The Emerging Role of Checkpoint Inhibitor Therapy in Hodgkin Lymphoma

October 15, 2016

Ultimately, the management goal is not for patients with relapsed/refractory disease to live with chronic Hodgkin lymphoma while receiving immune checkpoint blockade therapy, but rather to cure more patients with first- or second-line therapy.

In their comprehensive review, Drs. Lin and Diefenbach discuss the scientific rationale for, and the clinical outcomes associated with, the use of checkpoint inhibitors for treatment of Hodgkin lymphoma.[1] The authors detail the mechanisms that lead to overexpression of programmed death ligands 1 and 2 (PD-L1 and PD-L2) on Hodgkin lymphoma tumor cells, a process that, in turn, causes dampening of the immune response against Hodgkin and Reed-Sternberg (HRS) cells. They also describe clinical trials that have incorporated checkpoint inhibition as a therapeutic strategy in Hodgkin lymphoma, including monoclonal antibody therapy against cytotoxic T-lymphocyte–associated antigen 4 and programmed death 1 (PD-1). As the authors describe, there are still many open questions regarding the use of checkpoint inhibitors in Hodgkin lymphoma, including the mechanisms of action underlying checkpoint blockade and the therapeutic applications in this patient population.[2-4]

Upregulation of PD-L1 and PD-L2, leading to evasion of the immune system, is a clear pathogenic mechanism in Hodgkin lymphoma. The recurrent chromosomal translocation of the 9p24.1 region in Hodgkin lymphoma leads to increased expression of PD-L1 and PD-L2, as well as amplification of the Janus kinase 2 (JAK2) locus, resulting in transcriptional activation of PD-L1.[5] Even in patients without genetic amplification of PD-L1 or PD-L2, alternate mechanisms promote enhanced PD-L1 and PD-L2 expression; these mechanisms include increases in JAK/STAT signaling, production of interferon gamma, and expression of an Epstein-Barr virus–associated protein, latent membrane protein 1.[6,7] The anti–PD-1 antibodies nivolumab and pembrolizumab interfere with the inhibitory interaction between PD-1 and PD-L1/PD-L2, leading to heightened immune responses against HRS cells. However, the mechanism by which checkpoint inhibitors enhance the T-cell or alternate effector cell response against the tumor cells is unclear. Further, biomarkers to predict differential responses to checkpoint inhibitors in Hodgkin lymphoma have not been elucidated.

In melanoma and lung cancer, higher levels of somatic mutation and higher tumor neoantigen burden have been reported to correlate with response to checkpoint blockade.[8,9] However, in Hodgkin lymphoma, the somatic mutational burden is difficult to characterize in patients treated with anti–PD-1 antibodies. This is due to the relative paucity of HRS cells in pathologic specimens, which hinders efforts to perform routine and comprehensive sequencing assessments. In solid tumors, a postulated mechanism of action for checkpoint blockade is presentation of tumor neoantigens by major histocompatibility complex (MHC) class I molecules on tumor cells, resulting in a CD8-positive T-cell–mediated response against the tumor. Intriguingly, in Hodgkin lymphoma, frequent inactivating mutations of the β-2-microglobulin (B2M) gene have been described that trigger the loss of MHC class I expression on HRS cells, making CD8-positive T cells unlikely effector cells in Hodgkin lymphoma.[10] Therefore, CD4-positive T cells may be the predominant effector cells in the anti-PD1–mediated antitumor response in HL, but, as Drs. Lin and Diefenbach describe, downregulation of MHC class II molecules has also been observed in Hodgkin lymphoma. Thus, there are unresolved questions about how checkpoint inhibitors may mediate antitumor responses in Hodgkin lymphoma; hypotheses include antitumor effects achieved via CD4-positive T-cell–mediated responses independent of MHC class II interaction, natural killer cell–mediated responses, and inhibition of regulatory T cells.[7]

Unlike in solid tumors, the degree of PD-L1 or PD-L2 expression in Hodgkin lymphoma is not a biomarker of response to checkpoint blockade. The recent phase Ib study of pembrolizumab described a treatment-induced expansion of T cells (both CD4 and CD8 subsets) and natural killer cells, as well as increases in gene signatures of interferon gamma, T-cell–receptor signaling, and immune-related genes; however, these changes were not clearly correlated with response.[3] Efforts to identify biomarkers of response to checkpoint blockade therapy are ongoing.

Data from initial phase I and II studies of the anti–PD-1 antibodies nivolumab and pembrolizumab demonstrated impressive overall response rates for these agents, ranging from 65% to 87%.[2-4] However, only 15% to 20% of patients achieved a complete response. Nevertheless, many patients who experience a partial response or stable disease derive significant clinical benefit from anti–PD-1 antibody therapy and can remain on treatment for a prolonged period of time. As Drs. Lin and Diefenbach report in their review, an update of the CheckMate-039 study at the 2015 American Society of Hematology Annual Meeting demonstrated that there is promising durability of response with nivolumab, with evidence of persistent complete and partial responses even after cessation of therapy. Also notable in this study was a single patient whose disease progressed after therapy was discontinued but who achieved a second complete response after reinitiation of treatment with nivolumab.[11]

These data give rise to the clinical question of how to optimally manage patients with relapsed or refractory Hodgkin lymphoma who respond to anti–PD-1 therapy. There are several potential management options: 1) continue checkpoint inhibition indefinitely; 2) stop therapy after achievement of best response and observe the patient, while reserving the potential option of re-treatment in the future; or 3) initiate consolidation therapy with allogeneic stem cell transplantation (SCT).[12] Given the current limited follow-up period with the use of immune checkpoint inhibitors in Hodgkin lymphoma, we do not know how durable the treatment responses will be, and it is unlikely that they have curative potential. Although allogeneic SCT has been considered potentially curative in refractory Hodgkin lymphoma, there may be an enhanced graft-vs-tumor effect after use of immune checkpoint blockade therapy in conjunction with allogeneic SCT, and this approach carries a substantial risk of treatment-related morbidity and mortality. Furthermore, these risks, particularly for graft-vs-host disease and veno-occlusive disease, may be increased following therapy with checkpoint inhibitors.[13] Currently, there are insufficient data to formulate a uniform management algorithm for patients with relapsed or refractory Hodgkin lymphoma who respond to treatment with anti–PD-1 agents. The treatment approach needs to be determined on an individual basis, and various factors must be considered, including, but not limited to: the age of the patient, his or her functional status and concomitant comorbidities, SCT sources and donor availability, depth of response to prior anti–PD-1 antibody therapy, the prior therapies received, and patient preferences.

Ultimately, the management goal is not for patients with relapsed/refractory disease to live with chronic Hodgkin lymphoma while receiving immune checkpoint blockade therapy, but rather to cure more patients with first- or second-line therapy. There are multiple ongoing efforts to incorporate checkpoint blockade therapy earlier in the disease course to improve outcomes, particularly in high-risk patients. The results of clinical trials in Hodgkin lymphoma in which immune checkpoint blockade is combined with chemotherapy, radiotherapy, and antibody-drug conjugates are highly anticipated. Indeed, immune checkpoint inhibitors hold great promise to further increase the curability rates of future patients with Hodgkin lymphoma.

Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Lin RJ, Diefenbach CS. Checkpoint inhibition in Hodgkin lymphoma: saving the best for last? Oncology (Williston Park). 2016;30:914-20.

2. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311-9.

3. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016;34:1-9.

4. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplant and brentuximab vedotin: a multicentre, single-arm phase 2 trial. Lancet Oncol. 2016;17:1283-94.

5. Green MR, Monti S, Rodig SJ, 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.

6. 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.

7. Vardhana S, Younes A. The immune microenvironment in Hodgkin lymphoma: T-cells, B-cells, and immune checkpoints. Haematologica. 2016;101:794-802.

8. Snyder A, Makarov V, Merghoub T, et al. Genetic bases for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.

9. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

10. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood. 2015;125:1061-72.

11. Ansell SM, Armand P, Timmerman JM, et al. Nivolumab in patients with relapsed or refractory classical Hodgkin lymphoma: clinical outcomes from extended follow-up of a phase I study (CA209-039). Blood. 2015;126(suppl):abstr 583.

12. Issa A, Westin J. What to do with success? The optimist’s creed in relapsed Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk. 2016 June 8. [Epub ahead of print]

13. Merryman RW, Kim HT, Zinzani PL, et al. Safety and efficacy of allogeneic hematopoietic stem cell transplant (HSCT) after treatment with programmed cell death 1 (PD-1) inhibitors. Blood. 2015;126(suppl):abstr 2018.