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. Precautions to avoid toxic
deaths
For > 45 year old and frail patients (IPS >3)
1. First BEA cycle as inpatient
2. Mandatory prophylactic cotrim or ciprobay
3. Prephase with VCR- Prednison day -7
4. Age limit for BEA esc 60 years of age

2. HD12 (5/2006): OS
All 4 Arms at 4 Years Med. Obs. Time
1.0
0.8
Probability
0.6
0.4 p = 0.753
4xBEA esc. + 4xBEA baseline
4xBEA esc. + 4xBEA baseline + RT
0.2 8xBEA esc.
8xBEA esc. + RT
0.0
0 6 12 18 24 30 36 42 48 54 60 66 72
Time [months]

3. HD15: 1st PET guided study
2050 pats recruited (2004-09)
Advanced stage HL
8x BEACOPP 6x BEACOPP 8x BEACOPP
Escalated (21) Escalated (21) Baseline (14)
EPO vs Placebo EPO vs Placebo EPO vs Placebo
Restaging: PR and residual tumor >2,5 cm
No
YES
PET - PET + Rtx 30Gy at
Follow up
residual tumor

4. Do we really need RT for ALL
patients with residual disease?
CR
PR PETneg
Is a negative PET predictive for “no-relapse”?
The GHSG HD15 study PET+
8 vs 6 esc BEA vs 8 BEA -14
+RT(10%)
ASH 2010: GHSG HD15-PET trial

5. HD15: PET guided therapy
is safe after chemotherapy
1.0
0.9
0.8 80%
p = 0.266
Progression-free Survival
70%
70%
0.7
60%
0.6 RADIOTHERAPY HD9
50%
0.5 40%
HD15
0.4 30%
20%
0.3 12% HD12 B+D
10%
0.2
0% HD12 A+C
0.1 HD9 HD15
0.0
0 6 12 18 24
Months after Randomisation

7. Entwicklung von SGN-35
in der GHSG
Randomisierte Phase II Studie mit 2 Armen
1. innovativ: EAC SGN35 DTIC, Dexa (ECADD-B)
2. konservativ: BEAC SGN35 PP (ECAPP-B)
“Targeted BEACOPP variants in patients with newly
diagnosed advanced classical Hodgkin Lymphoma (HL) – A
randomized phase II study”
7

9. Therapeutic progress in HL:
advanced stage disease
100 BEACOPPesc
(1993-99)
80
COPP+ABVD
60
(1988-93)
COPP
40
Alkylators (1975)
(1965)
20
No therapy
(1940)
0
0 1 2 3 4 5 years

10. BEACOPP escalated
Proof of Principle
in 3 Randomized Prospective Trials
in > 500 centers including
220 private oncologists all over Europe
> 4500 patients treated:
Results : (in comparison with ABVD)
Pros: Con:
higher CR-rates : >90% more hematoxicity (40-90%)
higher tumor cell kill PFS: 90% vs 70%more infertility M: 90% /F: 52% vs 34%
Cure rate 11% higher at 10 ys more AML/MDS: 0,8-1,2% vs < 0,5%
20% less need for salvage therapy!!

11. The Principle of BEACOPP:
Hit early and hard with the first hit!
(Early Intensification)
The Principle of most of the ongoing
global studies: UK, USA, Italy:
Start soft and hit hard with the 2nd hit!
(Late Intensification)

12. New Treatment Strategies
for
Advanced Hodgkin Lymphoma
Ongoing Global Studies
soon
answering the Question of
“Kairos” or “Chronos”

13. USA- Cooperative Group Trial
Advanced Hodgkin Lymphoma
IPS: 0-7
Neg ABVD x 4 no RT
2 ABVDPET
8-10 weeks duration! Pos BEACOPP esc x 6+IFRT
Caveat: BEACOPPesc might be 8 weeks too late!!
Better for IPS > 3 RFs: 2 esc BEACOPPPET neg: 6 ABVD
 PET pos: 4- 6 BEAesc

14. Effect of esc BEACOPP:
Early or Late Intensification
ts - PET vs. IPS
100
1
Cumulative failure-free survival
86%
8 esc BEA: early intensification (kairos)
PET +: (GHSG, Israel,EORTC)
0,8 Difference
26% 2 ABVDPET + 4 esc BEA+4 base BEA
Late intensification: (chronos) (Gallamini et al)
IP SandP ET
60%
60% IPS 0-2, P ET2ne
0,6 50
IPS 0-2, P ET2po
IPS 3-7, P ET2ne
IPS 3-7, P ET2po
0,4
No intensification!
0,2 2 ABVDPET +: 6 ABVD
0
0 log rank, p
Gallamini A, Hutchings M, Rigacci L, et al.: JCO 2007, accepted.

15. Ongoing HD18 trial for advanced stages
843 pats recruited 2009-2010
2 x BEACOPP
escalated (esc)
PET + PET -
(43%) (57%)
6xBEACOPPesc 6xR-BEACOPPesc 6xBEACOPPesc 2xBEACOPPesc
After chemo: PET; RX to PET+ res nodes >2.5 cm
PET-: Follow up

16. GELA 2011
Stage III/IV and high risk IIB Hodgkin Lymphoma
IPS 0-7
R Experimental Arm
Standard Arm
BEACOPP esc x 2 BEACOPP esc x 2
PET2 Neg / Pos Pos Neg
BEACOPP esc x 2 BEACOPP esc x 2 ABVD x 2
PET4 Neg Pos Neg Pos Neg
Salvage Salvage ABVD x 2
BEACOPP esc x 2 BEACOPP esc x 2
therapy therapy
Non inferiority of the experimental arm Courtesy of O Casasnovas
810 patients planned to be enrolled over 6 years

17. H11 advanced stage HL trial: EORTC
®
Experimental Arm Standard Arm
1 x ABVD 1 x BEAesc
PET/CT PET+ PET- PET+/-
3 x BEAesc 3 x ABVD 3 x BEAesc
CT CR / PR PD/ SD CR / PR PD/ SD* CR / PR PD/ SD
1 x BEAesc Off protocol 4 x ABVD Off protocol 4 x BEAbase Off protocol
3 x BEAbase
Post-chemotherapy PET/CT
RT 36 Gy to PET-positive residual masses

18. The Problem
of the management of Advanced Hodgkin Lymphoma
What is the Goldstandard induction regimen?
ABVD or BEACOPP ?
Does one size fit all??
Or do we need more differentiated approaches?
Thus far the dispute is similar to the fight between the
US Democrats and the RepublicanTea Party
Lots of emotional arguments,
Waiting for robust evidence!
Till then: we only should use hard facts and evidence

19. The new England Journal of Medicine
12july 21, 2011vol. 365no.
ABVD versus BEACOPP for Hodgkin’s Lymphoma When High-Dose Salvage Is
Planned
Simonetta Viviani, M.D., Pier Luigi Zinzani, M.D., Alessandro Rambaldi, M.D., Ercole Brusamolino, M.D., Alessandro Levis, M.D.,
Valeria Bonfante, M.D., Umberto Vitolo, M.D., Alessandro Pulsoni, M.D., Anna Marina Liberati, M.D., Giorgina Specchia,
M.D., Pinuccia Valagussa, B.S., Andrea Rossi, M.D., Francesco Zaja, M.D., Enrico M. Pogliani, M.D., Patrizia Pregno, M.D.,
Manuel Gotti, M.D., Andrea Gallamini, M.D., Delia Rota Scalabrini, M.D., Gianni Bonadonna, M.D., and Alessandro M.
Gianni, M.D., for the Michelangelo Foundation, the Gruppo Italiano di Terapie Innovative nei Linfomi, and the Intergruppo
Italiano Linfomi
My problem with this paper:
“After1.Small number of patients
completion of the overall planned treatment,
2.Short follow up
including salvage therapy,
3.Statistics full of flaws ,
the 7-year rate of freedom fromdifference is concluded, but never was
4.“Non-significance” for survival a second progression was
PFS=88% in the BEACOPP group and
investigated.
6%
PFS=82% inpatient numbers nor the(P=0.12),
5.Neither the ABVD group primary endpoint is reported correctly
6.With regard to its surprisingly deficient statistical analysis and reporting
and the 7-yearmanuscriptoverallamended in large parts to contribute to an
quality, the rate of must be survival was
OS= 89% and debate on the5%
undesigning treatment of advanced Hodgkin Lymphoma.
OS=84%,
respectively (P=0.39).
Severe adverse events occurred more frequently in the BEACOPP group
than in the ABVD group”.

20. The new England Journal of Medicine
12july 21, 2011vol. 365no.
ABVD versus BEACOPP for Hodgkin’s Lymphoma When High-Dose Salvage Is Planned
Simonetta Viviani, M.D., Pier Luigi Zinzani, M.D., Alessandro Rambaldi, M.D., Ercole Brusamolino, M.D., Alessandro Levis, M.D.,
Valeria Bonfante, M.D., Umberto Vitolo, M.D., Alessandro Pulsoni, M.D., Anna Marina Liberati, M.D., Giorgina Specchia,
M.D., Pinuccia Valagussa, B.S., Andrea Rossi, M.D., Francesco Zaja, M.D., Enrico M. Pogliani, M.D., Patrizia Pregno, M.D.,
Manuel Gotti, M.D., Andrea Gallamini, M.D., Delia Rota Scalabrini, M.D., Gianni Bonadonna, M.D., and Alessandro M.
Gianni, M.D., for the Michelangelo Foundation, the Gruppo Italiano di Terapie Innovative nei Linfomi, and the Intergruppo
Italiano Linfomi
...just some personal thoughts to a controversial paper....
At 7 ys:
PFS-difference : 12%
EFS-difference : 6%
OS-difference: 5%
HDCT+SCT : 45 pats after ABVD (2x more than with eBEA!)
20 pats after eBEA
My Conclusion:
USA: 4000 new pats with adv.HL/anno,
5% /4000 young patients = 200 young patients will die unnecessarily!
Possibly more since the paper is not powered for OS!!

21. 11% difference in OS
amounts to 440 young patients with adv HL
in the USA (4000new cases / anno)
who have to die unnecessarily !!
6eB= 95,3% OS
ABVD= 84% OS
VIVIANI, NEJM 11%
GHSG HD15 difference

22. I think ..
we all agree
that not faith or myths-
but scientific evidence
should lead our decisions...
for the best of our patients!

23. My Recommendations:
Hodgkin Lymphoma 2011
• Early Stages: 2 ABVD + 20 Gy IF-RT
2-4 ABVD no RT: tested in ongoing trials!!
• Interm.Stages: 2 esc BEA+2 ABVD + 20 Gy IF-RT or
4 ABVD + 30 Gy IF-RT
• Adv.Stages: IPS: 0-2 2 ABVD PET neg + 4 ABVD +/- RT
(70%
IPS: 3-7 2 escBEAPET neg  4 ABVD+/-RT
(30%) PET pos  4esc BEA+/-RT

24. GHSG Initiatives V
• 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

25. Future Perspectives
Comprehensive Aim:
Combine conventional
with targeted therapy

26. New Generation of Drugs other than Moabs
in Patients with refractory HL (Selection)
Drug Type Patients Response
(n) (%)
ZenaRX1) RIT (anti-CD25) 23 67
SGN-352) IT (anti-CD30) 217 67
MGCD01033) HDAC-Inhibitor 20 40
RAD0014) m-TOR-Inhibitor 14 42
Lenalidomide5) IMID 7 56
1)Waldmann ISHL 2007; 2) Younes et al ISHL 2007; 3)Younes et al ISHL 2007;
4)Johnston et al ISHL 2007; 5)Borchmann et al unpubl 2007

27. CD30- Antigen in Hodgin RS.cells

28. „Targeted therapy“ with Antibodies
in Hodgkin Lymphoma
Anti-CD30
Antibody
With
Hodgkin Reed Sternberg Auristatin
(a chemical bomb!)
cell
TRAF3 proteolysis
NFkB

29. Targeted (individualized) Therapy
Brentuximab Vedotin (SGN-35)
Phase 1, single-agent1
- Relapsed CD30-positive lymphomas (45 HL, 2 ALCL, 1 AITL)
- Well tolerated: Mostly grade 1 or 2 adverse events—fatigue, fever, diarrhea,
nausea, neutropenia, peripheral neuropathy
- MTD: 1.8 mg/kg every 3 weeks
- Across all dose levels: 44 evaluable patients; 39% objective response
(82% responded: 25% CR, 14% PR, 43% SD)
- At 1.2 mg/kg and higher: 15/28 patients (54%) objective response
Median duration of response: 9.7 months
Phase 2, pivotal single-agent2
- 1.8 mg/kg every 3 weeks for up to 16 doses
- 75% objective response
- Median duration of response: >6 months
- Granted fast track designation by FDA for HL
1) Younes A et al, NEJM 2010;363:1812-1821
2) Chen R et al, ASH 2010

30. Targeted (individualized) Therapy
Lenalidomide (Revlimid)
A new principle of targeted therapy in Hodgkin´s lymphoma
Interfering with the micro- enviroment
Mode of Action
-Thalidomide analogue
- Immune-modulatory properties
- down-regulation of pro-survival
cytokines (TNF-a, VEGF, Il-8, Il-6)
and
-interference with the
micro-enviroment
- stimulation of T-cells and NK-cells
- antiangionetic activity
- pro-apoptotic effect