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Follicular Lymphoma: First-Line Treatment Without Chemotherapy for Follicular Lymphoma

  • Lymphoma (JW Sweetenham, Section Editor)
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Opinion Statement

The optimal initial treatment of follicular lymphoma (FL) is not known, and initial management of patients varies considerably between providers and institutions. The assertion that patients with low tumor burden can be observed for a period of time is being challenged owing to the safety and tolerability of novel therapeutics and the movement of the field away from traditional chemotherapy agents. Single agent rituximab has become increasingly popular as initial management of patients with low tumor burden disease, and there is evidence that prolonged treatment with rituximab can improve progression-free survival (PFS) when compared to induction with rituximab or observation. Radioimmunotherapy (RIT) has similarly shown efficacy in low tumor burden disease. Novel agents such as lenalidomide, idelalisib, and ibrutinib are being studied in the first-line setting. Importantly, none of these strategies have demonstrated an improved overall survival in a randomized study versus observation. It is the opinion of the authors that endpoints such as PFS alone, while important, should not drive changes in management with limited resources. Composite endpoints including quality of life are more informative on the true impact of treatments on patients with follicular lymphoma. Providers should encourage all patients to be treated in the context of an appropriate clinical trial when possible. If a patient is not a clinical trial candidate, we typically treat patients with advanced stage and high tumor burden with chemoimmunotherapy. The decision to give maintenance rituximab is individualized to the patient, as there is no overall survival benefit. In patients with early stage disease, we favor consideration of radiation therapy if the patient is a candidate. Our initial recommendation to patients with advanced stage, low tumor burden disease, is close observation or “watch and wait.” We have observed that most patients become comfortable over time with an observation approach. If a patient is not comfortable with this recommendation, we will use single agent rituximab. If the patient responds to therapy, we do not recommend maintenance rituximab in low tumor burden disease but rather prefer a retreatment strategy or an extended schedule of four additional doses of rituximab.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992–2001. Blood. 2006;107:265–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. 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;27:1202–8.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol. 2005;23:8447–52.

    Article  CAS  PubMed  Google Scholar 

  4. Liu Q, Fayad L, Cabanillas F, et al. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006;24:1582–9.

    Article  PubMed  Google Scholar 

  5. Tan D, Horning SJ, Hoppe RT, et al. Improvements in observed and relative survival in follicular grade 1–2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122:981–7. This study provides evidence of improving survival of patients with follicular lymphoma.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Junlen HR, Peterson S, Kimby E, et al. Follicular lymphoma in Sweden: nationwide improved survival in the rituximab era, particularly in elderly women: a Swedish Lymphoma Registry Study. Leukemia. 2015;29:668–76. This study provides evidence of improving survival of patients with follicular lymphoma.

    Article  CAS  PubMed  Google Scholar 

  7. Rummel MJ, Niederle N, Maschmeyer G, et al. Study group indolent Lymphomas (StiL). 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;381:1203–10.

    Article  CAS  PubMed  Google Scholar 

  8. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105:1684–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Shirley MH, Sayeed S, Barnes I, Finlayson A, Ali R. Incidence of haematological malignancies by ethnic group in England, 2001–7. Br J Haematol. 2013;163:465–77.

    Article  PubMed  Google Scholar 

  10. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. <br />. Fourth ed. Geneva, Switzerland: World Health Organization; 2008.

  11. Bloomfield CD, Arthur DC, Frizzera G, et al. Nonrandom chromosome abnormalities in lymphoma. Cancer Res. 1983;43:2975–84.

    CAS  PubMed  Google Scholar 

  12. Graninger WB, Seto M, Boutain B, et al. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. JClin Invest. 1987;80:1512.

    Article  CAS  Google Scholar 

  13. Ngan BY, Chen-Levy Z, Weiss LM, et al. Expression in non-Hodgkin’s lymphoma of the bcl-2 protein associated with the t(8;14) chromosomal translocation. N Engl J Med. 1988;318:1638.

    Article  CAS  PubMed  Google Scholar 

  14. Tomita S, Kojima M, Imura J, et al. Extranodal diffuse follicular center lymphoma mimicking mantle cell lymphoma of the intestine. Am J Hematol. 2003;74:287–9.

    Article  PubMed  Google Scholar 

  15. Goodlad JR, MacPherson S, Jackson R, et al. Scotland and Newcastle Lymphoma Group. Extranodal follicular lymphoma: a clinicopathological and genetic analysis of 15 cases arising at non-cutaneous extranodal sites. Histopathology. 2004;44:268–76.

    Article  CAS  PubMed  Google Scholar 

  16. Fernandez de Larrea C, Martinez-Pozo A, Mercadal S, et al. Initial features and outcome of cutaneous and non-cutaneous primary extranodal follicular lymphoma. Br J Haematol. 2011;153:334–40.

    Article  PubMed  Google Scholar 

  17. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059–68. Updated consensus staging and response assessment recommendations for Hodgkin and non-Hodgkin lymphoma.

    Article  PubMed  Google Scholar 

  18. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69.

    Article  CAS  PubMed  Google Scholar 

  19. Sakhinia E, Glennie C, Hoyland JA, et al. Clinical quantitation of diagnostic and predictive gene expression levels in follicular and diffuse large B-cell lymphoma by RT-PCR gene expression profiling. Blood. 2007;109:3922–8.

    Article  CAS  PubMed  Google Scholar 

  20. Byers RJ, Sakhinia E, Joseph P, et al. Clinical quantitation of immune signature in follicular lymphoma by RT-PCR-based gene expression profiling. Blood. 2008;111:4764–70.

    Article  CAS  PubMed  Google Scholar 

  21. Kiaii S, Clear AJ, Ramsay AG, et al. Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. J Clin Oncol. 2013;31:2654–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Solal-Celigny P, Roy P, Colombat P, et al. Follicular lymphoma international prognostic index. Blood. 2004;104:1258–65.

    Article  CAS  PubMed  Google Scholar 

  23. Federico M, Bellei M, Marcheselli L, et al. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009;27:4555–62.

    Article  PubMed  Google Scholar 

  24. 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;15:1110–7.

    CAS  PubMed  Google Scholar 

  25. 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;362:516–22.

    Article  CAS  PubMed  Google Scholar 

  26. Solal-Celigny 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;30:3848–53.

    Article  PubMed  Google Scholar 

  27. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al. Clinical stage 1 non-Hodgkin’s lymphoma: long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer. 1994;69:1088–93.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol. 1996;14:1282–90.

    CAS  PubMed  Google Scholar 

  29. Wilder RB, Jones D, Tucker SL, et al. Long-term results with radiotherapy for stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys. 2001;51:1219–27.

    Article  CAS  PubMed  Google Scholar 

  30. Campbell BA, Voss N, Woods R, et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy. Cancer. 2010;116:3797–806.

    Article  PubMed  Google Scholar 

  31. Guckenberger M, Alexandrow N, Flentje M. Radiotherapy alone for stage I-III low grade follicular lymphoma: long-term outcome and comparison of extended field and total nodal irradiation. Radiat Oncol. 2012;7:103-717X-7-103.

    Google Scholar 

  32. Pugh TJ, Ballonoff A, Newman F, Rabinovitch R. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a surveillance, epidemiology, and end results database analysis. Cancer. 2010;116:3843–51.

    Article  PubMed  Google Scholar 

  33. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011;100:86–92.

    Article  PubMed  Google Scholar 

  34. Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol. 2012;30:3368–75.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Portlock CS, Rosenberg SA. No initial therapy for stage III and IV non-Hodgkin’s lymphomas of favorable histologic types. Ann Intern Med. 1979;90:10–3.

    Article  CAS  PubMed  Google Scholar 

  36. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med. 1984;311:1471–5.

    Article  CAS  PubMed  Google Scholar 

  37. Young RC, Longo DL, Glatstein E, et al. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol. 1988;25:11–6.

    CAS  PubMed  Google Scholar 

  38. 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;15:424–35. This is a large study which randomized patients to observation, rituximab induction and rituximab induction with maintenance rituximab for 2 years. While no overall survival benefit was noted, maintenance rituximab delayed time to chemotherapy and had a positive impact on quality of live assessments.

    Article  CAS  PubMed  Google Scholar 

  39. Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol. 1997;15:3266–74.

    CAS  PubMed  Google Scholar 

  40. Salar A, Avivi I, Bittner B, et al. Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study. J Clin Oncol. 2014;32:1782–91. Randomized study comparing subcutaneous rituximab to standard intravenous rituximab.

    Article  CAS  PubMed  Google Scholar 

  41. 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;103:4416–23.

    Article  CAS  PubMed  Google Scholar 

  42. 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;23:1103–8.

    Article  CAS  PubMed  Google Scholar 

  43. 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;23:1088–95.

    Article  CAS  PubMed  Google Scholar 

  44. 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;32:3096–102. Randomized study comparing maintenance rituximab to retreatment at progression strategies. Similar clinical outcomes noted with much less resource consumption in the retreatment arm.

    Article  CAS  PubMed  Google Scholar 

  45. Winiarska M, Bil J, Wilczek E, et al. Statins impair antitumor effects of rituximab by inducing conformational changes of CD20. PLoS Med. 2008;5, e64.

    Article  PubMed Central  PubMed  Google Scholar 

  46. Nowakowski GS, Maurer MJ, Habermann TM, et al. Statin use and prognosis in patients with diffuse large B-cell lymphoma and follicular lymphoma in the rituximab era. J Clin Oncol. 2010;28:412–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Samaras P, Heider H, Haile SR, et al. Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP. Ann Hematol. 2010;89:783–7.

    Article  CAS  PubMed  Google Scholar 

  48. Kohrt HE, Sagiv-Barfi I, Rafiq S, et al. Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood. 2014;123:1957–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Da Roit F, Engelberts PJ, Taylor RP, et al. Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica. 2015;100:77–86.

    Article  PubMed Central  PubMed  Google Scholar 

  50. 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;97:101–6.

    Article  CAS  PubMed  Google Scholar 

  51. Colombat P, Brousse N, Salles G, et al. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol. 2012;23:2380–5.

    Article  CAS  PubMed  Google Scholar 

  52. 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;28:4480–4.

    Article  CAS  PubMed  Google Scholar 

  53. Blommestein HM, Issa DE, Pompen M, et al. Cost-effectiveness of rituximab as maintenance treatment for relapsed follicular lymphoma: results of a population-based study. Eur J Haematol. 2014;92:398–406.

    Article  PubMed  Google Scholar 

  54. Chen Q, Ayer T, Nastoupil LJ, et al. Comparing the cost-effectiveness of rituximab maintenance and radioimmunotherapy consolidation versus observation following first-line therapy in patients with follicular lymphoma. Value Health. 2015;18:189–97.

    Article  PubMed  Google Scholar 

  55. 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;33:740–8. Analyzes quality of life outcomes between retreatment and maintenance rituximab strategies.

    Article  CAS  PubMed  Google Scholar 

  56. Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005;352:441–9.

    Article  CAS  PubMed  Google Scholar 

  57. Scholz CW, Pinto A, Linkesch W, et al. (90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial. J Clin Oncol. 2013;31:308–13.

    Article  CAS  PubMed  Google Scholar 

  58. Ibatici A, Pica GM, Nati S, et al. Safety and efficacy of (90) yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients. An Italian cooperative study. Br J Haematol. 2014;164:710–6.

    Article  CAS  PubMed  Google Scholar 

  59. Illidge TM, Mayes S, Pettengell R, et al. Fractionated (90)Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria. J Clin Oncol. 2014;32:212–8.

    Article  CAS  PubMed  Google Scholar 

  60. McQuillan AD, Macdonald WB, Turner JH. Phase II study of first-line I-rituximab radioimmunotherapy in follicular non-Hodgkin lymphoma and prognostic F-fluorodeoxyglucose positron emission tomography. Leuk Lymphoma. 2014;19:1–7.

    Google Scholar 

  61. Kaminski MS, Tuck M, Estes J, et al. Tositumomab and Iodine I-131 tositumomab for previously untreated, advanced-stage, follicular lymphoma: median 10 year follow-up results. Blood. 2009;114

  62. Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol. 2009;27:5404–9.

    Article  CAS  PubMed  Google Scholar 

  63. Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008;140:36–45.

    CAS  PubMed  Google Scholar 

  64. Wu L, Adams M, Carter T, et al. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008;14:4650–7.

    Article  CAS  PubMed  Google Scholar 

  65. Zhang L, Qian Z, Cai Z, et al. Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol. 2009;84:553–9.

    Article  CAS  PubMed  Google Scholar 

  66. Fowler NH, Davis RE, Rawal S, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15:1311–8. Phase 2 study evaluating the regimen of lenalidomide and rituximab in untreated patients with indolent lymphoma.

    Article  CAS  PubMed  Google Scholar 

  67. Martin P, Jung SH, Johnson JL, et al. CALGB(Alliance) 50803: a phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. J Clin Oncol. 2014;32

  68. Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008–18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  69. Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31:88–94.

    Article  CAS  PubMed  Google Scholar 

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Conflict of Interest

Patrick M. Reagan declares that he has no conflict of interest.

Jonathan W. Friedberg has received compensation from Seattle Genetics for service as a consultant and has served on Data Safety and Monitoring Boards (DSMB) for Trubion, Bayer, and Lilly.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. University of Rochester Medical Center, 601 Elmwood Ave, Box 704, Rochester, NY, 14642, USA

    Patrick M. Reagan M.D. & Jonathan W. Friedberg M.D., M.M.Sc.

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Correspondence to Patrick M. Reagan M.D..

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Reagan, P.M., Friedberg, J.W. Follicular Lymphoma: First-Line Treatment Without Chemotherapy for Follicular Lymphoma. Curr. Treat. Options in Oncol. 16, 32 (2015). https://doi.org/10.1007/s11864-015-0351-7

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