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John Kuruvilla, MD, FRCPC

John Kuruvilla, MD, FRCPC

Dr. John Kuruvilla is a Professor of Medicine at the University of Toronto and a hematologist in the Division of Medical Oncology and Hematology at the Princess Margaret Cancer Centre in Toronto. He is a member of the Lymphoma, Autologous Transplant and Immune Effector Cell Therapy programs. Dr. Kuruvilla’s research interest is the development of novel therapeutics in lymphoid malignancies and incorporating translational research into clinical trials. He is the Lymphoma Co-Chair for the Canadian Cancer Trials Group (CCTG) as well as the Chair of the Scientific Advisory Board of Lymphoma Canada.

Immunotherapy in Hodgkin Lymphoma: Current and Evolving Roles


Classical Hodgkin lymphoma (cHL) is a very curable form of cancer for the majority of patients that receive standard primary therapy.1 Many patients will have a second opportunity for cure at the time of first progression using approaches that incorporate high dose chemotherapy and autologous stem cell transplant (ASCT). In the non-curative setting, a group of patients (including patients with advanced age and comorbidities precluding standard therapy approaches and those with lymphoma that persists despite these treatments) will be treated with palliative intent. While these patients have had limited options in the past,2,3 novel therapies have rapidly become the standard of care in this setting. Antibodies targeting CD30 (the antibody drug conjugate brentuximab vedotin [BV]) and the immune checkpoint through PD1 (nivolumab and pembrolizumab) have now become standard approved treatments for patients beyond second-line treatment. The biology of PD1 appears particularly relevant in cHL, providing a strong clinical rationale for evaluating these agents in this malignancy.4 Clinicians in Canada now have several choices when making treatment decisions in patients with relapsed or refractory cHL (RR-cHL). Prospective trials are now determining the role of anti-PD1 antibodies in the curative setting.

Current role of Immunotherapy in cHL:
Relapsed or Refractory Disease

Both nivolumab and pembrolizumab are currently approved by Health Canada for the treatment of RR-cHL and funding is broadly available across the country for this indication. Both agents were initially evaluated in phase I studies that demonstrated excellent efficacy and a favourable toxicity profile.5,6  These initial trials were followed by phase 2 studies that included several different patient cohorts.

The CheckMate-205 study evaluated nivolumab in three cohorts of patients post-ASCT, representing a total of 243 patients.7-10 The cohorts included HL patients that were BV-naïve, patients post-ASCT and subsequently treated with BV, and patients post-BV at any time during their disease course. Protocol-mandated therapy was nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or toxicity. Patients in one cohort (BV before and/or after ASCT) could discontinue treatment after 1 year in persistent complete response (CR) and could resume treatment if they relapsed within 2 years of the last dose. The overall response rate (ORR) was 69% (95% CI, 63-75) and ranged between 65-73% in each cohort while the CR rate was 16%. The median progression-free survival (PFS) in all patients was 14.7 months (95% CI 11.3-18.5 months). The most common serious drug-related adverse events (AEs) included infusion-related reactions (2%); pneumonitis (1%), pneumonia (1%), pleural effusion (1%) and fever (1%). The most common immune-mediated AEs included hypothyroidism/thyroiditis (12%; all grade 1-2), and rash (9% with 4 classified as grade 3 events) while pneumonitis was only 4% (with no grade 3-4 events).

The KEYNOTE-087 was a single-arm phase II study that examined the efficacy of pembrolizumab in a multi-cohort  that included patients with relapse post ASCT (with or without BV exposure) or with chemoresistant disease.11 Pembrolizumab was administered with a fixed dose of 200 mg IV every 3 weeks and for a fixed duration of up to 2 years. The ORR was 71.9% (95% CI: 65.3-77.9%) and the CR rate was 27.6%. The median PFS was 13.7 months (95% CI: 11.1-17.0).12 The most common grade 3 treatment-related AEs were neutropenia and diarrhea. The most common immune-mediated AEs were hypothyroidism (15.7%), pneumonitis (4.8%; none grade 3 or greater) and hyperthyroidism (3.8%). Infusion-related reactions occurred in 5.2% of patients. Quality of life and patient reported outcomes were also studied. Patients reported an improvement in QLQ-C30 functional and symptom scores at 12 and 24 weeks into therapy across all cohorts.13

The CheckMate and KEYNOTE trials in RR-cHL both demonstrate consistent patient benefit with favourable efficacy and toxicity although it is important to highlight a few key differences in the trials (Table 1). KEYNOTE-087 enrolled a cohort of patients that did undergo ASCT while the CheckMate cohorts only included patients post-ASCT failure. The CheckMate studies generally continued treatment until progression (with one cohort allowed discontinuation of treatment if patients remained in CR for at least one year) while the KEYNOTE studies limited treatment to two years. Treatment administration was every two weeks with nivolumab in the CheckMate study while it was every three weeks for pembrolizumab in the KEYNOTE study. Additional studies in malignancy have demonstrated dosing can be extended to once every 4 weeks with nivolumab (480 mg per dose) and every 6 weeks for pembrolizumab (400 mg per dose). Clinicians should consider these dosing interval differences when selecting a specific antibody for an individual patient.


Confirmatory phase III trials were performed for both antibodies. Unfortunately, CheckMate-812 (NCT03138499) which evaluated nivolumab in combination with brentuximab vedotin versus a control of BV monotherapy was terminated prematurely due to insufficient enrolment. In contrast, KEYNOTE-204 evaluated pembrolizumab in patients with RR-cHL who had relapsed post-ASCT or were ineligible for ASCT. Patients received either pembrolizumab (200 mg IV) or BV (1.8 mg/kg IV) every 3 weeks for 35 cycles or until progression or unacceptable toxicity. Efficacy results have been reported and show that pembrolizumab demonstrated an improvement in PFS over BV (HR 0.65, CI 0.48-0.88, p=0.0027; median PFS 13.2 versus 8.3 months). The overall survival analysis is event driven and results are forthcoming. The overall response rate (ORR) for pembrolizumab was 65.6% (CR 25%) and was 54.2% (CR 24%) for BV but did not reach the pre-defined statistical threshold for superiority. Quality of life was also prospectively evaluated and reported.14 EORTC QLQ-C30 and EuroQoL EQ5D scales were utilized and demonstrated improved quality of life scores with pembrolizumab compared to worsening scores with BV.

The results from the KEYNOTE-204 study portend a potential new standard of care for patients with RR-cHL that have relapsed post-ASCT or are ineligible for transplantation. Pembrolizumab has shown both favourable efficacy and quality of life when compared to BV in this patient population and supports the use of anti-PD1 antibody therapy as the preferred choice. The potential for the combination of BV and anti-PD1 antibodies is of significant clinical interest which remains, to date, unanswered due to enrolment challenges associated with  CheckMate-812. Accepting that patients in Canada are increasingly likely to receive BV earlier in the disease course (either with primary treatment based on the results of the ECHELON-1 study or as maintenance treatment post-ASCT based on the results of the AETHERA study),15,16 the use of checkpoint antibodies in RR-cHL is a well-established gold standard. Clinicians now have a positive randomized controlled trial and two large phase II trials to guide practice in Canada.

Evolving Role of Immunotherapy in cHL:
Curative Disease

The clinical trials that will shed light on the role of both nivolumab and pembrolizumab in the curative setting are currently ongoing. Phase I and II studies have evaluated both antibodies in combination in the frontline and second-line curative setting. Published studies using these therapeutic agents have largely focused on younger patients and patients undergoing salvage therapy with a goal of ASCT.

Salvage therapy studies with nivolumab have been published evaluating combinations with BV and ICE (ifosfamide, carboplatin and etoposide given sequentially after nivolumab monotherapy and in combination with nivolumab) chemotherapy.17,18 These trials highlight favourable ORR (85-95%) and CR rates (65-90%) and appear to compare favourably with traditional chemotherapy ORR and CR rates.19 Clinicians should be aware that historical results with regimens such as the GDP (gemcitabine, dexamethasone, cisplatin)  phase II experience in Canada used older outcome measures and CT (not FDG PET) imaging.20 Similar studies are being performed with pembrolizumab with a published single-arm study describing the combination with GVD (gemcitabine, vinorelbine and liposomal doxorubicin). An impressive CR rate of 92% was noted for patients in the two-cycle cohort.21 Interpretation of these studies is challenging given the lack of a randomized control arm. The Canadian Cancer Trials Group (CCTG) is currently recruiting for a randomized phase II trial of pembrolizumab and brentuximab vedotin versus GDP, followed by high dose chemotherapy and ASCT for RR-cHL.

In the frontline setting, combinations of anti-PD1 antibodies have been evaluated in combination with AVD (doxorubicin, vinblastine, dacarbazine). Nivolumab has been evaluated in the localized early unfavourable setting by the German Hodgkin Study Group (GHSG) and in an industry-sponsored study in advanced disease.22,23 Both studies demonstrated the feasibility of nivolumab-AVD in these settings. Currently, a study from the North American Intergroup is currently evaluating nivolumab-AVD versus BV-AVD in a large phase III trial (NCT03907488). Pembrolizumab has also been explored in a single arm feasibility phase II trial with 3 cycles of pembrolizumab followed by sequential AVD in early unfavourable or advanced stage cHL.24 The combination of pembrolizumab and AVD in untreated cHL is currently being studied in a larger single-arm phase II trial (NCT03331341). It is important to note the cautionary experience of nivolumab in combination with BV in the primary treatment setting for patients that were ineligible for traditional chemotherapy as this study did not meet its primary efficacy endpoint.25

Table 1 Comparison of patients’ characteristics and overall results for nivolumab, pembrolizumab, phase II trials for rr-cHL.
IRC = independent review committee; IRRs = infusion-related reactions; NR = not reported; TRAEs = treatment-related adverse events. NOTE: Comparisons are not meaningful between nivo/pembro because of highly different eligibility criteria and follow-up times. Even toxicities are difficult to compare due to the very different follow-up times.
§ In arm C only, patients were to discontinue nivolumab after one year in persistent CR and treatment could be resumed if relapse occurred within two years from the last dose; ¶ Patients attaining CR could stop treatment after a minimum of six months and 2 doses after CR; †numbers in parentheses are interquartile range (IQR); §§ 60 years; †† median duration of response for CRs versus PRs: for nivolumab 32 versus 13 months and for pembrolizumab not reached versus 10.9 months; ¶ most frequent causes; Nivolumab: IMRAEs including pneumonitis (2%) and autoimmune hepatitis (1%); Pembrolizumab: pneumonitis (3%), IRRs (1%)


Immunotherapy with nivolumab and pembrolizumab has been a major advance in the treatment of RR-cHL based on well conducted clinical trials. Current studies are evaluating these agents in combination with standard therapy for primary treatment and in the second-line curative setting. Frontline trials will require long-term follow-up and consideration of efficacy and late effects to better integrate these agents into this setting.


1. Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin’s lymphoma. N Engl J Med 2016;374:2419-29.

2. Arai S, Fanale M, Devos S, et al. Defining a Hodgkin lymphoma population for novel therapeutics after relapse from autologous hematopoietic cell transplant. Leukemia & Lymphoma 2013;54:2531-3.

3. Fermé C, Mounier N, Diviné M, et al. Intensive salvage therapy with high-dose chemotherapy for patients with advanced Hodgkin’s disease in relapse or failure after initial chemotherapy: results of the Groupe d’Etudes des Lymphomes de l’Adulte H89 Trial. Journal of Clinical Oncology 2002;20:467-75.

4. 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. Clinical Cancer Research 2012;18:1611-8.

5. 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.

6. Armand P, Shipp MA, Ribrag V, et al. Programmed death-1 blockade with pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure. Journal of Clinical Oncology 2016;34:3733.

7. Timmerman JM, Engert A, Younes A, et al. Checkmate 205 Update with Minimum 12-Month Follow up: A Phase 2 Study of Nivolumab in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma. Blood 2016;128:1110-.

8. Younes A, Santoro A, Shipp M, 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;17:1283-94.

9. Zinzani PL, Engert A, Younes A, et al. Checkmate 205 Cohort C: Nivolumab in patients with classical Hodgkin lymphoma after prior brentuximab vedotin and autologous hematopoetic stem cell transplantation. Haematologica 2016;101:43-4.

10. Armand P, Engert A, Younes A, 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.

11. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. Journal of Clinical Oncology 2017;35:2125.

12. Chen R, Zinzani PL, Lee HJ, et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 2019;134:1144-53.

13. von Tresckow B, Fanale M, Ardeshna KM, et al. Patient-reported outcomes in KEYNOTE-087, a phase 2 study of pembrolizumab in patients with classical Hodgkin lymphoma. Leukemia & lymphoma 2019.

14. Zinzani PL, Ramchandren R, Santoro A, et al. Effect of Pembrolizumab Monotherapy Versus Brentuximab Vedotin (BV) on Symptoms Associated with Health-Related Quality of Life (HRQoL) in Relapsed/Refractory (R/R) Classical Hodgkin Lymphoma (cHL) in the Randomized, Phase 3, Keynote-204 Study. Blood 2020;136:19-20.

15. 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.

16. Moskowitz CH, Nademanee A, Masszi T, 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.

17. Advani RH, Moskowitz AJ, Bartlett NL, et al. Brentuximab vedotin in combination with nivolumab in relapsed or refractory Hodgkin lymphoma: 3-year study results. Blood 2021;138:427-38.

18. Mei MG, Lee HJ, Palmer J, et al. Response-adapted anti-PD1 based salvage therapy for Hodgkin lymphoma with nivolumab +/- ICE (NICE). Blood 2022.

19. Kuruvilla J, Keating A, Crump M. How I treat relapsed and refractory Hodgkin lymphoma. Blood 2011;117:4208-17.

20. Baetz T, Belch A, Couban S, 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.

21. Moskowitz AJ, Shah G, Schöder H, et al. Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma. Journal of Clinical Oncology 2021:JCO. 21.01056.

22. Brockelmann PJ, Goergen H, Keller U, et al. Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma: The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial. JAMA Oncol 2020.

23. Ramchandren R, Domingo-Domenech E, Rueda A, et al. Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. J Clin Oncol 2019;37:1997-2007.

24. Allen PB, Savas H, Evens AM, et al. Pembrolizumab followed by AVD in untreated early unfavorable and advanced stage classical Hodgkin lymphoma. Blood 2020.

25. Cheson BD, Bartlett NL, LaPlant B, et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2020;7:e808-e15.