Immuun Checkpoint blockade bij lymfomen Gregor Verhoef
Immuun Checkpoint blockade bij lymfomen
Gregor Verhoef
Prize motivation: "for their discovery of cancer therapy by inhibition of negative immune regulation."
James P. Allison Tasuku Honjo
Lymphoma immune evasion mechanisms.
Marie de Charette, and Roch Houot Haematologica 2018;103:1256-1268
Overview of lymphoma immune escape mechanisms
Lymphoma immune escape mechanisms
Type of immune escape
HL GC-DLBCL ABC-DLBCL PMBCL PTCL-NOS
PDL1 expression 97% 36% 4% 71% 60%
PDL2 expression 60% 26%
6
In Advanced tumors, the PD-1 Pathway May Be Exploited to Evade the Immune Response
APC = antigen-presenting cell; MHC = major histocompatibility complex; NSCLC = non‒small cell lung cancer; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor.
Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.
•SPC Keytruda®, 09/2018
•Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.
• Emerging research has identified PD-1 as a key immune checkpoint pathway involved in inhibiting the T-cell–mediated immune response
• Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD‐L1 and PD‐L2
• PD-L1 and PD-L2 engage the PD-1 receptor on T cells to inactivate them, which may allow tumor cells to evade the immune response
Antigen
MHCTCR
Activated cytotoxicT cell Tumor cell/APC
PD-L2
PD-L1PD-1
Antigen
MHCTCR
Inactivated cytotoxicT cell
PD-1
PD-L2
PD-L1
Tumor cell/APC
7
PD-1 Receptor Blockade With Pembrolizumab
• By inhibiting the PD-1 receptor from binding to its ligands, pembrolizumab/nivolumab reactivates tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and reactivates antitumor immunity1
APC = antigen-presenting cell; MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor.Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.
• SPC Keytruda®, 09/2018 • 2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.
Antigen
MHCTCR
Activated cytotoxicT cell
PD-1
KEYTRUDA
PD-L2
PD-L1
Tumor cell/APC
Antigen
MHCTCR
Inactivated cytotoxicT cell
PD-1
PD-L2
PD-L1
Tumor cell/APC
KEYTRUDA
Ribas A. N Engl J Med 2015;373:1490-1492.
T-cell Activation in the Lymph Node.
MA Postow et al. N Engl J Med 2018;378:158-168.
Immune Checkpoint–Blocking Antibodies Approved by the Food and Drug Administration.*
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma
Ansell et al, N Engl Med 2015;372:311-9
Ansell et al, N Engl Med 2015;372:311-9
Ansell SM et al. N Engl J Med 2015;372:311-319.
15
Checkpoint inhibitor therapy: a new spectrum of adverse events
Champiat et al. Annals of Oncology, 2016;27:559-74.
Ansell et al, N Engl Med 2015;372:311-9
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
Younes et al, Lancet Oncol 2016; 17:1283-94
Baseline characteristics
All patients (n=80)Previous lines of therapy
median 4(4-7)Previous autologous 80 (100%)
One 74 (93%)Two or more 6 (8%)
Previous brentuximab vedotin 80 (100%)
Younes et al, Lancet Oncol 2016; 17:1283-94
Objective response and best overall response
IRRC assessed(n=80)
Investigator assessed(n=80)
Objective response 53 (66,3%) 58 (72.5%)Best overall response
CR 7 (9%) 22 (28%)PR 46 (58%) 36 (45%)Stable disease 18 (23%) 18 (23%)
Progressive disease 6 (8%) 3 (4%)Unable to determine 3 (4%) 1 (1%)
Younes et al, Lancet Oncol 2016; 17:1283-94
Figure 1
The Lancet Oncology 2016 17, 1283-1294DOI: (10.1016/S1470-2045(16)30167-X) Younes et al, Lancet Oncol 2016; 17:1283-94
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
Armand et all, J Clin Oncol 36:1428-1439, 2018
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Fig 1. CONSORT diagram. (*) Includes seven patients who discontinued nivolumab because of persistent complete remission for 1 year. AE, adverse event.
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Table 2. Objective and Best Overall Response per IRC
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Fig A2. Duration of response in cohorts A, B, and C. All values are median (95% CI).
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Fig A3. Progression-free survival (PFS) in cohorts A, B, and C. All values are median (95% CI).
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Published in: Philippe Armand; Andreas Engert; Anas Younes; Michelle Fanale; Armando Santoro; Pier Luigi Zinzani; John M. Timmerman; Graham P. Collins; Radhakrishnan Ramchandren; Jonathon B. Cohen; Jan Paul De Boer; John Kuruvilla; Kerry J. Savage; Marek Trneny; Margaret A. Shipp; Kazunobu Kato; Anne Sumbul; Benedetto Farsaci; Stephen M. Ansell; Journal of Clinical Oncology 2018, 36, 1428-1439.DOI: 10.1200/JCO.2017.76.0793Copyright © 2018 American Society of Clinical Oncology
Fig 4. Cumulative incidence of (A) transplant-related mortality (TRM) and disease progression, (B) acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD), and (C) overall survival (OS) and progression-free survival (PFS) after allogeneic hematopoietic cell transplantation (allo-HCT). Cumulative incidence (95% CI) at 100 days and 6 months for TRM, disease progression, and GVHD, and median (95% CI) PFS and OS are shown. Death was considered a competing risk to GVHD, and post-transplant disease progression was considered a competing event to TRM. G, grade; NA, not available; NE, not estimable. Journal of Clinical Oncology 2018, 36, 1428-1439
Programmed Death-1 blockade with Pembrolizumab in patients with classical
Hodgkin lymphoma after Brentuximab vedotin failure (phase 1b Keynote-013 study)
Armand et al, J Clinic Oncol 34:3733-39, 2016
Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology
Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology
Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology
Fig 1. Response to treatment. (A) Maximum percentage change from baseline in target lesions. (B) Change from baseline in target lesions. (C) Treatment exposure and response duration. Three patients had a formal response assessment before the protocol-required time point of 12 weeks. One patient only received one dose of pembrolizumab, discontinued treatment because of toxicity at 4 weeks, and had nonprotocol scans to assess response, which showed CR. The other two patients had nonprotocol scans to confirm the clinical impression of progressive disease before the 12-week time point. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.
Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology
Published in: Philippe Armand; Margaret A. Shipp; Vincent Ribrag; Jean-Marie Michot; Pier Luigi Zinzani; John Kuruvilla; Ellen S. Snyder; Alejandro D. Ricart; Arun Balakumaran; Shelonitda Rose; Craig H. Moskowitz; Journal of Clinical Oncology 2016, 34, 3733-3739.DOI: 10.1200/JCO.2016.67.3467Copyright © 2016 American Society of Clinical Oncology
Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic
Hodgkin lymphoma
Chen et al, J Clin Oncol 35:2125-32, 2017
Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology
Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology
Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology
Fig 3. Distribution of programmed death-ligand 1 expression scores and response to pembrolizumab across all cohorts. A total of 177 patients across all cohorts had evaluable pretreatment tumor tissue and best evaluable response per central review. Three scores were reported separately: (A) staining intensity score (0-3); (B) membrane staining score (percentage of tumor cells with membrane staining 0%, > 0 to < 50%, ≥ 50 to < 100%, or 100%); and (C) histiocyte score (1-3; semiquantitative assessment of histiocytes/macrophages staining positive for programmed death-ligand 1). CR, complete remission; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease.
Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology
Published in: Robert Chen; Pier Luigi Zinzani; Michelle A. Fanale; Philippe Armand; Nathalie A. Johnson; Pauline Brice; John Radford; Vincent Ribrag; Daniel Molin; Theodoros P. Vassilakopoulos; Akihiro Tomita; Bastian von Tresckow; Margaret A. Shipp; Yinghua Zhang; Alejandro D. Ricart; Arun Balakumaran; Craig H. Moskowitz; Journal of Clinical Oncology 2017, 35, 2125-2132.DOI: 10.1200/JCO.2016.72.1316Copyright © 2017 American Society of Clinical Oncology
Nivolumab in patients with relapsed or refractory hematologic malignancies: preliminary results of
a phase Ib study
Lesokhin et al, J Clin Oncol 34:2698-2704, 2016
Lesokhin et al, J Clin Oncol 34:2698-2704, 2016
Lesokhin et al, J Clin Oncol 34:2698-2704, 2016
Lymphoma immune escape mechanisms
Type of immune escape
HL GC-DLBCL ABC-DLBCL PMBCL PTCL-NOS
PDL1 expression
97% 36% 4% 71% 60%
PDL2 expression
60% 26%
Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell
lymphoma
by Pier Luigi Zinzani, Vincent Ribrag, Craig H. Moskowitz, Jean-Marie Michot, John Kuruvilla, Arun Balakumaran, Yayan Zhang, Sabine Chlosta, Margaret A. Shipp, and
Philippe Armand
BloodVolume 130(3):267-270
July 20, 2017
Clinical outcome
N(%) (N=17)ORR 7 (41.2%)
CR 2 (11.8%)PR 5 (29.4%)
Stable disease 6 (35.3%)Progressive disease 3 (17.6%)No assessment 1 (5.9%)
Pier Luigi Zinzani et al. Blood 2017;130:267-270
Treatment response in the 16 pembrolizumab-treated patients with rrPMBCL who were evaluable (by imaging) for efficacy at the time of data cutoff.
Pier Luigi Zinzani et al. Blood 2017;130:267-270
PD1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma
(Nayak et al, Blood, 2017;129:3071-73
• Frequent 9p24.1/PD-L1/PD-L2 copy-number alterations and increased expression of the PD-1 ligands in PCNSZL and PTL
• N=5• 100% responses, 4 CR, 1 PR • Progression-free survival: 13+, 17, 17+, 14, 14+
Pre- and posttreatment head CTs with contrast in a patient with primary refractory PCNSL. (Left) The contrast-enhancing lesion before treatment with nivolumab.
Lakshmi Nayak et al. Blood 2017;129:3071-3073
PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase (Kwong
et al, Blood, 2017;129:2437-2442
• N=7• 100% responses, • After median follow up of 6 months: 5 patients remain in CR• Strong PDL1 expreesion on lymphoma cells in 4/5 patients tested
Actively recruiting trials of immunotherapy in lymphoma
MA Postow et al. N Engl J Med 2018;378:158-168.
Organs Affected by Immune Checkpoint Blockade.
54
Pembrolizumab:Immune-mediated Adverse Reactions1
Adverse ReactionPEMBROLIZUMAB
N=3830Grade 1-2 (%) Grade 3-5 (%) Total (%)
Pneumonitis 2,3 1,3 3,6Colitis 0,6 1,1 1,7Hepatitis 0,3 0,4 0,7Nephritis 0,1 0,2 0,3Hypophysitis 0,2 0,3 0,5Hyperthyroidism 3,2 0,1 3,3Hypothyroidism 9,6 0,2 9,8Cutaneous irAE 0,3 1,4 1,7
1. Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018
• Evaluation based on 4,439 patients with advanced melanoma, NSCLC, cHL urothelial carcinoma and HNSCC.
Grafiek1
PneumonitisPneumonitis
ColitisColitis
HepatitisHepatitis
NephritisNephritis
HypophysitisHypophysitis
HyperthyroidismHyperthyroidism
HypothyroidismHypothyroidism
Cutaneous irAECutaneous irAE
Grade 1-2
Grade 3-5
2.3
1.3
0.6
1.1
0.3
0.4
0.1
0.2
0.2
0.3
3.2
0.1
9.6
0.2
0.3
1.4
Sheet1
Fatigue21%
Pruritus16%
Rash13%
Diarrhoea12%
Nausea10%
G1-2G3-5Total
Pneumonitis2.31.33.6
Colitis0.61.11.7
Hepatitis0.30.40.7
Nephritis0.10.20.3
Hypophysitis0.20.30.5
Hyperthyroidism3.20.13.3
Hypothyroidism9.60.29.8
Cutaneous irAE0.31.41.7
Sheet1
Grade 1-2
Grade 3-5
Sheet2
Sheet3
55
Pembrolizumab: Immune-mediated Adverse Reactions Median Time to Onset and Median Duration1
• mo = months; NR = not reached; NSCLC = non‒small cell lung cancer; cHL: classical Hodgkin lymphoma; HNSCC: head and neck squamous cell carcinoma
• Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018
• Median time to onset and median duration of immune-mediated adverse reactions are presented based on 4,439 patients with advanced melanoma, NSCLC, cHLurothelial carcinoma and HNSCC.
Months
Median Time to Onset
Months
Median Duration
NR
(2 days–21.3 mo)
(7 days–16.2 mo)
(8 days–21.4 mo)
(1 day–17.7 mo)
(1 day–21.9 mo)
(1 day–18.9 mo)
(12 days–21.4 mo)
(1 day–17.2+ mo)
(1 day–8.7+ mo)
(8 days–20.9+ mo)
(4 days–12.7+ mo)
(10 days–15.5+ mo)
(2 days–29.9+ mo)
(10 days–10.5+ mo)
Grafiek1
Nephritis
Hypothyroidism
Hyperthyroidism
Hypophysitis
Hepatitis
Colitis
Pneumonitis
Series 1
4.9
3.5
1.4
3.7
2.0
3.6
3.4
4.9
3.5
1.4
3.7
2
3.6
3.4
Sheet1
Series 1
Nephritis4.9
Hypothyroidism3.5
Hyperthyroidism1.4
Hypophysitis3.7
Hepatitis2
Colitis3.6
Pneumonitis3.4
mTollulmDllul
Pneumonitis3.70.066666666721.32.10.033333333317.2
Colitis3.60.233333333316.21.30.03333333338.7
Hepatitis1.30.266666666721.41.50.266666666720.9
Nephritis4.90.412.81.80.333333333310.5
Hypophysitis3.70.033333333317.73.30.133333333312.7
Hyperthyroidism1.40.033333333321.92.10.333333333315.5
Hypothyroidism3.50.033333333318.90.066666666729.9
Cutaneous irAE2.50.133333333321.520.117.8
Grafiek1
Nephritis
Hypothyroidism
Hyperthyroidism
Hypophysitis
Hepatitis
Colitis
Pneumonitis
Series 1
1.8
2.0
3.3
1.7
1.2
2.0
1.8
2
3.3
1.7
1.2
2
Sheet1
Series 1
Nephritis1.8
Hypothyroidism
Hyperthyroidism2
Hypophysitis3.3
Hepatitis1.7
Colitis1.2
Pneumonitis2
56
Pembrolizumab: Immune-mediated Adverse ReactionsRate of Discontinuation1
• NSCLC = non‒small cell lung cancer; cHL= classical Hodgkin lymphoma; HNSCC: head and neck squamous cell carcinoma
• Prescribing Information KEYTRUDA® (pembrolizumab), SPC Keytruda®, 09/2018
Patients, %
• Rate of discontinuation from treatment due to immune-mediated adverse reactions is presented based on 4,439 patients with advanced melanoma, NSCLC, cHL urothelial carcinoma and HNSCC.
Rate of Discontinuation
Open questions checkpoint blocking in lymphoma
• Duration of therapy?• Bridge to allo-transplant?• Treatment option for other types of lymphoma?• Combination therapy?• Second or first line therapy?• Biological markers for predicting response?
Immuun Checkpoint blockade bij lymfomenSlide Number 2Slide Number 3Overview of lymphoma immune escape mechanismsLymphoma immune escape mechanismsIn Advanced tumors, the PD-1 Pathway May Be Exploited to Evade the Immune ResponsePD-1 Receptor Blockade With PembrolizumabRibas A. N Engl J Med 2015;373:1490-1492.MA Postow et al. N Engl J Med 2018;378:158-168.PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphomaSlide Number 12Slide Number 13Ansell SM et al. N Engl J Med 2015;372:311-319.Checkpoint inhibitor therapy: a new spectrum of adverse eventsSlide Number 16Slide Number 17Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trialBaseline characteristicsObjective response and best overall responseSlide Number 21Nivolumab 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 trialSlide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Programmed Death-1 blockade with Pembrolizumab in patients with classical Hodgkin lymphoma after Brentuximab vedotin failure (phase 1b Keynote-013 study)Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Phase II study of the efficacy and safety of Pembrolizumab for relapsed/refractory classic Hodgkin lymphomaSlide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Nivolumab in patients with relapsed or refractory hematologic malignancies: preliminary results of a phase Ib studySlide Number 43Slide Number 44Lymphoma immune escape mechanismsSlide Number 46Clinical outcomeSlide Number 48PD1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma�(Nayak et al, Blood, 2017;129:3071-73Slide Number 50PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase (Kwong et al, Blood, 2017;129:2437-2442Slide Number 52MA Postow et al. N Engl J Med 2018;378:158-168.Pembrolizumab:�Immune-mediated Adverse Reactions1Pembrolizumab: �Immune-mediated Adverse Reactions �Median Time to Onset and Median Duration1Pembrolizumab: �Immune-mediated Adverse Reactions�Rate of Discontinuation1Open questions checkpoint blocking in lymphoma