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

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. EARLY STAGE HODGKIN HISTORY 5-10 yr. relapse rate lower for chemotherapy + IF RT than EF RT alone (JCO 24: 3128-35, 2006; JC0 25: 3495-3502, 2007; NEJM 357: 1916-27, 2008) No difference in OS at 4-5-yrs. between ABVD alone and ABVD + RT for patients with limited stage non-bulky HL (Blood 104: 3483-89, 2004; JCO 23: 4634-42, 2005) RT is associated with late 2 nd malignancies and cardiovascular events especially after 10 yrs. (JCO 21: 3431-9, 2003; NEJM 355: 1572-82, 2006; JCO 27 [Suppl.] abs. 8547, 2009 courtesy Straus,D

4. Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression. Meyer RM et al. N Engl J Med 2012;366:399-408

5. Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression among Patients with an Unfavorable Risk Profile. Meyer RM et al. N Engl J Med 2012;366:399-408

6. What role does PET Scans play in this effort? May interim PET/CAT scans be of value or should scans be used only at the end of treatment?

7. In Vivo Treatment Sensitivity With Positron Emission /Computed Tomography After One Cycle of Chemotherapy for Hodgkin Lymphoma Martin Hutchings, Lale Kostakoglu, Morton Coleman, et al. JCO 32: 2705-2711, 2014

8. 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

9. Participating Nations Denmark United States Italy Poland (Nine Institutions)

10. Patient Population:126 Pts. Stage I 8% Stage 2 46% Stage 3 19% Stage4 27% B Sxs 56% Bulky 37%

11. Comparison of the prognostic value of PET 1 and PET 2: Progression Free Survival at 2 Years PET 1 PET2 Negative predictive value 98% 91% Positive predictive value 63% 85% Sensitivity 94% 61% Specificity 86% 97% Concordance >90%

12. Involved Field Radiotherapy Versus No Further Treatment in Patients with Early- Stage Hodgkin Lymphoma and Negative PET Scan After 3 ABVD Cycles: Resuts of the UK NCRI RAPID Trial Proc ASH 120,2012; Abstract 547 Radford J, Barrington S, Counsell N, et al

13. Initial treatment: ABVD x 3 Reassessment: if NR/PD, patient goes off study 571ptsif CR/PR, FDG-PET scan performed 4 th cycle ABVD then IFRT Randomization IFRT (209 pts) No further treatment (211pts) PET-positive (145pts) PET negative (420 pts) RAPID Trial Design Radford J, et al. Blood. 2012;120: Abstract 547.

14. PET negative; randomized to IFRT (n = 209) PET negative; randomized to NFT (n = 211) PET positive; 4th cycle ABVD/IFRT (n = 145) Progressions92011 Deaths818 PFS at 3 years93.8%90.7%85.9% OS at 3 years97.0%99.5%93.9% Outcomes After Median Follow-Up of 45.7 Months Radford J, et al. Blood. 2012;120: Abstract 547.

15. Summary 602 pts registered between 2003 and 2010 75% PET-negative at central review after ABVD x 3 In the randomized PET-negative population, 3 yr PFS is 92.8% IFRT and 90% NFT Risk difference -3% is within the maximum allowable difference of -7% Radford J, et al. Blood. 2012;120: Abstract 547.

16. Commentary These data are similar to those reported from Argentina several years ago for all stages of disease when PETs were obtained after 3 cycles (Pavlosky, et al.) CAUTION: Were the deaths in the IFRT arm ‘flukes’ and not related to the IFRT? If so, would the data and conclusions be different. Radford J, et al. Blood. 2012;120: Abstract 547.

17. An Individual Patient-Data Comparison of Combined Modality Therapy and ABVD Alone for Patients with Limited Stage Hodgkin Lymphoma A study of the NCIC (HD 6) and the German Hodgkin Study Group (HD 10 &11) Hay AE, Klimm B, Chen BE, et al Annals of Oncology 24 (12) 3065-3069, 2013

18. Favorable: CS IA,IB, IIA, IIB without risk factors Unfavorable: CS IA, IB, with at least one of the risk factors a-d given below or CS IIB with risk factor c, d, or both given below: and IIA a) Large mediastinal mass (≥1/3 of maximum transverse thorax diameter) b) Extranodal involvement c) High erythrocyte sedimentation rate (≥50 mm/h in patients without B-symptoms, ≥30 mm/h in patients with B- symptoms) d) 3 or more involved lymph node areas Eich HT, et al. J Clin Oncol. 2011;28:4199-4206. GHSG Early-Stage HL Risk Factors

19. HD.6 Trial Meyer RM, et al. N Engl J Med. 2012;366:399-408. Study schema of a randomized trial comparing a strategy that includes radiation therapy with ABVD in patients with limited-stage Hodgkin lymphoma Patients with Clinical Stage I-IIA Hodgkin Lymphoma Exclude low-risk patients Stage IA with single node of Hodgkin lymphoma and all of: Lymphocyte predominant or nodular sclerosis histology Bulk <3cm ESR <50 mm/hour Disease involving high neck or epitrochlear region only Exclude high-risk patients Patients with either: Bulk >10 cm or ≥1/3 chest wall diameter, or Intra-abdominal disease Favorable or unfavorable cohort Unfavorable cohort patients have any of: Age ≥40 years ESR ≥50 mm/hour Mixed cellularity or lymphocyte deplete histology ≥4 sites of disease Treatment that includes radiation therapy Favorable cohort: subtotal nodal radiation therapy Unfavorable cohort: combined modality therapy with ABVD x 2 cycles plus subtotal nodal radiation therapy ABVD as a single modality Both cohorts: ABVD x 2 cycles IF CR or CRu, ABVD x 2 more cycles (total 4 cycles) If <CR or CRu, ABVD x 4 more cycles (total 6 cycles) Stratify Randomly Assign

20. 2 ABVD + 20 Gy IFRT Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and Preferred Arms 4 ABVD + 30 Gy IFRT 4 – 6 ABVD alone Early, unfavorable HD11 Early, favorable HD10 Advanced HD.6 Favorable Unfavorable NCIC CTG GHSG Advanced Not necessarily to scale Hay AE, et al. Blood. 2012;120: Abstract 549.

21. Very good prognosis B or Bulk Early, unfavorable HD11 Early, favorable HD10 Advanced HD.6 Favorable Unfavorable NCIC CTG GHSG Advanced Not necessarily to scale Hay AE, et al. Blood. 2012;120: Abstract 549. Comparison of NCIC CTG HD.6 and GHSG HD10 and HD11 Staging, Eligibility and Preferred Arms

22. Attribution of Death: All Patients Cause of Death Number Med. F/U GHSG HD10/11 406 7.6 Years NCIG CTG HD.6 182 11.2 Years Hodgkin lymphoma Immediate toxicity 5252 4141 Second cancer Cardiac Other 2 4 6* 320320 Total1910 *Other deaths were: 1 suicide, 1 respiratory failure, 1 cerebral hemorrhage, 1 progression of NHL, 2 unknown Hay AE, et al. Blood. 2012;120: Abstract 549.

23. Outcomes: All Patients Hay AE, et al. Blood. 2012;120: Abstract 549. Endpoint Number Med. F/U GHSG HD10/11 406 7.6 Years NCIG CTG HD.6 182 11.2 Years HR (95% CI) GHSG PD/OS NCIC CTG PD/OS 8-yr TTP93%87%0.44 (0.24, 0.78)25/023/0 8-yr PFS89%86%0.71 (0.42, 1.18)25/1323/4 8-yr OS95% 1.09 (0.49, 2.40)1910

24. Overall Commentary Combined modality therapy (CMT) improves disease control by 4%-7% Could this difference in control have been obviated by the use of PET scans after one cycle of therapy since there was a 7% difference in PET negative results between cycles 1 and 2, much less cycle 3? The relatively long term outcomes associated with IFRT remain to be clarified

25. Omitting Radiotherapy in Early Positron Emission Tomography- Negative Stage I/II Hodgkin Lymphoma Is Associated With an Increased Risk of Early Relapse: Clinical Results of the Preplanned Interim Analysis of the Randomized EORTC/LTSA/FIL H10 Trial Raemaekers, J.M.M., Andre, Marc P.E., Federico, M. JCO 32:1188-1194, 2014

26. Study design of European Organisation for Research and Treatment of Cancer, Lymphoma Study Association, and Fondazione Italiana Linfomi H10 20551 trial of patients age 15 to 70 years with untreated supradiaphragmatic clinical stage I/II Hodgkin lymphoma Raemaekers J M et al. JCO 2014;32:1188-1194 2014 by American Society of Clinical Oncology

27. Flowchart of patients included in interim analysis. Raemaekers J M et al. JCO 2014;32:1188-1194 2014 by American Society of Clinical Oncology

28. Results: Progression Favorable: no RT – 9 (5%) with RT-1 (0.5%) Unfavorable: no RT-16 (5%) with RT-7 (2.6%) Study is now closed.

29. Early-Stage Hodgkin's Disease: The Utilization of Radiation Therapy and Its Impact on Overall Survival Rahul R. Parikh, M.D. 1, Joachim Yahalom, M.D. 2, James A. Talcott, M.D. 3, Michael L. Grossbard, M.D. 3, & Louis B. Harrison, M.D. 4 1 Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System, Department of Radiation Oncology, New York, NY 2 Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY 3 Mt. Sinai Beth Israel Medical Center & Mt. Sinai St. Luke’s-Roosevelt Hospitals, Mount Sinai Health System, Department of Hematology-Oncology, New York, NY 4 Department of Radiation Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL Abstract No: CT-08

30. Background  National Cancer Database (NCDB)  Joint program of the Commission on Cancer and the American Cancer Society  Prospectively collected; Nationwide outcomes database covering 75% of all newly diagnosed cancers (>1,500 U.S. hospitals);  Not population-based dataset  Not geographically limited (care in all states included)  Reflects contemporary treatment programs  RT specifics available for analysis (modality, dose, fx, volume/site)

31. Aims of the Study  Primary Endpoint:  Determine relationship between use of RT and overall survival in patients with early- stage Hodgkin’s Disease  Secondary Endpoints:  Determine the trends of utilization rates of RT  Determine other factors (socioeconomic factors, timing of chemotherapy, co-morbid conditions) associated with overall survival

32. Methods Did NOT receive Radiation Therapy (N = 20,897, 51%) Did NOT receive Radiation Therapy (N = 20,897, 51%) Received Radiation Therapy as part of CMT (N = 20,523, 49%)  Median RT dose = 30.6 Gy Received Radiation Therapy as part of CMT (N = 20,523, 49%)  Median RT dose = 30.6 Gy Hodgkin’s Disease, Stage I/II, diagnosed 1998-2011 (N = 41,420)  Median f/u = 6.4 years;  Median age = 37 years (range: 18-90)  Multi-agent chemotherapy given to 96% of the pts Hodgkin’s Disease, Stage I/II, diagnosed 1998-2011 (N = 41,420)  Median f/u = 6.4 years;  Median age = 37 years (range: 18-90)  Multi-agent chemotherapy given to 96% of the pts  Evaluated clinical features & survival outcomes  The association between RT use, co-variables, and outcome was assessed in a multivariate Cox proportional hazards model.  Survival was estimated using the Kaplan-Meier method.

33. Prognostic FactorHR (95% CI)p-value RT No1.00 (Ref.) <0.0001* Yes0.51 (0.48-0.54) Age (years) at Diagnosis ≤ 400.19 (0.18- 0.20) <0.0001* > 401.00 (Ref.) Gender Male1.00 (Ref.) <0.0001* Female0.81 (0.76-0.86) Stage 11.00 (Ref.) <0.0001* 20.70 (0.66-0.74) Presence of “B” Symptoms No1.00 (Ref.) <0.0001* Yes1.65 (1.46-1.87) Charlson/Deyo co- morbidity score 01.00 (Ref.) <0.0001* 13.14 (2.76-3.57) 25.19 (4.23-6.36) Transplant Proc. No1.00 (Ref.) 0.012* Yes1.64 (1.15-2.35) Prognostic FactorHR (95% CI)p-value Timing of Chemotherapy ≤30 days from dx0.67 (0.64- 0.72) <0.0001* >30 days from dx1.00 (Ref) Education (% not HS grad) ≥ 29%1.00 (Ref.) <0.0001* 20-28.9%0.84 (0.76-0.92) 14-19.9%0.75 (0.69-0.82) <14%0.62 (0.56-0.67 Household Income < $30,0001.00 (Ref.)<0.0001* $30,000-34,9990.92 (0.83-1.01) $35,000-45,9990.79 (0.72-0.87) ≥ $46,0000.62 (0.57-0.68) Insured Status<0.0001* Insured (Medicare, Private / Managed Care) 1.00 (Ref.) Not Insured / Medicaid 5.27 (4.97-5.59) Facility Type Comm. Cancer Prog.1.00 (Ref.) <0.0001* Comprehen Cancer Prog0.84 (0.77-9.23) Academic/Res. Prog.0.66 (0.60-0.73) Other0.96 (0.77-1.19) Univariate Survival Analysis (OS)

34. HRLCLUCL Utilization of RT (yes vs. no) 0.470.430.53 Age (≤40 vs. >40)0.230.200.26 Race (black vs. white)0.930.791.11 Race (other vs. white)0.810.690.91 Insured status (Uninsured vs. Insured)3.483.133.87 Stage (1 vs. 2)0.890.77 1.02 B Symptoms (yes vs. no)1.721.501.97 Transplant performed (yes vs. no)2.661.594.45 Co-morbidity score (1 vs. 0)1.941.692.23 Co-morbidity score (2 vs. 0)2.932.343.65 Timing of chemo (≤30 days vs. >30days) 0.840.760.94 Factors Associated with Overall Survival (MVA)

35. Overall Survival by RT use 84% 76%

36. RT Utilization Reason for No RadiationFreq.% Radiation was not part of the planned initial treatment strategy18,48286.30 Radiation was contraindicated1850.86 Radiation recommended but not administered1,0414.86 Radiation recommended but refused by the patient2791.30 Radiation recommended, unknown whether delivered8724.07 Unknown if recommended or administered5612.62 Total21,420100.00 ` 41% 2011 56% 1998

37. Conclusions  Largest contemporary dataset of patients with early- stage HD (n=41,420)  The use of RT is associated with improved 10-yr OS (84% vs. 76%, HR=0.51, p<0.00001) BUT THIS MAY BE DUE TO A POPULATION WITH AN INHERENT BETTER PROGNOSIS  Utilization of RT has decreased by 15% from 1998 to 2011 (56  41%; not part of initial treatment strategy) Specific factors (socioeconomic, insurance status, facility type) were associated with underutilization of RT which may be targeted to improve patient access to RT, IF RT IS INDEED INDICATED

38. 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 MMAE disrupts microtubule network ADC-CD30 complex traffics to lysosome MMAE is released Apoptosis G2/M cell cycle arrest

39. Frontline Therapy With Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced-Stage Hodgkin Lymphoma Abstract 798, ASH 2012 Ansell SM, Connors JM, Park SI, et al

40. 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 – I-6, II-13, III-6, IV-6, expansion-20 A(B)VD Brentuximab Vedotin Cycle 1 Cycle 2 Cycle 3 6 Cycles +/- XRT Weeks 0 24681012 Ansell SM, et al. Blood. 2012;120: Abstract 798.

41. Response Results at End of Front-Line Therapy Response per Investigator a ABVD with brentuximab vedotin N = 22 AVD with brentuximab vedotin N = 25 Response at end of front-line therapy, n (%) Complete remission21 (95)24 (96) Progressive disease01 (4) Not evaluable due to AEs1 b (5)0 a Assessed using Cheson 2007 b Patient had a Grade 5 event of pulmonary toxicity prior to the end of front-line therapy Response results at end of front-line therapy: ◦ ABVD cohorts: 21 of 22 CR (95%) ◦ AVD cohorts: 24 of 25 CR (96%) In addition, 1 patient withdrew consent and 3 patients were lost to follow-up prior to completion of front-line therapy and were not evaluable for response Ansell SM, et al. Blood. 2012;120: Abstract 798.

42. CONCLUSIONS: EARLY STAGE HL PET SCANS HAVE ALLOWED THE REDUCTION OF CHEMOTHERAPY CYCLES IN EARLY STAGE HL. COMBINED MODALITY THERAPY (CMT)PROVIDES ABOUT ABOUT A 5% (+/- 3%)ADVANTAGE OVER CHEMOTHEAPY ALONE IN PFS ALTHOUGH OS ADVANTAGE REMAINS TO BE PROVEN. THE LONG TERM TOXICITY OF LIMITED OR NODAL FIELD RT IS STILL UNKNOWN. ACUTE TOXICITY MAY PLAY A ROLE IN REDUCING OS? PET SCANS AFTER 1 CYCLE MAY REDUCE THE PFS ADVANTAGE OF CMT. PATIENT SELECTION IS CRITICAL IN DECIDING WHAT RX TO ADMINISTER. WILL BRENTUXIMAB VEDOTIN REPLACE THE ‘NEED’ FOR RT?

43. Acknowledgment Clinical Research (Cornell) Jia Ruan, M.D., Ph.D. Richard Furman, M.D. John P. Leonard, M.D. Peter Martin, M.D. Maureen Joyce, R.N. Patricia Glenn, R.N. Jamie Ketas Jessica Hansen Karen Weil Jennifer O’Loughlin Wayne Tam, M.D. Amy Chadburn, M.D. (Northwestern) Elizabeth Hyjek, M.D., Ph.D. Biostatistician Madhu Mazumdar, Ph.D. (Cornell) Translational Core Maureen Lane, Ph.D. (Cornell) Maureen Ward Laboratory Research Ari Milneck, M.D., Ph.D.(Cornell) Katherine Hajjar, M.D. (Cornell) Shahin Rafii, M.D. (Cornell) Lymphoma Research Foundation ASCO Foundation (YIA, CDA) NIH / NHLBI

44. THANK YOU FOR YOUR ATTENTION