Current Oncology Reports

, Volume 11, Issue 5, pp 386–393

Second-line treatment paradigms for diffuse large B-cell lymphomas

Article

Abstract

Despite recent major advances in treating diffuse large B-cell lymphoma with dose-intense regimens and the addition of the anti-CD20 monoclonal antibody rituximab, a significant proportion of patients will experience early treatment failure, partial response, or relapse after initial chemotherapy. For more than 10 years, the standard treatment for chemosensitive relapses has been based on salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation in selected patients. However, several important questions remain: What is the best salvage regimen? What is the efficacy of rituximab in an era when R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is accepted as standard care for frontline therapy? What are the risk factors in second-line therapy? What is the best treatment when high-dose therapy and autologous stem cell transplantation are not possible? This article reviews all these issues and discusses new biologic therapies, with the knowledge that improvements in outcome may be achieved through a greater understanding of the biologic parameters associated with poorer prognosis.

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References and Recommended Reading

  1. 1.
    Pfreundschuh M, Trumper L, Kloess M, et al.: Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004, 104:634–641.PubMedCrossRefGoogle Scholar
  2. 2.
    Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002, 346:235–242.PubMedCrossRefGoogle Scholar
  3. 3.
    Feugier P, Van Hoof A, Sebban C, et al.: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005, 23:4117–4126.PubMedCrossRefGoogle Scholar
  4. 4.
    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 1995, 333:1540–1545.PubMedCrossRefGoogle Scholar
  5. 5.
    Bosly A, Coiffier B, Gisselbrecht C, et al.: Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen. J Clin Oncol 1992, 10:1615–1623.PubMedGoogle Scholar
  6. 6.
    Chau I, Webb A, Cunningham D, et al.: An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin’s lymphoma. Br J Haematol 2001, 115:786–792.PubMedCrossRefGoogle Scholar
  7. 7.
    Corazzelli G, Capobianco G, Arcamone M, et al.: Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol 2009 Feb 15 (Epub ahead of print).Google Scholar
  8. 8.
    El Gnaoui T, Dupuis J, Belhadj K, et al.: Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol 2007, 18:1363–1368.PubMedCrossRefGoogle Scholar
  9. 9.
    Gisselbrecht C, Glass B, Mounier N, et al.: R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell transplantation: CORAL study [abstract]. J Clin Oncol 2009, 27(15 Suppl):8509.Google Scholar
  10. 10.
    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 2004, 103:3684–3688.PubMedCrossRefGoogle Scholar
  11. 11.
    Lopez A, Gutierrez A, Palacios A, et al.: GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol 2008, 80:127–132.PubMedCrossRefGoogle Scholar
  12. 12.
    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 2008, 111:537–543.PubMedCrossRefGoogle Scholar
  13. 13.
    Martin A, Conde E, Arnan M, et al.: R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica 2008, 93:1829–1836.PubMedCrossRefGoogle Scholar
  14. 14.
    Khouri IF, Saliba RM, Hosing C, et al.: Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin’s lymphomas. J Clin Oncol 2005, 23:2240–2247.PubMedCrossRefGoogle Scholar
  15. 15.
    Horwitz SM, Negrin RS, Blume KG, et al.: Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood 2004, 103:777–783.PubMedCrossRefGoogle Scholar
  16. 16.
    Chen L, Monti S, Juszczynski P, et al.: SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma. Blood 2008, 111:2230–2237.PubMedCrossRefGoogle Scholar
  17. 17.
    Friedberg J, Sharman J, Schaefer-Cutillo J, et al.: Fostamatinib disodium (FosD), an oral inhibitor of Syk, is well-tolerated and has significant clinical activity in diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (SLL/CLL) [abstract]. Blood (ASH Annual Meeting Abstracts) 2008, 112:3.Google Scholar
  18. 18.
    Robertson MJ, Kahl BS, Vose JM, et al.: Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 2007, 25:1741–1746.PubMedCrossRefGoogle Scholar
  19. 19.
    Morschhauser F, Zinzani PL, Burgess M, et al.: Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar. 3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma 2007, 48:708–715.PubMedCrossRefGoogle Scholar
  20. 20.
    Park CM, Bruncko M, Adickes J, et al.: Discovery of an orally bioavailable small molecule inhibitor of prosurvival B-cell lymphoma 2 proteins. J Med Chem 2008, 51:6902–6915.PubMedCrossRefGoogle Scholar
  21. 21.
    Dean M, Fojo T, Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer 2005, 5:275–284.PubMedCrossRefGoogle Scholar
  22. 22.
    Cilley J, Winter JN: Radioimmunotherapy and autologous stem cell transplantation for the treatment of B-cell lymphomas. Haematologica 2006, 91:114–120.PubMedGoogle Scholar
  23. 23.
    Gisselbrecht C, Bethge W, Duarte RF, et al.: Current status and future perspectives for yttrium-90 ((90)Y)-ibritumomab tiuxetan in stem cell transplantation for non-Hodgkin’s lymphoma. Bone Marrow Transplant 2007, 40:1007–1017.PubMedCrossRefGoogle Scholar
  24. 24.
    Krishnan A, Nademanee A, Fung HC, et al.: Phase II trial of a transplantation regimen of yttrium-90 ibritumomab tiuxetan and high-dose chemotherapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2008, 26:90–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Shimoni A, Zwas ST, Oksman Y, et al.: Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin’s lymphoma. Exp Hematol 2007, 35:534–540.PubMedCrossRefGoogle Scholar
  26. 26.
    Chiesa C, Botta F, Di Betta E, et al.: Dosimetry in myeloablative (90)Y-labeled ibritumomab tiuxetan therapy: possibility of increasing administered activity on the base of biological effective dose evaluation. Preliminary results. Cancer Biother Radiopharm 2007, 22:113–120.PubMedCrossRefGoogle Scholar
  27. 27.
    Blay J, Gomez F, Sebban C, et al.: The International Prognostic Index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PARMA trial. Parma Group. Blood 1998, 92:3562–3568.PubMedGoogle Scholar
  28. 28.
    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 1998, 16:3264–3269.PubMedGoogle Scholar
  29. 29.
    Porrata LF, Ristow K, Habermann TM, et al.: Absolute lymphocyte count at the time of first relapse predicts survival in patients with diffuse large B-cell lymphoma. Am J Hematol 2009, 84:93–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Panovska-Stavridis I, Georgievski B, Cevreska L, et al.: Rituximab plus ICE regimen for relapsed and refractory aggressive non-Hodgkin lymphoma [abstract]. Haematologica 2004, 89(Suppl 1):763.Google Scholar
  31. 31.
    Obrlikova PO, Vackova B, Pylik R, et al.: Effects of pretransplantation treatment with rituximab on outcomes of autologous stem-cell transplantation for diffuse large B-cell lymphoma [abstract]. Haematologica 2006, 91:217.Google Scholar
  32. 32.
    Herishanu Y, Terstman S, Perri C, et al.: The combination of rituximab, etoposide, ifosfamide, and carboplatin (RICE) is safe and effective salvage therapy for elderly patients with aggressive non-Hodgkin’s lymphoma [abstract]. Haematologica 2005, 90:999.Google Scholar
  33. 33.
    Mey UJ, Olivieri A, Orlopp KS, et al.: DHAP in combination with rituximab vs DHAP alone as salvage treatment for patients with relapsed or refractory diffuse large B-cell lymphoma: a matched-pair analysis. Leuk Lymphoma 2006, 47:2558–2566.PubMedCrossRefGoogle Scholar
  34. 34.
    Shrestha S, Johnson C, Jain S, et al.: ESHAP +/- rituximab as salvage therapy for relapsed lymphoma prior to stem cell transplant: single institution experience [abstract]. Blood (ASH Annual Meeting Abstracts) 2004, 104:4601.Google Scholar
  35. 35.
    Venugopal P, Gretory SA, Showel J, et al.: Rituximab (Rituxan) combined with ESHAP chemotherapy is highly active in relapsed/refractory aggressive non-Hodgkin’s lymphoma [abstract]. Blood (ASH Annual Meeting Abstracts) 2004, 104:4636.Google Scholar
  36. 36.
    Hicks L, Buckstein R, Mangel J, et al.: Rituximab increases response to ESHAP in relapsed, refractory, and transformed aggressive B-cell lymphoma [abstract]. Blood (ASH Annual Meeting Abstracts) 2006, 108:3067.Google Scholar
  37. 37.
    Arnold C, Cuthbert R, Morris TCM, et al.: Rituximab-ESHAP as salvage therapy in relapsed aggressive B cell lymphoma [abstract]. Haematologica 2005, 90(Suppl 1):1146.Google Scholar
  38. 38.
    Bieker R, Kessler T, Berdel WE, Mesters RM: Rituximab in combination with platinum-containing chemotherapy in patients with relapsed or primary refractory diffuse large B-cell lymphoma. Oncol Rep 2003, 10:1915–1917.PubMedGoogle Scholar
  39. 39.
    Aydin S, Duhrsen U, Nuckel H: Rituximab plus ASHAP for the treatment of patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma: a single-centre study of 20 patients. Ann Hematol 2007, 86:271–276.PubMedCrossRefGoogle Scholar
  40. 40.
    Rupolo M, Spina M, Michieli M, et al.: R-DHAOX as salvage regimen in patients (pts) with relapsed/resistant non-Hodgkin’s lymphoma (NHL) [abstract]. Blood (ASH Annual Meeting Abstracts) 2004, 104:1323.Google Scholar
  41. 41.
    Wenger C, Stern M, Herrmann R, et al.: Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non Hodgkin’s lymphoma? Leuk Lymphoma 2005, 46:71–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Corazzelli G, Russo F, Capobianco G, et al.: Gemcitabine, ifosfamide, oxaliplatin and rituximab (R-GIFOX), a new effective cytoreductive/mobilizing salvage regimen for relapsed and refractory aggressive non-Hodgkin’s lymphoma: results of a pilot study. Ann Oncol 2006, 17(Suppl 4):iv18–iv24.PubMedCrossRefGoogle Scholar
  43. 43.
    Cabanillas F, Liboy I, Rodriguez-Monge E, et al.: A dose dense low toxicity salvage regimen for histologically aggressive non-Hodgkin’s lymphoma (NHL): gemcitabine, rituximab, oxaliplatin combination (GROC) plus pegfilgrastim [abstract]. J Clin Oncol 2006, 24(June 20 Suppl):17513.Google Scholar
  44. 44.
    Smith S, Toor A, Klein J, et al.: The combination of gallium nitrate, rituximab and dexamethasone is effective and safe as a salvage regimen for diffuse large B-cell lymphoma [abstract]. J Clin Oncol 2006, 24(June 20 Suppl):17510.Google Scholar
  45. 45.
    Strauss SJ, Morschhauser F, Rech J, et al.: Multicenter phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol 2006, 24:3880–3886.PubMedCrossRefGoogle Scholar
  46. 46.
    Niitsu N, Kohuri M, Higashihara M, Bessho M: Phase II study of the CPT-11, mitoxantrone and dexamethasone regimen in combination with rituximab in elderly patients with relapsed diffuse large B-cell lymphoma. Cancer Sci 2006, 97:933–937.PubMedCrossRefGoogle Scholar
  47. 47.
    Younes A, McLaughlin P, Romaguera J, et al.: Paclitaxel plus topotecan plus rituximab (TTR): an effective salvage program for the treatment of patients with relapsed/refractory aggressive B-cell non Hodgkin’s lymphoma [abstract 220]. Presented at the Ninth International Conference on Malignant Lymphoma (ICML). Lugano, Switzerland; June 8–11, 2005.Google Scholar
  48. 48.
    Canales M, Sanjurjo M, García-Vela J, et al.: Paclitaxel and topotecan in combination with rituximab as effective second-line salvage regimen in resistant aggressive non-Hodgkin’s lymphoma [abstract 494]. Presented at the Ninth International Conference on Malignant Lymphoma (ICML). Lugano, Switzerland; June 8–11, 2005.Google Scholar
  49. 49.
    Woehrer S, Hejna M, Skrabs C, et al.: Rituximab, Ara-C, dexamethasone and oxaliplatin is safe and active in heavily pretreated patients with diffuse large B-cell lymphoma. Oncology 2005, 69:499–502.PubMedCrossRefGoogle Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  1. 1.Hôpital Saint Louis, Hemato-OncologieInstitut Universitaire d’HématologieParisFrance

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