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)

16

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