Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ 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. It 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 percent of adult non-Hodgkin lymphomas (NHL) 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, and 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. + CLINICAL FEATURES Download Section PDF Listen +++ +++ 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 mass. Approximately 10 percent 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 medical history, physical examination (with attention to the lymph nodes in Waldeyer ring and size and involvement of liver and spleen); 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, serum uric acid level); lymph node biopsy; marrow aspiration and biopsy; flow cytometric analysis of blood, marrow, and lymph node cells; and computed tomography (CT) of the chest, abdomen, and pelvis. 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, positron emission tomography (PET)/CT imaging, measurement of the cardiac ejection fraction, serum protein electrophoresis, quantitative immunoglobulins, and hepatitis C testing may be useful. + LABORATORY FEATURES Download Section PDF Listen +++ +++ Lymph Node Morphology ++ Exhibits a predominantly nodular lymph node pattern; however, the neoplastic follicles are distorted and as the disease progresses, the malignant follicles efface the nodal architecture. The World Health Organization has developed a three grade classification system according to the proportion of centroblasts detected microscopically. Nearly all authorities now agree, however, that grade 3B FL behaves aggressively and should be treated with anthracycline-containing regimens (e.g., 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. This alteration occurs in 85 to 90 percent of cases and 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. 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 percent of patients, most commonly, loss of 1p, 6q, 10q, and 17p, and gains of 1, 6p, 7, 8, 12q, X, and 18q/dup. + PROGNOSTIC FACTORS Download Section PDF Listen +++ +++ 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. ≤, 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). See Fig. 62–1 for outcomes following chemotherapy with and without rituximab. ++ FIGURE 62–1 Progression-free survival of 827 patients with FL stratified by the Follicular Lymphoma International Prognostic Index (FLIPI) into low risk (0–1 risk factors, 40% of patients, black lines), intermediate risk (2 risk factors, 33% of patients, blue lines), or high risk (3–5 risk factors, 27% of patients, red lines). Of the 827 patients, 267 were treated with chemotherapy regimens without rituximab (dotted lines) and 560 were treated with rituximab-containing regimens (solid lines). (Reproduced with permission from Federico M, Bellei M, Pro B, et al: J Clin Oncol June 20;25(185):8008, 2007.) (Source: Williams Hematology, 8th ed, Chap. 101, Fig. 101–3, p.1567.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ 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 (e.g., CD7, CD8B1, ITK, LEF1, and STAT4) as well as genes that are highly expressed in macrophages (e.g., 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 (e.g., TLR5, FCGR1A, SEPT10, LGMN, and C3AR1). + THERAPY Download Section PDF Listen +++ +++ Radiotherapy ++ Patients with stage I or II FL represent only 10 to 30 percent 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 to 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 percent were free from the requirement for treatment for at least 10 years and 86 percent 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. 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 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 62–1). ++Table Graphic Jump LocationTABLE 62–1THERAPEUTIC REGIMENS FOR FOLLICULAR LYMPHOMAView Table||Download (.pdf) TABLE 62–1 THERAPEUTIC REGIMENS FOR FOLLICULAR LYMPHOMA Agent(s) Dose Route Day(s) of Treatment Repeat Cycle at Day Single agents Chlorambucil 0.08–0.12 mg/kg PO Daily or 0.4–1.0 mg/kg PO 1 28 Cyclophosphamide 50–100 mg/m2 PO Daily or 300 mg/m2 PO 1–5 28 Fludarabine 25 mg/m2/day IV 1–5 28 Pentostatin 4 mg/m2 IV 1 14 Cladribine 0.1 mg/kg/day IV 1–7 28 or 0.14 mg/kg/day IV (2 h) 1–5 28 Bendamustine 100–120 mg/ m2/day IV 1, 2 21 or 28 Rituximab 375 mg/m2/day IV 1, 8, 15, 22 Combination therapy Stanford CVP Cyclophosphamide 400 mg/m2 PO 1–5 21 Vincristine 1.4 mg/m2 (maximum 2 mg) IV 1 21 Prednisone 100 mg/m2 PO 1–5 21 R-CVP Rituximab 375 mg/m2 IV 1 21 Cyclophosphamide 1000 mg/m2 IV 1 21 Vincristine 1.4 mg/m2 (maximum 2 mg) IV 1 21 Prednisone 100 mg PO 1–5 21 R-CHOP Rituximab 375 mg/m2 IV 1 21 Cyclophosphamide 750 mg/m2 IV 1 21 Doxorubicin 50 mg/m2 IV 1 Vincristine 1.4 mg/m2 IV 1 Prednisone 100 mg PO 1–5 FND Fludarabine 25 mg/m2 IV 1–3 28 Mitoxantrone 10 mg/m2 IV 1 Dexamethasone 20 mg IV or PO 1–5 CF Cyclophosphamide 600–1000 mg/m2 IV 1 Fludarabine 20 mg/m2 IV 1–5 21–28 Source: Williams Hematology, 8th ed, Chap. 101, Table 101–1, p. 1568. +++ 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 percent, including a 6 percent complete response rate and a median time to progression of approximately 1 year. In one study, 38 patients received rituximab as initial and maintenance therapy, experiencing an overall response rate (ORR) of 76 percent, with a complete response rate of 37 percent and a median progression-free survival of 34 months. Two radioimmunoconjugates targeting the CD20 antigen, 131iodine-tositumomab (Bexxar) and 90yttrium-ibritumomab tiuxetan (Zevalin), have been approved by the U.S. Food and Drug Administration for relapsed, refractory, and transformed indolent lymphomas. In a randomized study comparing treatment of patients with relapsed FL with either 90 Y-ibritumomab tiuxetan or rituximab, the ORR (86 vs. 55% and the complete response (CR) rate (30 vs. 15%) were both statistically superior in the group treated with the radioimmunoconjugate. Similarly, 131I-tositumomab was compared with unlabeled tositumomab in a randomized trial of relapsed indolent lymphoma and both the ORR (55 vs. 19% and the CR rate (33 vs. 8%) were higher in patients receiving the radiolabeled antibody. The major toxicity of radioimmunotherapy is delayed myelosuppression. Growth factor administration and transfusions are required in approximately 20 percent of patients. A potential long-term concern with both radiolabeled antibody formulations is the potential development of myelodysplasia and acute leukemia as late complications. Hypothyroidism may also occur as a delayed toxicity of 131I-labeled tositumomab in approximately 10 percent of patients. +++ Combination Chemotherapy ++ In one study, induction therapy consisting of eight cycles of rituximab/cyclophosphamide/vincristine/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 = 0.029). 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 < 0.001), duration of response (p = 0.001), and OS (p = 0.016) compared with CHOP alone. +++ Hematopoietic Stem Cell Transplantation ++ The role of high-dose chemoradiotherapy and allogeneic hematopoietic stem cell transplantation in the management of patients remains highly controversial. A randomized trial of 89 patients with relapsed disease showed that transplanted patients experience a marginal OS advantage compared with patients randomized to continued conventional salvage chemotherapy without transplantation.When used as part of initial therapy for high-risk patients, randomized studies demonstrate no improvement in OS. 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 percent. Although allogeneic hematopoietic transplantation affords long-term progression free survival for approximately 40 to 50 percent of patients with relapsed disease, transplant-related mortality rates range from 20 to 40 percent because of the usual advanced age of patients. ++ For a more detailed discussion, see Oliver W. Press: Follicular Lymphoma. Chap. 101, p. 1565 in Williams Hematology, 8th ed.
For a more detailed discussion, see Oliver W. Press: Follicular Lymphoma. Chap. 101, p. 1565 in Williams Hematology, 8th ed.