Prise en charge des lymphomes de Hodgkin avancés

O. Casasnovas

Hématologie Clinique

CHU Dijon, France

Stratification EORTC/GELA GHSG

Médiastin/Thorax > 0.35

4 aires ganglionnaires

B et VS 30

ou A et VS 50

Age 50

Médiastin/Thorax > 0.33

3 aires ganglionnaires

B et VS 30

ou A et VS 50

Atteinte extra-nodale

Aucun facteur: Favorable Facteur 1+: Défavorable

Aucun facteur: Favorable Facteur 1+: Intermédiaire

Exclus: Stades IIB [M/T>0.33, AEN]

Stades I -II

Stades III -IV LH avancé + Stades IIB [M/T>0.33, AEN]

LH avancé

FORMES AVANCÉES QUELLE CHIMIOTHÉRAPIE?

Lymphome de Hodgkin

Long-Term Follow-up

Advanced HL: stages IIB-LMM, III, IV

Failure-free survival Overall survival

Years after study entry

Canellos et al. NEJM, 2002

HL : Chemotherapy

ABVD regimen Dose D1 D15

Doxorubicin 25 mg/m2 (IV) X X

Bleomycin 10 mg/m2 (IV) X X

Vinblastine 6 mg/m2 (IV) X X

Dacarbazine 375 mg/m2 (IV) X X

BEACOPPesc

regimen Dose D1 D2 D3 D4 D5 D6 D7 D8

D9 to D14

Bleomycin 10 mg/m2 (IV) X Etoposide 200 mg/m2 (IV) X X X

Doxorubicin 35 mg/m2 (IV) X Cyclophosphamide 1250 mg/m2 (IV) X

Vincristine 1,4 mg/m2 (IV) [2mg max] X Procarbazine 100 mg/m2 (PO) X X X X X X X Prednisone 40 mg/m2(PO) X X X X X X X X X

1973

1993

ABVD • Contrôle de la maladie insuffisant pour 25 à 30 % des pts

• Toxicité – Pulmonaire

• Mayo clinic (n = 141): 18% des patients • MSKCC (n = 152): 22% d’arret précoce de la bleomycine • Hoskin et al (UK) : 10% de toxicité pulmonaire g>3 • RATHL: Réduction de DLCO moyenne = 11% après 6 ABVD

= 4.3% après 2 ABVD + 4 AVD

n CR 5y-PFS Follow-up

Gordon JCO 2013 404 73% 74% 77 months

Chisesi JCO 2011 126 89% 78% 86 months

Viviani NEJM 2011 166 76% 73% 61 months

Federico JCO 2009 102 84% 68% 41 months

Hoskin JCO 2009 261 67% 76% 52 months

CS IIB-IIIA with risk factors

CS IIIB-IV

Arm A

4 × COPP+ABVD

RT

Arm B

8 × BEACOPP

baseline

RT

Arm C

8 × BEACOPP

escalated

RT

RT to initial bulk and residual tumor

GHSG: HD9 Trial Design (1992 - 96)

Randomisation

Diehl et al, NEJM, 2003

BEACOPP baseline regimen

Dose D1 D2 D3 D4 D5 D6 D7 D8

D9

to

D14

Started

at D9

Blemomycin 10 mg/m2 (IV) X

Etoposide 100 mg/m2 (IV) X X X

Doxorubicin 25 mg/m2 (IV) X

Cyclophosphamide 650 mg/m2 (IV) X

Vincristine 1,4 mg/m2 (IV) [2mg max]

X

Procarbazine 100 mg/m2 (PO) X X X X X X X

Prednisone 40 mg/m2(PO) X X X X X X X X X

G-CSF 5 mg/kg/day (SC) X

BEACOPPesc regimen

Dose D1 D2 D3 D4 D5 D6 D7 D8

D9

to

D14

Started

at D9

Blemomycin 10 mg/m2 (IV) X

Etoposide 200 mg/m2 (IV) X X X

Doxorubicin 35 mg/m2 (IV) X

Cyclophosphamide 1250 mg/m2 (IV) X

Vincristine 1,4 mg/m2 (IV) [2mg max]

X

Procarbazine 100 mg/m2 (PO) X X X X X X X

Prednisone 40 mg/m2(PO) X X X X X X X X X

G-CSF 5 mg/kg/day (SC) X

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 Riskyears

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

HD9 – 10-years outcome by treatment arm

BEA esc

C/ABVD

82%

64%

Engert A, JCO 2009; 27: 2548

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 Riskyears

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

BEA esc 86%

C/ABVD 75%

FFTF

OS

BEACOPP vs ABVD

FFP OS

Median FU = 41 months

Federico M, JCO ,2009

Stage IIB- IV BEACOPP [esc x 4 + Baseline x 2] vs ABVD x 6

BEACOPP vs ABVD

FFP OS

Median FU = 61 months

Viviani S, NEJM 2011; 365: 203

Stage IIB- IV BEACOPP [esc x 4 + Baseline x 4] vs ABVD x 6/8

P = 0.004 P = 0.39

GELA H3-4 Trial IPS <3

Doxorubicine J1 et J15 : 25

Bleomycin J1 et J15 : 10 Vinblastine J1 et J15 : 6 DTIC J1 et J15 : 375

Bleomycin J1 10 10 Etoposide J1-3 200 100 Doxorubicine J1 35 25 Cyclophosphamide J1 1250 650 Vincristine J8 1.4 1.4 Procarbazine J1-7 100 100 Prednisone J1-14 40 40

8 x BEACOPP

R

3 1 2 5 6 7 4 8

1 2 3 4 5 7 8 6

CT scan

8 x ABVD

N =77

N =68

5y PFS* 5y OS £ 75% 92% 93% 99%

Mounier N, Ann Oncol 2014

*p= 0.008 £ p= 0.08

BEACOPP: Toxicité aigue

Diehl et al, NEJM, 2003

BEACOPPesc : Fertilité

• Hommes

90% Azoospermie après 8 x BEACOPPesc

• Femmes: Aménorrhée 4 ans après fin Chimio

Sienawski, Ann Oncol, 2008

6-8 BEACOPPesc

2 BEACOPPesc + 2 ABVD ou

4 ABVD

Behringer K, JCO, 2013

HD9 Secondary malignancy

Secondary AML/MDS

Engert A, JCO 2009; 27: 2548

HD15

Engert A, Lancet 2012

5y FFTF: 6 Besc = 90.8% 8 Besc = 84.9% P<0.01

5y OS: 6 Besc = 96.2% 8 Besc = 91.8% P<0.01

Causes of death - N (%) BEACOPPesc x 8 (N=705) BEACOPPesc x 6 (N=711)

Total 53 (7.5) 33 (4.6)

Hodgkin lymphoma 13 (1.8) 11 (1.5)

Toxicity of chemo 15 (2.1) 6 (0.8)

2nd Neoplasia 13 (1.8) 5 (0.7)

Toxicity of salvage treatment 2 (0.3) 2 (0.3)

Other 10 (1.4) 9 (1.3)

Chimiothérapies de référence en 2014

Quel patient requière du BEACOPPesc?

5y-PFS 5y-OS

6 à 8 x ABVD 75% 90%

6 x BEACOPPesc 90% 96%

BEACOPPesc est plus éradicateur que l’ABVD, avec un meilleur contrôle de la maladie mais

sans bénéfice sur la survie démontré

FORMES AVANCÉES PATIENTS REQUÉRANT DU BEACOPP : VERS UNE STRATÉGIE ADAPTÉE

Lymphome de Hodgkin

International Prognostic Score

• Age > 45 y

• Male

• Albumin < 40 g/l

• Hb < 10,5 g/100ml

• WBC > 15000 /mm3

• Ly < 600 /mm3 < 8%

• Stage IV

Score FFP OS

0 (7%) 84 4 89 2

1 (22%) 77 3 90 2

2 (29%) 67 2 81 2

3 (23%) 60 3 78 3

4 (12%) 51 4 61 4

5 (7%) 42 5 56 5

Hasenclever NEJM 1998; 339: 1506

IPS

Hasenclever D, NEJM 1998; 339: 1506

HD9: IPS

Engert A, JCO 2009; 27: 2548

PFS and DSS according to tumor micro-environment CD68+ cells

Steidl C, NEJM 2010; 262: 875

Scott D, JCO 2012; 31: 692

A 23 Gene expression predictor in formalin-fixed paraffin-embedded tissue

Training set Validation set

Scott D, JCO 2012; 31: 692

PFS according to IL1RA IL6 CD30s signature in stages III & IV

Score 0

Score 1-2

Score 3

P<.0001

10%

63%

27%

Casasnovas O, JCO 2007; 25: 1732

Early PET

Hutchings M, Blood 2006; 107: 52 Gallamini A, JCO 2007; 25: 3746

PET2-

PET2+

Response adapted therapy of stages III–IV Hodgkin Lymphoma based on

interim FDG-PET imaging: US intergroup S0816

• Objective: increase 2y-PFS from 70 % to 78 %

• s

ABVD x 2

5PS < 4

HL Stage III-IV

18-60 y

n = 357

TEP

BEACOPP esc x 6

n = 55 (17 %)

ABVD x 4

n = 277

5PS = 4-5

0 12 24 36 48

0

20

40

60

80

100 PET2-: ABVD

Mois

% PET2+: BEACOPPesc

Press O, Cologne 2013 – Abst T108

PFS 61%

79%

2y-PFS = 76%

Median FU = 16 months

GITIL/FIL HD0607

Positive PET2

BEACOPP esc x 4 + BEACOPP b x 4

ABVD x 2

Negative

ABVD x 5 R-BEACOPP esc x 4 + R-BEACOPP b x 4

N = 330

N = 59 (18%) N = 271 (82%)

2y-PFS 85% 61%

Gallamini A, Cologne 2013 – Abst P006 Median FU = 32 months

LYSA: AHL 2011

Standard Arm Experimental Arm

Neg / Pos

Salvage therapy

Pos Neg

PET4

PET2

Neg Pos Neg Pos Neg

Salvage therapy

BEACOPP esc x 2

BEACOPP esc x 2 BEACOPP esc x 2

BEACOPP esc x 2

R

ABVD x 2

Non inferiority of the experimental arm

ABVD x 2 BEACOPP esc x 2

BEACOPP esc x 2

GHSG: HD18

Negative PET2

BEACOPP esc x 2

BEACOPP esc x 2

BEACOPP esc x 4

Positive

End of therapy AND residual nodes > 2.5 cm:

PET positive: Rx PET negative: Follow up

BEACOPP esc x 4

PFS according to the total metabolic tumor volume at baseline (TMTV0)

TMTV0 ≤225ml

TMTV0 >225ml

P= 0.001

Kanoun S et al , EJNM 2014, 41:1735-43

PFS according to MTV0 and DSUVmaxPET0-2

N = 37 (63%)

N = 17 (29%)

N = 5 (8%)

Kanoun S et al , EJNM 2014, 41:1735-43

FORMES AVANCÉES CHIMIOTHERAPIE + ANTICORPS

Lymphome de Hodgkin

MAb + ABVD in advanced HL

n RC 5y-PFS Median FU

ABVD Gordon JCO 2013 404 73% 74% 77 months

ABVD Chisesi JCO 2011 126 89% 78% 86 months

ABVD Viviani NEJM 2011 166 76% 73% 61 months

R-ABVD Younes Blood 2012 78 93% 82% 68 months

R-ABVD Kasamon Blood 2012 49 81% 83% 33 months

BV-ABVD Ansell ASH 2012 / Cologne 2013

22 95% -

BV-AVD 25 96% -

Adcetris combiné à A(B)VD • 51 Hodgkin avancés (45% stade IV, 25% IPS>3, 33% Bulk)

• Aucune DLT observée (Cycle 1)

BV-ABVD BV-AVD

Inclus (n) 25 26

BV 0.6mg/kg 6 0

BV 0.9mg/kg 13 0

BV 1.2mg/kg 6 26

Tox pulmonaire gr>0/ gr≥3/gr=5 11 (44%)/ 6 (24%)/ 2 (8%) 0

Embolie pulmonaire gr≥3 3 (12%) 0

Neuropathie gr>0 18 (73%) 20 (72%)

Neutropénie fébrile gr≥3 5 (20%) 2 (8%)

ECHELON 1

Standard Arm Experimental Arm

5PS = 1-4 PET2

ABVD x 2 AVD-A x 2

R

ABVD x 4

Stage III/IV

5PS = 1-4

AVD-A x 4

Planned Accrual = 1040 pts Primary endpoint: PFS

5PS = 5

Protocol Therapy or

Salvage therapy

Drug Day 6x

BEACOPP

escalated

6x

BrECADD („experimental“)

6x

BrECAPP („standard“)

Bleomycin 8 10

Etoposide 1-3(2-4) 200 150 200

Adriamycin 1(2) 35 40 35

Cyclophosphamide 2 1250 1250 1250

Vincristine 8 1.4

Brentuximab vedotin 1 1.8 1.8

Procarbazine 1-7 (2-8) 100 100

Prednisone 1-14(2-15) 40 40

Dacarbazine 2-3 2x 250

Dexamethasone 2-5 40

Targeted BEACOPP

INTERET D’UNE INTENSIFICATION DE PREMIÈRE LIGNE?

HD-01 trial EBMT/SFGM/GELA

• Stage IIIB-IV, < 55 y

• High risk according to Strauss criteria

– M / T >0.45

– Stage IV > 1 extranodal site

– LDH

– Inguinal node involvement

– Hb <12 (male) / 10 (female)

– Bone marrow involvement

ABVD x 4

ABVD x 4

ASCT

HD-01 trial EBMT/SFGM/GELA

8 x ABVD 4 x ABVD ASCT

n 80 80

IPS(%) 0-2

3+

39

61

44

56

5y FFS 82 75

5y OS 88 90 Median FU 50 months

Federico M, JCO 2003; 21: 2320

HD-01 trial EBMT/SFGM/GELA

Federico M, JCO 2003; 21: 2320

H97-HR GOELAMS (1997 – 2004)

• Stage IIB,III, IV; 18-60 y

• High risk:

– M / T ≥ 0.45

– Stage IV ≥ 2 extranodal site

– ≥ 5 nodal area involvement

ABVD x 4 + ASCT (BEAM)

R

VABEM x 3 + Radiotherapy 20Gy + Boost

H97-HR GOELAMS (1997 – 2004)

n = 158

79%

75%

87%

86%

Arakelyan N, Cancer 2008; 113: 3323

FORMES AVANCÉES PLACE DE LA RADIOTHÉRAPIE

Lymphome de Hodgkin

H89

8x

ABVPP

6x

ABVPP +STNI

6x

MOPP/ABV

+STNI

8x

MOPP/ABV

n 116 96 114 92

CR (%) 99 91 95 91

10y-EFS (%) 67 69 77 71

10y-OS (%) 90 87 82 78

Ferme C, et al. Blood 2006; 107: 4636

Advanced HL in first CR after 6-8 MOPP/ABV

Aleman B, et al. NEJM 2003;348: 2396

Advanced HL (stage III-IV) after 6-8 MOPP/ABV

Aleman B, et al. NEJM 2003;348: 2396

HD12

Residual disease after chemo Initial bulk without residual disease after chemo

Borchmann P, et al. JCO 2011;29: 4234

HD15: study 2126 pts Dose density and reduction of toxicity

A B C

8 x

BEACOPP 14

( baseline)

6 x

BEACOPP

escalated

8 x

BEACOPP

escalated

Randomization

Residual tumor mass?

(>2.5 cm)

follow up

No

PET-study

PET negative:

follow up

PET positive:

RT 30 Gy 9% of all pts!

Yes

HD 15 Trial 8 vs 6 BEAesc vs 8 BEA-14

739 patients randomized and evaluable for outcome

PET after end of chemotherapy for >2,5cm rests:

Patients with rests >2,5 cm:

548 (74%) PET neg: no RT: 540 4y-PFS: 91.5%

n = 739

191 (26%) PET pos: IF-RT: 180 4y-PFS: 86.1%

PFS of patients with a residual mass >2.5cm according to PET results

Kobe C, et al. JCO 2014;32: 1776

PFS of patients with a residual mass >2.5cm according to PET results and tumor shrinkage

Kobe C, et al. JCO 2014;32: 1776

Conclusions • Pas de bénéfice démontré chez les patients en 1ère réponse:

– de la radiothérapie – de l’intensification avec autogreffe de CSH

• 6-8 x ABVD ou 6 x BEACOPPesc – BEACOPPesc est le traitement le plus éradicateur au prix d’une

toxicité immédiate et retardée significative – Pas d’éléments pronostiques simples pour cibler les patients

devant recevoir l’un ou l’autre des schémas • Risques liés à l’hématotoxicité • Fertilité

– Les stratégies TEP guidées pourraient permettre de limiter le nombre de cycles de BEACOPPesc pour les patients répondeurs précoces (>80% ?) et donc la toxicité

• BV-AVD futur challenger du BEACOPPesc ?