Follicular lymphoma (Low-grade)

Follicular lymphoma is the most common indolent lymphoma accounting for approximately 22% of cases of NHL in North America.

Follicular lymphoma (FL) is a heterogeneous entity

FL outcomes are based on clinical and pathologic characteristics. 

Has an annual incidence of approximately 3.18 cases per 100,000 people.

The incidence has been stable overtime.

The highest incidence is among White individuals.

Second most common B cell lymphoma in Western countries.

Accounts for about 22% of B-cell lymphomas.

Median survival about 14 years and has been increasing with use of monoclonal antibody treatments.

Second most common type of non-Hodgkin’s lymphoma, making up about 30% of such lymphomas in North America.

Incidence in elderly Americans increased by 1.8% between 1999 and 2001.

Frequency of 1 case per 20-25,000 people per year.

Annual incidence of 2.7 per 100,000 in the U.S

Affects 5-7 people out of every 100,000, making it the second most common type of lymphoma.

Median age of diagnosis is 59 years,  but a large proportion of cases also occurs in younger adults.

Prevalence on the rise.

FL consists of malignant lymphomas consisting of follicle center cells, a mixture of cleaved cells (centrocutes) and non-cleaved  large cells (centroblasts).

FL grading depends on the number of centroblasts and centrocutes in a given sample.

FL is a germinal center derive neoplasm that grows in the follicular pattern.

High-grade follicular lymphoma (grade 3) has two categories FL 3A and FL3B.

FL3B falls in an aggressive course matching that of diffuse large B cell lymphoma.

FL3A may have either an indolent course or could be characterized by features such as or a more aggressive course which can be cured with chemotherapy.

The KI 67 proliferation index is higher than 20 in FL grade 3, and is generally less than 20 in most cases of FL grade one or two.

Follicular lymphoma (FL) is a heterogeneous entity with disparate outcomes based on clinical and pathologic characteristics. 

A majority of the prospective landmark trials in FL have excluded patients with high-grade FL.

Great majority have translocation of chromosomes 14 and 18, which frequently leads to overexpression of the bcl-2 gene on chromosome 18 which is an inhibitor of apoptosis.

A chromosomal translocation commonly occurs between the fourteenth and the eighteenth chromosomes – t(14;18) – which places the Bcl-2 gene from chromosome 18 next to the immunoglobulin heavy chain locus on chromosome 14 in follicular lymphoma.

First molecular step toward its development is the acquisition of t(14;18) by pre-B cells during immunoglobulin rearrangement in the bone marrow.

t(14;18) cells meet an antigen and are driven into a T cell dependent reaction within the lymph node germinal center and acquire a proliferative and survival advantage.

It has heterogeneous clinical behavior, ranging from extremely indolent disease over decades to a clinically highly aggressive course with short duration of response after treatment and recurrence of disease within 1-2 years after initial treatment.

FL is divided into four different grades: most cases are grade 1 or 2.

The clinical course and optimal treatment regimen for FL grade 3 are less certain than those for grades 1 and 2. FL grade 3 has been subdivided into grade 3A (FL3A) and grade 3B (FL3B). Although a consensus exists that FL3B follows an aggressive course matching that of diffuse large B-cell lymphoma (DLBCL), there is less certainty about the course of FL3A. 

Some authors suggest that it is similar to the indolent clinical course of FL grades 1 and 2, which is characterized by features such as slow progression, frequent relapse, and a limited possibility of cure.

Others, however, suggest that FL3A has a clinical course similar to that of FL3B, which is more aggressive but can be cured with chemotherapy.

Approximately 90% of patients have t14; 18) which results in overexpression of B cell leukemia/lymphoma 2 (BCL2) an oncogene that blocks apoptosis leading to prolonged cell survival.

Translocation (14;18)gives rise to BCL2-IGH fusion and originates from bone marrow pre B cells.

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

A key abnormality that occurs in virtually all patients with follicular lymphoma is disruption of the cross talk between two surface receptors: the TNF receptor superfamily 14 and inhibitory B and T lymphocyte attenuator receptor.

The interaction between these receptors blocks the growth of lymphoma B cells.

Malignant follicular lymphoma clones derive from germinal center B cells transformation in a secondary lymphoid organ.

One in six patients with follicular lymphoma present mutations in RagC, a gene on the mTOR signaling pathway.

RagC mutations may play a role in the origin of the disease.

Pathological grading of follicular lymphoma-1, 2, 3A, 3B is based on increasing number of centroblasts and is prognostic and predictive.


A large proportion, 50-70%, of healthy individuals have low levels of circulating t(14;18) positive cells, but never develop follicular lymphoma indictating that BCL2 ectopic expression is necessary but not sufficient for tumor progression.

Neoplastic B cells exit the bone marrow and seed peripheral lymph nodes where duplicate germinal center formation and lymphoid follicle formation.

Bone marrow involvement is detected in about 40% of cases.

Almost always FDG avid so that PET scan is a useful tool for staging and followup.

PET scans are more sensitive and accurate in staging than are CT scans.

Indolent lymphomas have a lower uptake on PET scan than progressive lymphomas.

Patients with positive PET scan after induction therapy at significantly worse outcomes than patients with PET negative scans.

Most neoplastic follicles expressed Bcl-2 protein resulting from chromosomal translocation.

Bcl-2 expression turns off apoptosis settings in germinal centers resulting in cellular immortalization.

Biomarkers is the Bcl-2, Bcl-6, CD10 should be measured in all patients.

Evaluation should include routine blood counts, chemistries, uric acid, LDH, and B2-microglobulin levels.

Staging workup includes bone marrow biopsy, CT scans and occasionally PET scans to evaluate the process.

Bone marrow biopsies indicate the presence of involvement in 60% of newly diagnosed cases.

Bone marrow flow cytometry can demonstrate follicular lymphoma markers CD 19, CD 20 and, in particular, CD 10 positivity.

When neoplastic B cells localize in the lymph node follicle they undergo repeated cell divisions and acquire further cytogenetic changes.

When lymphoid cells undergo chromosomal aberrations that include the development of de novo DLBCL (Diffuse Large B Cell Lymphoma) harboring t(14;18).

Serves as a paradigm for the management of indolent disease.

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

About 25% of patients with low-grade lymphomas will have a poor outcome.

Typically has an immunophenotype characterized by expression of CD19, CD20, CD10, CD22, CD79, and BCL-2, BCL-6, and is negative for CD5 andCD43, and CD23.

Makes up 75-80% of indolent B-cell lymphomas.

Germinal center derived B cell malignancy.

Rarely curable in advanced stages.

While indolent and responds to many agents, it exhibits a continuous pattern of relapse and decreased sensitivity to treatment over time.

Incidence of histologic transformation to diffuse large B cell lymphoma ranges from 16-60% depending on the length of follow-up and rebiospy rate.

Risk of transformation declines after 15 years of follow-up.

The transformation to diffuse large B cell lymphoma occurs in approximately 2-3% of patients annually, rendering the lymphoma more aggressive and difficult to treat.

Incidence similar in men and women.

Many patients are asymptomatic when they present, despite the presence of widespread disease.

Many patients present with painless lymphadenopathy that may wax and wane before the diagnosis is made.

Hilar and mediastinal lymph nodes are frequently involved, but bulky disease is rare.

The symptoms of night sweats, weight loss, and fever are encountered in approximately 20% of cases.

Higher grade follicular lymphoma  tends to involve the bone marrow or peripheral blood and is associated with larger lymph nodes.

Approximately 65 to 70% of patients with follicular lymphoma grade 3% with advanced disease.

Because of its indolent nature many patients present with advanced disease.

Work up includes an excisional biopsy of a lymph node for evaluation by microscopic examination, flow cytometry, and histochemical staining for selected tumor markers.

Mixed cell type histology lesions may be curable with aggressive therapy.

Course of disease typically reflects a response to initial treatment with subsequent relapses and an association with histological transformation to a higher grade lymphoma.

Patients who did not progress within two years of initial treatment have an overall survival consistent with age-matched population without lymphoma.

For those who progress within two years have a long-term survival the ranges ar 30 to 40%.


Treatment options vary from observation to aggressive chemotherapy but with no consensus at this point.

There is no compelling evidence that therapy at the time of diagnosis yields improved outcomes in asymptomatic patients with follicular lymphoma: watchful waiting is present standard management.

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

Approximately 90% of patients with follicular lymphoma will require treatment.
In patients who receive initial remission, it may last for well over a decade.
Commonly used chemo immunotherapy regimens are bendamustine and rituximab, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Approximately half of patients will eventually transformatrequire a second therapy .

Treatment should be initiated for patients with advanced disease stage II-IV when symptoms develop to include fever, sweats, weight loss, pain, cytopenias, splenomegaly, impairment of major organ function, bulky adenopathy of greater than seven cm in one lymph node, or three nodes greater than 3 cm, pleural effusions, ascites or marked lymphocytosis.

Indolent lymphoma typically responsive to radiation and chemotherapy bur usually associated with multiple relapses.

Attaining a complete response is the factor most predictive of the longer overall survival.

For relapses chemotherapy with single or multiple agents and steroids are used but likelihood of response decreases with each relapse.

FLIPI criteria for prognosis: Include clinical and laboratory parameters of age, Ann Arbor stage, number of nodal areas of involvement, LDH levels, and hemoglobin levels divided into three major subgroups of survival: low risk (0-1 risk factors), intermediate risk (2 risk factors), and high risk (3-5 risk factors).

Poor prognosis associated with advanced age, male sex, increased number of nodal and extranodal sites, the presence of bulky disease, increased LDH levels, increased Beta-2 microglobulin levels, low hemoglobin levels and poor performance status.

Extranodal sites include Waldeyer’s ring, ocular adnexa, salivary glandsand intestines.

Most patients with indolent lymphomas, including elderly, die of their lymphomas and not other causes.

WHO cassfication:grades 1 and 2 being indolent, and grade 3 is more aggressive.

90% of patients present with disseminated disease.

For low-grade lymphomas stage does not necessarily correlate with prognosis, as most patients have advanced disease.

Average patients receive therapy at three year interval.


Newly diagnosed patients do not require immediate therapy.

Asymptomatic patients with low tumor burden can be followed with a watch and wait strategy.

First line therapy considerations include: watchful waiting, monoclonal antibody therapy, chemoimmunotherapy and chemotherapy free treatment with targeted agents.

Patients with high tumor burden or symptoms should be started on treatment.

The most common management is with non-chemotherapy agents such as bendamustine combined with rituximab.

Progression gree survival is higher with rituximab/Bendamustine versus R-CHOP but the overall survival remains the same.

Rituximab maintenance after rituximab and bendamustine does not improve survival .

In the StiL trial bendamustine and rituximab showed substantial superiority of R-CHOP at more than 9 years of follow-up BR had a median PFS of 69 months vs 31 months for R-CHOP.

Other first-line treatments include rituximab alone, or R-CHOP.

Treatment selection requires evaluation of stage, underlying health status, comorbidities, stage of disease, tumor burden, and presence or absence of symptoms.

Increasingly aggressive therapy produces more durable remissions, however such therapy tends to produce more adverse events and impaired quality of life, at least in the short-term.

In a perspective, randomized , randomized, international trial comparing up front rituximab four weekly doses, four weekly doses followed by maintenance rituximab every two months or watchful waiting among 463 patients with asymptomatic stage II-IV non-bulky follicular lymphoma: upfront rituximab resulted in a significant delay in the need to initiate therapy at three years compared with watchful waiting 80% and 91% versus 48% for rituximab induction and rituximab induction plus maintenance versus watchful waiting (Ardeshna KM et al).

Therapeutic interventions include single agent chemotherapy, combination chemotherapy, monoclonal antibodies, radioimmunoconjugates and stem cell transplantation.

Stage I or II may be curable with external-beam radiation to involved sites.

Treatment includes single agents including: chlorambucil, cyclophosphamide, fludarabine, rituximab and combination agents CVP (cyclophosphamide, vincristine, prednisone), CHOP (cyclophosphamide, vincristine, doxyrubicin, prednisone), fludarabine/mitoxantrone.

Fludarabine based regimen with mitoxanthone has an overall response rate of 96% with 68% complete remissions compared to a 98% response rate and a 39% complete remission rate with CHOP.

Anti CD-20 monoclonal antibody rituximab induces a 48% objective response rate with a 6% complete remission rate.

The addition of rituximab significantly enhances initial response to chemotherapy.

A combination of fludarabine and rituximab for stage III and IV disease results in a complete remission rate of 80%.

Combination of CHOP and rituximab produces a complete remission rate of 87% and median time to progression of more than 82 months.

In untreated patients with indolent B-cell lymphoma rituximab and bendamustine is equivalent to R-CHOP.

In a phase III study of Bendamustine plus Rituximab vs R-CHOP in patients with newly diagnosed stage III/IV indolent lymphoma or mantle cell lymphoma: After median of 45 months of followup median progression free survival was 69.5% vs 31.2%

Overall response rate 92.7% for bendamustine plus rituximab compared to 91% for CHOP-R, CR 39.6% vs 30% respectively, progression free survival median 54.9 months bor Bendamustisne +R compared to 34.8 months for CHOP-R (Rummel MJ).

In the above study, the trial was associated with less toxicity and fewer hematologic events bendamustine/rituximab as opposed to R-CHOP.

In a study comparing bendamustine and rituximab with standard R-CHOP therapy in 514 patients with untreated indolent non-Hodgkin’s lymphoma or mantle cell lymphoma: at a median follow-up of 45 months, median progression free survival was 69.5 months in the bendamustine group versus 31.2 months for the R-CHOP group (Rummel MJ et al).

Bendamustine-rituximab should be considered first-line therapy for indolent lymphomas or mantle cell lymphoma.

Bendamustine/rituximab being increasingly used as initial therapy for indolent lymphoma, as a result.

Idelalisib is approved for relapsed follicular lymphoma..

Idelalisib is an oral, small molecule inhibitor of phosphoinositide 3-kinase delta.

Idelalisib overall response rate in refractory disease is 54%.

Lenalidomide has impressive activity and when combined with rituximab has high response rates.

Lenalidomide Improves Efficacy of Rituximab in Recurrent Indolent Lymphoma

Use of lenalidomide in combination with rituximab is safe and improves the efficacy of rituximab in patients with recurrent indolent lymphoma.

In a Phase 3, multi-center clinical trial of lenalidomide plus rituximab versus placebo plus rituximab in patients with relapsed/refractory follicular or marginal zone lymphoma.

Lenalidomide or placebo was administered for 12 cycles along with rituximab given once weekly for 4 weeks in cycle 1 and on day 1 of cycles 2 through 5.

The primary end point of the trial was progression-free survival.

Lenalidomide plus rituximab demonstrated a significantly improved PFS over placebo plus rituximab.

The median PFS was 39.4 months with lenalidomide plus rituximab versus 14.1 months with rituximab alone.

It is suggested that lenalidomide plus rituximab should replace rituximab monotherapy as a standard of care for patients with relapsed or refractory indolent NHL.

At three years the RELEVANCE study showed  Rituximab plus lenalidomide showed no progressive free survival or overall survival benefit compared with Rituximab/chemotherapy.

Maintenance therapy with rituximab improves progression free survival and overall survival.

In a study using rituximab monotherapy maintenance therapy overall survival was not increased compared to patients treated at relapse (Hainsworth JD et al).

The use of maintenance rituximab in patients with high tumor burden in a randomized study of 1019 patients after rituximab chemotherapy induction revealed a significant difference in progression free survival at 36 months of roughly 75% with rituximab maintenance versus 58% with observation alone (Salles G et al).

The use rituximab maintenance increases 2 year complete response rates from 52-72% when given after first-line induction therapy and increases overall survival when administered in the setting of relapsed or refractory disease.

Rituximab maintenance is current standard of care for FL.

If patients have relapse within 2 years after treatment they have a long-term survival of 30-40%.

In a study of 289 patient’s randomly assigned to retreatment rituximab for maintenance rituximab, with a median follow-up of 4-1/2 years estimated median time to treatment failure was 3.9 years for patients receiving retreatment and 4.3 years for those receiving maintenance rrituximab (Kahl BS et al).

In the above study the 3 year freedom from cytotoxic therapy was 84% for those receiving retreatment and 95% for those receiving maintenance rituximab: the conclusion is in low tumor burden follicular lymphoma a retreatment program uses less rituximab and provides disease control comparable to that achieved with maintenance therapy.

The RESORT (Rituximab Extended Schedule for Retreatment Trial) revealed that patients with low tumor burden retreating with rituximab at the time of progression provides long-term disease control comparable to that maintenance rituximab (Kahl B et al).

Bortezomib plus rituximab vs rituximab alone: response rate 63% vs 49% and progression free survival 12.8 months vs. 11months (Coiffier B et sl).

Aliqopa (copanlisib) approved for recurrent disease with a 59% response rate.

Radioimmunotherapy with radioactive I131-tositumomab (Bexxar) results in overall response rate of 95%, 75% complete remission rate and undetectable BCL-2 translocation in 80% of those who achieve complete remission.

3 FIT study utilizing radioactive ibritumomab tiuxetan (RIT) linked to yttrium-90 as consolidation for chemotherapy patient with a response to treatment: After 5.5 years of followup this agent was significantly associated with improved progression free survival versus patients without maintenance therapy (Hagenbeek A et al).

Frontline therapy with atezolizumab, obintuzumab, and bendmustine had a response rate of 85%, with a 75% complete remission rate.

In the above studies after 3.5 years of followup patients receiving RIT had a progression free survival of 36.5 months versus 13.3 months in the control group, a median progression free survival of 49 months in the RIT group versus 14 months in the control group at 5.5 years of followup, a median progression free survival was not reached in those who had a complete response at 92 months and 32 months with the control group.

High dose chemoradiotherapy with bone marrow or hematopoietic stem cell transplantation is a potentially curable treatment but few patients can undergo such therapy secondary to comorbidities and advanced age.

Allogeneic stem cell transplantation can result in long-term survival in patients with this entity, in part through an immune-mediated graft-versus-lymphoma effect.

In a comparison retrospective study there was a significantly lower relapse rate in patients with FL who underwent allogeneic transplantation compared with those who underwent autologous transplantation (Peniket AJ): However high treatment mortality with allogeneic transplantation of 30-40% and the high incidence of severe graft versus host disease offset any potential survival benefit.

In a study of nonmyeloablative stem cell transplantation patients with FL treated with a conditioning treatment of fludarabine, cyclophosphamide, rituximab followed by HLA matched hematopoietic cells with tacrolimus and methotrexate prophylaxis: All patients had a complete remission with only 2 relapses and a median follow up time 60 months (Khouri I).

Following induction therapy post treatment PET scan is a strong prognostic factor, with those patients who have had positive scans at the end of induction had an inferior progression free survival at 42 months (Trottman J et al).

Typically the disease recurs between 3 and 6 years after initial treatment, and most patients require several lines of treatment throughout the course of the disease.

First-line treatment with lenalidomide plus rituximab significantly improved outcomes among patients with follicular lymphoma (SAKK trial).

At 6 months, a significantly higher rate of CR/CRu was reported by investigators in the rituximab plus lenalidomide arm (36%) versus the rituximab-alone arm (25%).

After a median follow-up of 4 years, significantly higher 30-month rates of CR/CRu were reported in the rituximab plus lenalidomide arm, as well as longer progression-free survival (PFS) and time to next treatment.

The overall survival was similar between the 2 arms at 90%.

Non-Hodgkin lymphomas are generally resistant to checkpoint inhibitors.

((Umbralisib)) approved for use in adult patients with relapsed/refractory follicular lymphoma who have previously received at least 3 lines of systemic treatment.

Copanlisib is approved for relapsed or resistant follicular lymphoma.

PIK3 inhibitors are also approved for R/R follicular lymphoma and include idealisib.

CAR-T cell therapy with anxicabtagene  and tisagenleeucel are the two agents that are approved for relapsed or resistant follicular lymphoma.

Mosumatuzumab is a bispecific antibody approved for a relapsed/refractory follicular lymphoma: response rates, 80% with a CR of 60%, median, progression free, survival 18 months.


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