Skip to main content

Advertisement

SpringerLink
Log in

Advances in Therapy for Relapsed or Refractory Hodgkin Lymphoma

  • Lymphomas (MR Smith, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of review

The landscape of relapsed or refractory (R/R) Hodgkin lymphoma (HL) treatment has changed significantly since the FDA approval of brentuximab vedotin in 2011. In this review, we summarize the recent advances in the therapy for R/R classical Hodgkin lymphoma (cHL).

Recent findings

Immunotherapies with pembrolizumab, nivolumab, and ipilimumab, and chimeric antigen receptor (CAR) T cell therapies have shown promising results in early phase trials. Other novel agents under investigation include targeted therapies with histone deacetylase inhibitors, Janus kinase 2 inhibitors, and immunomodulators.

Summary

While further studies with larger populations and longer follow-up times are needed to determine the safe and effective combinations, these novel approaches represent a growing list of treatment options that are on the horizon to improve the cure rate and increase duration of remission for R/R HL patients.

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

Similar content being viewed by others

References

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

  1. Cancer Stat Facts: Hodgkin Lymphoma. NIH, Natl Cancer Institute, SEER Data. at https://seer.cancer.gov/statfacts/html/hodg.html.

  2. Kuruvilla J. Standard therapy of advanced Hodgkin lymphoma. ASH Education Program Book. 2009;2009:497–506.

    Google Scholar 

  3. Filatova LV, Tarasenkova AA, Gershanovich ML, Semiglazov T. Relapse in Hodgkin lymphoma. Vopr Onkol. 2012;58:265–74.

    CAS  PubMed  Google Scholar 

  4. 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;359:2065–71.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Moskowitz CH, Nimer SD, Zelenetz AD, Trippett T, Hedrick EE, Filippa DA, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97:616–23.

    CAS  PubMed  Google Scholar 

  7. Hertzberg MS, Crombie C, Benson W, Taper J, Gottlieb D, Bradstock KF. Outpatient-based ifosfamide, carboplatin and etoposide (ICE) chemotherapy in transplant-eligible patients with non-Hodgkin’s lymphoma and Hodgkin’s disease. Ann Oncol. 2003;14(Suppl 1):i11–6.

    PubMed  Google Scholar 

  8. Josting A, Rudolph C, Reiser M, Mapara M, Sieber M, Kirchner HH, et al. Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13:1628–35.

    CAS  PubMed  Google Scholar 

  9. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol. 1999;10:593–5.

    CAS  PubMed  Google Scholar 

  10. Baetz T, Belch A, Couban S, Imrie K, Yau J, Myers R, et al. Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol. 2003;14:1762–7.

    CAS  PubMed  Google Scholar 

  11. Bartlett NL, Niedzwiecki D, Johnson JL, Friedberg JW, Johnson KB, 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;18:1071–9.

    CAS  PubMed  Google Scholar 

  12. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007;92:35–41.

    CAS  PubMed  Google Scholar 

  13. Josting A, Muller H, Borchmann P, et al. Dose intensity of chemotherapy in patients with relapsed Hodgkin’s lymphoma. J Clin Oncol. 2010;28:5074–80.

    PubMed  Google Scholar 

  14. 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;119:1665–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. ADCETRIS [EU summary of product characteristics]. Taastrup, Denmark: Takeda Pharma A/S; 2015.

  16. ADCETRIS [US package insert]. Bothell, WA: Seattle Genetics, 2016.

  17. 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;30:631–7.

    CAS  PubMed  Google Scholar 

  18. Horie R, Watanabe T. CD30: expression and function in health and disease. Semin Immunol. 1998;10:457–70.

    CAS  PubMed  Google Scholar 

  19. Schwab U, Stein H, Gerdes J, Lemke H, Kirchner H, Schaadt M, et al. Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells. Nature. 1982;299:65–7.

    CAS  PubMed  Google Scholar 

  20. Hagenbeek A, Zijlstra JM, Plattel WJ, et al. Combining brentuximab vedotin with DHAP as salvage treatment in relapsed/refractory Hodgkin lymphoma: the phase II HOVON/LLPC transplant BRaVE study. Blood. 2018;132:2923.

    Google Scholar 

  21. Cassaday RD, Fromm JR, Cowan AJ, et al. Radiographic and high-throughput sequencing (HTS)-based response assessment after brentuximab vedotin (BV) plus ifosfamide, carboplatin, and etoposide (ICE) for relapsed/refractory (Rel/ref) classical Hodgkin lymphoma (cHL): updated results of a phase I/II trial. Blood. 2017;130:2806.

    Google Scholar 

  22. Garcia-Sanz R, Sureda A, de la Cruz F, et al. Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodgkin lymphoma patients (long-term results of a trial by the Spanish GELTAMO group). Ann Oncol. 2019;30:612–20.

    PubMed  Google Scholar 

  23. LaCasce AS, Bociek RG, Sawas A, et al. Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood. 2018;132:40–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Picardi M, Della Pepa R, Giordano C, Pugliese N, Mortaruolo C, Trastulli F, et al. Brentuximab vedotin followed by bendamustine supercharge for refractory or relapsed Hodgkin lymphoma. Blood Adv. 2019;3:1546–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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;385:1853–62.

    CAS  PubMed  Google Scholar 

  26. • Armand P, Chen YB, Redd RA, et al. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation. Blood. 2019;134:22–9 Although the data from this phase II trial of pembrolizumab, which showed an 18-month PFS and OS of 82% and 100%, respectively, are promising, the use of PD-1 blockade in the post-ASCT setting is limited by its adverse events.

    CAS  PubMed  Google Scholar 

  27. Younes A, Gopal AK, Smith SE, 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;30:2183–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Herrera AF, Palmer J, Martin P, Armenian S, Tsai NC, Kennedy N, et al. Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Ann Oncol. 2018;29:724–30.

    CAS  PubMed  Google Scholar 

  29. •• Connors JM, Jurczak W, Straus DJ, et al. Brentuximab Vedotin with chemotherapy for stage III or IV Hodgkin's lymphoma. N Engl J Med. 2018;378:331–44 The ECHELON-1 trial, which showed a difference of 4.9 percentage points in modified 2-year PFS favoring A+AVD over ABVD, led to the FDA approval of BV as a frontline therapy in combination with chemotherapy in advanced stage HL. The impact of integrating BV into earlier lines of therapy on the role of BV as a salvage therapy is yet to be determined.

    CAS  PubMed  Google Scholar 

  30. Bartlett NL, Chen R, Fanale MA, et al. Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol. 2014;7:24.

    PubMed  PubMed Central  Google Scholar 

  31. Roemer MG, Advani RH, Ligon AH, Natkunam Y, Redd RA, Homer H, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. 2016;34:2690–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Green MR, Rodig S, Juszczynski P, 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. 2012;18:1611–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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;116:3268–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Armand P, Engert A, Younes A, Fanale M, Santoro A, Zinzani PL, et al. Nivolumab for relapsed/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 trial. J Clin Oncol. 2018;36:1428–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35:2125–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Diefenbach CS, Hong F, Cohen JB, et al. Preliminary safety and efficacy of the combination of brentuximab vedotin and ipilimumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412). Blood. 2015;126:585.

    Google Scholar 

  37. Diefenbach CS, Hong F, David KA, et al. Title: a phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412 arms D and E). Blood. 2016;128:1106.

    Google Scholar 

  38. •• Diefenbach C, Hong F, Ambinder RF, et al. A phase I study with an expansion cohort of the combinations of ipilimumab, nivolumab and brentuximab vedotin in patients with relapsed/refractory hodgkin lymphoma: a trial of the ECOG-ACRIN research group (E4412: Arms G-I). Blood. 2018;132:679 In the E4412 trial, the triplet combination of BV, ipilimumab and nivolumab was generally well-tolerated and showed the ORR of 95% and CR rate of 79% in R/R HL patients. The follow-up phase II trial comparing the combination of BV and nivolumab to the triplet is ongoing.

    Google Scholar 

  39. •• Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2018;131:1183–94 Similarly in this phase I/II trial, the doublet of BV and nivolumab was well-tolerated and showed an ORR of 82% with CR rate of 61%, confirming the efficacy and safety of combining BV with immunotherapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Levis M, Piva C, Filippi AR, et al. Potential benefit of involved-field radiotherapy for patients with relapsed-refractory Hodgkin's lymphoma with incomplete response before autologous stem cell transplantation. Clin Lymphoma Myeloma Leuk. 2017;17:14–22.

    PubMed  Google Scholar 

  41. Constine LS, Yahalom J, Ng AK, et al. The role of radiation therapy in patients with relapsed or refractory Hodgkin lymphoma: guidelines from the international lymphoma radiation oncology group. Int J Radiat Oncol Biol Phys. 2018;100:1100–18.

    PubMed  Google Scholar 

  42. Arai S, Fanale M, deVos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leuk Lymphoma. 2013;54:2531–3.

    PubMed  Google Scholar 

  43. Ramos CA, Bilgi M, Gerken C, et al. CD30-chimeric antigen receptor (CAR) T cells for therapy of hodgkin lymphoma (HL). Abstract #79 Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 23, 2019; Houston, TX 2019.

  44. Grover NS, Park SI, Ivanova A, et al. A phase Ib/II study of anti-CD30 chimeric antigen receptor T cells for relapsed/refractory CD30+ lymphomas. Abstract #83 Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 23, 2019; Houston, TX 2019.

  45. Dickinson M, Johnstone RW, Prince HM. Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect. Investig New Drugs. 2010;28(Suppl 1):S3–20.

    Google Scholar 

  46. Younes A, Sureda A, Ben-Yehuda D, et al. Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol. 2012;30:2197–203.

    CAS  PubMed  Google Scholar 

  47. Hu B, Younes A, Westin JR, et al. Phase-I and randomized phase-II trial of panobinostat in combination with ICE (ifosfamide, carboplatin, etoposide) in relapsed or refractory classical Hodgkin lymphoma. Leuk Lymphoma. 2018;59:863–70.

    CAS  PubMed  Google Scholar 

  48. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009;2:36.

    PubMed  PubMed Central  Google Scholar 

  49. 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;118:5119–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Christian B, Wei L, Sexton J, et al. A phase I/II trial of the histone deacetylase (HDAC) inhibitor, panobinostat, in combination with lenalidomide in patients with relapsed/refractory Hodgkin’s lymphoma (HL). Blood. 2014;124:3099.

    Google Scholar 

  51. Carbone A, Gloghini A, Castagna L, Santoro A, Carlo-Stella C. Primary refractory and early-relapsed Hodgkin’s lymphoma: strategies for therapeutic targeting based on the tumour microenvironment. J Pathol. 2015;237:4–13.

    PubMed  Google Scholar 

  52. Van Den Neste E, Andre M, Gastinne T, et al. A phase II study of the oral JAK1/JAK2 inhibitor ruxolitinib in advanced relapsed/refractory Hodgkin lymphoma. Haematologica. 2018;103:840–8.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. NYU Langone Hematology & Medical Oncology Fellowship Program, 550 First Avenue, New York, NY, 10016, USA

    Yun Choi

  2. Division of Hematology and Medical Oncology, Perlmutter Cancer Center at NYU Langone Health, New York University School of Medicine, Langone Medical Center, 240 East 38th Street, 19th Floor, New York, NY, 10016, USA

    Catherine S. Diefenbach

Authors
  1. Yun Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine S. Diefenbach
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine S. Diefenbach.

Ethics declarations

Conflict of Interest

Yun Choi declares that she has no conflict of interest.

Catherine S. Diefenbach has received research funding from Bristol-Myers Squibb, Merck, and Seattle Genetics and has received compensation from Bristol-Myers Squibb, Merck, and Seattle Genetics for service as a consultant.

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

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Lymphomas

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Choi, Y., Diefenbach, C.S. Advances in Therapy for Relapsed or Refractory Hodgkin Lymphoma. Curr Oncol Rep 22, 6 (2020). https://doi.org/10.1007/s11912-020-0866-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-020-0866-3

Keywords

Search

Navigation