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Treatment of relapsed or refractory follicular lymphoma

INTRODUCTION

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".)

The vast majority of patients treated for FL will have an initial response to therapy with 40 to 80 percent demonstrating a complete response, depending upon the initial regimen used. Unfortunately, conventional therapy for FL is not curative and virtually all of these patients will ultimately develop progressive disease. In addition, less than 10 percent of patients treated with initial chemoimmunotherapy will not respond to treatment (ie, refractory disease).

The treatment of relapsed or refractory FL is discussed here. The treatment of previously untreated FL is presented separately as are the epidemiology, clinical presentation, pathologic features, diagnosis, and pathobiology of follicular lymphoma. (See "Initial treatment of advanced stage (III/IV) follicular lymphoma" and "Initial treatment of limited stage (I/II) 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".)

EVALUATION OF SUSPECTED RELAPSE OR RESISTANCE

Definitions — After initial therapy, patients are followed at routine intervals to monitor for treatment-related complications and relapse. At these visits, patients are evaluated with a history, physical examination, and blood work. Imaging studies are reserved for the evaluation of suspected relapse. (See "Initial treatment of limited stage (I/II) follicular lymphoma", section on 'Surveillance for relapse' and "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Long-term management'.)

Progressive disease (PD) or relapse after complete remission (CR) most commonly presents as asymptomatic enlargement of the lymph nodes, liver, or spleen. PD or relapse after CR reflects the appearance of any new lesion, a 50 percent increase in the longest diameter of a previously identified lesion, or new/recurrent involvement of the bone marrow (table 1). Not all patients with PD or relapsed disease require imaging studies or biopsy at the time of progression:

                        

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Literature review current through: Nov 2014. | This topic last updated: Oct 31, 2014.
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References
Top
  1. Ansell SM, Ristow KM, Habermann TM, et al. Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol 2002; 20:3885.
  2. Justice TE, Martenson JA, Wiseman GA, Witzig TE. Safety and efficacy of external beam radiation therapy for non-Hodgkin lymphoma in patients with prior 90Y-ibritumomab tiuxetan radioimmunotherapy. Cancer 2006; 107:433.
  3. Peyrade F, Italiano A, Fontana X, et al. Retreatment with 90Y-labelled ibritumomab tiuxetan in a patient with follicular lymphoma who had previously responded to treatment. Lancet Oncol 2007; 8:849.
  4. Dosik AD, Coleman M, Kostakoglu L, et al. Subsequent therapy can be administered after tositumomab and iodine I-131 tositumomab for non-Hodgkin lymphoma. Cancer 2006; 106:616.
  5. Genentech/Idec Rituxan letter warns of fatal mucocutaneous reactions. The Pink Sheet. F-D-C Reports. volume 63, number 21. May 21, 2001. p.32.
  6. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood 2013; 122:1137.
  7. Salles GA, Morschhauser F, Solal-Céligny P, et al. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol 2013; 31:2920.
  8. Foon KA, Sherwin SA, Abrams PG, et al. Treatment of advanced non-Hodgkin's lymphoma with recombinant leukocyte A interferon. N Engl J Med 1984; 311:1148.
  9. Rohatiner A, Radford J, Deakin D, et al. A randomized controlled trial to evaluate the role of interferon as initial and maintenance therapy in patients with follicular lymphoma. Br J Cancer 2001; 85:29.
  10. Smalley RV, Andersen JW, Hawkins MJ, et al. Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med 1992; 327:1336.
  11. 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. Groupe d'Etude des Lymphomes de l'Adulte. N Engl J Med 1993; 329:1608.
  12. Arranz R, García-Alfonso P, Sobrino P, et al. Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin's lymphoma: results from a prospective, multicenter trial with double randomization. J Clin Oncol 1998; 16:1538.
  13. Hagenbeek A, Carde P, Meerwaldt JH, et al. Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol 1998; 16:41.
  14. Solal-Céligny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol 1998; 16:2332.
  15. Rohatiner AZ, Gregory WM, Peterson B, et al. Meta-analysis to evaluate the role of interferon in follicular lymphoma. J Clin Oncol 2005; 23:2215.
  16. Aviles A, Duque G, Talavera A, Guzman R. Interferon alpha 2b as maintenance therapy in low grade malignant lymphoma improves duration of remission and survival. Leuk Lymphoma 1996; 20:495.
  17. Fisher RI, Dana BW, LeBlanc M, et al. Interferon alpha consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin's lymphoma: results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol 2000; 18:2010.
  18. Cheson BD. The curious case of the baffling biological. J Clin Oncol 2000; 18:2007.
  19. Davis TA, Grillo-López AJ, White CA, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000; 18:3135.
  20. 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.
  21. Lazzarino M, Arcaini L, Orlandi E, et al. Immunochemotherapy with rituximab, vincristine and 5-day cyclophosphamide for heavily pretreated follicular lymphoma. Oncology 2005; 68:146.
  22. 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.
  23. Davis TA, Maloney DG, Grillo-López AJ, et al. Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res 2000; 6:2644.
  24. Friedberg JW, Neuberg D, Gribben JG, et al. Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma. Br J Haematol 2002; 117:828.
  25. 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.
  26. 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.
  27. Rummel MJ, Al-Batran SE, Kim SZ, 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; 23:3383.
  28. Robinson KS, Williams ME, van der Jagt RH, et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol 2008; 26:4473.
  29. van Oers MH, 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; 108:3295.
  30. van Oers MH, Van Glabbeke M, Giurgea L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol 2010; 28:2853.
  31. Tam CS, Wolf M, Prince HM, et al. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer 2006; 106:2412.
  32. Sacchi S, Pozzi S, Marcheselli R, et al. Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma. Cancer 2007; 110:121.
  33. 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.
  34. Forstpointner R, Dreyling M, Repp R, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2004; 104:3064.
  35. de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol 2009; 27:5023.
  36. Baiocchi RA, Alinari L, Lustberg ME, et al. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer 2010.
  37. Coiffier B, Osmanov E, Hong X, et al. A Phase 3 Trial Comparing Bortezomib Plus Rituximab with Rituximab Alone In Patients with Relapsed, Rituximab-Naive or -Sensitive, Follicular Lymphoma (abstract 857). Blood 2010; 116.
  38. Coiffier B, Osmanov EA, Hong X, et al. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol 2011; 12:773.
  39. Salles G. Is there a role for bortezomib combinations in the management of patients with follicular lymphoma? J Clin Oncol 2011; 29:3349.
  40. Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011; 117:2807.
  41. Fowler N, Kahl BS, Lee P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol 2011; 29:3389.
  42. Cheson BD. Radioimmunotherapy of non-Hodgkin lymphomas. Blood 2003; 101:391.
  43. Leonard JP, Siegel JA, Goldsmith SJ. Comparative physical and pharmacologic characteristics of iodine-131 and yttrium-90: implications for radioimmunotherapy for patients with non-Hodgkin's lymphoma. Cancer Invest 2003; 21:241.
  44. Forero A, Weiden PL, Vose JM, et al. Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy for B-cell non-Hodgkin lymphoma. Blood 2004; 104:227.
  45. Hernandez MC, Knox SJ. Radiobiology of radioimmunotherapy: targeting CD20 B-cell antigen in non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 2004; 59:1274.
  46. Weigert O, Illidge T, Hiddemann W, Dreyling M. Recommendations for the use of yttrium-90 ibritumomab tiuxetan in malignant lymphoma. Cancer 2006; 107:686.
  47. Witzig TE, White CA, Wiseman GA, et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol 1999; 17:3793.
  48. US Food and Drug Administration. Drugs to be discontinued. http://www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm050794.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery#tositumomab (Accessed on February 25, 2014).
  49. Davis TA, Kaminski MS, Leonard JP, et al. The radioisotope contributes significantly to the activity of radioimmunotherapy. Clin Cancer Res 2004; 10:7792.
  50. Wiseman GA, Gordon LI, Multani PS, et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood 2002; 99:4336.
  51. Vose JM, Wahl RL, Saleh M, et al. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2000; 18:1316.
  52. Davies AJ, Rohatiner AZ, Howell S, et al. Tositumomab and iodine I 131 tositumomab for recurrent indolent and transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2004; 22:1469.
  53. Horning SJ, Younes A, Jain V, et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-cell lymphoma, progressive after rituximab. J Clin Oncol 2005; 23:712.
  54. Buchegger F, Antonescu C, Delaloye AB, et al. Long-term complete responses after 131I-tositumomab therapy for relapsed or refractory indolent non-Hodgkin's lymphoma. Br J Cancer 2006; 94:1770.
  55. Leahy MF, Seymour JF, Hicks RJ, Turner JH. Multicenter phase II clinical study of iodine-131-rituximab radioimmunotherapy in relapsed or refractory indolent non-Hodgkin's lymphoma. J Clin Oncol 2006; 24:4418.
  56. Fisher RI, Kaminski MS, Wahl RL, et al. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol 2005; 23:7565.
  57. Leahy MF, Turner JH. Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients. Blood 2011; 117:45.
  58. Gordon LI, Molina A, Witzig T, et al. Durable responses after ibritumomab tiuxetan radioimmunotherapy for CD20+ B-cell lymphoma: long-term follow-up of a phase 1/2 study. Blood 2004; 103:4429.
  59. Witzig TE, Molina A, Gordon LI, et al. Long-term responses in patients with recurring or refractory B-cell non-Hodgkin lymphoma treated with yttrium 90 ibritumomab tiuxetan. Cancer 2007; 109:1804.
  60. Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2001; 19:3918.
  61. Emmanouilides C, Witzig TE, Wiseman GA, et al. Safety and efficacy of yttrium-90 ibritumomab tiuxetan in older patients with non-Hodgkin's lymphoma. Cancer Biother Radiopharm 2007; 22:684.
  62. 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; 20:2453.
  63. Kaminski MS, Radford JA, Gregory SA, et al. Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who had previously responded to I-131 tositumomab. J Clin Oncol 2005; 23:7985.
  64. GSK to balance Bexxar expanded indication against lowered response rates. "The Pink Sheet" F-D-C Reports 2005; 67:9. January 10. Information also available on revised drug label.
  65. Bennett JM, Kaminski MS, Leonard JP, et al. Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and iodine I131 tositumomab. Blood 2005; 105:4576.
  66. Czuczman MS, Emmanouilides C, Darif M, et al. Treatment-related myelodysplastic syndrome and acute myelogenous leukemia in patients treated with ibritumomab tiuxetan radioimmunotherapy. J Clin Oncol 2007; 25:4285.
  67. Witzig TE, White CA, Gordon LI, et al. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J Clin Oncol 2003; 21:1263.
  68. Tennvall J, Fischer M, Bischof Delaloye A, et al. EANM procedure guideline for radio-immunotherapy for B-cell lymphoma with 90Y-radiolabelled ibritumomab tiuxetan (Zevalin). Eur J Nucl Med Mol Imaging 2007; 34:616.
  69. Dillman RO. Radiolabeled anti-CD20 monoclonal antibodies for the treatment of B-cell lymphoma. J Clin Oncol 2002; 20:3545.
  70. http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf (Accessed on July 24, 2013).
  71. Montoto S, Corradini P, Dreyling M, et al. Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-Lymphoma Working Party. Haematologica 2013; 98:1014.
  72. 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.
  73. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: an evidence-based review. Biol Blood Marrow Transplant 2010; 16:443.
  74. Ingram W, Devereux S, Das-Gupta EP, et al. Outcome of BEAM-autologous and BEAM-alemtuzumab allogeneic transplantation in relapsed advanced stage follicular lymphoma. Br J Haematol 2008; 141:235.
  75. Hosing C, Saliba RM, McLaughlin P, et al. Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma. Ann Oncol 2003; 14:737.
  76. van Besien K, Loberiza FR Jr, Bajorunaite R, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma. Blood 2003; 102:3521.
  77. 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; 48:1409.
  78. Evens AM, Vanderplas A, LaCasce AS, et al. Stem cell transplantation for follicular lymphoma relapsed/refractory after prior rituximab: a comprehensive analysis from the NCCN lymphoma outcomes project. Cancer 2013; 119:3662.
  79. Ganem G, Cartron G, Girinsky T, et al. Localized low-dose radiotherapy for follicular lymphoma: history, clinical results, mechanisms of action, and future outlooks. Int J Radiat Oncol Biol Phys 2010; 78:975.
  80. Rossier C, Schick U, Miralbell R, et al. Low-dose radiotherapy in indolent lymphoma. Int J Radiat Oncol Biol Phys 2011; 81:e1.
  81. Chan EK, Fung S, Gospodarowicz M, et al. Palliation by low-dose local radiation therapy for indolent non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2011; 81:e781.
  82. Russo AL, Chen YH, Martin NE, et al. Low-dose involved-field radiation in the treatment of non-hodgkin lymphoma: predictors of response and treatment failure. Int J Radiat Oncol Biol Phys 2013; 86:121.
  83. 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.
  84. 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.
  85. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf?et_cid=34165715&et_rid=789337055&linkid=http%3a%2f%2fwww.accessdata.fda.gov%2fdrugsatfda_docs%2flabel%2f2014%2f206545lbl.pdf (Accessed on July 23, 2014).
  86. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370:1008.
  87. Flinn IW, Kahl BS, Leonard JP, et al. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma. Blood 2014; 123:3406.