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Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

Treatment for Aggressive, Recurrent Adult NHL

Standard Treatment Options for Aggressive, Recurrent Adult NHL

Standard treatment options for aggressive, recurrent adult non-Hodgkin lymphoma (NHL) include the following:

Bone marrow or stem cell transplantation

Bone marrow transplantation (BMT) is the treatment of choice for patients whose lymphoma has relapsed.[1] Preliminary studies indicate that approximately 20% to 40% of patients will have a long-term disease-free status, but the precise percentage depends on patient selection and the specific treatment used. Preparative drug regimens have varied; some investigators also use total-body irradiation. Similar success has been achieved using autologous marrow, with or without marrow purging, and allogeneic marrow.[2-6]

Evidence (BMT):

  1. In a prospective, randomized study, (EORTC-PARMA), 215 patients in first or second relapse of aggressive lymphoma, younger than 60 years, and with no bone marrow or central nervous system involvement, were given two cycles of intensive combination chemotherapy. The 109 patients who responded were randomly assigned to receive four more cycles of chemotherapy and involved-field radiation therapy (IF-XRT) versus autologous BMT followed by IF-XRT. With a 5-year median follow-up, the event-free survival (EFS) was significantly improved with transplantation (46% vs. 12%). Overall survival (OS) was also significantly better with transplantation (53% vs. 32%).[7][Level of evidence: 1iiA] Salvage BMT was unsuccessful for patients on the nontransplant arm whose disease relapsed.

    In general, patients who responded to initial therapy and who responded to conventional therapy for relapse prior to the BMT have had the best results.[8]

  2. In a prospective trial, patients who relapsed late (>12 months after diagnosis) had better OS than patients who relapsed earlier (8-year survival was 29% vs. 13%, P = .001).[9][Level of evidence: 3iiiA]

Peripheral stem cell transplantation (SCT) has yielded results equivalent to standard autologous transplantation.[10,11] Even patients who never experienced complete remission with conventional chemotherapy may have prolonged progression-free survival (31% at 5 years) after high-dose chemotherapy and hematopoietic SCT if they retain chemosensitivity to reinduction therapy.[12][Level of evidence: 3iiiDiii] Some patients who relapse after a previous autologous transplantation can have durable remissions after myeloablative or nonmyeloablative allogeneic SCT.[13,14]; [15][Level of evidence: 3iiiDiv]

Evidence (peripheral SCT):

  • In a randomized prospective trial, 396 patients with diffuse large B-cell lymphoma in first relapse or who were refractory to first-line therapy received either R-ICE (rituximab, ifosfamide, etoposide, and carboplatin) or R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) followed by autologous SCT; there was no difference in 3-year EFS or OS.[16][Level of evidence: 1iiA]

Re-treatment with standard agents

In general, re-treatment with standard agents rarely produces a cure in patients whose lymphomas relapse.[17] Several salvage chemotherapy regimens are available.[18-20]

  • Rituximab alone can induce responses in 33% of patients with relapsing aggressive lymphoma of appropriate phenotype (CD20-positive).[21]; [22][Level of evidence: 3iiiDiv]
  • Radiolabeled anti-CD20 monoclonal antibodies, such as iodine-131 tositumomab (no longer commercially available) and yttrium-90 ibritumomab, induce 60% to 80% response rates in patients with relapsed or refractory B-cell lymphoma.[23,24]; [25][Level of evidence: 3iiiDiv]
  • Denileukin diftitox, a fusion protein combining diphtheria toxin and interleukin-2, resulted in a 25% objective response rate in 45 heavily pretreated patients, as evidenced in E-1497 (NCT00003615), for example, with aggressive B-cell NHL (CD25, i.e., interleukin-2 receptor, expression was not correlated with response).[26][Level of evidence: 3iiiDiv]
  • In two phase II trials, 49 patients showed a 19% to 35% overall response rate to lenalidomide with or without rituximab.[27,28][Level of evidence: 3iiiDiv]

Durable responses to radiolabeled monoclonal antibodies have been reported for transformed low-grade B-cell lymphoma.[23,24] Not infrequently, an aggressive lymphoma may relapse as a small cell (indolent) lymphoma. Such a situation occurs with indolent lymphoma in the bone marrow and aggressive lymphoma in a nodal site. Patients may present in such a manner, and chemotherapy might successfully eradicate the peripheral disease while failing to eliminate the small cell component from the bone marrow. The clinical significance and natural history of this pattern of disease is not well defined.

Palliative radiation therapy

In general, patients with aggressive lymphoma who relapse with indolent histology will benefit from palliative therapy.[29] Palliation may be achieved with very low-dose (4 Gy) IF-XRT for patients with indolent and aggressive relapsed disease.[30]

Treatment Options Under Clinical Evaluation for Aggressive, Recurrent Adult NHL

Treatment options under clinical evaluation include the following:

  • SCT. The indolent lymphomas may relapse with an aggressive histology (i.e., histologic conversion). The durability of the second remission may be short, and clinical trials, such as autologous or allogeneic peripheral SCT, should be considered.[31-34]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with aggressive, recurrent adult non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.


  1. Shipp MA, Abeloff MD, Antman KH, et al.: International Consensus Conference on high-dose therapy with hematopoietic stem-cell transplantation in aggressive non-Hodgkin's lymphomas: report of the jury. Ann Oncol 10 (1): 13-9, 1999. [PUBMED Abstract]
  2. Freedman AS, Takvorian T, Anderson KC, et al.: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol 8 (5): 784-91, 1990. [PUBMED Abstract]
  3. Phillips GL, Fay JW, Herzig RH, et al.: The treatment of progressive non-Hodgkin's lymphoma with intensive chemoradiotherapy and autologous marrow transplantation. Blood 75 (4): 831-8, 1990. [PUBMED Abstract]
  4. Chopra R, Goldstone AH, Pearce R, et al.: Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data. J Clin Oncol 10 (11): 1690-5, 1992. [PUBMED Abstract]
  5. Ratanatharathorn V, Uberti J, Karanes C, et al.: Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma. Blood 84 (4): 1050-5, 1994. [PUBMED Abstract]
  6. Mills W, Chopra R, McMillan A, et al.: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin's lymphoma. J Clin Oncol 13 (3): 588-95, 1995. [PUBMED Abstract]
  7. Philip T, Guglielmi C, Hagenbeek A, et al.: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333 (23): 1540-5, 1995. [PUBMED Abstract]
  8. Vellenga E, van Putten WL, van 't Veer MB, et al.: Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood 111 (2): 537-43, 2008. [PUBMED Abstract]
  9. Guglielmi C, Gomez F, Philip T, et al.: Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol 16 (10): 3264-9, 1998. [PUBMED Abstract]
  10. Vose JM, Anderson JR, Kessinger A, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma. J Clin Oncol 11 (10): 1846-51, 1993. [PUBMED Abstract]
  11. Liberti G, Pearce R, Taghipour G, et al.: Comparison of peripheral blood stem-cell and autologous bone marrow transplantation for lymphoma patients: a case-controlled analysis of the EBMT Registry data. Lymphoma Working Party of the EBMT. Ann Oncol 5 (Suppl 2): 151-3, 1994. [PUBMED Abstract]
  12. Vose JM, Zhang MJ, Rowlings PA, et al.: Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 19 (2): 406-13, 2001. [PUBMED Abstract]
  13. van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011. [PUBMED Abstract]
  14. Freytes CO, Loberiza FR, Rizzo JD, et al.: Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry. Blood 104 (12): 3797-803, 2004. [PUBMED Abstract]
  15. Rezvani AR, Norasetthada L, Gooley T, et al.: Non-myeloablative allogeneic haematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience. Br J Haematol 143 (3): 395-403, 2008. [PUBMED Abstract]
  16. Gisselbrecht C, Glass B, Mounier N, et al.: Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 28 (27): 4184-90, 2010. [PUBMED Abstract]
  17. Larouche JF, Berger F, Chassagne-Clément C, et al.: Lymphoma recurrence 5 years or later following diffuse large B-cell lymphoma: clinical characteristics and outcome. J Clin Oncol 28 (12): 2094-100, 2010. [PUBMED Abstract]
  18. Rodriguez MA, Cabanillas FC, Velasquez W, et al.: Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol 13 (7): 1734-41, 1995. [PUBMED Abstract]
  19. Rizzieri DA, Sand GJ, McGaughey D, et al.: Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma. Cancer 100 (11): 2408-14, 2004. [PUBMED Abstract]
  20. Kewalramani T, Zelenetz AD, Nimer SD, et al.: Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood 103 (10): 3684-8, 2004. [PUBMED Abstract]
  21. Coiffier B, Haioun C, Ketterer N, et al.: Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92 (6): 1927-32, 1998. [PUBMED Abstract]
  22. Tobinai K, Igarashi T, Itoh K, et al.: Japanese multicenter phase II and pharmacokinetic study of rituximab in relapsed or refractory patients with aggressive B-cell lymphoma. Ann Oncol 15 (5): 821-30, 2004. [PUBMED Abstract]
  23. 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 23 (30): 7565-73, 2005. [PUBMED Abstract]
  24. 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 20 (10): 2453-63, 2002. [PUBMED Abstract]
  25. 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 99 (12): 4336-42, 2002. [PUBMED Abstract]
  26. Dang NH, Hagemeister FB, Pro B, et al.: Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma. J Clin Oncol 22 (20): 4095-102, 2004. [PUBMED Abstract]
  27. Zinzani PL, Pellegrini C, Gandolfi L, et al.: Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk 11 (6): 462-6, 2011. [PUBMED Abstract]
  28. Wiernik PH, Lossos IS, Tuscano JM, et al.: Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 26 (30): 4952-7, 2008. [PUBMED Abstract]
  29. Lee AY, Connors JM, Klimo P, et al.: Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B. J Clin Oncol 15 (5): 1745-53, 1997. [PUBMED Abstract]
  30. Haas RL, Poortmans P, de Jong D, et al.: Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 41 (12): 1724-30, 2005. [PUBMED Abstract]
  31. Yuen AR, Kamel OW, Halpern J, et al.: Long-term survival after histologic transformation of low-grade follicular lymphoma. J Clin Oncol 13 (7): 1726-33, 1995. [PUBMED Abstract]
  32. Bastion Y, Sebban C, Berger F, et al.: Incidence, predictive factors, and outcome of lymphoma transformation in follicular lymphoma patients. J Clin Oncol 15 (4): 1587-94, 1997. [PUBMED Abstract]
  33. Williams CD, Harrison CN, Lister TA, et al.: High-dose therapy and autologous stem-cell support for chemosensitive transformed low-grade follicular non-Hodgkin's lymphoma: a case-matched study from the European Bone Marrow Transplant Registry. J Clin Oncol 19 (3): 727-35, 2001. [PUBMED Abstract]
  34. Tsimberidou AM, O'Brien S, Khouri I, et al.: Clinical outcomes and prognostic factors in patients with Richter's syndrome treated with chemotherapy or chemoimmunotherapy with or without stem-cell transplantation. J Clin Oncol 24 (15): 2343-51, 2006. [PUBMED Abstract]
  • Updated: February 13, 2015