Chapter 61: Follicular Lymphoma

• Follicular lymphoma (FL) is an indolent lymphoid neoplasm that is derived from mutated germinal center B cells and exhibits a nodular or follicular histologic pattern.

  — FL is typically composed of a mixture of small, cleaved follicle center cells referred to as centrocytes and large noncleaved follicular center cells referred to as centroblasts.

  — The disease has masqueraded under multiple previous monikers, including “nodular lymphoma” in the Rappaport classification and “follicle center cell lymphoma” in the Working Formulation.

• FL accounts for approximately 20% to 25% of adult non-Hodgkin lymphomas (NHLs) in the United States, with an annual incidence of approximately 14,000 new cases per year.

• The disease is uncommon in persons younger than age 20 years. Pediatric cases appear to represent a separate disease entity that is typically localized, lacks the translocation 14;18 and BCL-2 expression, and has a very good prognosis.

Symptoms and Signs

• Patients with FL usually present with painless diffuse lymphadenopathy.

• Less frequently, patients may have vague abdominal complaints, including pain, early satiety, and increasing girth, which are caused by a large abdominal lymphomatous mass.

• Approximately 10% of patients present with B symptoms (fever, drenching night sweats, or loss of 10% of their body weight).

Staging the Disease

• Evaluation involves performance of a (1) medical history; (2) physical examination (with attention to the lymph nodes in the Waldeyer ring and size and involvement of liver and spleen); (3) laboratory testing, including a complete blood count, examination of the blood film and a differential white cell count, lactic acid dehydrogenase [LDH], β₂-microglobulin, comprehensive metabolic panel, and serum uric acid level; (4) lymph node biopsy; (5) marrow aspiration and biopsy; (6) flow cytometric analysis of blood, marrow, and lymph node cells; and (7) computed tomography (CT) of the chest, abdomen, and pelvis or positron emission tomography (PET)-CT (favored imaging modality).

• Excisional lymph node biopsies are strongly preferred for the initial histologic diagnosis, although in cases in which nodal masses are inaccessible, generous needle core biopsies may suffice.

• The diagnosis should not be established solely on the basis of flow cytometry of the blood or marrow, or on cytologic examination of aspiration needle biopsies of lymph node or other tissue.

• In selected circumstances, additional CT scans of the neck, PET-CT imaging, measurement of the cardiac ejection fraction, serum protein electrophoresis, quantitative immunoglobulins, and hepatitis C testing may be useful.

• Hepatitis B serology should be done before administering rituximab.

Lymph Node Morphology

• A predominantly nodular lymph node pattern is evident; however, the neoplastic follicles are distorted and as the disease progresses, the malignant follicles efface the nodal architecture (Figure 61–1).

• The World Health Organization has developed a three-grade classification system according to the proportion of centroblasts (ie, large noncleaved follicular center cells) detected microscopically:

  — Grade 1: 0 to 5 centroblasts per high-power field

  — Grade 2: 6 to 15 centroblasts per high-power field

  — Grade 3: > 15 centroblasts per high-power field; A, with mixture of centrocytes and centroblasts, and 3B, with sheets of centroblasts.

• Most authorities agree that grade 3B FL behaves aggressively and should be treated with anthracycline-containing regimens (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]) similar to diffuse large B-cell lymphoma.

Cytogenetics

• The classic cytogenetic finding is the t(14;18)(q32;q21) translocation that juxtaposes the BCL-2 gene on band q21 of chromosome 18 with the immunoglobulin (Ig) heavy-chain gene on band 32 of chromosome 14 (Figure 61–2).

  — This translocation occurs in 85% to 90% of cases and in virtually all cases with a grade 1 histopathology (≥ 95% centrocytes).

• The Ig enhancer element results in amplified expression of the translocated gene product and thus overexpression of BCL-2 protein, leading to inhibition of apoptosis of affected B cells (Figure 61–3).

• However, detection of the t(14;18) translocation in lymphoid cells is neither necessary nor sufficient for the diagnosis of FL.

• Additional cytogenetics abnormalities are found in 90% of patients: most commonly, loss of 6q and 17p, and gains of 2, 5, 6p, 7, 8, 12, 17q, 18, 21, and X.

Clinical and Laboratory Values

• There are five adverse prognostic factors: age (> 60 years vs ≤ 60 years), Ann Arbor stage (III–IV vs I–II), hemoglobin level (< 120 g/L vs ≥ 120 g/L), number of nodal areas (> 4 vs ≤ 4), and serum LDH level (high vs normal).

• Three risk groups are defined: low risk (0–1 adverse factors, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (≥3 adverse factors, 27% of patients, HR = 4.3). Figure 61–4 shows outcomes following chemotherapy with and without rituximab.

Gene Expression Profiling

• Two gene expression signatures allow construction of a survival predictor that enables segregation of patients into four quartiles with disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independent of clinical prognostic variables.

• One signature (immune response 1) is associated with a good prognosis and includes genes encoding T-cell markers (eg, CD7, CD8B1, ITK, LEF1, and STAT4) as well as genes that are highly expressed in macrophages (eg, ACTN1 and TNFSF13B).

• The immune response 2 signature is associated with a poor prognosis and includes genes preferentially expressed in macrophages, dendritic cells, or both (eg, TLR5, FCGR1A, SEPT10, LGMN, and C3AR1).

• Next-generation sequencing has identified mutations in specific epigenetic regulators (eg, MLL2, CREBBP, EP300, and EZH2) in almost all cases.

Limited Stage I or II

Radiotherapy

• Patients with stage I or II FL represent only 10% to 30% of all cases in most series.

• Standard management for stage I or limited contiguous stage II disease involves the administration of involved field radiotherapy (35–40 Gy).

• Adjuvant chemotherapy does not appear to improve survival in this setting.

Observation (Watch and Wait)

• Excellent survival has also been observed in patients with early-stage disease who received no initial therapy.

• In a group of 43 selected patients, 56% were free from the requirement for treatment for at least 10 years and 86% were alive 10 years after diagnosis.

• Based on this study, many authorities have concluded that “watchful waiting” is an acceptable alternative to radiotherapy for stage I or II FL.

Advanced Stage II to IV

Observation (Watch and Wait)

• Because there is no conclusive evidence that survival of FL patients is improved by immediate institution of therapy, or that conventional management (other than allogeneic hematopoietic stem cell transplantation) can cure the disease, a “watch-and wait” approach is also recommended for patients with asymptomatic extensive stage II or stage III or IV FL.

Single-Agent Chemotherapy

• Patients can be palliated effectively with a variety of single chemotherapy agents (Table 61–1).

Monoclonal Antibody Therapy

• Four weekly infusions of rituximab were administered at a dose of 375 mg/m² to patients with FL. The response rate was 48%, including a 6% complete response rate and a median time to progression of approximately 1 year.

• Rituximab as initial and maintenance therapy has an overall response rate (ORR) of approximately 70%, with a complete response rate of approximately 20% and a median progression-free survival of 34 months. Ongoing or maintenance rituximab prolongs remission duration.

• New monoclonal anti-CD20 antibodies being studied include ofatumumab, veltuzumab, and obinutuzumab.

• A radioimmunoconjugates ⁹⁰yttrium (⁹⁰Y)-ibritumomab tiuxetan (Zevalin) is approved by the US Food and Drug Administration for relapsed, refractory, and transformed indolent lymphomas.

• In a randomized study comparing treatment of patients with relapsed FL with either ⁹⁰Y-ibritumomab tiuxetan or rituximab, the ORR (8% vs 55%) and the complete response (CR) rate (30% vs 15%) were both statistically superior in the group treated with the radioimmunoconjugate.

• The major concern with the use of ⁹⁰Y-ibritumomab tiuxetan therapy is the potential for delayed myelosuppression. Growth factor administration and transfusions are required in approximately 20% of patients. A potential long-term concern with radiolabeled antibody formulations is the potential development of myelodysplasia and acute leukemia as late complications.

Combination Chemotherapy and Rituximab

• In one study, induction therapy consisting of eight cycles of rituximab/cyclophosphamide, vincristine, and prednisone (R-CVP) was compared with eight cycles of CVP without rituximab in 321 patients with newly diagnosed disease. R-CVP was superior to CVP alone in terms of ORR (81% vs 57%), CR rate (41% vs 10%), time to progression (32 months vs 15 months), time to treatment failure (27 months vs 7 months), and overall survival (OS: 83% vs 77% at 4 years, P = .029).

• Similarly, R-CHOP was compared with CHOP for first-line treatment of 428 patients with advanced stage FL. R-CHOP exhibited a superior ORR (96% vs 90%), time to treatment failure (P < .001), duration of response (P = .001), and OS (P = .016) compared with CHOP alone.

• Randomized trials have shown that R-CHOP and R-fludarabine containing regimens both have a superior progression-free survival (PFS) than R-CVP. Because fludarabine-containing regimens have more hematological toxicity and a greater risk of secondary malignancies, R-CHOP has generally been thought to be the preferred regimen.

• Bendamustine-rituximab has been shown to have similar efficacy and less toxicity than R-CHOP, and it is frequently utilized.

Maintenance Rituximab

• The PRIMA study showed that 2 years of maintenance rituximab yielded a higher 2-year PFS (75% vs 58%) than no ongoing rituximab. However, there was no improvement in OS in this or other trials.

Idiotype Vaccines

• Phase 2 trials showed favorable results with vaccines directed against the idiotypic immunoglobulin protein expressed on the lymphoma cells.

• However, phase 3 trials have failed to confirm the phase 2 results.

Hematopoietic Stem Cell Transplantation

• The role of high-dose chemoradiotherapy and allogeneic hematopoietic stem cell transplantation in the management of patients remains controversial. This lack of clear advantage may be related to its application usually in refractory or relapsed advanced stage patients.

• When allogeneic and autologous hematopoietic stem cell transplant results are compared in patients with relapsed FL, the long-term survival rates are comparable.

• Adverse outcomes of autologous hematopoietic stem cell transplantation include treatment-related mortality (3%–5%) and a substantial increase in the incidence of secondary myelodysplasia and acute myelogenous leukemia, occurring in approximately 15% of patients.

• Although allogeneic hematopoietic transplantation affords long-term PFS for approximately 40% to 50% of patients with relapsed disease, transplant-related mortality rates range from 20% to 40%. Nonmyeloablative and reduced-intensity allogeneic transplant conditioning regimens to exploit the benefit of a graft-versus-lymphoma effect while minimizing transplant morbidity and mortality show promising results.

• Adverse outcomes associated with autologous hematopoietic stem cell transplantation include treatment-related mortality (3%–5%) and a substantial increase in the incidence of secondary myelodysplasia and acute myelogenous leukemia, occurring in 7% to 19% of patients.

• Although allogeneic hematopoietic transplantation affords long-term PFS for approximately 40% to 50% of patients with relapsed disease, transplant-related mortality rates range from 20% to 40% and the usual advanced age of patients.

Transformed Follicular Lymphoma

• As many as 30% to 40% of patients with FL transform to diffuse large B-cell lymphoma (Table 61–2) with a poor survival after transformation (Table 61–3).

• Transformation often presents as explosive growth of nodes in one nodal or extranodal site.

• Autologous transplantation may yield better outcomes than immunochemotherapy.

• The OS of patients with FL is improving (Table 61–4).