Download - The Treatment of Hodgkin's Disease (Part 1)
Hodgkin Lymphoma Management:State of the Art 2011
Volker Diehlfor the
German Hodgkin Study Group (GHSG)
Hackensack, New York3.November 2011
EBV: yes
Tuberculosis: no
Syphilis: no
Active Innate Immunity-Microenvironment
Monoclonal B-cell-Lymphoma
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
The German Hodgkin Study Group Experience
1978–2010 6 Generations of Hodgkin
Trials20.000 pats documented since
1978 400 centers recruiting220 private hem-oncologists
In Germany, Austria, Switzerland, Tschechia, Holland
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
GHSG Iniative IPersonalize Therapy
Tumor
Targeted Therapy
Host-ImmuneResponse/Microenvironment
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)
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
CS I–II without risk factors
ABVDABVD
30 Gy IF
ABVDABVD
ABVDABVDABVDABVD
ABVDABVDABVDABVD
30 Gy IF20 Gy IF 20 Gy IF
2003: 1375 patients recruited.Trial closed 1/2003.
Early Favorable Stage : GHSG: HD10- Trial
GHSG 2009 – HD10
HD10: Early Stage HLOverall Survival
Median observation time = 91 months
57530 Gy RT 570 561 556 551 534 468 351 227 124 3258920 Gy RT 584 576 569 561 539 467 346 232 131 25
Pts. at Risk Time [months]
30 Gy RT 20 Gy RT
Ove
rall
Surv
ival
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 84 96 108 120
No difference for2 ABVD vs 4 ABVD
and 20 vs 30 GY
Stages I, II without RF
AVDAVD204 pats
30 Gy IF-RT
AVAV
201 pats
ABVABV
203 pats
ABVD ABVD200 pats
30 Gy IF-RT
30 Gy IF-RT
30 Gy IF-RT
A B C D
30 Gy because of the reduction of chemotherapy!
Early Favorable GroupCurrent GHSG Study HD13
(985 patients recruited!)
CS I/II ohne RF*
2 x ABVDPET-
20 Gy IF
2 x ABVDPET+
2 x ABVDPET (+/-)
Follow up 20 Gy IF
StandardArm
Experimental Arms
HD16: GHSG-Study for Early favorable Stages
*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
Early Favorable StagesOngoing 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
Early favourable
Early unfavor-able
Advancedstages
Hodgkin Lymphoma: Risk Adaptationin the GHSG
Advanced Stages
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
HD14 study (GHSG)for early unfavorable HL
Stages I, IIA with RF a-d; IIB with RF c,d
BEACOPP escalatedBEACOPP escalated ABVD
ABVDABVDABVD 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
P < 0.0015-year FFTF 95%CI
Arm A 87,3% [83,8% - 90,2%]
Arm B 95,0% [93,0% - 96,4%]
difference 7,6% [4,0% - 11,3%]
FFTF
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60
761A 723 698 637 557 466 388 306 238 184 103758B 722 695 653 561 490 413 331 259 199 127
Pts. at Risk Time [months]
A B
GHSG HD14 - Final Analysis July 2010 - V.2.0 (October 2010)
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Progression and Relapse
ITT analysis setArm A
(ABVD)N=818
Arm B(“2+2”)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
Median observation time = 42 months
Progress in Intermediate stages
GHSG data
Trial Chemotherapy Failure Rate
HD 8
HD11
4 C/ABVD
4 BEACOPP or 4 ABVD
18%
16%
HD14 2 BEAesc + 2 ABVD 3%
amenorrhea: NO 119 87.5 109 83.8
amenorrhea: YES
Pregnancy, offspring, or ammenorrhea after therapy
fertility status > 1y AFTER therapy
4x ABVD (arm A)
„2+2“ (arm B)
N % N %
pregnancy/child: NO 114 89 93 82
pregnancy/child: YES 14 11 21 18
Only women up to 40 y from the ongoing HD14 fertility survey project
Men: fathered 12% 5%
17 12,5 21 16,2
Early unfavorable HL
30 Gy IF
2xBEACOPP esc + 2xABVD
Follow-up
PET -
No Rx
PET +
30 Gy IF 30 Gy IN
GHSG 2010
Next GHSG trialfor early unfavorable (HD17)
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
What is the best Induction Therapy
for Advanced Hodgkin Lymphoma?
ABVD compared with BEACOPP in advanced stage HL trials (% of pts)
Source Chemotherapy 5-y FFS 5-y OS
6-8 ABVD 61 73
8-10 ABVD 63 82
Viviani 2011
Diehl 2003 HD9
8 ABVD
8 x 4+4 e/b BEA
4 (COPP+ABVD)
73 (7ys)
85(7ys)
68
82 (7ys)
88 (7ys)
83
8 BEACOPP esc. 88 92
Canellos
Duggan 2003
GHSG 2011 HD15 6 BEACOPP esc 90,3 95,3
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)
Advanced HLIs Stanford V superior to ABVD?
The UK Study ISRCTN 64141244, Hoskin et al., J Clin Oncol 27:5390-5396. 2009
Stanford V in the UK study:
PFS @ 5 years 74%
53% stage I/II
73% irradiated
The US Study ECOG E2496, Gordon et al., ASH, 2010
Stanford V in the US study:
PFS @ 5 years 72%
stage I/IIA included
SummaryAre 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-difew patients, needs confirmation in larger trial, cardio-tox!
BEACOPPwhat is it´s impact???
B Bleomycin
E Etoposide
A Doxorubicin
C Cyclophos.
O Vincristine
P Procarbazin.
P Prednisone
[mg/m2]
10
100
25
650
1.4
100
40
[mg/m2]
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
Basis Escalated
The BEACOPP Schedule
Advanced HL:De-escalation of BEACOPP and RT
in5 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
261A 194 173 146 110 75 19 0469B 378 332 282 222 106 26 0466C 412 384 321 234 92 14 0
p = <.001
Pts. at Risk years
A B C
Pro
babi
lity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
HD9 – 10 Yrs FFTF by Treatment Arm
Log-rank tests:
A v B v C p < 0.0001
A v B p = 0.040
B v C p < 0.0001
A v C p < 0.0001
BEA esc
C/ABVD
GHSG. 2007. HD9.
261A 238 218 196 147 107 30 0469B 436 392 344 272 134 36 0466C 441 412 357 270 113 18 0
p = <.001
Pts. at Risk years
A B C
Prob
abili
ty
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
HD9 – 10 Yrs OS by Treatment Arm
Log-rank tests:
A v B v C p = 0.0005
A v B p = 0.19
B v C p = 0.0053
A v C p < 0.0001
BEA esc
C/ABVD
11%
42A 34 25 20 13 4 047B 40 29 15 8 1 025C 17 12 7 5 1 0
p = 0.235
Pts. at Risk years
A B C
Pro
ba
bil
ity
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Salvagebility: Survival after Relapse at 10 ys
C/ABVDBEAesc
BEA base
30 Gy(initial bulk,
residual)
„no RT“ 30 Gy (initial bulk,
residual)
„no RT“
central diagnostic panel
Arm D4 x B esc
+4 x B bas
Arm B
8 x B esc
Arm C4 x B esc
+4 x B bas
Arm A
8 x B esc
CS IIB with large mediastinal mass / E-lesions;CS III and IV (1590 pats)
randomisation
HD12 Trial Design
Cycle
Pat
ient
s W
ith W
HO
Gra
de II
I-IV
(%)
8 Besc
HD12 (5/2006): Acute HematologicalToxicity Per Chemotherapy Cycle Per Arm
0
10
20
30
40
50
60
70
1 2 3 4 5 6 7 8Cycle
4 + 4
1 2 3 4 5 6 7 8
LeukopeniaThrombopeniaAnaemiaInfection
0
10
20
30
40
50
60
70