Checkpoint Inhibitors Hodgkin Lymphoma and Non-Hodgkin Lymphoma
Purpose of the Review
The ligation of PD-1 with PD-L1 activates a critical immune checkpoint leading to T cell dysfunction, exhaustion, and tolerance. Anti-PD-1 or anti-PD-L1 monoclonal antibodies can reverse the immune checkpoint, releasing the brake on T cell responses. We provide a comprehensive review of the literature on the activity of checkpoint inhibitors in lymphoma.
We discuss the latest findings with checkpoint inhibitors in lymphoma and new promising studies incorporating these agents.
Classical Hodgkin lymphoma is very sensitive to PD1/PL1 blockade due to genetic alterations in 9p21.1 leading to the high expression of PDL1. Although majority of NHLs have a much lower sensitivity to PD1/PDL1 blockade, a few subtypes such as primary CNS lymphoma, primary testicular lymphoma, primary mediastinal lymphoma harbor 9p21.1 alterations making them vulnerable to PD1 blockade. EBV-associated lymphomas have a virally mediated increased expression of PDL1 making them sensitive to PD1 blockade.
KeywordsImmunotherapy Checkpoint blockade Non-Hodgkin lymphoma Hodgkin lymphoma PD-1 PD-L1 Nivolumab Pembrolizumab
Compliance with Ethical Standards
Conflict of Interest
Nilanjan Ghosh reports personal fees from Seattle Genetics, Pharmacyclics, Gilead, Abbvie, Celgene, Juno Therapeutics, outside the submitted work. Ryan Jacobs reports personal fees from Pharmacyclics, Genentech, Astra Zeneca, TG Therapeutics, Gilead, Spectrum and Juno therapeutics. Bei Hu has no conflict of interest.
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.
Papers of particular interest, published recently, have been highlighted as: •• Of major importance
- 8.Armand P, et al. Pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure: long term efficacy from phase Ib Keynote-013 study. Blood. 2016;128:1108.Google Scholar
- 9.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.PubMedPubMedCentralGoogle Scholar
- 10.Fanale M, Engert A, Younes A, Armand P, Ansell S, Zinzani PL, et al. Nivolumab for relapsed/refractory classical Hodgkin lymphoma after autologous transplant: full results after extended follow-up of the phase 2 CHECKMATE 205 trial. Hematol Oncol. 2017;35(S2):135–6.Google Scholar
- 12.Zinzani PL, et al. Pembrolizumab monotherapy in patients with primary refractory classical Hodgkin lymphoma : subgroup analysis of the phase 2 KEYNOTE-087 study. Hematol Oncol. 2017;35(S2):136–7.Google Scholar
- 14.Ansell S, et al. A phase I study of nivolumab in combination with ipilimumab for relapsed or refractory hematologic malignancies (CheckMate 039). Blood. 2016;128:183.Google Scholar
- 20.Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial. J Clin Oncol. 2013;31(33):4199–206.PubMedPubMedCentralGoogle Scholar
- 22.Jain N et al. Nivolumab combined with ibrutinib for CLL and Richter transformation: a phase II trial. Am Soc Hematology. 2016.Google Scholar
- 24.Palomba ML, Till BG, Park SI, Morschhauser F, Cartron G, Marks R, et al. A phase IB study evaluating the safety and clinical activity of atezolizumab combined with obinutuzumab in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Hematol Oncol. 2017;35:137–8.Google Scholar
- 25.Nastoupil LJ, Westin JR, Fowler NH, Fanale MA, Samaniego F, Oki Y, et al. Response rates with pembrolizumab in combination with rituximab in patients with relapsed follicular lymphoma: interim results of an on open-label, phase II study. J Clin Oncol. 2017;35:7519–9.Google Scholar
- 26.Younes A et al. Safety and efficacy of atezolizumab in combination with obinutuzumab and bendamustine in patients with previously untreated follicular lymphoma: an interim analysis. Blood. 2017;481.Google Scholar
- 27.Khodadoust M et al. Pembrolizumab for treatment of relapsed/refractory mycosis fungoides and Sezary syndrome: clinical efficacy in a Citn multicenter phase 2 study. Am Soc Hematology. 2016.Google Scholar
- 31.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.PubMedPubMedCentralGoogle Scholar
- 35.Cohen JB, et al. Nivolumab treatment beyond investigator-assessed progression: outocmes in patients with relapsed/refractory classical Hodgkin lymphoma from the Phase 2 CHECKMATE 205 study. Blood. 2017;130:650.Google Scholar
- 39.Shi M, Roemer MGM, Chapuy B, Liao X, Sun H, Pinkus GS, et al. Expression of programmed cell death 1 ligand 2 (PD-L2) is a distinguishing feature of primary mediastinal (thymic) large B-cell lymphoma and associated with PDCD1LG2 copy gain. Am J Surg Pathol. 2014;38(12):1715–23.PubMedPubMedCentralGoogle Scholar
- 45.Rossille D, Azzaoui I, Feldman AL, Maurer MJ, Labouré G, Parrens M, et al. Soluble programmed death-ligand 1 as a prognostic biomarker for overall survival in patients with diffuse large B-cell lymphoma: a replication study and combined analysis of 508 patients. Leukemia. 2017;31(4):988–91.PubMedPubMedCentralGoogle Scholar
- 53.Ramsay AG, Clear AJ, Fatah R, Gribben JG. Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer. Blood. 2012;120(7):1412–21.PubMedPubMedCentralGoogle Scholar
- 66.Rogers KA, Huang Y, Ruppert AS, Salem G, Stephens DM, Heerema NA, et al. A single-institution retrospective cohort study of first-line R-EPOCH chemoimmunotherapy for Richter syndrome demonstrating complex chronic lymphocytic leukaemia karyotype as an adverse prognostic factor. Br J Haematol. 2018;180(2):259–66.PubMedGoogle Scholar
- 69.He R, Ding W, Viswanatha DS, Chen D, Shi M, van Dyke D, et al. PD-1 expression in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and large B-cell Richter transformation (DLBCL-RT): a characteristic feature of DLBCL-RT and potential surrogate marker for clonal relatedness. Am J Surg Pathol. 2018;42(7):843–54.PubMedGoogle Scholar