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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
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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
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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
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