Volker Diehl, M.D., Professor, University of Cologne, Germany Customization: The Treatment of Hodgkin's Disease Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. Hodgkin Lymphoma Management:
State of the Art 2011
Volker Diehl
for the
German Hodgkin Study Group
(GHSG)
Hackensack, New York
3.November 2011

2. Hodgkin´s Disease 1865
 Hodgkin Lymphoma 1991
A malignant Lymphoma with features of an
innate immunity driven tumor -
a chimera between
Infection- Inflammation and Tumor
EBV: yes
Tuberculosis: no
Syphilis: no
Monoclonal B-cell- Active Innate Immunity-
Lymphoma Microenvironment

3. The German Hodgkin Study
Group Experience
1978–2010
6 Generations of Hodgkin
Trials
20.000 pats documented since
1978
 400 centers recruiting
220 private hem-oncologists
In Germany, Austria, Switzerland,
Tschechia, Holland

4. How to personalize therapy?
..until we have the right targets...
Use:
1.Risk Factor Prediction (IPS, GHSG-EORTC- Criteria)
2.Response Adaptation (FDG-PET)
3.Molecular-Genetic Markers
f.e. CD68+ macrophages: Steidl et al, NEJM, 2010
9

5. GHSG Iniative I
Personalize Therapy
1. Search for the molecular target
2. Specify the role of the microenvironment
3. Find molecular- genetic risk/prognostic markers
f.e. CD68+ macrophages (Steidl et al NEJM)
Host-
Tumor ImmuneResponse/
Microenvironment
Targeted Therapy

6. GHSG Initiatives II
• Early favorable Stages:
- chemotherapy alone for PET neg pats
• Early unfavorable stages:
- intensify chemotherapy
- no RT for PET neg pats at end of chemo
• Advanced Stages:
- detoxify BEACOPP, maintain efficacy
• Refract/Relapse:
- optimize 2nd response with targeted therapy

7. Early Favorable Stage :
GHSG: HD10- Trial
CS I–II without risk factors
ABVD ABVD ABVD ABVD
ABVD ABVD ABVD ABVD
ABVD ABVD
ABVD ABVD
30 Gy IF 20 Gy IF 30 Gy IF 20 Gy IF
2003: 1375 patients recruited.
Trial closed 1/2003.

8. HD10: Early Stage HL
Overall Survival
Median observation time = 91 months
1.0
0.9
0.8
0.7
No difference for
Overall Survival
0.6
0.5 2 ABVD vs 4 ABVD
0.4
and
0.3
0.2
20 vs 30 GY
0.1
30 Gy RT 20 Gy RT
0.0
0 12 24 36 48 60 72 84 96 108 120
Time [months]
Pts. at Risk
30 Gy RT 575 570 561 556 551 534 468 351 227 124 32
20 Gy RT 589 584 576 569 561 539 467 346 232 131 25
GHSG 2009 – HD10

9. Early Favorable Group
Current GHSG Study HD13
(985 patients recruited!)
Stages I, II without RF
A B C D
ABVD ABV AVD AV
ABVD ABV AVD AV
203 pats
200 pats 204 pats 201 pats
30 Gy 30 Gy 30 Gy 30 Gy
IF-RT IF-RT IF-RT IF-RT
30 Gy because of the reduction of chemotherapy!

10. HD16:
GHSG-Study for Early favorable Stages
CS I/II ohne RF*
Standard Experimental
Arm Arms
2 x ABVD 2 x ABVD 2 x ABVD
PET (+/-) PET- PET+
20 Gy IF Follow up 20 Gy IF
*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

11. Early Favorable Stages
Ongoing Studies
• GHSG HD16: 2 ABVD  PET neg Nil
• UK- RAPID Trial : 3 ABVD  PET neg Nil
• EORTC HD10: 4 ABVD  PET neg Nil
• USA-Intergroup: 4 ABVD  PET neg Nil

12. Hodgkin Lymphoma: Risk Adaptation
in the GHSG
Early
favourable
Early Advanced
unfavor Advanced Stages
stages
-able

13. GHSG Initiatives III
• Early favorable Stages:
- chemotherapy alone for PET neg pats
• Early unfavorable stages:
- intensify chemotherapy
- no RT for PET neg pats at end of chemo
• Advanced Stages:
- detoxify BEACOPP, maintain efficacy
• Refract/Relapse:
- optimize 2nd response with targeted therapy

14. HD14 study (GHSG)
for early unfavorable HL
Stages I, IIA with RF a-d; IIB with RF c,d
BEACOPP escalated
ABVD BEACOPP escalated
ABVD
ABVD
ABVD ABVD
ABVD
30 Gy IF 30 Gy IF
*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

15. HD-14: FFTF
median observation time = 42 months
1.0
0.9
0.8
0.7 P < 0.001
0.6 5-year FFTF 95%CI
FFTF
0.5 Arm A 87,3% [83,8% - 90,2%]
0.4 Arm B 95,0% [93,0% - 96,4%]
0.3 difference 7,6% [4,0% - 11,3%]
0.2
0.1
A B
0.0
0 12 24 36 48 60
Pts. at Risk Time [months]
A 761 723 698 637 557 466 388 306 238 184 103
B 758 722 695 653 561 490 413 331 259 199 127
15

16. Progression and Relapse
Median observation time = 42 months
Arm A Arm B
ITT analysis set (ABVD) (“2+2”)
N=818 N=805
Type of event N % N %
progression 24 2.9 7 0.9
Early relapse 23 2.8 7 0.9
Late relapse 19 2.3 7 0.9
Ʃ 66 8,1 21 2,6
GHSG HD14 - Final Analysis July 16
2010 - V.2.0 (October 2010)

17. Progress in
Intermediate stages
GHSG data
Trial Chemotherapy Failure Rate
HD 8 4 C/ABVD 18%
HD11 4 BEACOPP or 4 ABVD 16%
HD14 2 BEAesc + 2 ABVD 3%

18. Pregnancy, offspring, or
ammenorrhea after therapy
Only women up to 40 y from the ongoing HD14 fertility survey project
fertility status 4x ABVD „2+2“
> 1y AFTER therapy (arm A) (arm B)
N % N %
pregnancy/child: NO 114 89 93 82
pregnancy/child:
14 11 21 18
YES
amenorrhea: NO 119 87.5 109 83.8
amenorrhea: YES 17 12,5 21 16,2
Men: fathered 12% 5%

19. Next GHSG trial
for early unfavorable (HD17)
Early unfavorable HL
2xBEACOPP esc +
2xABVD
PET - PET +
30 Gy IF No Rx 30 Gy IF 30 Gy IN
Follow-up
GHSG 2010

20. GHSG Initiatives IV
• Early favorable Stages:
- chemotherapy alone for PET neg pats
• Early unfavorable stages:
- intensify chemotherapy
- no RT for PET neg pats at end of chemo
• Advanced Stages:
- detoxify BEACOPP, maintain efficacy
• Refract/Relapse:
- optimize 2nd response with targeted therapy

21. What is the best
Induction Therapy
for
Advanced Hodgkin Lymphoma?

22. ABVD compared with BEACOPP
in advanced stage HL trials (% of pts)
Source Chemotherapy 5-y FFS 5-y OS
Canellos 6-8 ABVD 61 73
Duggan 2003 8-10 ABVD 63 82
8 ABVD 73 (7ys) 82 (7ys)
Viviani 2011 8 x 4+4 e/b BEA 85(7ys) 88 (7ys)
Diehl 2003 HD9 4 (COPP+ABVD) 68 83
8 BEACOPP esc. 88 92
GHSG 2011 HD15 6 BEACOPP esc 90,3 95,3

23. Fourth-Generation Regimens:
Are They Superior to ABVD??
1. ABVD + RITUXIMAB (YOUNES . ET AL, ASH 2007)
2. STANFORD V (HORNING ET AL, ASH 2007)
3. COPP-EBV-CAD (GOBBI, JCO 2005; FEDERICO, COLOGNE 2007)
4. ABVD dd-di ( RUSSO ET AL,2009)
5. BEACOPP (DIEHL ET AL, 1998)

24. Advanced HL
Is Stanford V superior to ABVD?
Stanford V in the UK study:
PFS @ 5 years 74%
53% stage I/II
73% irradiated
Stanford V in the US study:
PFS @ 5 years 72%
stage I/IIA included
The UK Study ISRCTN 64141244, Hoskin et al., J Clin Oncol 27:5390-5396. 2009
The US Study ECOG E2496, Gordon et al., ASH, 2010

25. Summary
Are the fourth generation regimen better than ABVD
ABVD + Ritux > ABVD???
not yet evaluable, needs confirmation in large trials
Stanford V = ABVD.
needs 90% RT ! Coop-trial results: ABVD vs Stf V: no difference
COPP-EBV-CAD = ABVD:
more toxic, more costly
ABVD-dd-di
few patients, needs confirmation in larger trial, cardio-tox!
BEACOPP
what is it´s impact???

26. The BEACOPP Schedule
Basis Escalated
[mg/m2] [mg/m2]1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22
B Bleomycin 10 10 restart
E Etoposide 100 200
A Doxorubicin 25 35
C Cyclophos. 650 1250
O Vincristine 1.4 1.4
P Procarbazin. 100 100
P Prednisone 40 40
G-CSF sc

27. Advanced HL:
De-escalation of BEACOPP and RT
in
5 Generations of Trials
1992-2013
• HD- 9 8 esc BEA + 70% RT
• HD- 12 4+4 esc+ base BEA + 36% RT
• HD- 15 6 esc BEA + 12% RT
• HD- 18 2+2 (PET-) esc BEA + 12% RT
• HD- 21 6 new BEA (BRECADD) + ?? RT

28. HD9 – 10 Yrs FFTF by Treatment Arm
1.0
0.9 BEA esc
0.8
0.7
0.6
Probability
0.5 C/ABVD
0.4 Log-rank tests:
0.3 A v B v C p < 0.0001
0.2
p = <.001 AvB p = 0.040
BvC p < 0.0001
0.1
A B C AvC p < 0.0001
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
years
Pts. at Risk
A 261 194 173 146 110 75 19 0
B 469 378 332 282 222 106 26 0
C 466 412 384 321 234 92 14 0

29. HD9 – 10 Yrs OS by Treatment Arm
1.0
0.9 BEA esc
0.8 11%
0.7
C/ABVD
0.6
Probability
0.5 Log-rank tests:
0.4 A v B v C p = 0.0005
0.3 AvB p = 0.19
0.2
p = <.001 BvC p = 0.0053
0.1 AvC p < 0.0001
A B C
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Pts. at Risk years
A 261 238 218 196 147 107 30 0
B 469 436 392 344 272 134 36 0
C 466 441 412 357 270 113 18 0
GHSG. 2007. HD9.

30. Salvagebility: Survival after Relapse at 10 ys
1.0
0.9
0.8
0.7
0.6
Probability
0.5
C/ABVD
0.4 BEAesc
0.3
p = 0.235 BEA base
0.2
0.1
A B C
0.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
years
Pts. at Risk
A 42 34 25 20 13 4 0
B 47 40 29 15 8 1 0
C 25 17 12 7 5 1 0

31. HD12 Trial Design
CS IIB with large mediastinal mass / E-lesions;
CS III and IV (1590 pats)
randomisation
Arm A Arm B Arm C Arm D
4 x B esc 4 x B esc
8 x B esc 8 x B esc + +
4 x B bas 4 x B bas
central diagnostic panel
30 Gy 30 Gy
(initial bulk,
„no RT“ (initial bulk,
„no RT“
residual) residual)

32. HD12 (5/2006): Acute Hematological
Toxicity Per Chemotherapy Cycle Per Arm
Leukopenia
8 Besc 4+4 Thrombopenia
70 70
Anaemia
Patients With WHO Grade III-IV (%)
Infection
60 60
50 50
40 40
30 30
20 20
10 10
0 0
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Cycle Cycle