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Novel Targeted Therapies in Hodgkin Lymphoma

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Part of the Molecular Pathology Library book series (MPLB)

Abstract

Although Hodgkin lymphoma (HL) is considered a highly curable cancer, a substantial portion of patients are relapsed/refractory to first-line therapies and even after subsequent autologous stem cell transplantation. These patients carry a poor prognosis with poor survival rates. In this area of high unmet medical need, development of novel targeted therapeutics is a significant priority. Fortunately, increased understanding of the molecular biology of HL has given rise to a number of new classes of drugs such as antibody drug conjugates, PD-1 and PD-L1 inhibitors, PI3K inhibitors, histone deacetylase inhibitors, Akt/mTOR pathway inhibitors, and immunomodulators. Numerous clinical trials evaluating these novel drugs have demonstrated a variety of responses and activities. This review will focus on recent developments and the growing armamentarium of drugs available to treat this disease.

Keywords

Immunotherapy PD-1 CD30 Relapsed Refractory Antibody Brentuximab vedotin Nivolumab Pembrolizumab 

References

  1. Aizawa S, Nakano H, Ishida T, Horie R, Nagai M, Ito K et al (1997) Tumor necrosis factor receptor-associated factor (TRAF) 5 and TRAF2 are involved in CD30-mediated NFkappaB activation. J Biol Chem 272(4):2042–2045CrossRefPubMedGoogle Scholar
  2. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319CrossRefPubMedGoogle Scholar
  3. Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J et al (2016) Programmed Death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. pii: JCO673467Google Scholar
  4. Bartlett NL, Chen R, Fanale MA, Brice P, Gopal A, Smith SE et al (2014) Retreatment with brentuximab vedotin in patients with CD30-positive hematologic malignancies. J Hematol Oncol 7:24CrossRefPubMedPubMedCentralGoogle Scholar
  5. Batlevi CL, Kasamon Y, Bociek RG, Lee P, Gore L, Copeland A et al (2016) ENGAGE-501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica 101(8):968–975CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Klasa R et al (2010) Results of a pivotal phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma. Blood 116(21):abstract #283Google Scholar
  7. Chen R, Palmer JM, Thomas SH, Tsai NC, Farol L, Nademanee A et al (2012) Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma. Blood 119(26):6379–6381CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chen R, Palmer JM, Tsai NC, Thomas SH, Siddiqi T, Popplewell L et al (2014) Brentuximab vedotin is associated with improved progression-free survival after allogeneic transplantation for Hodgkin lymphoma. Biol Blood Marrow Transplant 20(11):1864–1868CrossRefPubMedPubMedCentralGoogle Scholar
  9. Chen R, Palmer JM, Martin P, Tsai N, Kim Y, Chen BT et al (2015a) 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 21(12):2136–2140CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chen R, Palmer J, Martin P, Armenian S, Tsai N, Mott M et al (2015b) Post transplant outcome of a multicenter phase II study of brentuximab vedotin as first line salvage therapy in relapsed/refractory HL prior to AHCT. Blood 126(23):abstract#519Google Scholar
  11. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ et al (2016a) Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 126(23):pii: blood-2016-02-699850Google Scholar
  12. Chen RW, Zinzani PL, Fanale MA, Armand P, Johnson N, Ribrag V et al (2016b) Pembrolizumab for relapsed/refractory classical Hodgkin lymphoma (R/R cHL): phase 2 KEYNOTE-087. J Clin Oncol 34(Suppl):abstract#7555Google Scholar
  13. Connors JM, Ansell S, Park SI, Fanale MA, Younes A (2014) Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed advanced stage Hodgkin lymphoma: Long term outcomes. Blood 124(21):abstract#292Google Scholar
  14. Doronina SO, Toki BE, Torgov MY, Mendelsohn BA, Cerveny CG, Chace DF et al (2003) Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21(7):778–784CrossRefPubMedGoogle Scholar
  15. Dutton A, Reynolds GM, Dawson CW, Young LS, Murray PG (2005) Constitutive activation of phosphatidyl-inositide 3 kinase contributes to the survival of Hodgkin’s lymphoma cells through a mechanism involving Akt kinase and mTOR. J Pathol 205(4):498–506CrossRefPubMedGoogle Scholar
  16. Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA et al (2011) A phase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood 118(19):5119–5125CrossRefPubMedPubMedCentralGoogle Scholar
  17. Forero-Torres A, Holkova B, Goldschmidt J, Chen R, Olsen G, Boccia RV et al (2015) Phase 2 study of frontline brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood 126(26):2798–2804CrossRefPubMedPubMedCentralGoogle Scholar
  18. Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Mills GB, Younes A (2006) Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol 132(4):503–511PubMedGoogle Scholar
  19. Gopal AK, Ramchandren R, O’Connor OA, Berryman RB, Advani RH, Chen R et al (2012) Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 120(3):560–568CrossRefPubMedPubMedCentralGoogle Scholar
  20. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249CrossRefPubMedGoogle Scholar
  21. Johnston PB, Pinter-Brown L, Rogerio J, Warsi G, White K, Ramchandren R (2013) Phase 2 study everolimus for relapsed/refractory classical Hodgkin lymphoma (cHL). Haematologica 98(Suppl 2):51, abstract#T126Google Scholar
  22. Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704CrossRefPubMedGoogle Scholar
  23. Kirschbaum MH, Goldman BH, Zain JM, Cook JR, Rimsza LM, Forman SJ et al (2012) A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. Leuk Lymphoma 53(2):259–262CrossRefPubMedGoogle Scholar
  24. Kronke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M et al (2014) Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343(6168):301–305CrossRefPubMedGoogle Scholar
  25. LaCasce AS, Bociek G, Sawas A, Caimi PF, Agura E, Matous J et al (2015) Brentuximab vedotin plus bendamustine: A highly active salvage treatment regimen for patients with relapsed or refractory Hodgkin lymphoma. Blood 126(23):abstract#3982Google Scholar
  26. Moskowitz AJ, Schoder H, Yahalom J, McCall SJ, Fox SY, Gerecitano J et al (2015a) 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 16(3):284–292CrossRefPubMedGoogle Scholar
  27. Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH et al (2015b) 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 385(9980):1853–1862CrossRefPubMedGoogle Scholar
  28. Newland AM, Li JX, Wasco LE, Aziz MT, Lowe DK (2013) Brentuximab vedotin: a CD30-directed antibody-cytotoxic drug conjugate. Pharmacotherapy 33(1):93–104CrossRefPubMedGoogle Scholar
  29. Oki Y, Buglio D, Fanale M, Fayad L, Copeland A, Romaguera J et al (2013) Phase I study of panobinostat plus everolimus in patients with relapsed or refractory lymphoma. Clin Cancer Res 19(24):6882–6890CrossRefPubMedPubMedCentralGoogle Scholar
  30. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4):252–264CrossRefPubMedPubMedCentralGoogle Scholar
  31. Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, Reiners KS et al (2015) A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood 125(26):4024–4031CrossRefPubMedPubMedCentralGoogle Scholar
  32. Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63(1):11–30CrossRefPubMedGoogle Scholar
  33. van de Donk NW, Dhimolea E (2012) Brentuximab vedotin. MAbs 4(4):458–465CrossRefPubMedPubMedCentralGoogle Scholar
  34. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M et al (2008) PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood 111(6):3220–3224CrossRefPubMedGoogle Scholar
  35. Younes A, Kadin ME (2003) Emerging applications of the tumor necrosis factor family of ligands and receptors in cancer therapy. J Clin Oncol 21(18):3526–3534CrossRefPubMedGoogle Scholar
  36. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al (2010) Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363(19):1812–1821CrossRefPubMedGoogle Scholar
  37. Younes A, Oki Y, Bociek RG, Kuruvilla J, Fanale M, Neelapu S et al (2011) Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol 12(13):1222–1228CrossRefPubMedPubMedCentralGoogle Scholar
  38. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ et al (2012a) Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30(18):2183–2189CrossRefPubMedPubMedCentralGoogle Scholar
  39. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM et al (2012b) Panobinostat in patients with relapsed/refractory Hodgkin’s lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol 30(18):2197–2203CrossRefPubMedGoogle Scholar
  40. Younes A, Connors JM, Park SI, Fanale M, O’Meara MM, Hunder NN et al (2013a) Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin’s lymphoma: a phase 1, open-label, dose-escalation study. Lancet Oncol 14(13):1348–1356CrossRefPubMedGoogle Scholar
  41. Younes A, Moskowitz AJ, Moskowitz CH, Fanale MA, Shustov A, Peterman S et al (2013b) Pilot phase 2 study of idelalisib, a selective inhibitor of P13Kdelta, in patients with heavily pretreated Hodgkin lymphoma (HL). Hematol Oncol 31(Suppl 1):142, abstract#39Google Scholar
  42. Younes A, Santoro A, Shipp M, Zinzani PL, Timmerman JM, Ansell S et al (2016) 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 17(9):1283–1294.  https://doi.org/10.1016/S470-2045(16)30167-X CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Hematology and Hematopoietic Cell TransplantationToni Stephenson Lymphoma Center, City of HopeDuarteUSA

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