1. The document discusses differences in staging and treatment approaches for Hodgkin lymphoma between Europe and North America. Europe considers Stage II bulky and II B advanced stage, while North America considers them limited stage if meeting other criteria. 2. Treatment also differs, with Europe using more intensive chemotherapy such as BEACOPP for unfavorable early and advanced stages. North America reserves more intensive treatment for true advanced stages. 3. Studies have found BEACOPP improves progression-free and overall survival compared to ABVD alone for advanced Hodgkin lymphoma.

1. Transatlantic Differences in the Treatment of Hodgkin Lymphoma Joseph M Connors Centre for Lymphoid Cancer British Columbia Cancer Agency University of British Columbia Center for Lymphoid Cancer Lymphoma Leukemia Myeloma

6. Hodgkin Lymphoma Clinical Trial Treatment Groups North America Stage Limited stage CS IA, IIA, non-bulky CS IIB Advanced stage CS IIA, bulky CS III – IV

7. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe Europe Stage (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB B Sx & ESR > 30 ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Derivation To estimate likelihood of finding intra-abdominal involvement at laparotomy Based on lymphangiography without CT scanning

8. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada Clinical trial goal (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Reduce toxicity ??????? Increase disease control

9. Hodgkin Lymphoma, Stage II Where does the “Unfavorable” patient fit? 16 cm Limited stage Unfavorable stage II Advanced stage

13. 5-y TTP 83 % median follow-up 8 y

14. II A bulky II B bulky II B non-bulky P = 0.30 By group II A bulky, II B non-bulky, II B bulky

15. II B bulky P = 0.62 By stage group 5-y OS 94 % II A bulky II B non- bulky

16. I A, II A, non-bulky 2BB P < 0.0001 HR 4.2 I A, II A non-bulky n = 459 ABVD x 2 + IFRT (= true limited stage) 2BB n = 416 ABVD x 6 +/- IFRT By stage group, 2BB vs true limited

17. Stage III or IV 2BB P = 0.0059 HR = 1.5 By stage group, 2BB vs III or IV 2BB n = 416 ABVD x 6 +/- IFRT III or IV n = 673 ABVD x 6 +/- IFRT

18. Stage III or IV 2BB P < 0.0001 II A, II A, non-bulky By stage group 5-y TTP Lim 95 % 2BB 83 % III, IV 77 % 6 %, HR 1.5 12%, HR > 4

19. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada Clinical trial goal (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age Reduce toxicity Increase disease control Increase disease control

21. Hodgkin Lymphoma Clinical Trial Treatment Groups Europe vs North America Europe Stage USA / Canada (GSHG, GELA, EORTC) Early favorable stage CS I,IIA,B no risk factors Limited stage Early unfavorable stage CS I,IIA,B with risk factors Advanced stage CS III – IV, Selected CS IIB Advanced stage (intermediate) B Sx ESR > 50 mm Bulky disease > 3 Nodal sites Men over 40 y of age

25. ABVD v MOPP v MOPP/ABVD Failure-free survival Overall survival Canellos et al, NEJM, 2002

27. Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV

28. Intergroup CALGB, ECOG, SWOG, NCIC: ABVD vs MOPP/ABV

32. International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD

33. 42 % 12 % 26 % 94 % 675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compared to Original IPFP Publication

34. International Prognostic Factors Project on Advanced Hodgkin Lymphoma Treatment era = 1980s, ABVD 50 %

35. 675 Consecutive Adult Patients with Advanced Stage Hodgkin Lymphoma Treated at BCCA through 2009 Compared to Original IPFP Publication 50 %

36. B Bleomycin E Etoposide A Adriamycin C Cyclophos O Vincristine P Procarbazine P Prednisone Std mg/m 2 10 100 25 650 1,4 100 40 BEACOPP - schedule Escalated mg/m 2 10 200 35 1250 1,4 100 40 G-CSF sc 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22 restart

37. HD9 Trial Design( 1992-97 ) (1281 patients recruited) CS IIB-IIIA with risk factors CS IV Arm A 4x COPP+ABVD  RT Arm B 8x BEACOPP standard  RT Arm C 8x BEACOPP escalated  RT+G-CSF RT to initial bulk and residual tumor

38. Engert, JCO 2009; 27:4548 Kaplan-Meier analysis of the probability of (A) freedom from treatment failure COPP/ABVD arm closed early > 15 y ago

39. Kaplan-Meier analysis of the probability of (B) overall survival in each treatment arm Engert, JCO 2009; 27:4548

40. 1990s 1980s 1970s 1960s n = 2170 Progression = 80 % Progression = 20 % Time to Progression (years)

41. German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 n 161 117 HSCT Chemo

42. German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo

43. Early relapse < 12 months n = 38 German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo

44. Late relapse > 12 months n = 55 German Hodgkin Study Group, Schmitz, Lancet 2002;359:2065 HSCT Chemo

46. Cure esc BEACOPP Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma ABVD High dose chemotherapy + autologous stem cell transplant Progression Endpoints = PFS RFS EFS TTP Endpoints = OS FF2F Progression Cure

47. Potential Strategies to Cure Advanced Stage Hodgkin Lymphoma Study Regimen 5-y PFS (%) P 5-y OS (%) P Reference GHSG HD9 eBEACOPP 87 0.001 91 0.02 Diehl, 2003 COPP/ABVD 69 83 GISL HD2000 eBEACOPP 81 0.038 92 NS Federico, 2009 ABVD 68 84 GSM-HD eBEACOPP 85 0.004 89 0.39 Gianni, 2008 ABVD 73 86

48. Kaplan-Meier analysis of the probability of the progression-free survival and overall survival according to intention to treat. Federico M et al. JCO 2009;27:805-811 ©2009 by American Society of Clinical Oncology Endpoint = PFS Endpoint = OS

49. ABVD for Advanced Stage Hodgkin Lymphoma ~ 90 % 5-y OS % Year of publication First author 73 1992 Canellos 78 1998 Hasenclever 82 2003 Duggan 83 2003 Diehl 86 2008 Gianni 84 2009 Federico 90 2009 Hoskin 91 2009 Moccia 88 2010 Gordon

53. Thanks and acknowledgements Berthe Aleman Gianni Bonadonna George Canellos Vincent DeVita Volker Diehl David Duggan Andreas Engert Massimo Federico Alessandro Gianni Leo Gordon Dirk Hasenclever Sandra Horning Peter Johnson Andrew Lister Alden Moccia Saul Rosenberg Norbert Schmitz Donnall Thomas

55. Eich, JCO 2010;28:4199-4206 German Hodgkin Study Group HD 11 Trial ABVD x 4 or BEACOPP x 4 + IFRT 20 Gy vs 30 Gy 5-y TTP 85 % 2BB 5-y TTP 83 % B Sx 30 % Bulky 20 % Multivariate only bulk significant (HR ~1.8)

56. Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4 + IFRT 5-y OS 94 % 2BB 5-y OS 93 %

58. Hodgkin Lymphoma Stage II B or Stage II Bulky Disease Stage group n PFS% TTP% OS% 5-y 10-y 5-y 10-y 5-y 10-y II A bulky 135 85 85 85 85 94 93 II B non-bulky 134 80 70 80 77 95 88 II B bulky 147 78 72 82 79 94 90 All patients 416 81 76 83 81 94 90

59. Eich, JCO 2010;28:4199-4206 ABVD x 4 Or BEACOPP x 4 + IFRT

60. EFRT INRT IFRT