Skip to main content
SpringerLink
Log in

Follicular Lymphoma: Therapeutics and Management

  • Chapter
  • First Online:
Follicular Lymphoma and Mantle Cell Lymphoma

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

  • 440 Accesses

Abstract

Follicular lymphoma (FL) is the second most common form of non-Hodgkin lymphoma and the most common indolent lymphoma. In the modern era, prognosis is often favorable with many patients achieving long-term disease control. Management depends on disease stage, symptoms, and overall disease burden. Patients with limited-stage disease can often be cured with involved-site radiation. Upfront therapy is indicated in patients with advanced stage disease, including anti-CD20 monoclonal antibody monotherapy, combination chemoimmunotherapy, or radioimmunotherapy. Maintenance therapy may be beneficial as well. Relapsed or refractory FL is treated with similar chemoimmunotherapy regimens or with a number of novel agents. Hematopoietic stem cell transplant is an option in appropriately selected patients with high-risk disease. The treatment strategies presented pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are best treated according to guidelines for aggressive B-cell lymphomas.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 69.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 89.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Similar content being viewed by others

References

  1. Wahlin BE, Yri OE, Kimby E, et al. Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. Br J Haematol. 2012;156(2):225–33. https://doi.org/10.1111/j.1365-2141.2011.08942.x.

    Article  PubMed  Google Scholar 

  2. Guadagnolo BA, Li S, Neuberg D, et al. Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys. 2006;64(3):928–34. https://doi.org/10.1016/j.ijrobp.2005.08.010.

    Article  PubMed  Google Scholar 

  3. 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(5):1219–27. https://doi.org/10.1016/s0360-3016(01)01747-3.

    Article  CAS  PubMed  Google Scholar 

  4. 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 Off J Am Soc Clin Oncol. 1996;14(4):1282–90. https://doi.org/10.1200/JCO.1996.14.4.1282.

    Article  CAS  Google Scholar 

  5. Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(8):1454–9. https://doi.org/10.1200/JCO.2004.10.086.

    Article  Google Scholar 

  6. 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 Off J Am Soc Clin Oncol. 2012;30(27):3368–75. https://doi.org/10.1200/JCO.2011.40.6546.

    Article  CAS  Google Scholar 

  7. 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 Off J Am Soc Clin Oncol. 1997;15(3):1110–7. https://doi.org/10.1200/JCO.1997.15.3.1110.

    Article  CAS  Google Scholar 

  8. Kahl BS, Yang DT. Follicular lymphoma: evolving therapeutic strategies. Blood. 2016;127(17):2055–63. https://doi.org/10.1182/blood-2015-11-624288.

    Article  CAS  PubMed  Google Scholar 

  9. Portlock CS. No initial therapy for stage III and IV non-Hodgkin’s lymphomas of favorable histologic types. Ann Intern Med. 1979;90(1):10. https://doi.org/10.7326/0003-4819-90-1-10.

    Article  CAS  PubMed  Google Scholar 

  10. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin’s lymphomas. N Engl J Med. 1984;311(23):1471–5. https://doi.org/10.1056/NEJM198412063112303.

    Article  CAS  PubMed  Google Scholar 

  11. 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(9383):516–22. https://doi.org/10.1016/s0140-6736(03)14110-4.

    Article  CAS  PubMed  Google Scholar 

  12. Young RC, Longo DL, Glatstein E, Ihde DC, Jaffe ES, DeVita VT. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol. 1988;25(2 Suppl 2):11–6.

    CAS  PubMed  Google Scholar 

  13. 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(4):424–35. https://doi.org/10.1016/S1470-2045(14)70027-0.

    Article  CAS  PubMed  Google Scholar 

  14. Hiddemann W. 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(12):3725–32. https://doi.org/10.1182/blood-2005-01-0016.

    Article  CAS  PubMed  Google Scholar 

  15. 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(28):4579–86. https://doi.org/10.1200/JCO.2007.13.5376.

    Article  CAS  PubMed  Google Scholar 

  16. Herold M, Dölken G, Fiedler F, et al. Randomized phase III study for the treatment of advanced indolent non-Hodgkin’s lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus rituximab. Ann Hematol. 2003;82(2):77–9. https://doi.org/10.1007/s00277-002-0581-1.

    Article  CAS  PubMed  Google Scholar 

  17. 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(1):101–6. https://doi.org/10.1182/blood.v97.1.101.

    Article  CAS  PubMed  Google Scholar 

  18. Ghielmini M, Schmitz S-FH, 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 × 4 schedule. Blood. 2004;103(12):4416–23. https://doi.org/10.1182/blood-2003-10-3411.

    Article  CAS  PubMed  Google Scholar 

  19. 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 Off J Am Soc Clin Oncol. 2005;23(6):1103–8. https://doi.org/10.1200/JCO.2005.12.052.

    Article  CAS  Google Scholar 

  20. Martinelli G, Schmitz S-FH, 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 Off J Am Soc Clin Oncol. 2010;28(29):4480–4. https://doi.org/10.1200/JCO.2010.28.4786.

    Article  CAS  Google Scholar 

  21. 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(12):1506–13. https://doi.org/10.1200/JCO.2012.45.0866.

    Article  CAS  PubMed  Google Scholar 

  22. Luminari S, Ferrari A, Manni M, et al. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2017;36(7):689–96. https://doi.org/10.1200/JCO.2017.74.1652.

    Article  PubMed  Google Scholar 

  23. 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(9873):1203–10. https://doi.org/10.1016/S0140-6736(12)61763-2.

    Article  CAS  Google Scholar 

  24. 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(19):2944–52. https://doi.org/10.1182/blood-2013-11-531327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fowler NH, Davis RE, Rawal S, et al. Safety, activity, and immune effects of lenalidomide and rituximab in untreated indolent lymphoma. Lancet Oncol. 2014;15(12):1311–8. https://doi.org/10.1016/S1470-2045(14)70455-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus Lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934–47. https://doi.org/10.1056/NEJMoa1805104.

    Article  CAS  PubMed  Google Scholar 

  27. Marcus R, Davies A, Ando K, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331–44. https://doi.org/10.1056/NEJMoa1614598.

    Article  CAS  Google Scholar 

  28. Hiddemann W, Barbui AM, Canales MA, et al. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018;36(23):2395–404. https://doi.org/10.1200/JCO.2017.76.8960.

    Article  CAS  Google Scholar 

  29. 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 Off J Am Soc Clin Oncol. 2014;32(27):3059–68. https://doi.org/10.1200/JCO.2013.54.8800.

    Article  Google Scholar 

  30. Dupuis J, Berriolo-Riedinger A, Julian A, et al. Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d’Etudes des Lymphomes de l’Adulte and GOELAMS. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(35):4317–22. https://doi.org/10.1200/JCO.2012.43.0934.

    Article  CAS  Google Scholar 

  31. Luminari S, Biasoli I, Versari A, et al. The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL). Ann Oncol Off J Eur Soc Med Oncol. 2014;25(2):442–7. https://doi.org/10.1093/annonc/mdt562.

    Article  CAS  Google Scholar 

  32. Galimberti S, Luminari S, Ciabatti E, et al. Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20(24):6398–405. https://doi.org/10.1158/1078-0432.CCR-14-0407.

    Article  CAS  Google Scholar 

  33. 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(9759):42–51. https://doi.org/10.1016/S0140-6736(10)62175-7.

    Article  CAS  PubMed  Google Scholar 

  34. Carlotti E, Wrench D, Matthews J, et al. Transformation of follicular lymphoma to diffuse large B-cell lymphoma may occur by divergent evolution from a common progenitor cell or by direct evolution from the follicular lymphoma clone. Blood. 2009;113(15):3553–7. https://doi.org/10.1182/blood-2008-08-174839.

    Article  CAS  PubMed  Google Scholar 

  35. Lossos IS, Alizadeh AA, Diehn M, et al. Transformation of follicular lymphoma to diffuse large-cell lymphoma: alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proc Natl Acad Sci U S A. 2002;99(13):8886–91. https://doi.org/10.1073/pnas.132253599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Martinez-Climent JA, Alizadeh AA, Segraves R, et al. Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood. 2003;101(8):3109–17. https://doi.org/10.1182/blood-2002-07-2119.

    Article  CAS  PubMed  Google Scholar 

  37. Davies AJ, Lee AM, Taylor C, et al. A limited role for TP53 mutation in the transformation of follicular lymphoma to diffuse large B-cell lymphoma. Leukemia. 2005;19(8):1459–65. https://doi.org/10.1038/sj.leu.2403802.

    Article  CAS  PubMed  Google Scholar 

  38. Feugier P, Filliatre-Clement L. Recent advances in the first-line treatment of follicular non-Hodgkin lymphoma. F1000Research. 2019;8:294. https://doi.org/10.12688/f1000research.16686.1.

    Article  Google Scholar 

  39. Al-Tourah AJ, Gill KK, Chhanabhai M, et al. Population-based analysis of incidence and outcome of transformed non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(32):5165–9.

    Article  Google Scholar 

  40. Montoto S, Davies AJ, Matthews J, et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol. 2007;25(17):2426–33.

    Article  Google Scholar 

  41. Wagner-Johnston ND, Link BK, Byrtek M, et al. Outcomes of transformed follicular lymphoma in the modern era: a report from the National LymphoCare Study (NLCS). Blood. 2015;126(7):851–7. https://doi.org/10.1182/blood-2015-01-621375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sarkozy C, Trneny M, Xerri L, et al. Risk factors and outcomes for patients with follicular lymphoma who had histologic transformation after response to first-line immunochemotherapy in the PRIMA trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(22):2575–82. https://doi.org/10.1200/JCO.2015.65.7163.

    Article  CAS  Google Scholar 

  43. Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Cancer. 2010;116(1):106–14. https://doi.org/10.1002/cncr.24714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081–93. https://doi.org/10.1016/S1470-2045(16)30097-3.

    Article  CAS  PubMed  Google Scholar 

  45. Cheson BD, Chua N, Mayer J, et al. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018;36(22):2259–66. https://doi.org/10.1200/JCO.2017.76.3656.

    Article  CAS  PubMed  Google Scholar 

  46. Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of Yttrium-90–Labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2002;20(10):2453–63. https://doi.org/10.1200/JCO.2002.11.076.

    Article  CAS  PubMed  Google Scholar 

  47. Mondello P, Cuzzocrea S, Navarra M, Mian M. 90 Y-ibritumomab tiuxetan: a nearly forgotten opportunity. Oncotarget. 2015;7(7):7597–609. https://doi.org/10.18632/oncotarget.6531.

    Article  PubMed Central  Google Scholar 

  48. 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 Off J Am Soc Clin Oncol. 2013;31(16):1977–83. https://doi.org/10.1200/JCO.2012.45.6400.

    Article  CAS  Google Scholar 

  49. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18. https://doi.org/10.1056/NEJMoa1314583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dreyling M, Morschhauser F, Bouabdallah K, et al. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol Off J Eur Soc Med Oncol. 2017;28(9):2169–78. https://doi.org/10.1093/annonc/mdx289.

    Article  CAS  Google Scholar 

  51. van Besien K, Loberiza FR, Bajorunaite R, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood. 2003;102(10):3521–9. https://doi.org/10.1182/blood-2003-04-1205.

    Article  CAS  PubMed  Google Scholar 

  52. Rezvani AR, Storer B, Maris M, et al. Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2016. https://doi.org/10.1200/JCO.2007.11.5477.

  53. Khouri IF, Saliba RM, Erwin WD, et al. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012;119(26):6373–8. https://doi.org/10.1182/blood-2012-03-417808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Schouten HC, Qian W, Kvaloy S, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003;21(21):3918–27. https://doi.org/10.1200/JCO.2003.10.023.

    Article  CAS  PubMed  Google Scholar 

  55. Rohatiner AZS, Nadler L, Davies AJ, et al. Myeloablative therapy with autologous bone marrow transplantation for follicular lymphoma at the time of second or subsequent remission: long-term follow-up. J Clin Oncol. 2007;25(18):2554–9. https://doi.org/10.1200/JCO.2006.09.8327.

    Article  PubMed  Google Scholar 

  56. 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(8):2540–4. https://doi.org/10.1182/blood-2006-03-013193.

    Article  CAS  PubMed  Google Scholar 

  57. 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(8):4004–13. https://doi.org/10.1182/blood-2007-10-116749.

    Article  CAS  PubMed  Google Scholar 

  58. Al Khabori M, de Almeida JR, Guyatt GH, Kuruvilla J, Crump M. Autologous stem cell transplantation in follicular lymphoma: a systematic review and meta-analysis. JNCI J Natl Cancer Inst. 2012;104(1):18–28. https://doi.org/10.1093/jnci/djr450.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dartmouth Hitchcock Medical Center, Department of Hematology and Oncology, Lebanon, NH, USA

    Allison H. Smith, Lukas P. Emery & Frederick Lansigan

Authors
  1. Allison H. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lukas P. Emery
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frederick Lansigan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Frederick Lansigan .

Editor information

Editors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH, USA

    Prabhjot Kaur

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Smith, A.H., Emery, L.P., Lansigan, F. (2020). Follicular Lymphoma: Therapeutics and Management. In: Kaur, P. (eds) Follicular Lymphoma and Mantle Cell Lymphoma. Molecular and Translational Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-49741-5_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-49741-5_5

  • Published:

  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-49740-8

  • Online ISBN: 978-3-030-49741-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation