Residency · Residency · Hematology Thrombosis

Follicular and Marginal Zone Lymphomas

Introduction

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are the two most common indolent B-cell non-Hodgkin lymphomas. Follicular lymphoma is the second most common NHL overall, accounting for approximately 20 to 25% of all cases, while marginal zone lymphoma accounts for 7 to 10%. The natural history of these diseases is characteristically indolent, with prolonged survival measured in years to decades, but they are generally considered incurable with standard therapy. Treatment strategies emphasize a watch-and-wait approach for asymptomatic patients and sequential therapies when treatment is required. Transformation to aggressive lymphoma, most commonly diffuse large B-cell lymphoma, is a major clinical concern in both entities.

Follicular Lymphoma

Pathology

Follicular lymphoma arises from neoplastic germinal center B cells, consisting of centrocytes (small cleaved cells) and centroblasts (large noncleaved cells), which recapitulate the follicular architecture of normal lymphoid tissue. The immunophenotype is characteristic: CD20-positive, CD10-positive, BCL6-positive, BCL2-positive (paradoxically, since normal germinal center B cells are BCL2-negative), CD5-negative, and CD43-negative. The hallmark genetic abnormality is the t(14;18)(q32;q21) translocation, present in approximately 85% of cases, which juxtaposes the BCL2 gene with the immunoglobulin heavy chain (IGH) locus, leading to constitutive overexpression of the anti-apoptotic BCL2 protein.

Histologic grading is based on the number of centroblasts per high-power field. Grades 1 and 2 are predominantly composed of centrocytes and behave indolently. Grade 3A shows an increased number of centroblasts (more than 15 per high-power field) but retains indolent behavior. Grade 3B, characterized by sheets of centroblasts without admixed centrocytes, is treated as an aggressive lymphoma akin to DLBCL.

Staging and Prognosis

The majority of patients with follicular lymphoma present at an advanced stage (stage III-IV), accounting for approximately 80% of cases. The Follicular Lymphoma International Prognostic Index (FLIPI) incorporates five adverse factors: age above 60, stage III-IV disease, hemoglobin below 12 g/dL, LDH above the upper limit of normal, and involvement of more than 4 nodal areas. Patients are stratified into low risk (0-1 factors), intermediate risk (2 factors), and high risk (3-5 factors), with 10-year overall survival rates in the pre-rituximab era of 71%, 51%, and 36%, respectively. The FLIPI-2 incorporates beta-2-microglobulin, bone marrow involvement, hemoglobin, longest lymph node dimension, and age. The m7-FLIPI integrates mutations in 7 genes (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11) with the FLIPI score and identifies a high-risk subset of approximately 20% of patients with a 5-year PFS of only about 25%.

Progression of disease within 24 months of initial chemoimmunotherapy (POD24) has emerged as the most clinically relevant adverse prognostic marker in follicular lymphoma, identifying patients with biologically aggressive disease and a 5-year overall survival of approximately 50%, compared to approximately 90% for patients who do not experience POD24.

Watch and Wait

A central principle of follicular lymphoma management is that treatment should be deferred in asymptomatic patients with low tumor burden. Criteria for observation include the absence of symptoms, non-bulky disease, absence of organ compromise, and stable disease on serial imaging. The GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria define the indications for treatment initiation: B symptoms, any nodal mass exceeding 7 cm, 3 or more involved lymph nodes each exceeding 3 cm, symptomatic splenomegaly, organ compression, cytopenias from marrow infiltration, clinically significant effusions, or elevated LDH or beta-2-microglobulin. Many patients remain under observation for years before requiring therapy, with a median time from diagnosis to first treatment of approximately 3 to 5 years.

First-Line Treatment

Limited Stage (I-II)

Limited-stage follicular lymphoma represents a unique clinical scenario with potential for cure. Involved-site radiation therapy at 24 to 30 Gy delivers curative intent, with 10-year PFS of 45 to 50% and a potential for long-term cure in approximately 40% of patients. Alternative approaches include rituximab with or without radiation therapy. Observation is also a reasonable strategy for selected patients with stage I disease, particularly those with small-volume disease in locations where radiation would cause significant morbidity.

Advanced Stage (III-IV)

When treatment is indicated by GELF criteria in advanced-stage disease, rituximab-based chemoimmunotherapy is the standard approach. Rituximab-bendamustine (R-bendamustine) demonstrated superior PFS compared to R-CHOP in the StiL NHL 1 trial (median not reached versus 40.9 months), with less alopecia and less nausea but more frequent skin reactions. R-CHOP for 6 cycles remains a traditional standard option. R-CVP is a less intensive alternative for patients who cannot tolerate bendamustine or CHOP. The chemo-free regimen of rituximab plus lenalidomide (R2) was shown to be non-inferior to rituximab-chemotherapy in the RELEVANCE trial, offering an attractive option for patients wishing to avoid cytotoxic chemotherapy. Lenalidomide is administered at 20 mg daily for 21 days of each 28-day cycle in combination with rituximab for 12 cycles, followed by rituximab maintenance.

Obinutuzumab-based chemoimmunotherapy, evaluated in the GALLIUM trial, demonstrated a PFS advantage compared to rituximab-based chemoimmunotherapy (hazard ratio 0.73) but at the cost of increased toxicity including infusion reactions and infections, with no overall survival benefit detected. Rituximab maintenance therapy for 2 years following induction improves PFS, as demonstrated in the PRIMA trial (6-year PFS 59.2% versus 42.7%), though no OS benefit has been proven, and the infection risk during prolonged maintenance must be weighed against the PFS gain.

<image>A treatment algorithm for follicular lymphoma. Start with "Newly Diagnosed FL (Grade 1-3A)." First branch: Limited stage (I-II) vs. Advanced stage (III-IV). For limited stage: ISRT 24 Gy (curative intent, 40% long-term disease-free) OR rituximab ± RT OR observation. For advanced stage: assess for GELF treatment criteria. If not meeting criteria: watch and wait (observe). If meeting criteria: treatment options shown as parallel boxes - R-Bendamustine (preferred per StiL data), R-CHOP, R-CVP, R-Lenalidomide (R2, chemo-free). After induction, show rituximab maintenance x 2 years (PRIMA trial). Include a "Relapse" pathway: if early relapse (POD24) → consider DLBCL-like treatment approach, CAR T, or clinical trial. If late relapse: re-treat with alternate regimen, PI3K inhibitor, EZH2 inhibitor, lenalidomide-rituximab, or bispecific antibody. Show response rates and key trial names for each option. Clean clinical algorithm with color-coded decision paths.</image>

Relapsed/Refractory FL

Second Line and Beyond

At relapse, retreatment typically employs an alternative chemoimmunotherapy backbone (switching from R-bendamustine to R-CHOP or vice versa). Lenalidomide plus rituximab (R2), evaluated in the AUGMENT trial, demonstrated significantly superior PFS compared to rituximab alone (39.4 versus 14.1 months) in relapsed/refractory indolent lymphoma. PI3K inhibitors, including copanlisib (evaluated in CHRONOS-1, an intravenous agent with an ORR of 59%) and duvelisib, are available but carry a significant toxicity burden including hepatotoxicity, pneumonitis, colitis, and opportunistic infections, leading to declining use. Tazemetostat, an EZH2 inhibitor, is approved for relapsed/refractory follicular lymphoma, with an ORR of 69% in EZH2-mutated cases (approximately 20% of FL) and 35% in wild-type cases, and is notably well tolerated. Mosunetuzumab, a CD20 by CD3 bispecific antibody, achieved an ORR of 80% and a CR rate of 60% in relapsed/refractory FL and received FDA approval in 2022 for patients after 2 or more prior lines of therapy.

CAR T-Cell Therapy

Axicabtagene ciloleucel (Yescarta) is FDA-approved for relapsed/refractory follicular lymphoma after 2 or more prior lines of therapy based on the ZUMA-5 trial, which demonstrated an ORR of 94% and a CR rate of 79%. The responses have been durable in many patients, and CRS and ICANS are manageable.

Transformation to DLBCL

Histologic transformation to DLBCL occurs at a cumulative rate of approximately 3% per year, with a lifetime risk of 30 to 40%. Clinical features suggesting transformation include rapid nodal growth, new B symptoms, rising LDH, and discordant PET uptake with a single site demonstrating an SUV of 10 to 12 or higher. PET-guided biopsy targeting the area of highest uptake is essential for diagnosis. Treatment of transformed disease typically consists of R-CHOP or Pola-R-CHP if the patient has not received prior anthracycline therapy, with autologous HSCT in first complete remission for chemosensitive disease. Prognosis is poor in patients with prior anthracycline exposure, and CAR T-cell therapy should be considered.

Marginal Zone Lymphoma

Subtypes

Marginal zone lymphoma encompasses three distinct subtypes. Extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma) is the most common, accounting for approximately 70% of cases. Splenic MZL (SMZL) accounts for approximately 20%, and nodal MZL (NMZL) accounts for approximately 10%.

MALT Lymphoma

MALT lymphoma arises from acquired mucosa-associated lymphoid tissue that develops in the setting of chronic antigenic stimulation, typically from infectious agents or autoimmune conditions. The key pathogenic associations are among the most elegant examples of infection-driven lymphomagenesis in medicine. Gastric MALT lymphoma is associated with Helicobacter pylori infection in more than 90% of cases, and the t(11;18)/API2-MALT1 translocation is found in H. pylori-negative cases. Ocular adnexal MALT is associated with Chlamydophila psittaci. Cutaneous MALT may be linked to Borrelia burgdorferi. Small intestinal immunoproliferative small intestinal disease (IPSID) is associated with Campylobacter jejuni. Salivary and lacrimal gland MALT is associated with Sjogren syndrome and hepatitis C virus. Pulmonary and thyroid MALT may arise in the setting of Hashimoto thyroiditis.

The management of gastric MALT lymphoma is paradigmatic. In H. pylori-positive, t(11;18)-negative disease, H. pylori eradication therapy alone achieves complete remission in 75 to 80% of patients. Response is monitored with serial endoscopy and biopsy every 3 to 6 months, and histologic remission may require 12 to 18 months to develop, demanding patience before concluding that antibiotic therapy has failed. In H. pylori-positive disease with the t(11;18) translocation, the response rate to antibiotics is lower (approximately 30%), and radiation therapy or rituximab should be considered earlier. For H. pylori-negative gastric MALT, involved-field radiation therapy at 30 Gy is highly effective. For non-gastric disseminated MALT lymphoma, rituximab with or without chemotherapy is the treatment approach.

Splenic MZL

Splenic MZL presents with splenomegaly that is frequently massive, accompanied by lymphocytosis and cytopenias from hypersplenism. The peripheral blood smear may demonstrate villous lymphocytes in approximately 30% of cases (historically termed splenic lymphoma with villous lymphocytes). The immunophenotype is CD20-positive with CD5, CD10, CD23, and CD43 all negative, and surface IgM positive. Hepatitis C virus infection is an important association, and treatment of HCV with direct-acting antiviral therapy can induce lymphoma remission in HCV-associated cases. Treatment options include rituximab monotherapy (with overall response rates exceeding 90%), splenectomy (which is both diagnostic and therapeutic), and rituximab plus bendamustine for refractory disease.

Nodal MZL

Nodal MZL is the rarest subtype, presenting with disseminated nodal disease without significant extranodal involvement. Treatment follows the principles established for follicular lymphoma, with rituximab-based chemoimmunotherapy as the backbone.

Key Clinical Pearls

• POD24 in follicular lymphoma identifies a high-risk subset with inferior survival; these patients should be considered for clinical trials or aggressive salvage strategies
• H. pylori eradication cures the majority of gastric MALT lymphomas; histologic response may take up to 12-18 months - patience is required
• t(11;18)/API2-MALT1 in gastric MALT predicts antibiotic-refractory disease; radiation or rituximab should be considered earlier
• Mosunetuzumab (CD20 x CD3 bispecific) achieves CR rates of 60% in multiply relapsed FL with a fixed-duration treatment course; a transformative advance
• Rituximab maintenance after induction improves PFS in FL but has not shown OS benefit; weigh infection risk against PFS gain
• Always screen for HCV in splenic MZL; direct-acting antiviral therapy may induce lymphoma remission

References

1. Freedman A, Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol. 2023;98(2):316-323.
2. Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas (StiL NHL 1). Lancet. 2013;381(9873):1203-1210.
3. Leonard JP, et al. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019;37(14):1188-1199.
4. Zucca E, et al. Marginal zone lymphomas: ESMO Clinical Practice Guidelines. Ann Oncol. 2020;31(1):17-29.
5. Budde LE, et al. Mosunetuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. Lancet Oncol. 2022;23(8):1055-1065.

Read this lecture as Markdown