Linfoma di Hodgkin:La miglior strategia terapeutica iniziale

43° Congresso Nazionale SIENapoli 16-19- 2011

Ercole BrusamolinoClinica EmatologicaFondazione IRCCS Policlinico San Matteo, PaviaE-mail: ebrusa@smatteo.pv.it

Masaccio:“L’ombra di San Pietro guarisce il cieco”Cappella Brancacci, Firenze

Hodgkin lymphomaA success story

3

Today:

CompleteRemissionrate:85‐95%Relapserate:‐5%inearlystage‐25‐30%inadvancedstage

Rates of death from Hodgkin’s disease1935-2000

Cause di morte nel linfoma di Hodgkin

Causes of death according to stage

0

20

40

60

80

100

I-IIA IIB-IV

Not-relatedRespiratory eventsCardiac eventsSolid tumorsLeukemiaHD progression

Ematologia, Pavia

Late effects to avoidas cures increase

• Secondary MDS/AML from alkylating agents

• Solid tumours from extended field radiation

• Pulmonary fibrosis from bleomycin

• Ischaemic heart disease from mediastinalirradiation and doxorubicin

• Infertility from alkylating agents

Prognosi del Linfoma di Hodgkin

Fattori prognostici

• Età• Sesso• Istotipo (LD, NS)• Genotipo (GST)

• Sintomi B• VES• Hb, WBC, Ly• Albumina• IL-1, IL-6, IL-10

Biologia

Traffico citochinico

Fattori prognostici

• Bulk• Tumor burden• Numero linfonodi• sCD30• LDH

• Tipo di terapia• Chemiosensibilità

Massa tumorale

Terapia

Initial stage : Prognostic factors

EORTC/GELAEORTC/GELA GHSGGHSG USA/CanadaUSA/Canada

Bulky mediastinum Bulky mediastinum

Age ≥ 50 Age > 40

ESR ≥ 50 ESR > 50 ESR > 50

≥ 4 nodes ≥ 3 nodes ≥ 3 nodes

B and ESR > 30 B or extranodal site

Hodgkin lymphomaHD7 trial (GHLSG)

12

In early stage disease, CT+RT is superior to RT alone

ABVD x 4 + IF-RT: RFS

Brusamolino CCR 2006

Limited disease: EFS

Brusamolino CCR 2006

ABVD x 4 + IF-RT: EFS

Limited disease: OS

Brusamolino CCR 2006

ABVD x 4 + IF-RT: OS

Late events: 22 (18%)

Events No. %Cardiovascular 9 7Second neoplasia 6 5Hypothyroidism 5 4Mediastinal fibrosis 3 2

Brusamolino CCR 2006

GHSG-HD10 trial: Early favorableGHSG-HD10 trial: Early favorableCR % 5-yr PFS % 5-yr OS %

ABVD x 2 97 91.2 96.6ABVD x 4 97 93.5 97.1RT 20 Gy 97 93.2 97.5RT 30 Gy 99 93.7 97.6

More adverse events for 4 ABVD vs 2 ABVD (52% vs 33%)and for 30 Gy vs 20 Gy RT (9% vs 3%)

2 ABVD + 20 Gy RT is the new standard2 ABVD + 20 Gy RT is the new standard

Engert et al, NEJM 363: 640; 2010

•• ABVD + 20 Gy is inferior to ABVD + 30 GyABVD + 20 Gy is inferior to ABVD + 30 Gy•• BEACOPP + 20 or 30 Gy is not superior to ABVD + 30GyBEACOPP + 20 or 30 Gy is not superior to ABVD + 30Gy

Therapy arms

4 ABVD + 30 Gy

4 ABVD + 20 Gy

4 BEACOPP base + 30 Gy

4 BEACOPP base + 20 Gy

Results in the whole group

CR rate 94.1%

5 yr-PFS 86 %

5 yr OS 94.5 %

In terms of 5-yr FFTF

GHSG-HD11 trial: Early unfavorableGHSG-HD11 trial: Early unfavorable

4 ABVD + 30 Gy RT is the new standard4 ABVD + 30 Gy RT is the new standard

Eich et al, JCO 28: 4199; 2010

Prognosi Linee Guida SIE 2009 2011

Favorevole ABVD x 3 + RT (30 Gy) ABVD x 2 + RT (20 Gy)

Sfavorevole ABVD x 4 + RT (30 Gy) ABVD x 4 + RT (30 Gy)

Terapia di prima linea:Stadi inziali

Hasenclever D. NEJM 1988; 339:1506

HD prognostic score

7% or the patients

Advanced HL prognostic score: 7y-FFP & OS

Hasenclever D. NEJM 1988; 339:1506

HD9 trial:(GHLSG)

Anni

Advanced stage disease

FFP at 10 years:

(A) COPP/ABVD: 64%;(B) BEACOPP baseline: 70%;(C) BEACOPP escalated: 82%

Diehl et al, NEJM 2003

Advanced stage:ABVD vs BEACOPP

Studio IIL-GITIL-Michelangelo

Study Outline

HL diseaseStage IIB-IV

Stratify: Site; IPS ≤ 2 vs ≥ 3 Random 1:1

ABVDx 6-8

BEACOPP exc x 4BEACOPP std x 4

CR, CRU, PR > 80%RT on bulk

or residual mass(30 Gy)

CR, CRU, PR > 80%RT on bulk

or residual mass(30 Gy)

R< 80%, PD, RelapseHigh-dose

Salvage + RT(20-25 Gy)

R< 80%, PD, RelapseHigh-dose

Salvage + RT(20-25 Gy)

Main patient characteristics in %

Total(321 patients)

ABVD(166 patients)

BEACOPP(155 patients)

IPS 1-2 45 46 45IPS ≥ 3 55 54 55Males 59 60 57Nodal extent only 54 54 55Bulky disease mediastinum

5846

5544

6148

NS Histology 80 78 81Systemic symptoms 84 84 85Age ≤ 45 78 77 80

Viviani et al, NEJM 2011

ABVDABVD(166 pts)(166 pts)

BEACOPPBEACOPP (155 pts) (155 pts)

CR after CT 65 73CR after CT + RT 77 85PR > 80% 8 4No response 5 2PD 10 4

Response rate after first-line treatment

Viviani et al, NEJM 2011

Freedom from first progression

.25

1.00

.75

.50

1 5432 Years

PROBABILITY

BEACOPP

Pts Events HR p

ABVD

155 18 0.43 0.01

166 42

86% 85%

70% 69%

Viviani et al, NEJM 2011

Event-free survival

.25

1.00

.75

.50

1 5432 Years

PROBABILITY

BEACOPP

Pts Events HR p

ABVD

155 29 0.69 0.12

166 43

80% 78%

72% 69%

Viviani et al, NEJM 2011

ABVD BEACOPP

Evaluable patients 37 16

Median time to furtherprogression/death

17 mo(1-65)

6.5 mo(1-38)

CR 22 (59%) 6 (38%)

In continuous CR atcut-off date

17/37(46%)

3/16(18%)

Effects of salvage therapy

Viviani et al, NEJM 2011

Freedom from second progression1.00

.25

.75

.50

1 5432 Years

PROBABILITY

BEACOPP

Pts Events HR p

ABVD

155 11 0.61 0.17

166 20

91% 88%

85% 82%

Viviani et al, NEJM 2011

Overall survival

.25

1.00

.75

.50

1 5432 Years

PROBABILITY

BEACOPP

ABVD

90% 87%89%

86%

Pts Events HR p

155 14 1.03 0.94

166 15

Viviani et al, NEJM 2011

GISL HD2000 trialGISL HD2000 trial

Random

ABVD x 3 CEC x 3 BEACOPP x 3

CR/PR

<PR IGEV + HDT

ABVD x 3 CEC x 3 BEACOPP

X 1 escalated+ 2 standard

Federico, M. et al. J Clin Oncol; 27:805-811 2009

FFS, PFS, RFS, OS by intention to treat

Ovarian toxicity after BEACOPP

Regular menses at dx 90%

Amenorrhea(8 BEACOPP escalated)

57%

Age > 30 years p = 0.006

Advanced stage p < 0.0001

No estro-progestinics p = 0.0002

GHLSG

Gonadal toxicity after ABVD

4 to 6 cycles

Oligospermia 5-8%Amenorrhea< 25 yrs> 25 yrs

2-4%4-8%

Recovery in male > 90%

Recovery in female < 25 yrs 85%

INT-MI and Pavia

Terapia di prima linea:Malattia avanzata

Linee Guida 2009 2011

ABVD x 6-8 ABVD x 6-8

How can we target patients at ahigh chance of failure?

PET - CT

CT-PET: Last-born imaging technique in lymphoma

CT: anatomic detail PET: viability of cells

CT-PET= high-specificity (CT), high-sensitivity (PET)

Interim PET as indicator in advanced diseaseInterim PET as indicator in advanced disease

543210

Time in years

1

0,8

0,6

0,4

0,2

0

Failu

re-fr

ee su

rviv

al

IPS 3-7, PET2posIPS 3-7, PET2negIPS 0-2, PET2posIPS 0-2, PET2neg

IPSandPET

log rank, p ~ 0

Gallamini, Blood 2007

Rigacci, Cologne 2010

months

100806040200

Prog

ress

ion

free

surv

ival

1,0

,8

,6

,4

,2

0,0

PET2-negative

PET2-positive

P < 0.001

Interim FDG-PET in early-stage HL

PET-oriented trials

• H10 trial (EORTC-GELA-IIL)• GHSH HD16• RAPID trial (UK)• HD 0801 (IIL)• GITIL 06/07

Si può omettere la RT negli stadi iniziali?

STUDIO EORTC-GELA-IIL H10

H10: Study design

2 ABVD

2 ABVD

2 BEACOPPesc+INRT 30(+6)

FPET

2 ABVD

1 ABVD+INRT 30 GyPET

-

+

2 ABVD

4 ABVD

2 BEACOPPesc+INRT 30(+6)

PET

2 ABVD

2 ABVD+INRT 30 GyPET

-

+

R

Hodgkin - CS I/II – untreated - 15-70 yrs - no NLPHL

U R

2 ABVD

4 ABVD

H10: Study emendment(August 2010)

2 ABVD

2 ABVD

2 BEACOPPesc+INRT 30(+6)

FPET

2 ABVD

1 ABVD+INRT 30 GyPET

-

+

2 ABVD

4 ABVD

2 BEACOPPesc+INRT 30(+6)

PET

2 ABVD

2 ABVD+INRT 30 GyPET

-

+

R

Hodgkin - CS I/II – untreated - 15-70 yrs - no NLPHL

U R

1 ABVD+INRT 30 Gy

2 ABVD+INRT 30 Gy

GHSG HD16 trial: Early favorableGHSG HD16 trial: Early favorable

ABVD x 2ABVD x 2

Standard arm Experimental arm

ABVD x 2 ABVD x 2

PET neg PET pos

No RTNo RT

PET neg or pos

RTRT RT (30 Gy)RT (30 Gy)

Initial treatment: ABVD x 3Re-assessment with PET in CR/PR patients

4th cycle ABVD + IFRT Random

IFRT No further Tx

PET pos PET neg

RAPID trial design: Early stages (no bulky)RAPID trial design: Early stages (no bulky)

RandomRandom

RT bulkyRT bulky No RTNo RT

SalvageSalvageIIL-HD0802IIL-HD0802

Stage IIB-IVStage IIB-IV

Baseline CT/PETBaseline CT/PET

2 ABVD2 ABVD

PETPET

IIL-HD0801 OutlineIIL-HD0801 Outline

- +

PETPET- +

4 ABVD4 ABVD

ABVD x 2

CT/PET

+ -ABVD x 4

IIB-IV; IPS 0-7

CT/PET- +

Follow up

HD0607

RT

CT/PET

+ -

ASCT

RNo RT

RR-BEACOPP-esc. x 4BEACOPP-esc. x 4

R-BEACOPP-bas. x 4BEACOPP-bas. x 4

- Biopsy +

CT/PET

Shared featuresShared features

• ABVD as first-line therapy• Early FDG-PET evaluation (PET-2)• Switch of therapy in PET-2 positive pts• RT vs no RT in pts in CR with prior bulk

FDG-PET Fstand

Fexper

Ustand

Uexper Total

negative (%) 85 88 73 77 80

positive (%) 15 12 27 23 20

Total patients 212 218 316 334 1080

PET after 2 ABVD

André, ASH 2009

Accrual:305

ABVDx2

PET-2: 263

ABVDx4 SalvageaFerPET‐2:50

PET‐6:147

IIL‐HD0801

RT:28 NoRT:30

R

SalvageaFerPET‐6:12

As of September 2011

199 neg (76%) 64 pos (24%)

13 PET pos134 PET neg

Interim Analysis

Interim PET during ABVD in HLInterim PET during ABVD in HL

• Nearly 70-75% of patients show anegative interim-PET

• Nearly 20% of patients show a positiveinterim-PET

• Nearly 5-10% of patients show a minimalresidual uptake (MRU) at interim-PET

PET 0

PET 6

PET 2

MRU: SUV Max=2.8

What is Minimal Residual Uptake (MRU) ?

Cut-off for positivity

The Deauville score: Sensitive

1 no uptake2 uptake ≤ mediastinum

3 uptake > mediastinum but ≤ liver4 moderately increased uptake compared to liver5 markedly increased uptake compared to liver

The Deauville score: Specific

1 no uptake2 uptake ≤ mediastinum3 uptake > mediastinum but ≤ liver

4 moderately increased uptake compared to liver5 markedly increased uptake compared to liver

It may not be a perfect wheel, but it’s a state-of–the-art wheel