Skip to main content

Advertisement

SpringerLink
Log in

Management of Relapsed or Refractory Hodgkin Lymphoma with Second-Generation Antibody–Drug Conjugates: Focus on Brentuximab Vedotin

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Brentuximab vedotin (Adcetris, Seattle Genetics) is an antibody–drug conjugate (ADC) that joins an anti-CD 30 monoclonal antibody with the anti-tubulin agent monomethyl auristatin E via a dipeptide linker. It has demonstrated significant activity in CD 30-positive lymphomas and is currently approved by the US FDA for treatment of Hodgkin lymphoma that has relapsed following autologous stem-cell transplantation, or after two lines of chemotherapy in non-transplant candidates. Brentuximab vedotin has also been approved for the treatment of relapsed anaplastic large-cell lymphoma after front-line chemotherapy. We briefly review the biology of Hodgkin lymphoma, with a focus on the pathogenic role of CD 30 as well as the development of CD 30-targeted therapy. We also discuss both the current role of brentuximab vedotin in the management of relapsed and refractory Hodgkin lymphoma and the likely future developments for this agent.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kuppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9(1):15–27. doi:10.1038/nrc2542.

    Article  PubMed  Google Scholar 

  2. Diehl V, Sextro M, Franklin J, Hansmann ML, Harris N, Jaffe E, et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease. J Clin Oncol. 1999;17(3):776–83.

    CAS  PubMed  Google Scholar 

  3. Cossman J, Annunziata CM, Barash S, Staudt L, Dillon P, He WW, et al. Reed–Sternberg cell genome expression supports a B-cell lineage. Blood. 1999;94(2):411–6.

    CAS  PubMed  Google Scholar 

  4. Marafioti T, Hummel M, Foss HD, Laumen H, Korbjuhn P, Anagnostopoulos I, et al. Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood. 2000;95(4):1443–50.

    CAS  PubMed  Google Scholar 

  5. Schmid C, Pan L, Diss T, Isaacson PG. Expression of B-cell antigens by Hodgkin’s and Reed–Sternberg cells. Am J Pathol. 1991;139(4):701–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Foss HD, Reusch R, Demel G, Lenz G, Anagnostopoulos I, Hummel M, et al. Frequent expression of the B-cell-specific activator protein in Reed–Sternberg cells of classical Hodgkin’s disease provides further evidence for its B-cell origin. Blood. 1999;94(9):3108–13.

    CAS  PubMed  Google Scholar 

  7. Schwarzer R, Dorken B, Jundt F. Notch is an essential upstream regulator of NF-kappaB and is relevant for survival of Hodgkin and Reed–Sternberg cells. Leukemia. 2012;26(4):806–13. doi:10.1038/leu.2011.265.

    Article  CAS  PubMed  Google Scholar 

  8. Re D, Muschen M, Ahmadi T, Wickenhauser C, Staratschek-Jox A, Holtick U, et al. Oct-2 and Bob-1 deficiency in Hodgkin and Reed Sternberg cells. Cancer Res. 2001;61(5):2080–4.

    CAS  PubMed  Google Scholar 

  9. Torlakovic E, Tierens A, Dang HD, Delabie J. The transcription factor PU.1, necessary for B-cell development is expressed in lymphocyte predominance, but not classical Hodgkin’s disease. Am J Pathol. 2001;159(5):1807–14. doi:10.1016/S0002-9440(10)63027-1.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Mathas S, Janz M, Hummel F, Hummel M, Wollert-Wulf B, Lusatis S, et al. Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol. 2006;7(2):207–15. doi:10.1038/ni1285.

    Article  CAS  PubMed  Google Scholar 

  11. Küppers R. New insights in the biology of Hodgkin lymphoma. ASH Educ Program Book. 2012;2012(1):328–34. doi:10.1182/asheducation-2012.1.328.

    Google Scholar 

  12. Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. The classical Hodgkin’s lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol. 2010;221(3):248–63. doi:10.1002/path.2711.

    Article  CAS  PubMed  Google Scholar 

  13. Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. J Clin Oncol. 2011;29(14):1812–26. doi:10.1200/JCO.2010.32.8401.

    Article  CAS  PubMed  Google Scholar 

  14. Armitage JO. Early-Stage Hodgkin’s Lymphoma. N Engl J Med. 2010;363(7):653–62. doi:10.1056/NEJMra1003733.

    Article  CAS  PubMed  Google Scholar 

  15. Moccia AA, Donaldson J, Chhanabhai M, Hoskins PJ, Klasa RJ, Savage KJ, et al. International prognostic score in advanced-stage Hodgkin’s lymphoma: altered utility in the modern era. J Clin Oncol. 2012;30(27):3383–8. doi:10.1200/JCO.2011.41.0910.

    Article  PubMed  Google Scholar 

  16. Bonadonna G, Zucali R, Monfardini S, De Lena M, Uslenghi C. Combination chemotherapy of Hodgkin’s disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer. 1975;36(1):252–9.

    Article  CAS  PubMed  Google Scholar 

  17. Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, et al. ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med. 2011;365(3):203–12. doi:10.1056/NEJMoa1100340.

    Article  CAS  PubMed  Google Scholar 

  18. Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, et al. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992;327(21):1478–84. doi:10.1056/NEJM199211193272102.

    Article  CAS  PubMed  Google Scholar 

  19. Gordon LI, Hong F, Fisher RI, Bartlett NL, Connors JM, Gascoyne RD, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31(6):684–91. doi:10.1200/JCO.2012.43.4803.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Kuruvilla J, Keating A, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood. 2011;117(16):4208–17. doi:10.1182/blood-2010-09-288373.

    Article  CAS  PubMed  Google Scholar 

  21. Moskowitz AJ, Perales MA, Kewalramani T, Yahalom J, Castro-Malaspina H, Zhang Z, et al. Outcomes for patients who fail high dose chemoradiotherapy and autologous stem cell rescue for relapsed and primary refractory Hodgkin lymphoma. Br J Haematol. 2009;146(2):158–63. doi:10.1111/j.1365-2141.2009.07727.x.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Sureda A, Canals C, Arranz R, Caballero D, Ribera JM, Brune M et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin’s lymphoma. Results of the HDR-ALLO study—a prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Medula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2012;97(2):310–7. doi:10.3324/haematol.2011.045757.

  23. von Wasielewski R, Mengel M, Fischer R, Hansmann ML, Hubner K, Franklin J, et al. Classical Hodgkin’s disease. Clinical impact of the immunophenotype. Am J Pathol. 1997;151(4):1123–30.

    Google Scholar 

  24. Durkop H, Foss HD, Eitelbach F, Anagnostopoulos I, Latza U, Pileri S, et al. Expression of the CD 30 antigen in non-lymphoid tissues and cells. J Pathol. 2000;190(5):613–8. doi:10.1002/(SICI)1096-9896(200004)190:5<613:AID-PATH559>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  25. Falini B, Pileri S, Pizzolo G, Durkop H, Flenghi L, Stirpe F, et al. CD 30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85(1):1–14.

    CAS  PubMed  Google Scholar 

  26. Aizawa S, Nakano H, Ishida T, Horie R, Nagai M, Ito K, et al. Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD 30-mediated NFkappaB activation. J Biol Chem. 1997;272(4):2042–5.

    Article  CAS  PubMed  Google Scholar 

  27. Baker SJ, Reddy EP. Modulation of life and death by the TNF receptor superfamily. Oncogene. 1998;17(25):3261–70. doi:10.1038/sj.onc.1202568.

    Article  PubMed  Google Scholar 

  28. Duckett CS, Thompson CB. CD 30-dependent degradation of TRAF2: implications for negative regulation of TRAF signaling and the control of cell survival. Genes Dev. 1997;11(21):2810–21.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Ho DS, REa AJ, Abraham LJ. Functional aspects of the CD 30 gene in Hodgkin’s lymphoma and anaplastic large cell lymphoma. Oncol Rev. 2009;3:89–101.

    Article  Google Scholar 

  30. Hirsch B, Hummel M, Bentink S, Fouladi F, Spang R, Zollinger R, et al. CD 30-induced signaling is absent in Hodgkin’s cells but present in anaplastic large cell lymphoma cells. Am J Pathol. 2008;172(2):510–20. doi:10.2353/ajpath.2008.070858.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Bartlett NL, Younes A, Carabasi MH, Forero A, Rosenblatt JD, Leonard JP, et al. A phase 1 multidose study of SGN-30 immunotherapy in patients with refractory or recurrent CD 30+ hematologic malignancies. Blood. 2008;111(4):1848–54. doi:10.1182/blood-2007-07-099317.

    Article  CAS  PubMed  Google Scholar 

  32. Forero-Torres A, Leonard JP, Younes A, Rosenblatt JD, Brice P, Bartlett NL, et al. A Phase II study of SGN-30 (anti-CD 30 mAb) in Hodgkin lymphoma or systemic anaplastic large cell lymphoma. Br J Haematol. 2009;146(2):171–9. doi:10.1111/j.1365-2141.2009.07740.x.

    Article  CAS  PubMed  Google Scholar 

  33. Ansell SM, Horwitz SM, Engert A, Khan KD, Lin T, Strair R, et al. Phase I/II study of an anti-CD 30 monoclonal antibody (MDX-060) in Hodgkin’s lymphoma and anaplastic large-cell lymphoma. J Clin Oncol. 2007;25(19):2764–9. doi:10.1200/JCO.2006.07.8972.

    Article  CAS  PubMed  Google Scholar 

  34. Schnell R, Dietlein M, Staak JO, Borchmann P, Schomaecker K, Fischer T, et al. Treatment of refractory Hodgkin’s lymphoma patients with an iodine-131-labeled murine anti-CD 30 monoclonal antibody. J Clin Oncol. 2005;23(21):4669–78. doi:10.1200/JCO.2005.09.098.

    Article  CAS  PubMed  Google Scholar 

  35. Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H, et al. Response of refractory Hodgkin’s disease to monoclonal anti-CD 30 immunotoxin. Lancet. 1992;339(8803):1195–6.

    Article  CAS  PubMed  Google Scholar 

  36. Schnell R, Staak O, Borchmann P, Schwartz C, Matthey B, Hansen H, et al. A phase I study with an anti-CD 30 ricin A-chain immunotoxin (Ki-4.dgA) in patients with refractory CD 30+ Hodgkin’s and non-Hodgkin’s lymphoma. Clin Cancer Res. 2002;8(6):1779–86.

    CAS  PubMed  Google Scholar 

  37. Hartmann F, Renner C, Jung W, da Costa L, Tembrink S, Held G, et al. Anti-CD16/CD 30 bispecific antibody treatment for Hodgkin’s disease: role of infusion schedule and costimulation with cytokines. Clin Cancer Res. 2001;7(7):1873–81.

    CAS  PubMed  Google Scholar 

  38. Brentuximab vedotin. Drugs R D. 2011;11(1):85–95. doi:10.2165/11591070-000000000-00000.

  39. Sanderson RJ, Hering MA, James SF, Sun MM, Doronina SO, Siadak AW, et al. In vivo drug-linker stability of an anti-CD 30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11(2 Pt 1):843–52.

    CAS  PubMed  Google Scholar 

  40. Bai R, Pettit GR, Hamel E. Dolastatin 10, a powerful cytostatic peptide derived from a marine animal. Inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol. 1990;39(12):1941–9.

    Article  CAS  PubMed  Google Scholar 

  41. Perez EA, Hillman DW, Fishkin PA, Krook JE, Tan WW, Kuriakose PA, et al. Phase II trial of dolastatin-10 in patients with advanced breast cancer. Invest New Drugs. 2005;23(3):257–61. doi:10.1007/s10637-005-6735-y.

    Article  CAS  PubMed  Google Scholar 

  42. von Mehren M, Balcerzak SP, Kraft AS, Edmonson JH, Okuno SH, Davey M, et al. Phase II trial of dolastatin-10, a novel anti-tubulin agent, in metastatic soft tissue sarcomas. Sarcoma. 2004;8(4):107–11. doi:10.1080/13577140400009163.

    Article  Google Scholar 

  43. Saad ED, Kraut EH, Hoff PM, Moore DF Jr, Jones D, Pazdur R, et al. Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer. Am J Clin Oncol. 2002;25(5):451–3.

    Article  PubMed  Google Scholar 

  44. Senter PD, Sievers EL. The discovery and development of brentuximab vedotin for use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. Nat Biotechnol. 2012;30(7):631–7. doi:10.1038/nbt.2289.

    Article  CAS  PubMed  Google Scholar 

  45. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778–84. doi:10.1038/nbt832.

    Article  CAS  PubMed  Google Scholar 

  46. Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD 30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458–65. doi:10.1182/blood-2003-01-0039.

    Article  CAS  PubMed  Google Scholar 

  47. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL, et al. Brentuximab vedotin (SGN-35) for relapsed CD 30-positive lymphomas. N Engl J Med. 2010;363(19):1812–21. doi:10.1056/NEJMoa1002965.

    Article  CAS  PubMed  Google Scholar 

  48. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183–9. doi:10.1200/jco.2011.38.0410.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Bartlett N, Brice P, Chen RW, Fanale MA, Gopal AK, Matous J, et al. Retreatment with brentuximab vedotin in CD 30-positive hematologic malignancies: a phase II study. ASCO Meeting Abstr. 2012;30((15_suppl)):8027.

    Google Scholar 

  50. Chen R, Palmer JM, Thomas SH, Tsai NC, Farol L, Nademanee A, et al. Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2012;119(26):6379–81. doi:10.1182/blood-2012-03-418673.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Gibb A, Jones C, Bloor A, Kulkarni S, Illidge T, Linton K, et al. Brentuximab vedotin in refractory CD 30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center. Haematologica. 2013;98(4):611–4. doi:10.3324/haematol.2012.069393.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Gopal AK, Ramchandren R, O’Connor OA, Berryman RB, Advani RH, Chen R, et al. Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood. 2012;120(3):560–8. doi:10.1182/blood-2011-12-397893.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  53. van de Donk NW, Dhimolea E. Brentuximab vedotin. MAbs. 2012;4(4):458–65. doi:10.4161/mabs.20230.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Nathwani N, Krishnan AY, Huang Q, Kim Y, Karanes C, Smith EP, et al. Persistence of CD 30 expression in Hodgkin lymphoma following brentuximab vedotin (SGN-35) treatment failure. Leuk Lymphoma. 2012;53(10):2051–3. doi:10.3109/10428194.2012.666543.

    Article  CAS  PubMed  Google Scholar 

  55. Ansell SM, Connors JM, Park SI, O’Meara MM, Younes A. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. ASH Annu Meeting Abstr. 2012;120(21):798.

    Google Scholar 

Download references

Acknowledgments and Disclosures

Dr. Robert Chen is a consultant and speaker for Seattle Genetics and has received research funding from Seattle Genetics. RC is supported by the National Cancer Institute of the National Institutes of Health under award number K12CA001727. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA

    Matthew Mei, Sandra Thomas & Robert Chen

Authors
  1. Matthew Mei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mei, M., Thomas, S. & Chen, R. Management of Relapsed or Refractory Hodgkin Lymphoma with Second-Generation Antibody–Drug Conjugates: Focus on Brentuximab Vedotin. BioDrugs 28, 245–251 (2014). https://doi.org/10.1007/s40259-013-0077-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-013-0077-7

Keywords

Search

Navigation