Prise en charge des lymphomes de Hodgkin avancés...
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Prise en charge des lymphomes de Hodgkin avancés O. Casasnovas Hématologie Clinique CHU Dijon, France
Transcript of Prise en charge des lymphomes de Hodgkin avancés...
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 ?
