Which is the best induction regimen in Hodgkin Lymphoma: ABVD or - - PowerPoint PPT Presentation

Which is the best induction regimen in Hodgkin Lymphoma: ABVD or BEACOPP?

Volker Diehl, MD

Honorary Chairman, German Hodgkin Study Group University Hospital of Cologne

The Best Treatment of Hodgkin Lymphoma is the one with the highest cure rates and the least toxicity?

Cure dependent on:

• a. salvagebility after failure
• b. stage

Hodgkin Lymphoma Hodgkin Lymphoma OS after salvage for relapse OS after salvage for relapse according to primary treatment according to primary treatment

120 120 108 108 96 96 84 84 72 72 60 60 48 48 36 36 24 24 12 12 1,0 1,0 ,8 ,8 ,6 ,6 ,4 ,4 ,2 ,2 0,0 0,0

p p < 0.0001 < 0.0001 Months Months Probability Probability Primary RT (14/107) Primary RT (14/107) 2 cycles CT (12/35) 2 cycles CT (12/35) 4 cycles CT (92/193) 4 cycles CT (92/193) 8 cycles CT (162/341) 8 cycles CT (162/341)

Overall Survival

GHSG

Risk groups

• Early favorable stages:

CS I/II without risk factors*

• Early unfavorable stages:

CS I/II with risk factors*

• Advanced stages:

CS III/IV; selected CS IIB

*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

GHSG HD10 trial for

early favorable HL

CS I/II without risk factors* 2 x ABVD 30 Gy IF 2 x ABVD 4 x ABVD 4 x ABVD 30 Gy IF 20 Gy IF 20 Gy IF

*Large mediastinal mass; extranodal disease; high ERS; 3 or more areas involved

NEJM, 2010

596 4xABVD 554 532 506 479 430 330 226 131 57 6 594 2xABVD 555 530 498 473 410 314 225 131 54 9

• Pts. at Risk

Time [months]

4xABVD 2xABVD

Freedom from Treatment Failure

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60 72 84 96 108 120

5y-FFTF difference -1,9%; 95% CI [-5,2%; 1,4%] p=0,39

NEJM, 2010

HD10 trial

CT-comparison (FFTF)

HD10 trial

RT-comparison (FFTF)

Arm difference in 5y-FFTF = -0,5% 95% CI [-3,6%; 2,6%]

p= 0,90

575 30 Gy RT 553 526 499 471 426 328 235 139 61 8 588 20 Gy RT 550 531 502 478 411 314 215 123 50 7

• Pts. at Risk

Time [months]

30 Gy RT 20 Gy RT

Freedom from Treatment Failure

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60 72 84 96 108 120

NEJM,2010

HL: Individualized Estimates

• f 2NPL Risks after Contemporary RT

Hodgson et al, Cancer 110: 2576, 2007

Age 20 Age 30

Breast Cancer Reduced 77% Lung Cancer Reduced 57%w

HodgkinLymphoma: Best Chemotherapy 2010

9

State of the Art

Early Favorable: 2 ABVD+ 20 Gy IFRT

Early Unfavorable: 4 ABVD or 2eBEA+2 ABVD + 20-30 Gy RT Advanced: Low Risk (IPS 0-2): 2 ABVDPET - : 4-6 ABVD +/- 30 Gy RT

2 ABVDPET+:4-6 esc BEA + 30 Gy RT High Risk (IPS>3) 2 escBEAPET -: 2 esc BEA: +/- RT 2 esc BEAPET+ 6esc BEA +/- RT

GHSG

Risk groups

• Early favorable stages:

CS I/II without risk factors*

• Early unfavorable stages:

CS I/II with risk factors*

• Advanced stages:

CS III/IV; selected CS IIB

*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

120 96 72 48 24 1,0 ,8 ,6 ,4 ,2 0,0 SV FFTF

Time ( Time (months months) ) Probability Probability

Overall results (all evaluable patients)

Overall results [95%CI] at 5 years: FFTF 82,6% [80;85] SV 91,1% [89;93]

4 C/ABVD

+ 30 GY RT

Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both??

Trial Chemotherapy + IF-RT Failure Rate

HD 8 HD11 4 COPP/ABVD 4 ABVD 4 BEACOPP 18% 15% 13% HD14 4 ABVD 2 BEAesc + 2 ABVD 13% 5%

BEACOPP

Baseline (base) and escalated (esc)

Drug base2 esc2 route schedule

Bleomycin 10 10 iv 8 Etoposide 100 200 iv 1-3 Adriamycin 25 35 iv 1 Cyclophosphamide 650 1250 iv 1 Vincristine 1.41 1.41

iv

8 Procarbazine 100 100 po 1-7 Prednison 40 40 po 1-14 G-CSF

• + sc

8-14

• 1max. 2,0 mg

2mg/m2

Freedom from Treatment Failure 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 12 24 36 48 60 72 84 96 108 356 330 308 293 271 255 206 136 73 40 341

BEACOPP+30Gy

313 293 278 275 249 203 138 78 34

p = 0.654

• Pts. at Risk

Time [months] ABVD + 30Gy BEACOPP + 30Gy

ABVD+30Gy

5 year estimate [95%-CI] 4xABVD: 85.3% [81.1% to 88.7%] 4xBEACOPP: 87.0% [82.8% to 90.2%]

HD11 trial: 30Gy arms

CT comparison (FFTF)

Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both??

Trial Chemotherapy + IF-RT Failure Rate

HD 8 HD11 4 COPP/ABVD 4 ABVD 4 BEACOPP 18% 15% 13% HD14 4 ABVD 2 BEAesc + 2 ABVD 13% 5%

Early unfavorable HL

Effective-dose calculation (4 cycles) Regimen D´ration ED

ABVD 16 15.0 BEACOPPbase 12 15.2 BEACOPP14 8 16.3 Besc/ABVD (2+2) 14 17.3 BEACOPPesc 12 19.8

GHSG, modified from Hasenclever, D.

HD14 study (GHSG)

for early unfavorable HL

Stages I, IIA with RF a-d; IIB with RF c,d BEACOPP escalated BEACOPP escalated ABVD ABVD ABVD ABVD

ABVD ABVD 30 Gy IF 30 Gy IF *a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

18

FFTF median observation time = 42 months

P < 0.001 5-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 12 24 36 48 60 761 A 723 698 637 557 466 388 306 238 184 103 758 B 722 695 653 561 490 413 331 259 199 127

• Pts. at Risk

Time [months] A B

2eBEA+2ABVD 4 ABVD

HD14 for early unfavorable HL

Treatment outcome and events (% of pts)

4xABVD

2+2

n=476 n=479

CR/CRu 93.7 95.5 Progress 3.9 1.4 Early relapse 2.3 0.6 Late relapse 3.1 1.4 Death 2.2 1.0

Progress in Intermediate stages GHSG data ABVD or BEACOPP or Both??

Trial Chemotherapy Failure Rate

HD 8 HD11 4 COPP/ABVD 4 ABVD 4 BEACOPP 18% 15% 13% HD14 4 ABVD 2 BEAesc + 2 ABVD 13% 5%

HodgkinLymphoma: Best Chemotherapy 2010

21

State of the Art

Early Favorable: 2 ABVD+ 20 Gy IFRT

Early Unfavorable: 4 ABVD +RT or 2eBEA+2 ABVD + 30 Gy IFRT Advanced: Low Risk (IPS 0-2): 2 ABVDPET - : 4-6 ABVD +/- 30 Gy RT

2 ABVDPET+:4-6 esc BEA + 30 Gy RT High Risk (IPS>3) 2 escBEAPET -: 2 esc BEA: +/- RT 2 esc BEAPET+ 6esc BEA +/- RT

GHSG

Risk groups

• Early favorable stages:

CS I/II without risk factors*

• Early unfavorable stages:

CS I/II with risk factors*

• Advanced stages:

CS III/IV; selected CS IIB

*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas

Advanded Stages:

• ABVD-

the Gold Standard?? No! It is not! At least not for all risk groups!

Nancy Bartlett : „One size does not fit all!“

ABVD compared with BEACOPP

in advanced stage HL trials (% of pts)

Source Chemotherapy 5-y FFS 5-y OS

Canellos 1992 6-8 ABVD 61 73 6 (MOPP+ABVD) 65 75 Duggan 2003 8-10 ABVD 63 82 8-10 MOPP/ABV 66 81 Diehl 2003 4 (COPP+ABVD) 68 83 8 BEACOPP esc. 88 92

Advanced Stages of HL HD-9 1994- 2001

8eBEA

+RT (70%)

HD-12 2001-2004

4eBEA+4 base BEA +/-RT (39%)

HD-15 2004-2007 6 eBEA vs 8 BEA-14 +RT (12%) HD-18 2008-2012 2 eBEAPET- 2eBEA +RT (12%) ongoing

Total: > 4500 patients treated

The GHSG- Successor- Trials De-escalation of BEACOPP

GHSG HD9 trial

FFTF by treatment arm

Engert et al; JCO 2009

p <0,001

Years

A (64%) B (70%) C (82%)

Percentage

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

18% Esc BEACOPP C/ABVD

HD15-PET trial for advanced-stage HL HD15-PET trial for advanced-stage HL

PFS in pts with PET PFS in pts with PET+

+ and PET

and PET-

• residues (n=275)

residues (n=275)

216 216 PET+ PET+ 211 211 207 207 151 151 95 95 59 59 PET - PET - 52 52 50 50 38 38 18 18

p = 0.011 p = 0.011

Pts at Risk Pts at Risk

• PFS

PFS

0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 6 6 12 12 18 18 24 24

Months Months

GHSG 2007 GHSG 2007

8 eBEA vs 6 eBEA vs 8 BEA-14 : PET end of chemo:

PT neg No RT PET pos + RT

PFS

p = 0.266 p = 0.266

Months after Randomisation Months after Randomisation

HD9 HD9 HD15 HD15 HD12 B+D HD12 B+D HD12 A+C HD12 A+C

Progression-free Survival Progression-free Survival

0.0 0.0 0.1 0.1 0.2 0.2 0.3 0.3 0.4 0.4 0.5 0.5 0.6 0.6 0.7 0.7 0.8 0.8 0.9 0.9 1.0 1.0 6 6 12 12 18 18 24 24

Comparison of GHSG trials HD9, HD12, HD15 Comparison of GHSG trials HD9, HD12, HD15 for

for advanced-stage HL (PFS) advanced-stage HL (PFS)

PFS:91% in >4500 patients

Trials in advanced HL

comparing BEACOPP and ABVD or Variants*

GHSG HD9

Italian Study

HD2000 Italian Study GITIL&IIL

COPP/ABVD BEACOPP 8esc ABVD BEACOPP 4+2 ABVD BEACOPP 4+4

N 260 466 95 91 166 155

FFTF

69 87 63 78 69 85 OS 83 91 86 91 86 87 But: two times more patients needed HDCT+SCT after ABVD than after BEAesc!!

P< 0,001

* @ 5 years

The different philosophies: early or late intensification in Advanced HL

2-4 BEACOPP esc Prog/Relapse 5-10%

6-8 ABVD

Progr/Relapse 30- 40% (IPS: >3)

HDCT/SCT

„2nd hit“ in 30-40% „1st hit“ „1st hit“ „2nd hit“ in 5-10% HDCT/SCT

1,2% AML/MDS!! 5-10% AML/MDS

4 BEA base

GHSG / GELA USA / UK / Italy

PFS 2-y: 59.0% PFS 2-y: 93.7%

Change of therapy according to Interim PET after 2 ABVD Outcome PFS

HR = 6 (95% CI 2.2 – 16)

PET-2 negative (ABVD x 6) PET-2 positive ABVDx2/BEACOPP)

p < 0.0001

Gallamini A, et al. EHA Berlin, 2009

Late Intensification!

HodgkinLymphoma: Best Chemotherapy 2010

32

State of the Art

Early Favorable: 2 ABVD+ 20 Gy RT

Early Unfavorable: 4 ABVD or 2eBEA+2 ABVD + 20-30 Gy RT Advanced: Low Risk (IPS 0-2): 2 ABVDPET - : 4-6 ABVD +/- 30 Gy RT

2 ABVDPET+:4-6 esc BEA + 30 Gy RT High Risk (IPS>3) 2 escBEAPET -: 2 esc BEA: +/- RT 2 esc BEAPET+ 6esc BEA +/- RT

What is the best induction in HL?

ABVD or BEACOPP?

• In early favorable HL, the GHSG HD10 trial indicates that

patients can safely be treated with 2xABVD plus 20Gy IFRT

• In early unfavorable, 2xBEACOPPesc + 2xABVD + 30Gy IFRT

new GHSG standard; outside GHSG, 4xABVD + 30Gy IFRT

• For advanced HL, BEACOPPesc is 18% better in FFTF and

11% in OS at 10y; all prognostic subgroups better

• More acute toxicity but not early mortality; more infertility
• Follow-up studies (HD12, 15, 18) aimed at reducing toxicity
• PET to individualize treatment
• Major goal in treating HL patients is highest cure rate with

primary therapy with as little toxicity as possible