates than single-agent chlorambucil is, but it has no impact on overall survival.

Bendamustine

Single-agent bendamustine can be well tolerated aside from neutropenia and thrombocytopenia. However, as with many other chemotherapy agents, there is a risk of secondary myelodysplastic syndrome (MDS), particularly in patients who will require subsequent chemotherapy.

Rituximab

Rituximab (Rituxan, Rituxan Hycela), a monoclonal antibody targeting the CD20 antigen expressed on the cell surface of most lymphoma cells, has demonstrated efficacy as a single agent and as part of combination chemotherapy regimens. It is generally well tolerated but is significantly more expensive than most other therapies. Clinical trials using rituximab as maintenance therapy have suggested that this strategy prolonged progression-free survival in patients who had an objective response or stable disease following rituximab monotherapy. [30, 31, 32, 33, 34]

A study by Vidal et al concluded that rituximab maintenance remains the standard of care for refractory or relapsed follicular lymphoma. [35]

A study by Davies et al concluded that subcutaneous rituximab can be safely administered with similar efficacy to intravenous rituximab. [36] The study randomized 410 patients to receive rituximab subcutaneously or intravenously. Overall response rates as well as adverse reaction rates were similar in the two arms. The most common grade 3 adverse event was neutropenia. Rituximab combined with combined with hyaluronidase human, which increases subcutaneous tissue permeability (Rituxan Hycela) was FDA approved in June 2017 for previously untreated or relapsed/refractory follicular lymphoma.

Idelalisib

Idelalisib (Zydelig), an oral phosphoinositide 3-kinase (PI3K) delta inhibitor, received accelerated approval from the FDA in July 2014 for relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies. The accelerated approval was based on a phase II open-label study involving 125 patients with indolent non-Hodgkin lymphomas that had not responded to treatment with rituximab and an alkylating agent or had relapsed within 6 months afterward. [37]

The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin lymphoma. [29]  

Possible adverse effects of idelalisib include pneumonitis, diarrhea from colitis, hepatitis, and neutropenia. Several studies with idelalisib were halted due to toxicities related to development of Pneumocystis jiroveci pneumonia (PJP) and reactivation of cytomegalovirus (CMV) infection. Therefore, PJP prophylaxis is strongly recommended.

Copanlisib

Copanlisib, a pan-PI3k inhibitor, was FDA approved for follicular lymphoma that has failed to respond to two prior therapies. Unlike idealisib, copanlisib is given intravenously. Approval was based on a phase II trial in 142 patients with follicular lymphoma in whom two prior lines of therapy had failed. [38] The objective response rate was 59%, with 12% complete responses. The median duration of response was 22.6 months. The median progression-free survival was 11.2 months, with the median overall survival not yet reached. The adverse effects of the drug include transient hyperglycemia, transient hypertension, neutropenia, and lung infection.

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Multiagent Chemotherapy

Combining multiagent chemotherapy and rituximab is the most common first-line treatment strategy in the United States. Several studies have compared combination chemotherapy with and without rituximab; the rituximab-containing regimens generally produce a higher response rate and a more durable response. A meta-analysis confirmed an improvement in overall survival in patients with follicular lymphoma associated with the addition of rituximab to combination chemotherapy regimens. [39] Relapse of follicular lymphoma within 24 months following rituximab-containing chemotherapy is associated with poor outcome, including high risk for death. [40]

Rituximab-containing regimens

Combination chemotherapy regimens vary and include the following:

  • Rituximab, cyclophosphamide, vincristine, prednisone (R-CVP) [7]
  • Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) [8]
  • Fludarabine, cyclophosphamide, rituximab (FCR)
  • Rituximab, fludarabine, cyclophosphamide, mitoxantrone (R-FCM)
  • Fludarabine, rituximab (FR)
  • Bendamustine, rituximab (BR)
  • Lenalidomide (Revlimid), rituximab (R 2, R-squared)

Rituximab has been evaluated as maintenance chemotherapy in patients with follicular lymphoma after initial chemotherapy. In a large European study, rituximab given every 2 months for 2 years increased disease-free survival, but not overall survival. [41]

In a retrospective analysis of 356 patients with treatment-naïve, advanced-stage, grade 1-2 follicular lymphoma, the 3-year progression-free survival rates with different regimens were as follows [42] :

  • R-CHOP: 60%
  • R-CHOP with maintenance rituximab: 72%
  • Bendamustine/rituximab: 63%
  • Bendamustine/rituximab with maintenance rituximab: 97%
  • R 2 (rituximab plus lenalidomide [Revlimid]): 87%

A study by Fowler et al also investigated the combination of rituximab with lenalidomide in 110 patients with previously untreated indolent lymphoma. [11] Of the 110 patients studied, 50 patients had follicular lymphoma. The complete response rate was 87% and 11% had partial response. The RELEVANCE trial is an ongoing randomized study examining the role of R2 in comparison with rituximab plus chemotherapy as frontline therapy for follicular lymphoma. On interim analysis, R2 was found to have similar efficacy to rituximab plus chemotherapy. The two regimens had different safety profiles, with more grade 3/4 neutropenia in the rituximab-chemotherapy arm than in the R2 arm (50% versus 32%, respectively). [43] These results offer the encouraging prospect of having a non-chemotherapeutic alternative for these patients.

Obinutuzumab

Obinutuzumab (Gazyva) is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre B- and mature B-lymphocytes. In February 2016, the FDA approved obinutuzumab for follicular lymphoma that is refractory to, or has relapsed after, a rituximab-containing regimen. Approval was based on the phase III GADOLIN study (n=396) comparing obinutuzumab plus bendamustine to bendamustine alone. On interim analysis, median progression-free survival was 14 months for bendamustine alone and 29 months for obinutuzumab plus bendamustine (P< 0.0001). [25]

Obinutuzumab is administered with bendamustine for six 28-day cycles, as follows:

  • Cycle 1: Obinutuzumab 1000 mg IV on days 1, 8, and 15 plus bendamustine 90 mg/m 2/day IV on days 1 and 2
  • Cycles 2-6: Obinutuzumab 1000 mg IV on day 1 plus bendamustine 90 mg/m 2/day IV on days 1 and 2
  • Monotherapy:  Patients who achieve stable disease, complete response, or partial response to the first 6 cycles should continue on obinutuzumab 1000 mg IV every 2 months for 2 years.

Obinutuzumab plus chemotherapy with obinutuzumab maintenance was compared with rituximab plus chemotherapy with rituximab maintenance in 1202 patients with previously untreated advanced-stage follicular lymphoma (either bulky stage II or stage III or IV). [44] In this study, The progression-free survival at 3 years was 80% in the obinutuzumab-containing arm versus 73.3% in the rituximab containing arm. The hazard ratio of progression, death, or relapse was 0.66. However, the rate of infusion-related reactions was higher in the obinutuzumab arm. The combination of obintuzumab with chemotherapy was approved by FDA in November 2017.

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Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) has a role in the treatment of follicular lymphoma, especially in younger patients with relapsed or recurrent disease. [45]  HSCT is generally reserved for patients with relapsed or refractory disease.

Allogeneic HSCT can induce long-term remissions in patients with follicular lymphoma, but transplant-related mortality is high. [46] Autologous HSCT has a low transplant-associated mortality and prolongs progression-free survival; in a randomized, controlled trial, improvement in overall patient survival was observed. [47] However, most patients eventually relapse after undergoing this therapy, and there is an increased rate of secondary malignancies.

A study by Al Khabori et al determined that available evidence indicates autologous transplantation in first remission is not indicated; however, the best time for transplantation is unclear. [48] Lunning et al compared outcomes in 44 patients with relapsed and refractory follicular lymphoma who underwent either autologous or allogeneic HSCT, and found that in patients whose remission had lasted for 12 months or less, event-free survival at 3 years was significantly greater with allogeneic versus autologous HSCT (80% versus 42%, respectively; P < 0.015). [49]

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Targeted Radioimmunotherapy

Follicular lymphoma is inherently radiosensitive, so the development of targeted radioimmunotherapy [50] to the CD20 marker expressed on B cells has been a significant advance. {ref51This technique enables the delivery of cytocidal doses of radiation to all sites of disseminated disease. Two agents are available for this type of treatment: iodine-131 (131I)–labeled tositumomab (Bexxar) and yttrium-90 (90Y)–labeled ibritumomab tiuxetan (Zevalin). [52] Both agents have produced high response rates in patients with relapsed or refractory and treatment-naive follicular lymphoma. [53, 54, 55]

Initial studies of 131I–labeled tositumomab and 90Y–labeled ibritumomab tiuxetan demonstrated improvements in progression-free survival but not in overall patient survival.

The use of radioimmunoconjugate agents is limited in the United States by the need for highly trained staff and specialized equipment, the expense of therapy, the risk for secondary malignancies, and the relatively short duration of follow-up.

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Consultations

Radiation therapy with curative intent should be used in patients with stage I disease, and although this represents a minority of cases of follicular lymphoma, one may seek consultation with a radiation oncologist. Radiation therapy also can be used to treat localized or bulky lymphadenopathy that is causing obstruction or when a more urgent response is desired to relieve obstruction. Radiation therapy is usually tolerated well, and in many instances can spare the patient the need for additional chemotherapy. The radiation oncologist is also involved in the care of patients receiving radioimmunotherapy.

It is recommended that surgeons consult with pathologists before obtaining biopsy specimens to discuss the proper handling of the specimen and the special tests required.

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Posttreatment Follow-up

Patients should be monitored periodically to facilitate early treatment of complications of the disease, such as biliary, ureteral, or bronchial obstruction due to increased adenopathy.  See also Clinical Evaluation for follow-up evaluation in patients.

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Prognosis and Prognostic Factors

The overall survival rate of patients with follicular lymphoma is 72-77% at 5 years. Median survival was approximately 8-10 years, [56]  but has lengthened since the introduction of rituximab.(ref57}

The Follicular Lymphoma International Prognostic Index (FLIPI) is predictive of survival in patients with follicular lymphomas. [58] Patients who have 4 or more of the following adverse prognostic factors have a 10-year survival rate of approximately 36% (compared with 71% for those with 1 or none of these variables) [58] :

  • Age 60 years or older
  • Ann Arbor Stage III or IV
  • Lactate dehydrogenase (LDH) level above the upper limit of normal at diagnosis
  • Hemoglobin less than 12 g/dL
  • Presence of more than 4 nodal sites of disease

Vitamin D insufficiency has been linked with increased risk of early clinical failure in follicular lymphoma. Kelly et al reported that in follicular lymphoma patients undergoing chemotherapy, progression-free survival was worse in those who had vitamin D insufficiency. [59] In a prospective study of 642 patients with follicular lymphoma, 19% of whom had vitamin D level less than 20 ng/mL, Tracy et al reported that vitamin D insufficiency was associated with inferior lymphoma-specific survival and overall survival regardless of the treatment used (obesrvation, immunotherapy, or chemotherapy). [60]

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Guidelines Summary

Guidelines contributors: Priyank P Patel, MD , Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo, Francisco J Hernandez-Ilizaliturri, MD, Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF) [61]  
  • Revised European-American Classification of Lymphoid Neoplasms (REAL) [18]
  • World Health Organization (WHO) classification [62]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J.  [61]  In 1994, the REAL classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities. [18]

The WHO classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin. [62]

Although considered obsolete, the IWF classification is still used mainly for historical data comparisons. [61]

World Health Organization Classification

In 2001, the WHO classification called for grading of follicular lymphoma (FL) from grades 1-3 based on the number of centroblasts per high-power field (hpf). However, the 2008 update consolidated cases with few centroblasts as FL grade 1-2 (low grade) and divided FL grade 3 into 3A (presence) and 3B (absence) of centrocytes. [62, 63]

National Comprehensive Cancer Network (NCCN) guidelines note that grade 3 FL is an area of controversy, with some experts treating grade 3A as FL and others treating it as diffuse large B-cell lymphoma (DLBCL); grade 3B is commonly treated as DLBCL, and FL of any grade with an area of DLBCL should be treated as DLBCL. [64]

Prior to 2008, primary cutaneous follicle center lymphoma (PCFCL) was classified as a variant of FL. In the 2008 update, its classification was changed to that of a distinct entity. PCFCL may contain a high proportion of large B cells, including large centrocytes and centroblasts. Dissemination beyond the skin is rare.

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the NCCN recommends the following studies to establish a diagnosis of FL [64] :

  • Immunohistochemistry panel: CD20, CD3, CD5, CD10, BCL2, BCL6, cyclin D1, CD21, or CD23
  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD19, CD20, CD5, CD23, CD10

European Society for Medical Oncology (ESMO) guidelines are in agreement with the NCCN that diagnosis follows the WHO classification and excisional biopsy is preferred. Core biopsy is considered only in cases where lymph nodes are not easily accessible. Fine-needle aspiration is not recommended. [65]

Risk Stratification

The Groupe d’Etude des Lymphomes Folliculaires (GELF) recommends the following criteria for identifying patients in whom immediate therapy is necessary [66] :

  • Three nodes in three distinct areas, with each node ≥3 cm in diameter
  • A tumor ≥7 cm in diameter
  • Presence of systemic symptoms
  • Symptomatic spleen enlargement
  • Ascites or pleural effusion
  • Cytopenias (leukocytes < 1.0 x 10  9/L and/or platelets < 100 x 10  9/L)
  • Leukemia (>5.0 x 10  9/L malignant cells)

The NCCN recommends both the GELF criteria and the 2004 Follicular Lymphoma International Prognostic Index (FLIPI) for risk stratification. [64]  The FLIPI includes the following risk factors [58] :

  • Age >60 y
  • Ann Arbor Stage III-IV
  • Lactate dehydrogenase (LDH) level above the upper limit of normal
  • Hemoglobin level < 12 g/dL
  • Four or more nodal sites of disease

For each factor, the patient receives 1 point. Based on the FLIPI score, patients can be categorized as follows [58] :

  • Low risk (0 or 1 point)
  • Intermediate risk (2 points)
  • High risk (≥3 points)

In 2009, the International Follicular Lymphoma Prognostic Factor Project published an updated score, FLIPI2. The FLIPI2 includes the following risk factors (as with FLIPI1, each factor is worth 1 point) [67] :

  • Age > 60y
  • β2-microglobulin (B2M) above the upper limit of normal
  • Bone marrow involvement
  • Hemoglobin level < 12 g/dL
  • Longest diameter of the largest involved node >6 cm

Based on the FLIPI2 score, patients can be categorized as follows [67] :

  • Low risk (0 or 1 point)
  • Intermediate risk (2 points)
  • High risk (≥3 points)

With this model, relapse-free and overall survival rates at 5 years are as follows:

  • 0-1 risk factors - 79%
  • Two risk factors - 51%
  • Three or more risk factors - 20%

FLIPI1 and FLIPI2 are used to predict prognosis but are not used to select treatment options.

Treatment

The NCCN and ESMO offer similar treatment recommendations, as follows [64, 65] :

  • Involved-site radiation therapy (ISRT), 24-30 Gy, is the preferred treatment option for stage I or II
  • If significant toxicity is expected from radiotherapy, initial observation may be more appropriate
  • Other first-line treatment options include rituximab, alone or in combination with other agents, and radioimmunotherapy
  • Combination treatment with involved-field radiation therapy (IFRT) and chemotherapy (see below) and/or radioimmunotherapy is recommended for more advanced stages
  • In asymptomatic patients with advanced-stage, low tumor burden disease, initiate treatment when the patients become symptomatic, as there is no survival advantage with immediate treatment versus a watch-and-wait approach

NCCN-recommended first-line chemotherapy regimens (category 1) for FL are as follows, in alphabetical order [64] :

  • Bendamustine+ obinutuzumab
  • Bendamustine + rituximab
  • CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + obinutuzumab
  • R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
  • CVP (cyclophosphamide, vincristine, prednisone) + obinutuzumab
  • RCVP (rituximab, cyclophosphamide, vincristine, prednisone)
  • In elderly or infirm patients who are unlikely to tolerate any of the above, single-agent rituximab (375 mg/m 2 weekly for 4 doses) is the preferred treatment
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