Follicular Lymphoma

Czech version

Authors: K. Benešová; M. Trněný
Authors‘ workplace: I. interní klinika – klinika hematologie 1. LF UK a VFN v Praze
Published in: Klin Onkol 2015; 28(Supplementum 3): 73-79
doi: https://doi.org/10.14735/amko20153S73

Overview

Follicular lymphomas represent the second most frequent lymphoma subtype. Translocation t(14;18)(q32;q21) is a characteristic biologic hallmark. It is not sufficient to drive follicular lymphomas development and subsequent molecular defect appears which lead to follicular lymphomas development and progression. The microenvironment plays an important role. The disease is usually diagnosed in an advanced clinical stage. The course is mostly indolent, but there is a subgroup characterized by rapid progression. The outcome has been improved with median of progression free survival between 6–7 years and overall survival between 10 and 15 years. The outcome improvement was caused by introduction of immunotherapy – rituximab, both in induction as well as in maintenance therapy. Despite this improvement, subsequent relapses occur, they can be managed by a variety of approaches based on many factors. The most adverse event is histological transformation. The present review briefly summarizes understanding of biology, clinical course and management.

Key words:
follicular lymphoma – diagnosis – treatment

This study was supported by grants of Internal Grant Agency of the Czech Ministry of Health No. NT13072-4/2012 and NT12193-5/2011.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Submitted:
29. 9. 2015

Accepted:
1. 10. 2015

Sources

1. Trneny M, Vasova I, Pytlik R et al. Distribuce podtypů non‑Hodgkinského lymfomu v České republice a jejich přežití. Klin Onkol 2007; 20(5): 341– 348.

2. Link BK, Maurer MJ, Nowakowski GS et al. Rates and outcomes of follicular lymphoma transformation in the immunochemotherapy era: a report from the University of Iowa/ MayoClinic Specialized Program of Research Excellence Molecular Epidemiology Resource. J Clin Oncol 2013; 31(26): 3272– 3278. doi: 10.1200/ JCO.2012.48.3990.

3. Goldin LR, Bjorkholm M, Kristinsson SY et al. Highly increased familial risks for specific lymphoma subtypes. Br J Haematol 2009; 146(1): 91– 94. doi: 10.1111/ j.1365‑ 2141.2009.07721.x.

4. 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(6): 981– 987. doi: 10.1182/ blood‑ 2013‑ 03‑ 491514.

5. Nabhan C, Aschebrook‑ Kilfoy B, Chiu BC et al. The impact of race, age, and sex in follicular lymphoma: a comprehensive SEER analysis across consecutive treatment eras. Am J Hematol 2014; 89(6): 633– 638. doi: 10.1002/ ajh.23708.

6. Janz S, Potter M, Rabkin CS. Lymphoma‑ and leukemia‑associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer 2003; 36(3): 211– 223.

7. Okosun J, Bodor C, Wang J et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet 2014; 46(2): 176– 181. doi: 10.1038/ ng.2856.

8. Ame‑ Thomas P, Tarte K. The yin and the yang of follicular lymphoma cell niches: role of microenvironment heterogeneity and plasticity. Semin Cancer Biol 2014; 24: 23– 32. doi: 10.1016/ j.semcancer.2013.08.001.

9. Solal‑ Celigny P, Lepage E, Brousse N et al. Recombinant interferon alfa‑2b combined with a regimen containing doxorubicin in patients with advanced follicular lymphoma. N Engl J Med 1993; 329(22): 1608– 1614.

10. 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(21): 2159– 2169.

11. Solal‑ Céligny P, Roy P, Colombat P et al. Follicular lymphoma international prognostic index. Blood 2004; 104(5): 1258– 1265.

12. 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(27): 4555– 4562. doi: 10.1200/ JCO.2008.21.3991.

13. Alvaro T, Lejeune M, Salvadó MT et al. Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol 2006; 24(34): 5350– 5357.

14. Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer 2014; 14(8): 517– 534. doi: 10.1038/ nrc3774.

15. Pastore A, Jurinovic V, Kridel R et al. Integration of gene mutations in risk prognostication for patients receiving first‑line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population‑based registry. Lancet Oncol 2015; 16(9): 1111– 1122.

16. Elstrom R, Guan L, Baker G et al. Utility of FDG‑ PET scanning in lymphoma by WHO classification. Blood 2003; 101(10): 3875– 3876.

17. Sykorova A, Belada D, Smolej L et al. Staging of non‑Hodgkin‘s lymphoma – recommendations of the Czech Lymphoma Study Group. Klin Onkol 2010; 23(3): 146– 154.

18. 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. J Clin Oncol 1997; 15(3): 1110– 1117.

19. 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– 522.

20. 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– 435. doi: 10.1016/ S1470‑ 2045(14)70027‑ 0.

21. Hudson BV, Hudson GV, 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– 1093.

22. Yahalom J. Radiotherapy of follicular lymphoma: updated role and new rules. Curr Treat Options Oncol 2014; 15(2): 262– 268. doi: 10.1007/ s11864‑ 014‑ 0286‑ 4.

23. Dedeckova K, Mocikova H, Belada D et al. The role of radiotherapy in the treatment of malignant lymphomas – recommendations of the Czech Lymphoma Study Group. Klin Onkol 2013; 26(2): 99– 109. doi: 10.14735/ amko201399.

24. 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(4): 1282– 1290.

25. 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– 934.

26. Eich HT, Heimann M, Stutzer H et al. Long‑term outcome and prognostic factors in early‑stage nodal low‑ grade non‑hodgkin‘s lymphomas treated with radiation therapy. Strahlenther Onkol 2009; 185(5): 288– 295. doi: 10.1007/ s00066‑ 009‑ 1937‑ 4.

27. Janikova A, Bortlicek Z, Campr V et al. Radiotherapy with rituximab may be better than radiotherapy alone in first line treatment of early‑stage follicular lymphoma. Is it time to change the standard strategy? Leuk Lymphoma. In press 2015.

28. Seymour JF, Pro B, Fuller LM J et al. Long‑term follow‑up of a prospective study of combined modality therapy for stage I– II indolent non‑Hodgkin‘s lymphoma. J Clin Oncol 2003; 21(11): 2115– 2122.

29. 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(9): 2380– 2385. doi: 10.1093/ annonc/ mds177.

30. 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(28): 3096– 3102. doi: 10.1200/ JCO.2014.56.5853.

31. 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(4): 1417– 1423.

32. Herold M, Pasold R, Srock S et al. Results of a Prospective randomised open label phase iii study comparing rituximab plus mitoxantrone, chlorambucile, prednisolone chemotherapy (R‑ MCP) versus MCP alone in untreated advanced indolent non‑Hodgkin‘s lymphoma (NHL) and mantle‑ cell‑lymphoma (MCL). ASH Annual Meeting Abstracts 2004; 104(11): 584.

33. 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(12): 3725– 3732.

34. 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(13): 4824– 4831. doi: 10.1182/ blood‑ 2008‑ 04‑ 153189.

35. Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol 2009; 27(9): 1492– 1501. doi: 10.1200/ JCO.2008.18.7252.

36. Rummel MJ, Al‑ Batran SE, Kim S‑ Z et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low‑ grade non‑Hodgkin‘s lymphoma. J Clin Oncol 2005; 23(15): 3383– 3389.

37. 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– 1210. doi: 10.1016/ S0140‑ 6736(12)61763‑ 2.

38. 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– 2952. doi: 10.1182/ blood‑ 2013‑ 11‑ 531327.

39. 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(12): 4416– 4423.

40. 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(29): 4480– 4484. doi: 10.1200/ JCO.2010.28.4786.

41. Bachy E, Brice P, Delarue R et al. Long‑term follow‑up of patients with newly diagnosed follicular lymphoma in the prerituximab era: effect of response quality on survival – a study from the groupe d‘etude des lymphomes de l‘adulte. J Clin Oncol 2010; 28(5): 822– 829.

42. Trotman J, Fournier M, Lamy T et al. Positron emission tomography‑ computed tomography (PET‑ CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET‑ CT in a subset of PRIMA trial participants. J Clin Oncol 2011; 29(23): 3194– 3200. doi: 10.1200/ JCO.2011.35.0736.

43. 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. doi: 10.1016/ S0140‑ 6736(10)62175‑ 7.

44. Janikova A, Bortlicek Z, Campr V et al. Impact of rituximab maintenance and maintenance schedule on prognosis in first‑line treatment of follicular lymphoma. Retrospective analysis from czech lymphoma study group (clsg) database. Leuk Lymphoma 2015: 1– 25.

45. Van Oers MHJ, Klasa R, Marcus RE et al. Rituximab maintenance improves clinical outcome of relapsed/ resistant follicular non‑Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006; 108(10): 3295– 3301.

46. 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(32): 5156– 5164. doi: 10.1200/ JCO.2008.17.2015.

47. Canales MA, Dlouhy I, Briones J et al. A Randomized phase II study comparing consolidation with a single dose of 90 y ibritumomab tiuxetan (Zevalin®) (Z) vs. maintenance with rituximab (R) for two years in patients with newly diagnosed follicular lymphoma (FL) responding to R‑ CHOP. Preliminary. Blood 2013; 122(21): 369– 369.

48. 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(9): 2667– 2674.

49. 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(5): 995– 1001. doi: 10.1182/ blood‑ 2008‑ 05‑ 160200.

50. 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– 2544.

51. McLaughlin P, Grillo L, Link BK et al. Rituximab chimeric anti‑CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four‑ dose treatment program. J Clin Oncol 1998; 16(8): 2825– 2833.

52. Pettengell R, Schmitz N, Gisselbrecht C et al. Rituximab purging and/ or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol 2013; 31(13): 1624– 1630. doi: 10.1200/ JCO.2012.47.1862.

53. Robinson SP, Canals C, Luang JJ et al. The outcome of reduced intensity allogeneic stem cell transplantation and autologous stem cell transplantation when performed as a first transplant strategy in relapsed follicular lymphoma: an analysis from the Lymphoma Working Party of the EBMT. Bone Marrow Transplant 2013; 48(11): 1409– 1414. doi: 10.1038/ bmt.2013.83.

54. Tomblyn MR, Ewell M, Bredeson C et al. Autologous versus reduced‑ intensity allogeneic hematopoietic cell transplantation for patients with chemosensitive follicular non‑Hodgkin lymphoma beyond first complete response or first partial response. Biol Blood Marrow Transplant 2011; 17(7): 1051– 1057. doi: 10.1016/ j.bbmt.2010.11.004.

55. Sehn LH, Goy A, Offner FC et al. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B‑ Cell non‑Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. In press 2015.

56. Czuczman MS, Fayad L, Delwail V et al. Ofatumumab monotherapy in rituximab‑ refractory follicular lymphoma: results from a multicenter study. Blood 2012; 119(16): 3698– 3704. doi: 10.1182/ blood‑ 2011‑ 09‑ 378323.

57. 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– 1018. doi: 10.1056/ NEJMoa1314583.

58. 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(12): 1311– 1318. doi: 10.1016/ S1470‑ 2045(14)70455‑ 3.

59. Wang M, Fowler N, Wagner‑ Bartak N et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase IIclinical trial. Leukemia 2013; 27(9): 1902– 1909. doi: 10.1038/leu.2013.95.