1. Hodgkin Lymphoma: Latest Concepts
Morton Coleman, M.D.
Director, Center for Lymphoma and Myeloma
Weill Cornell Medical Center
New York Presbyterian Hospital
New York, New York

2. THE MAIN INTENT: LESS TOXICITY
At least 85% of Hodgkin patients can anticipate a cure. The charge: cure even more patients with the least impact on their well being

3. New Techniques Interim PET scans Brentuximab vedotin
Checkpoint inhibitors

4. FDG-PET: After one (two treatments) versus two cycles (four treatments) of therapy
Early determination of treatment sensitivity in Hodgkin lymphoma: FDG-PET/CT after one cycle of therapy has a higher negative predictive value than after two cycles of therapy
Hutchings, M., Kostakoglu,L., Coleman, M., et al JCO 32: ,2014

5. Patient Population:126 Pts. Five Nation Study
Stage I 8%
Stage %
Stage %
Stage %
B Sxs %
Bulky %

6. Comparison of the prognostic value of PET 1 and PET 2: Progression Free Survival at 2 Years PET 1 PET2
Negative predictive value 98% %
Positive predictive value 63% %
Sensitivity % %
Specificity % %
Concordance >90%

7. Brentuximab Vedotin Mechanism of Action
Brentuximab vedotin (SGN-35) ADC
monomethyl auristatin E (MMAE), potent antitubulin agent
protease-cleavable linker
anti-CD30 monoclonal antibody
ADC binds to CD30
ADC-CD30 complex traffics to lysosome
MMAE is released
G2/M cell cycle arrest
MMAE disrupts microtubule network
Apoptosis

8. IMMUNE CHECKPOINT INHIBITION

9. PD-1 PATHWAY: CHECKPOINT INHIBITION AND IMMUNE SURVEILLANCE
PD-1 - programmed cell death-1 pathway.
PD-1 is expressed on the surface of activated T cells and dendritic cells.
PD-L1 and PD-L2 are overexpressed n some tumor cells.
The binding of the ligands and PD-1 inhibits cell activation.
Exhaustion of the effector cells allows the tumor to evade the immune response

10. APPLICATION: How to apply these recent techniques and reports to various forms of HL
By convention, stage I and stage II are considered local, limited or ‘early’ disease.
By convention, stage III and stage IV are considered ‘disseminated’ or advanced disease
By convention, refractory disease represents resistant or early relapsing disease. Relapse, particularly late relapse, is not the same as resistant disease.

11. Is Low Dose RT Necessary For Limited Stage HD In The Era of Interim PET?
Rapid (British) Randomized Trial: Pet after 3
PFS RT OS RT–
Canadian/German Retrospective: Pet after 2
PFS RT OS RT-
EORTC Randomized Trial: Pet after 2
PFS RT OS RT (not done)
National Cancer Database Retrospective:
PFS RT (not done) OS RT +

12. Conclusions
Even with interim PET scans, the use of RT, probably confers a 5-10 per cent improvement in disease control.
Whether the improved disease control confers much improvement in survival remains conjectural.
Long term toxicity of local RT is yet to be determined. There appears to be some short term toxicity.
Will brentuximab vedotin replace the need for RT? Would 1 cycle PET have been more accurate?

13. Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)

14. Advanced Hodgkin: What is the standard of care? ABVD v BEACOPP

15. Progression-Free Survival (Not a predefined study endpoint)
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)

16. Treatment Discontinuations for Toxicity
ABVD
n = 272
BEACOPP n = 269
Toxicity 10 28
Respiratory related (not including infections) 7 5
Hematological 4
Infection / meningitis / septicemia
Septic / toxic shock 1
Hepatic 2
Cardiac
Neurological
Allergy to etoposide
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)

17. Overall Survival
Carde et al. J Clin Oncol 30, 2012 (suppl; abs 8002)

18. The Italian Study Merli, F. et al. abs #499, ASH 2014
Long-Term Follow-up Analysis of HD2000 Trial Comparing ABVD v BEACOPP v COPP/EBV/CAD in Newly Diagnosed Advanced-Stage HL. A Study from the Fondazione Italiana Linfomi
Results: 10 yrs OS 84%,84%,86%; PFS better early with BEACOPP, but late toxicity, particularly cancer, with BEACOPP leveled out the PFS.

19. Conclusion
ABVD and BEACOPP are probably equivalent in overall survival
Any advantage of BEACOPP in disease control is lost by both early and late toxicities. The few extra ABVD failures can be rescued by ASCT obviating the need for the more intense therapy for most patients
About 30% of patients fail on therapy. Are there any new ways to enhance rx?

20. Connors, JM, et al. Abstract #292, ASH 2014
Brentuximab Vedotin Combined with ABVD or AVD for Patients with Newly Diagnosed Advanced Stage HL: Long Term Outcomes

21. Study Design Phase I, multicenter, dose-escalation study
Major eligibility criteria
Treatment-naïve HL patients
Age ≥18 to ≤60 years
Stage IIA bulky disease or Stage IIB-IV disease
Treatment design
28-day cycles (up to 6 cycles) with dosing on Days 1 and 15
Dose escalation cohorts: 0.6, 0.9, and 1.2 mgm/kg BV
Cycle 1
Cycle 2
Cycle 3
Brentuximab Vedotin
A(B)VD
6 Cycles +/- XRT 2 4 6 8 10 12
Weeks

22. Toxicity ‘Expected’ Toxicities (>10%) Nausea Neuropathy
Neutropenia: ABVD 20%,AVD 8%
Pulmonary: ABVD 44% (2),AVD 0%

23. Results:Median F/U ABVD +BV:36 Mos. AVD +BC:45 Mos.
3 Year Failure Free Survival:
AVD +BV: 92%
ABVD + BV: 79%
3 Year Overall Survival:
AVD + BV: 100%
ABVD + BV: 92%

24. Conclusions
The combination of BV with chemotherapy appears very promising
There may be some augmentation of neuropathy combining BV with vinblastine
Bleomycin should not be given with BV
ECHELON randomized study underway

25. Relapsed/Refractory HL:Does BV Have a Role in R/R disease?
Moskowitz,AJ et al. Hematologica 98:44-45, Pet-adapted therapy with BV followed by augmented ICE: 1/4 were PET neg from BV alone; 3/4 were PET net after A-ICE
Chen, R. et al. Abstract # 501 ASH, Results of a Phase II trial of BV as 1st line salvage rx in R/R HL prior to autologous HCT: 61% OOR, CR 36% PR 25%
LaCasce, A. Abstract #293 ASH, BV in combo with bendamustine (90mgm/m2) with HL who are relapsed or refractory after front line therapy: 96%OOR, CR 83%, PR13%

26. Conclusion
The data are quite impressive. Exactly how effective BV is alone, in combo or in sequence will to a large degree be determined by the size ot the cohorts between resistant and relapsing disease.
Most of the patients treated went to transplant without undue difficulty

27. Abstract #673, ASH 2014
The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin (BV) in the Treatment of Patients at Risk of Hodgkin Lymphoma Progression Following Autologous Stem Cell Transplant
CH Moskowitz, A Nademanee, T Masszi, E Agura, J Holowiecki, MH Abidi, AI Chen, P Stiff, AM Gianni, A Carella, D Osmanov, V Bachanova, J Sweetenham, A Sureda, D Huebner, EK Larsen, NN Hunder, and J Walewski
Title font , subtitle font (light gray) 27

28. Study Design, Eligibility Criteria, Treatment
Primary objective: compare progression-free survival (PFS) of brentuximab vedotin (BV) vs placebo after autotransplant for Hodgkin Lymphoma (HL)
Randomized, placebo-controlled: 78 sites in North America and Europe
Patient selection: primary-refractory; relapsed <12 mo from frontline therapy; or extranodal involvement
Patients: at least stable disease (SD) after pre-autotransplant salvage chemotherapy
329 patients randomized (1:1) to receive BV (n=165) or placebo (n=164) for 16 cycles BV (1.8 mg/kg) or placebo IV Q 21 days

29. Patient Characteristics
Brentuximab Vedotin (BV) (N=165)
Placebo (N=164)
Age, years; median (range)
33 (18–71)
32 (18–76)
Gender
46% M / 54% F
59% M / 41% F
No. prior systemic salvage therapies 1
94 (57)
86 (52) ≥2
71 (43)
78 (48)
HL status after frontline therapy
Refractory
99 (60)
97 (59)
Relapse <12 months
52 (32)
54 (33)
Relapse ≥12 months
13 (8)
Response to salvage therapy pre-HCT
Complete remission
61 (37)
62 (38)
Partial remission
57 (35)
56 (34)
Stable disease
47 (28)
46 (28)
Extranodal involvement at pre-HCT
53 (32)
B symptoms after frontline therapy
40 (24)
Pre-Transplant PET status
FDG avid
64 (39)
51 (31)
FDG negative
Not available
45 (27)

30. Patient Disposition and Exposure
Brentuximab Vedotin (BV) (N=165)
Placebo (N=164)
Treatment discontinuation, n (%)
Completed treatment
78 (47)
81 (49)
Progressive disease
24 (15)
69 (42)
Adverse event
54 (33)
10 (6)
Patient decision
9 (5)
4 (2)
All patients are off treatment
Median number treatment cycles 15 in both arms

31. Progression-Free Survival
PFS per Independent Review
PFS per Investigator BV
(N=165)
Placebo
(N=164)
HR (95% CI)
0.57 (0.40–0.81, P=0.001)
Events 60 75
Median PFS (months) 43 24
2-year PFS rate
63%
51% BV
(N=165)
Placebo
(N=164)
HR (95% CI)
0.50 (0.36–0.70)
Events 60 89
Median PFS (months) -- 16
2-year PFS rate
65%
45%

32. Overall Survival BV (N=165) Placebo (N=164) Hazard Ratio
Events 28 25
Median OS (months) --
2-year OS rate
88%
89%
Risk Factors
Relapsed <12 months or refractory to frontline therapy
Best response of PR or SD to most recent salvage therapy
Extranodal disease at pre-ASCT relapse
B symptoms at pre-transplant relapse
Two or more prior salvage therapies
No. Risk Factors N
PFS per IRF
HR (95% CI) OS ≥1
329
0.57 (0.40–0.81)
1.15 (0.67–1.97) ≥2
280
0.49 (0.34–0.71)
0.94 (0.53–1.67) ≥3
166
0.43 (0.27–0.68)
0.92 (0.45–1.88)
Ad hoc analysis

33. Conclusions
BV post-Auto HCT improved 2 year PFS in poor-risk HL patients (HR=0.57, P=0.001) of 65% BV vs 45% placebo; most benefit in highest risk subgroup
OS interim analysis: no difference between arms (HR=1.15, P=0.62), but more placebo group patients received allografts after relapse
Therapy well-tolerated; BV arm adverse events:
peripheral sensory neuropathy and neutropenia
BV consolidation therapy may be an important therapeutic option for HL patients undergoing Auto HCT to reduce relapse risk or progression

34. Presented on behalf of SWOG Lymphoma & BMT Committees and the BMT CTN
Abstract #676
SWOG 0410/BMT-CTN 0703: A Phase II Trial of Tandem Autologous Stem Cell Transplantation (AHCT) for Patients with Primary Progressive or Recurrent Hodgkin Lymphoma (HL)
Presented on behalf of SWOG Lymphoma & BMT Committees and the BMT CTN
Eileen P. Smith et al. 34

35. Pilot Study of Tandem AHCT for HL Rationale
Long term survival after auto HCT in SWOG 9011 is 54% but PFS of only 41%
Relapse is major cause of treatment failure
Patients in CR at HCT have better PFS and overall survival
5 year
54%
49 %
Henry Fung, Patrick Stiff, et al. BBMT 2007; 13: 35

36. Pilot Study of Tandem AHCT for HL Rationale
Hypothesis:
Cycle 1 cytoreduction + Auto HCT to achieve minimal disease state followed by cycle 2 augmented-conditioning regimen + Auto HCT could improve survival
Supporting Pilot Data:
Strategy of sequential high-dose chemotherapy plus tandem Auto HCT for poor prognosis HL was investigated at City of Hope & Loyola University Medical Center 36

37. Tandem Transplant Schema
Eligible patient
Progenitor cell collection for 2 Auto HCT procedures
(≥ 3.0 x 106 CD34/kg)
Melphalan 150 mg/m2 x 1 - followed by Auto HCT
Assess response
If SD or better: cycle 2 of BCNU or 12 Gy TBI plus etoposide & cyclophosphamide and Auto HCT 37

38. Consort Diagram: S0410/CTN 0703
Registered: 98
Ineligible: 6
-inadequate PFTs: 1
-Pathology issues: 2
Baseline testing incomplete: 3
Eligible: 92
Eligible, treated: 89
Eligible but did not start treatment: 3
98 patients enrolled from 10 sites, including the BTM CTN. A minimum of 28 days and maximum of 60 days was required between day zero of the first and second autologous transplant.
Completed tandem transplants: 82
No second transplant: 7
-poor engraftment: 1
-declined TBI: 1
-progression: 1
-interval between HCTs > 60 days: 4 38

39. Progression – Free Survival (PFS)
100%
80%
60%
40%
20%
At Risk
Failed
2-Year Estimate
5-Year Estimate 89 40
63%
55% 0% 24 48 72 96
Months After Registration

40. Overall Survival 5-Year Estimate 83% 100% 80% 60% 40% 20% At Risk
Deaths
2-Year Estimate
5-Year Estimate 89 15
91%
83% 0% 24 48 72 96
Months After Registration 40

41. Conclusions
With a 2 yr PFS of 63%, S0410/CTN 0703 met the predicted study endpoint of at least 15% improvement based on the historic 2 yr PFS of 45% on S9011
The better-than-expected OS of 91% is attributed to current therapy strategies for progressive & relapsed HL after Auto HCT, including brentuximab vedotin salvage & allogeneic HCT 41

42. Conclusions (con’t)
Primary refractory HL was not a prognostic factor impacting outcome after tandem Auto HCT in this phase II study in 89 pts
Suggests tandem approach is effective in subset of refractory HL patients shown to have a poor prognosis after single Auto HCT in prior studies
Results of tandem Auto HCT on S0410/CTN 0703, despite the promising results, may, in fact, simply represent a selection process where those most able to undergo a second transplant may inherently have had a better prognosis. We reported similar results more than 15 years ago, but could not rule out selection bias. Ahmed, T., Lake, D.E. , Coleman, M. Bone marrow transplant 19: , Single and double autotransplants for R/R HL: results of two consecutive trials. 42

43. Immune Checkpoint Inhibition in Hodgkin Lymphoma
PD-L is almost universally expressed on Reed-Sternberg cells
In classical HL, chromosome 9p24.1 gain is a frequent genetic structural alteration that leads to copy gain resulting in the increase of PD-1 ligands and their induction via JAK/STAT signaling.
The EB virus also increases the expression of the PD-1ligands in EBV-positive cHD

44. MONOCLONAL ANTIBODY CHECKPOINT TRIALS IN HL
Abstract #290 ASH 2014
PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Pts. with cHL after BV Failure: Preliminary Results from a Phase Ib Study (KEYNOTE-013) Moskowitz, C.H., et al.
Relapse from BV. Pembrolizumab 10mg/kg q 2 wks.
15 pts. OOR 53%, CR 20%, PR 33%

45. MONOCLONAL ANTIBODY CHECKPOINT TRIALS IN HL
Abstract #289 ASH 2014 Nivolumab in patients with relapsed of refractory HL-Preliminary Safely, Efficacy and Biomarker Results of a Phase I Study
Armand, P, et al.
Nivolumab: 3mgm/kg Q 2 wks.
23 pts heavily pretreated. OOR: 87%, CR 17%, PR 70%

46. MONOCLOANAL ANTIBODY CHECKPOINT TRIALS
SAFETY: GRADE 3 TOXICITIES IN BOTH TRIALS AROUND 10%, NO GRADE 4 TOXICITIES, NO DEATHS.
THIS APPROACH REPRESENTS A COMPLETELY NEW WAY TO TREAT HL AND HERALDS AN EXCITING BIOLOGIC TREATMENT FOR THE DISEASE.

47. CONCLUSIONS
Limited stage HL: Interim PET scans allow reduction of treatment cycles and may obviate the need for RT. Patient selection may determine the final rx decision. Cycle 1 negative PET may increase the accuracy of who is likely to remain in CR.
Advanced newly diagnosed HL: ABVD remains the gold standard. BV + AVD may increase the CR & possibly the PFS.
R/R HL: BV shows great promise as an adjunct to ASCT
R/R HL: The efficacy of double transplants is uncertain.
R/R HL: Interference of the PD-1 pathway by monoclonal antibodies is an exciting new approach to HL