Follicular lymphoma management

See follicular lymphoma

For limited disease, treatment options include: radiotherapy, rituximab monotherapy or combination regimens, and surveillance. 

Treatment of advanced disease is mostly determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. 

Presently, there is no consensus for treatment of patients with early or multiply relapsed disease.

Numerous agents, combination regimens, and transplant options have demonstrated efficacy. 

A personalized approach to management is based on disease biology, and patient characteristics.

Although incurable, prognosis has improved for early‐ and advanced‐stage disease, largely attributed to therapeutic advances.

Spontaneous regressions occur in about 5%–10% of patients.

Although many patients can be initially observed, most require therapy after a median of 3–4 years after diagnosis.

Approximately 20% of patients experience  an  early relapse within 2 years following current first‐line therapy.

It has a protracted course, with multiple remissions and relapses.

FL grading system is based  on proportions of centroblasts per high‐powered field, with a greater proportion indicative of a more aggressive phenotype.

FL transformation from an indolent to more aggressive disease is a complication during the natural disease history. 

Transformation to diffuse large B‐cell lymphoma (DLBCL) or other high‐grade morphology, usually accompanied by rapid progression of lymphadenopathy, extranodal disease outside the marrow, B symptoms, elevated serum lactate dehydrogenase, and, less commonly, hypercalcemia.

There is a transformation risk of 3% of patients annually,but is believed to be lower in the rituximab era.

An extensive number of genetic changes occur in FL.

There is a high prevalence of mutations in genes encoding proteins regulating the epigenome through specific histone post‐translational modifications: KMT2D, CREBBP, EP300, EZH2.

Mutations in genes involved in cellular processes such as JAK‐STAT, BCR‐NFkB, mTOR signal transduction, cell‐cycle regulation, immune modulation, and cellular differentiation also frequent exist, and are prognostic markers and 

therapeutic targets.

The best predictor of long‐term outcomes in FL is the length of first remission after front‐line therapy. 

Patients with progression of disease within 24 months of completing induction chemoimmunotherapy have poorer outcomes compared with those with longer remission durations- 5‐year overall survival: 50% vs. 90%, respectively.

FLIPI‐2 was developed as a more contemporary prognostic model using data reflective of treatment in the chemoimmunotherapy era.

It includes bone marrow involvement, nodal diameter, and β2‐microglobulin levels and was built on progression free survival (PFS) in chemoimmunotherapy‐treated patients. 

The PRIMA‐PI, uses a simplified algorithm of bone marrow involvement and β2‐microglobulin level to predict PFS.

Other tools to predict outcome in FL have been proposed, including: total metabolic tumor volume (TMTV) as determined from baseline positron emission tomography (PET), combining FLIPI‐2 with TMTV 43, and assessment of the presence of circulating peripheral blood lymphoma cells.

Criteria for Risk stratification and Prognosis

Follicular Lymphoma International Prognostic Index;


Age: >60 years

Ann Arbor Stage: III–IV

Hb concentration: <12 g/dL

Number of nodal sites: >4

Serum LDH concentration: >normal

Low: 0–1 risk factors 2‐year OS: 98%; 2‐year PFS: 84%

Intermediate: 2 risk factors 2‐year OS: 94%; 2‐year PFS: 72%

High: 3–5 risk factors 2‐year OS: 87%; 2‐year PFS: 65%


Age: >60 years

Bone marrow involvement: yes

Hb concentration: <12 g/dL

Greatest diameter of largest involved node: >6 cm

Serum β2 microglobulin concentration: >ULN

Low: 0–1 risk factors 3‐year PFS: 91%

Intermediate: 2 risk factors 3‐year PFS: 69%

High: 3–5 risk factors 3‐year PFS: 51%

Tumor size: any site >7 cm or ≥ 3 sites >3 cm

B symptoms: yes

Spleen: below umbilical line

Compressive symptoms: yes

Pleural or peritoneal effusion: yes

Leukemic phase >5 × 109/L

Neutropenia (<1 × 109/L) or thrombocytopenia (<100 × 109/L) due to disease

High tumor burden: ≥1 risk factors

End‐of‐induction PET was shown to be prognostic after first‐line FL therapy, correlating with outcome in prospective trials.

Assessment of a patient newly diagnosed with FL includes: disease burden, lymphoma‐related symptoms, presence of comorbidities, patient preference, and age. 

Patients with limited disease but high tumor burden should be treated as per patients with advanced disease and high tumor burden. 

Approximately 10%–15% of patients with FL have limited, nonbulky disease at diagnosis, which includes Ann Arbor stage I–II disease .

For Ann Arbor stage I or II disease, use of 24‐Gy involved‐field radiotherapy (IFRT) administered in 12 fractions is potentially curative and is often the preferred treatment option for disease encompassed in a single appropriate radiation port.

By restricting the radiation field size to smaller volumes, local relapses in or near irradiated fields are rare, and the vast majority of failures are distant.

In advanced disease, patients with mildly symptomatic, localized disease have been treated with rituximab monotherapy.

Different rituximab treatment strategies: alone, in combination with chemotherapy, or together with radiation therapy and comparison with radiotherapy alone in limited disease have been reported.

Combined modality approaches improved PFS compared with radiotherapy alone, no OS difference between treatment approaches was seen. 

Advanced Disease

Not all patients with advanced disease require immediate therapy. 

Surveillance is routinely favored for advanced disease, with therapy typically reserved for patients with symptoms from or significant burden or rapid pace of disease.

For advanced disease but low tumor burden and no disease‐related symptoms, surveillance or rituximab monotherapy may be considered front‐line therapy.

Rituximab monotherapy is a relevant consideration for such patients, particularly those who are frail and unsuitable for chemoimmunotherapy.

Patients with advanced disease treated with rituximab alone may not need further therapy for >10 years

Comparing the benefit of immediate rituximab treatment versus surveillance in asymptomatic, advanced‐stage disease: progression free survival benefit of immediate rituximab therapy versus observation but no overall survival difference.

Current standard of care for advanced FL with high disease burden is chemoimmunotherapy regimens that include a CD20 antibody-rituximab, obinutuzumab.

The  PRIMA study showed that 2 years of rituximab maintenance therapy after first‐line chemoimmunotherapy significantly improved PFS and >50% of patients did not require second‐line treatment 10 years after chemoimmunotherapy.

There continues to be no difference in OS with maintenance rituximab in this setting. 

A bendamustine backbone is as effective as rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R‐CHOP) and has a better‐tolerated side‐effect profile especially with regard to hematological toxicities and infection rates.

Obinutuzumab is a glycoengineered anti‐CD20 monoclonal antibody that has greater antibody‐dependent cellular toxicity and direct B‐cell killing compared with rituximab.

First‐line obinuzutuzumab in combination with chemotherapy was reported in the phase III GALLIUM study in indolent FL or marginal zone lymphoma:

An improvement in 3‐year PFS was observed with obtinuzumab‐based therapy 80% vs. 73%, with no difference in 3‐year OS. 

RELEVANCE trial in advanced, untreated FL indicated similar efficacy with rituximab plus lenalidomide compared with rituximab plus chemotherapy.

Superiority of lenalidomide in combination with rituximab versus rituximab‐based chemoimmunotherapy was not demonstrated-interim 3‐year PFS: 77% vs. 78%

FL remains largely characterized by multiple recurrences. 

Successive treatment lines will often be required in the disease course.

The choice of each treatment should aim to achieve disease control, promote quality of life and minimize treatment‐related toxicity.

Treatment of FL relapse or progression depends in part upon duration of remission with previous treatments.

For patients with relapse or progression on first‐line treatment who have a longer duration of remission, options can include chemoimmunotherapy followed by rituximab maintenance.

Obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance is another treatment  for patients with rituximab‐refractory FL.

Phase III GADOLIN trial of obinutuzumab plus bendamustine versus bendamustine alone in patients with CD20+ indolent NHL refractory to rituximab.

PFS was significantly longer with combination therapy than with bendamustine monotherapy (25.8 vs. 14.1 months; as was OS.

Obinutuzumab in combination with bendamustine represents a validated strategy for rituximab‐refractory patients not previously treated with either agent.

The oral PI3K‐δ inhibitor idelalisib is a second‐line treatment option in relapsed/refractory FL.

Idelalisib in combination regimens has been associated with increased risk of serious and potentially fatal adverse events (AEs) such as colitis or pneumonitis.

Copanlisib is an intravenously administered pan‐class I PI3K inhibitor for patients with relapsed FL who have received ≥2 prior systemic therapies.

Phase II CHRONOS‐1 trial in patients with indolent BCL (73% had FL) relapsing after or refractory to ≥2 prior therapies and who had received prior treatment with rituximab and an alkylating agent: After a median treatment duration of 6 months, ORR was 60.6% in the full population and 58.7% in patients with FL; overall median duration of response was 14.1 months, and median PFS was 12.5 months

Duvelisib, an oral PI3K inhibitor targeting both the δ and γ catalytic subunits, approved for relapsed/refractory indolent BCL including FL after ≥2 prior lines of therapy based on results of the phase II DYNAMO trial.

Duvelisib ORR was 46% and median PFS and OS were 8.4 and 18.4 months, respectively, among patients refractory to both rituximab and alkylating chemotherapy.

Phase III AUGMENT trial comparing rituximab and lenalidomide with rituximab monotherapy in patients with indolent NHL who were previously treated and had rituximab‐sensitve relapsed disease: improved PFS (39.4 vs. 14.1 months) and ORR (78% vs. 53%; compared with rituximab alone, although no significant OS benefit is yet seen at a median follow‐up of 28.3 months.

Radioimmunotherapy (RIT) regimens, in which radioisotopes are conjugated to antibodies (anti‐CD20 agents), have been used for the treatment of relapsed/refractory FL.

Response rates of approximately 60% and median PFS and OS of >4 years have been reported with RIT in patients who have received ≥1 prior therapy.

Currently, ibirtumomab tiuxetan is the only RIT on the market for FL treatment.

Patients with FL that experience  early relapse after initial therapy are at high risk of poor outcomes. 

High‐dose chemotherapy with autologous hematopoietic stem cell transplantation (auto‐HSCT) can prolong PFS and OS and should be considered as consolidative therapy in early relapse.

Findings suggest that outcomes are similar with either autologous or allogeneic transplant with minimal residual disease.

Currently, allo‐HSCT is largely restricted to fit patients who cannot achieve complete remission or have multiply relapsed disease.

In high‐risk FL and early relapse after initial chemoimmunotherapy, idelalisib had  a 59% lymph‐node response.

Lenalidomide in the phase III MAGNIFY trial in combination with rituximab in relapsed/refractory NHL, including FL 

the ORR was 48%.

A genetic hallmark of FL is the presence of mutations in histone‐modifying enzymes. 

The gene for one such enzyme, EZH2, is mutated in about 25% of cases. 

Oral inhibitors of EZH2 suggesting high response rates in EZH2‐mutated disease.

Chronic activation of B‐cell receptor (BCR) signaling is critical in FL progression, leading to activation of several signal transduction pathways: NF‐kB, PI3K‐AKT, promoting proliferation and survival of malignant B cells. 

Mutations in genes encoding proteins in BCR pathways are also common.

Mutations in the BCR and NF‐κB signaling pathway can occur in patients with FL.

Ibrutinib is a small‐molecule BTK inhibitor with effects on apoptosis, cellular adhesion, migration, but has limited monotherapy activity.

The programmed cell death‐1 (PD‐1) protein is widely expressed and found on activated T cells, B cells, and natural killer (NK) cells.

PD‐1 binding to programmed death ligand‐1 and ligand‐2 produces inhibitory signals leading to T‐cell apoptosis. 

Additionally, PD‐1 inhibits antitumor cytotoxicity through decreased NK cell‐mediated killing. 

Single‐agent  PD-1 inhibitor activity appears limited in FL 123, there may be synergy with other agents, including CD20 antibodies.

Antibody‐drug conjugates, designed to provide targeted delivery of cytotoxic agents to antigen‐expressing tumor cells: , are also being investigated in polatuzumab vedotin is active in FL in combination with rituximab, in combination with rituximab and bendamustine (ORR 100%) and in combination with obinutuzumab (ORR 78%).

Chimeric T-cell therapy is efficacious with 

Tisagenlecleucel and axicabtagene ciloleucel.

Identifying patients with limited disease who are candidates for radiation therapy versus rituximab monotherapy or chemoimmunotherapy regimens as front‐line management is not always apparent.

Surveillance should be a management option for these patients in the context of the availability of active and minimally toxic therapies.

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