Initial treatment of advanced stage (III/IV) follicular lymphoma
- Arnold S Freedman, MD
Arnold S Freedman, MD
- Section Editor — Lymphoproliferative Disorders
- Professor of Medicine
- Harvard Medical School
- Jonathan W Friedberg, MD
Jonathan W Friedberg, MD
- Professor of Medicine
- James P Wilmot Cancer Center, University of Rochester
Follicular lymphoma (FL, previously called follicle center lymphoma) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of the hematopoietic neoplasms".)
Treatment of FL depends upon the stage of disease at presentation (table 1). Patients with localized (stage I) disease are candidates for radiation therapy, which is curative in a percentage of patients. In contrast, the treatment of advanced (stage III/IV) disease is not curative and focuses largely on symptom control with chemoimmunotherapy with or without radiation therapy. Even so, patients with advanced stage FL generally have an excellent prognosis.
The management of patients with stage II FL is more variable, with some clinicians offering treatment similar to that used for stage I disease and others offering treatment similar to that used for advanced stage disease. (See "Initial treatment of limited stage (I/II) follicular lymphoma", section on 'Stage II FL'.)
The initial treatment of advanced stage (III/IV) FL is discussed here. The initial treatment of limited stage (I/II) FL and the management of relapsed or refractory FL are presented separately, as are the epidemiology, clinical presentation, pathologic features, diagnosis, and pathobiology of FL. Of importance, the recommendations presented here pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are treated as aggressive lymphomas (eg, diffuse large B cell lymphoma). (See "Initial treatment of limited stage (I/II) follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma" and "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma" and "Pathobiology of follicular lymphoma", section on 'Introduction' and "Pathobiology of follicular lymphoma".)
The initial evaluation of a patient with non-Hodgkin lymphoma (NHL) must establish the precise histologic subtype, the extent and sites of disease, and the performance status of the patient. These investigations are important for determining the treatment strategy and for predicting outcome with the Follicular Lymphoma International Prognostic Index (FLIPI) or one of its variants. General approaches to the diagnostic work-up and staging of NHL are presented separately (table 1). The pre-treatment evaluation for patients with advanced stage follicular lymphoma (FL) is the same as that of patients with limited stage FL. This is discussed in more detail separately. (See "Initial treatment of limited stage (I/II) follicular lymphoma", section on 'Pre-treatment evaluation' and "Clinical presentation and diagnosis of non-Hodgkin lymphoma" and "Evaluation and staging of non-Hodgkin lymphoma".)
- Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol 2009; 27:1202.
- Martin P, Byrtek M, Dawson K, et al. Patterns of delivery of chemoimmunotherapy to patients with follicular lymphoma in the United States: results of the National LymphoCare Study. Cancer 2013; 119:4129.
- Peterson BA, Petroni GR, Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol 2003; 21:5.
- Brice P, Bastion Y, Lepage E, et al. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 1997; 15:1110.
- Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet 2003; 362:516.
- Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med 1984; 311:1471.
- O'Brien ME, Easterbrook P, Powell J, et al. The natural history of low grade non-Hodgkin's lymphoma and the impact of a no initial treatment policy on survival. Q J Med 1991; 80:651.
- Gattiker HH, Wiltshaw E, Galton DA. Spontaneous regression in non-Hodgkin's lymphoma. Cancer 1980; 45:2627.
- Krikorian JG, Portlock CS, Cooney P, Rosenberg SA. Spontaneous regression of non-Hodgkin's lymphoma: a report of nine cases. Cancer 1980; 46:2093.
- Solal-Céligny P, Bellei M, Marcheselli L, et al. Watchful waiting in low-tumor burden follicular lymphoma in the rituximab era: results of an F2-study database. J Clin Oncol 2012; 30:3848.
- Ardeshna KM, Qian W, Smith P, et al. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol 2014; 15:424.
- Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17:1244.
- Marcus R, Imrie K, Belch A, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105:1417.
- Marcus R, Imrie K, Solal-Celigny P, et al. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 2008; 26:4579.
- Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25:1986.
- Salles G, Mounier N, de Guibert S, et al. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood 2008; 112:4824.
- Hiddemann W, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106:3725.
- Schulz H, Bohlius JF, Trelle S, et al. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2007; 99:706.
- Schulz H, Bohlius J, Skoetz N, et al. Chemotherapy plus Rituximab versus chemotherapy alone for B-cell non-Hodgkin's lymphoma. Cochrane Database Syst Rev 2007; :CD003805.
- Davies A, Merli F, Mihaljevic B, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol 2014; 15:343.
- Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet 2013; 381:1203.
- Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014; 123:2944.
- Federico M, Luminari S, Dondi A, et al. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol 2013; 31:1506.
- Czuczman MS, Weaver R, Alkuzweny B, et al. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol 2004; 22:4711.
- Watanabe T, Tobinai K, Shibata T, et al. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 2011; 29:3990.
- Sehn LH, MacDonald D, Rubin S, et al. Bortezomib ADDED to R-CVP is safe and effective for previously untreated advanced-stage follicular lymphoma: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2011; 29:3396.
- Czuczman MS, Koryzna A, Mohr A, et al. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol 2005; 23:694.
- McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 2000; 27:37.
- Kahl BS, Hong F, Williams ME, et al. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: eastern cooperative oncology group protocol e4402. J Clin Oncol 2014; 32:3096.
- Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood 2004; 103:4416.
- Martinelli G, Schmitz SF, Utiger U, et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol 2010; 28:4480.
- Colombat P, Salles G, Brousse N, et al. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood 2001; 97:101.
- Conconi A, Martinelli G, Thiéblemont C, et al. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood 2003; 102:2741.
- Hainsworth JD, Litchy S, Shaffer DW, et al. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2005; 23:1088.
- Witzig TE, Vukov AM, Habermann TM, et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 2005; 23:1103.
- Hainsworth JD, Burris HA 3rd, Morrissey LH, et al. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood 2000; 95:3052.
- Hainsworth JD, Litchy S, Burris HA 3rd, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol 2002; 20:4261.
- Wagner LI, Zhao F, Hong F, et al. Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT). J Clin Oncol 2015; 33:740.
- Anderson T, Chabner BA, Young RC, et al. Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute. Cancer 1982; 50:2699.
- Morschhauser F, Radford J, Van Hoof A, et al. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008; 26:5156.
- Morschhauser F, Radford J, Van Hoof A, et al. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the International, Randomized, Phase III First-LineIndolent trial. J Clin Oncol 2013; 31:1977.
- Press OW, Unger JM, Rimsza LM, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus (131)iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol 2013; 31:314.
- Samaniego F, Berkova Z, Romaguera JE, et al. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease. Br J Haematol 2014; 167:207.
- Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 2004; 104:2667.
- Lenz G, Dreyling M, Schiegnitz E, et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22:4926.
- Deconinck E, Foussard C, Milpied N, et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005; 105:3817.
- Gyan E, Foussard C, Bertrand P, et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113:995.
- Sebban C, Mounier N, Brousse N, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006; 108:2540.
- Ladetto M, De Marco F, Benedetti F, et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111:4004.
- Schaaf M, Reiser M, Borchmann P, et al. High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults. Cochrane Database Syst Rev 2012; 1:CD007678.
- Al Khabori M, de Almeida JR, Guyatt GH, et al. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2012; 104:18.
- Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: a new entity? Blood 2005; 105:74.
- Hermine O, Lefrère F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002; 347:89.
- Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther 2005; 21:653.
- Vallisa D, Bernuzzi P, Arcaini L, et al. Role of anti-hepatitis C virus (HCV) treatment in HCV-related, low-grade, B-cell, non-Hodgkin's lymphoma: a multicenter Italian experience. J Clin Oncol 2005; 23:468.
- Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377:42.
- Zhou H, Zhang B, Zhang J, et al. Rituximab maintenance therapy for follicular lymphoma. Lancet 2011; 377:1150.
- Vidal L, Gafter-Gvili A, Salles G, et al. Rituximab maintenance for the treatment of patients with follicular lymphoma: an updated systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2011; 103:1799.
- Vitolo U, Ladetto M, Boccomini C, et al. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol 2013; 31:3351.
- Taverna C, Martinelli G, Hitz F, et al. Rituximab Maintenance for a Maximum of 5 Years After Single-Agent Rituximab Induction in Follicular Lymphoma: Results of the Randomized Controlled Phase III Trial SAKK 35/03. J Clin Oncol 2016; 34:495.
- PRE-TREATMENT EVALUATION
- ADVANCED STAGE DISEASE
- Therapeutic strategy
- - Indications for treatment
- - Asymptomatic patients
- Immunotherapy-based treatment
- - Overview of benefit
- - Chemoimmunotherapy
- - Immunotherapy alone
- Radiation therapy
- - Autologous HCT
- - Allogeneic HCT
- SPECIAL SITUATIONS
- Grade 3b FL
- Patients with hepatitis C
- Histologic transformation
- EVALUATION OF RESPONSE TO THERAPY
- LONG-TERM MANAGEMENT
- Maintenance therapy
- - After chemoimmunotherapy
- - After immunotherapy
- Surveillance for relapse
- CLINICAL TRIALS
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS