Skip to main content

Advertisement

Log in

Where Do the New Drugs Fit in for Relapsed/Refractory Hodgkin Lymphoma?

  • B-cell NHL, T-cell NHL, and Hodgkin Lymphoma (D Persky, Section Editor)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

The standard approach for relapsed or refractory (rel/ref) Hodgkin lymphoma (HL) following frontline treatment failure is salvage therapy followed by consolidation with high-dose therapy and autologous stem cell transplant (HDT/ASCT). While this overall treatment paradigm has been in place for several decades, recent studies have aimed to improve the efficacy and tolerability of salvage therapies by incorporating newer drugs, such as brentuximab vedotin (BV) and checkpoint inhibitors. Following HDT/ASCT, survival is improved due to the availability of BV and the checkpoint inhibitors, nivolumab and pembrolizumab; however, for patients responding to checkpoint inhibition, the appropriate length of treatment and the role of allogeneic stem cell transplant are unclear. In this review, we discuss our management of rel/ref HL, with particular focus on how BV, nivolumab, and pembrolizumab are currently incorporated into the treatment paradigms for rel/ref HL.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. 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.

    Article  CAS  PubMed  Google Scholar 

  2. Linch DC, Winfield D, Goldstone AH. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin's disease: results of a BNLI randomised trial. Lancet. 1993;341(8852):1051–4.

    Article  CAS  PubMed  Google Scholar 

  3. Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359(9323):2065–71.

    Article  CAS  PubMed  Google Scholar 

  4. Alperovich A, Younes A. Targeting CD30 using brentuximab vedotin in the treatment of Hodgkin lymphoma. Cancer J (Sudbury, Mass). 2016;22(1):23–6.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016;128(12):1562–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Moskowitz AJ, Schoder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study. Lancet Oncol. 2015;16(3):284–92.

    Article  CAS  PubMed  Google Scholar 

  8. Keir M, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.

    Article  CAS  PubMed  Google Scholar 

  9. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4.

    Article  CAS  PubMed  Google Scholar 

  10. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O'Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O'Donnell E, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res Off J Am Assoc Cancer Res. 2012;18(6):1611–8.

    Article  CAS  Google Scholar 

  12. •• Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283–94. This study led to FDA approval for nivolumab in HL after failed treatment with autologous SCT and brentuximab vedoitin

  13. •• Moskowitz CH, Zinzani PL, Fanale MA, Armand P, Johnson NA, Radford JA, et al. Pembrolizumab in relapsed/refractory classical Hodgkin lymphoma: primary end point analysis of the phase 2 keynote-087 study. Blood. 2016 2016-12-02;128:1107. en. This study led to FDA approval for pembrolizumab in HL for patients who have failed three or more prior lines of therapy.

  14. Cassaday RD, Fromm J, Cowan AJ, Libby EN, Philip M, Behnia S, et al. Safety and activity of brentuximab vedotin (BV) plus ifosfamide, carboplatin, and etoposide (ICE) for relapsed/refractory (rel/ref) classical Hodgkin lymphoma (cHL): initial results of a phase I/II trial. Blood. 2016;128(22):1834.

    Google Scholar 

  15. Moskowitz CH, Matasar MJ, Zelenetz AD, Nimer SD, Gerecitano J, Hamlin P, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Moccia AA, Hitz F, Hoskins P, Klasa R, Power MM, Savage KJ, et al. Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma. Leuk Lymphoma. 2017;58(2):324–32.

    Article  CAS  PubMed  Google Scholar 

  17. Abali H, Urun Y, Oksuzoglu B, Budakoglu B, Yildirim N, Guler T, et al. Comparison of ICE (ifosfamide-carboplatin-etoposide) versus DHAP (cytosine arabinoside-cisplatin-dexamethasone) as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Investig. 2008;26(4):401–6.

    Article  CAS  Google Scholar 

  18. Balzarotti M, Brusamolino E, Angelucci E, Carella AM, Vitolo U, Russo E, et al. B-IGEV (bortezomib plus IGEV) versus IGEV before high-dose chemotherapy followed by autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: a randomized, phase II trial of the Fondazione Italiana Linfomi (FIL). Leuk Lymphoma. 2016;57(10):2375–81.

    Article  CAS  PubMed  Google Scholar 

  19. Gentzler RD, Evens AM, Rademaker AW, Weitner BB, Mittal BB, Dillehay GL, et al. F-18 FDG-PET predicts outcomes for patients receiving total lymphoid irradiation and autologous blood stem-cell transplantation for relapsed and refractory Hodgkin lymphoma. Br J Haematol. 2014;165(6):793–800.

    Article  CAS  PubMed  Google Scholar 

  20. Akhtar S, Al-Sugair AS, Abouzied M, Alkadhi Y, Dingle M, Abdelsalam M, et al. Pre-transplant FDG-PET-based survival model in relapsed and refractory Hodgkin's lymphoma: outcome after high-dose chemotherapy and auto-SCT. Bone Marrow Transplant. 2013;48(12):1530–6.

    Article  CAS  PubMed  Google Scholar 

  21. Devillier R, Coso D, Castagna L, Brenot Rossi I, Anastasia A, Chiti A, et al. Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin's lymphoma responding to prior salvage therapy. Haematologica. 2012;97(7):1073–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Smeltzer JP, Cashen AF, Zhang Q, Homb A, Dehdashti F, Abboud CN, et al. Prognostic significance of FDG-PET in relapsed or refractory classical Hodgkin lymphoma treated with standard salvage chemotherapy and autologous stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17(11):1646–52.

    Article  Google Scholar 

  23. Mocikova H, Pytlik R, Markova J, Steinerova K, Kral Z, Belada D, et al. Pre-transplant positron emission tomography in patients with relapsed Hodgkin lymphoma. Leukemia & lymphoma. 2011;52(9):1668–74.

    Article  Google Scholar 

  24. Jabbour E, Hosing C, Ayers G, Nunez R, Anderlini P, Pro B, et al. Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer. 2007;109(12):2481–9.

    Article  PubMed  Google Scholar 

  25. Moskowitz AJ, Yahalom J, Kewalramani T, Maragulia JC, Vanak JM, Zelenetz AD, et al. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116(23):4934–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Moskowitz AJ, Schöder H, Yahlom J, McCall SJ, Fox SY, Gerecitano J, et al. PET-adapted therapy with brentuximab vedotin and augmented ICE for relapsed/refractory Hodgkin lymphoma—lack of improvement with 3 versus 2 cycles of weekly brentuximab vedotin. Haematologica. 2016;101(s5):10th International symposium on Hodgkin lymphoma.

  27. Chen R, Palmer JM, Martin P, Tsai N, Kim Y, Chen BT, et al. Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin lymphoma. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2015;21(12):2136–40.

    Article  CAS  Google Scholar 

  28. Chen R, Palmer J, Martin P, Armenian S, Tsai N, Mott M, et al. Post transplant outcome of a multicenter phase II study of brentuximab vedotin as first line salvage therapy in relapsed/refractory HL prior to AHCT. 2015 2015-12-03. en.

  29. LaCasce AS, Bociek G, Sawas A, Caimi PF, Agura E, Matous J, et al. Brentuximab vedotin plus bendamustine: a highly active salvage treatment regimen for patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;126(23):3982.

    Google Scholar 

  30. Garcia-Sanz R, Sureda A, Gonzalez AP, De la Cruz F, Sanchez-Gonzalez B, Rodriguez A, et al. Brentuximab vedotin plus ESHAP (BRESHAP) is a highly effective combination for inducing remission in refractory and relapsed Hodgkin lymphoma patients prior to autologous stem cell transplant: a trial of the Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO). Blood. 2016;128(22):1109.

    Google Scholar 

  31. Hagenbeek A, Zijlstra J, Lugtenburg P, van Imhoff G, Hutchings M, Liu R, et al. Transplant BRaVE: combining brentuximab vedotin with DHAP as salvage treatment in relapsed/refractory Hodgkin lymphoma, a phase 1 dose-escalation study Haematologica. 2016;101(s5):10th International Symposium on Hodgkin Lymphoma.

  32. Herrera AF, Bartlett NL, Ramchandren R, Vose JM, Moskowitz AJ, Feldman TA, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2016;128(22):1105.

    Google Scholar 

  33. Santoro A, Mazza R, Pulsoni A, Re A, Bonfichi M, Zilioli VR, et al. Bendamustine in combination with gemcitabine and vinorelbine is an effective regimen as induction chemotherapy before autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma: final results of a multicenter phase II study. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(27):3293–9.

    Article  CAS  Google Scholar 

  34. Schmitz N, Pfistner B, Sextro M. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359(9323):2065–71.

    Article  CAS  PubMed  Google Scholar 

  35. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015;385(9980):1853–62.

    Article  CAS  PubMed  Google Scholar 

  36. Moskowitz C, Sweetenham J, Chen A, Ayala E, Masszi T, Holowiecki J, et al. Brentuximab vedotin after autologous stem cell transplant yields the strongest benefit after autologous stem cell transplant in Hodgkin lymphoma patients with ≥2 risk factors: results of a multivariate analysis Haematologica. 2016;101(s5):10th International Symposium on Hodgkin lymphoma.

  37. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Karuturi MSAS, Chen RW, Gopal AK, Feng L, Yuan Y, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, Ramchandren R. Overall survival benefit for patients with relapsed Hodgkin lymphoma treated with brentuximab vedotin after autologous stem cell transplant. Blood. 2012;120(21):3701.

    Google Scholar 

  39. Anderlini P, Saliba RM, Ledesma C, Plair T, Alousi AM, Hosing CM, et al. Gemcitabine, fludarabine, and melphalan for reduced-intensity conditioning and allogeneic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2016;22(7):1333–7.

    Article  CAS  Google Scholar 

  40. Peggs KS, Hunter A, Chopra R, Parker A, Mahendra P, Milligan D, et al. Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet. 2005;365(9475):1934–41.

    Article  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Raiola AM, Dominietto A, di Grazia C, Lamparelli T, Gualandi F, Ibatici A, et al. Unmanipulated haploidentical transplants compared with other alternative donors and matched sibling grafts. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2014;20(10):1573–9.

    Article  Google Scholar 

  44. Burroughs LM, O'Donnell PV, Sandmaier BM, Storer BE, Luznik L, Symons HJ, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplantation: journal of the American Society for Blood Marrow Transplant. 2008;14(11):1279–87.

    Article  Google Scholar 

  45. Gayoso J, Balsalobre P, Pascual MJ, Castilla-Llorente C, Lopez-Corral L, Kwon M, et al. Busulfan-based reduced intensity conditioning regimens for haploidentical transplantation in relapsed/refractory Hodgkin lymphoma: Spanish multicenter experience. Bone Marrow Transplant. 2016;51(10):1307–12.

    Article  CAS  PubMed  Google Scholar 

  46. Merryman RW, Kim HT, Zinzani PL, Carlo-Stella C, Ansell SM, Perales MA, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017.

  47. Bartlett N, Niedzwiecki D, Johnson J, Friedberg J, Johnson K, van Besien K, et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin's lymphoma: CALGB 59804. Ann Oncol. 2007;18(6):1071–9.

    Article  CAS  PubMed  Google Scholar 

  48. Moskowitz AJ, Hamlin PA Jr, Perales MA, Gerecitano J, Horwitz SM, Matasar MJ, et al. Phase II study of bendamustine in relapsed and refractory Hodgkin lymphoma. J Clin Oncol. 2013;31(4):456–60.

    Article  CAS  PubMed  Google Scholar 

  49. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, Kabat BF, Habermann TM, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010;85(5):320–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, et al. A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hamadani M, Balasubramanian S, Hari PN. Ibrutinib in refractory classic Hodgkin's lymphoma. N Engl J Med. 2015;373(14):1381–2.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Alison J. Moskowitz.

Ethics declarations

Conflict of Interest

Niloufer Khan declares no potential conflicts of interest.

Alison J. Moskowitz received grants from Seattle Genetics and BMS and honoraria from Seattle Genetics, BMS, Takeda, and Merck.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on B-cell NHL, T-cell NHL, and Hodgkin Lymphoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khan, N., Moskowitz, A.J. Where Do the New Drugs Fit in for Relapsed/Refractory Hodgkin Lymphoma?. Curr Hematol Malig Rep 12, 227–233 (2017). https://doi.org/10.1007/s11899-017-0384-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-017-0384-z

Keywords

Navigation