Precautions to avoid toxic deaths

For > 45 year old and frail patients (IPS >3)

1. First BEA cycle as inpatient2. Mandatory prophylactic cotrim or ciprobay3. Prephase with VCR- Prednison day -74. Age limit for BEA esc 60 years of age

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

0.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Time [months]

p = 0.7534xBEA esc. + 4xBEA baseline4xBEA esc. + 4xBEA baseline + RT8xBEA esc. 8xBEA esc. + RT

HD12 (5/2006): OSAll 4 Arms at 4 Years Med. Obs. Time

Rtx 30Gy at residual tumor

PET +

Advanced stage HL

6x BEACOPPEscalated (21)

EPO vs Placebo

8x BEACOPPBaseline (14)

EPO vs Placebo

Restaging: PR and residual tumor >2,5 cm

8x BEACOPPEscalated (21)

EPO vs Placebo

No

PET -Follow up

HD15: 1st PET guided study 2050 pats recruited (2004-09)

YES

Do we really need RT for ALL patients with residual disease?

ASH 2010: GHSG HD15-PET trial

Is a negative PET predictive for “no-relapse”?The GHSG HD15 study

CRPR PETneg

8 vs 6 esc BEA vs 8 BEA -14 +RT(10%)

PET+

p = 0.266

Months after Randomisation

HD9

HD15

HD12 B+D

HD12 A+C

Pro

gres

sion

-free

Sur

viva

l

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24

HD15: PET guided therapy is safe after chemotherapy

0%

10%

20%

30%

40%

50%

60%

70%

80%

HD9 HD15

RADIOTHERAPY

70%

12%

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”

100 BEACOPPesc (1993-99)

Therapeutic progress in HL: advanced stage disease

0

20

0 1 2 3 4 5 years

Alkylators (1965)

No therapy (1940)

40

60

80

COPP+ABVD (1988-93)

COPP (1975)

BEACOPP escalated

Proof of Principle in 3 Randomized Prospective Trials

in > 500 centers including220 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!!

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)

New Treatment Strategies for

Advanced Hodgkin Lymphoma

Ongoing Global Studiessoon

answering the Question of“Kairos” or “Chronos”

USA- Cooperative Group TrialAdvanced Hodgkin Lymphoma

2 ABVDPETPos BEACOPP esc x 6+IFRT

Neg ABVD x 4 no RT

Caveat: BEACOPPesc might be 8 weeks too late!!

Better for IPS > 3 RFs: 2 esc BEACOPPPET neg: 6 ABVD

PET pos: 4- 6 BEAesc

IPS: 0-7

8-10 weeks duration!

Effect of esc BEACOPP:Early or Late Intensification

ts - PET vs. IPS

1

0,8

0,6

0,4

0,2

0

Cum

ulati

ve fa

ilure

-free

surv

ival

IPS 3-7, PET2poIPS 3-7, PET2neIPS 0-2, PET2poIPS 0-2, PET2ne

IPSandPET

log rank, p

Gallamini A, Hutchings M, Rigacci L, et al.: JCO 2007, accepted.

8 esc BEA: early intensification (kairos)(GHSG, Israel,EORTC)

2 ABVDPET + 4 esc BEA+4 base BEALate intensification: (chronos) (Gallamini et al)

2 ABVDPET +: 6 ABVD

PET +: Difference 26%

No intensification!

100

60%

50

0

86%

60%

Ongoing HD18 trial for advanced stages843 pats recruited 2009-2010

2 x BEACOPP escalated (esc)

PET + PET -

After chemo: PET; RX to PET+ res nodes >2.5 cm

PET-: Follow up

6xBEACOPPesc6xBEACOPPesc 6xR-BEACOPPesc 2xBEACOPPesc

(57%) (43%)

GELA 2011Stage III/IV and high risk IIB Hodgkin Lymphoma

Standard Arm Experimental Arm

Neg / Pos

Salvagetherapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

Salvagetherapy

BEACOPP esc x 2

IPS 0-7

BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm 810 patients planned to be enrolled over 6 years

ABVD x 2BEACOPP esc x 2

BEACOPP esc x 2

Courtesy of O Casasnovas

®Standard ArmExperimental Arm

1 x BEAesc

PET/CT

3 x BEAesc

RT 36 Gy to PET-positive residual masses

CT

Post-chemotherapy PET/CT

CR / PR PD/ SD

1 x ABVD

PET+ PET-

3 x ABVD3 x BEAesc

CR / PR PD/ SD

Off protocol4 x BEAbase

CR / PR PD/ SD*

1 x BEAesc3 x BEAbase

Off protocol Off protocol4 x ABVD

H11 advanced stage HL trial: EORTC

PET+/-

The Problemof 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

The new England Journal of Medicine12july 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

“After completion of the overall planned treatment,including salvage therapy, the 7-year rate of freedom from a second progression was PFS=88% in the BEACOPP group and PFS=82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was OS= 89% and OS=84%,respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group”.

6%

5%

My problem with this paper:

1.Small number of patients2.Short follow up3.Statistics full of flaws , 4.“Non-significance” for survival difference is concluded, but never was investigated.5.Neither patient numbers nor the primary endpoint is reported correctly6.With regard to its surprisingly deficient statistical analysis and reporting quality, the manuscript must be amended in large parts to contribute to an undesigning debate on the treatment of advanced Hodgkin Lymphoma.

The new England Journal of Medicine12july 21, 2011vol. 365no.

ABVD versus BEACOPP for Hodgkin’s Lymphoma When High-Dose Salvage Is PlannedSimonetta 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

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

...just some personal thoughts to a controversial paper....

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!!

VIVIANI, NEJM

6eB= 95,3% OS

ABVD= 84% OS

11% difference in OSamounts to 440 young patients with adv HLin the USA (4000new cases / anno) who have to die unnecessarily !!

GHSG HD15 11% difference

I think ..we all agree

that not faith or myths-but scientific evidence

should lead our decisions... for the best of our patients!

• Early Stages: 2 ABVD + 20 Gy IF-RT2-4 ABVD no RT: tested in ongoing trials!!

• Interm.Stages: 2 esc BEA+2 ABVD + 20 Gy IF-RT or4 ABVD + 30 Gy IF-RT

• Adv.Stages: IPS: 0-2 2 ABVD PET neg + 4 ABVD +/- RT

IPS: 3-7 2 escBEAPET neg 4 ABVD+/-RT

(30%) PET pos 4esc BEA+/-RT

My Recommendations:Hodgkin Lymphoma 2011

(70%

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

Future Perspectives

Comprehensive Aim:

Combine conventional with targeted therapy

New Generation of Drugs other than Moabsin 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

CD30- Antigen in Hodgin RS.cells

„Targeted therapy“ with Antibodies in Hodgkin Lymphoma

NFkB

TRAF3 proteolysis

Anti-CD30 AntibodyWithAuristatin(a chemical bomb!)

Hodgkin Reed Sternberg cell

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 responseMedian 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

Targeted (individualized) TherapyBrentuximab Vedotin (SGN-35)

1) Younes A et al, NEJM 2010;363:1812-18212) Chen R et al, ASH 2010

Targeted (individualized) TherapyLenalidomide (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