Lymphome de Hodgkinaihemato.cluster013.ovh.net/AIH/documents/Cours DES/DES...2 approhes limitant...
Transcript of Lymphome de Hodgkinaihemato.cluster013.ovh.net/AIH/documents/Cours DES/DES...2 approhes limitant...
Lymphome de Hodgkin avancé
Olivier CasasnovasHématologie cliniqueINSERM UMR 1231
CHU Dijon Bourgogne - France
StratificationEORTC/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: FavorableFacteur 1+: Défavorable
Aucun facteur: FavorableFacteur 1+: Intermédiaire
Exclus: Stades IIB [M/T>0.33, AEN]
Stades I -II
Stades III -IVLH avancé + Stades IIB [M/T>0.33, AEN]
LH avancé
La TEP modifie-elle la prise en charge initiale?
n D Stade(%)
D management (%)
Shah (2000) LNH/LH 29 - 31
Raannani (2005) LNH/LH 103 36 45
Hernandez (2006) LNH/LH 47 23 15
Naumann (2004) LH 88 20 18
Hutchings (2006) LH 30 - 33
Rigacci (2007) LH 186 16 -
Baseline PET improve staging and outcome of HL patients
U Metzer, Radiology 2019 in press
26% of limited stage58% of equivocal stage
Baseline PET improves staging and outcome of HL patients
U Metzer, Radiology 2019 in press
HL : Bone marrow involvement
454 HL pts at diagnosis
El Galaly T, JCO 2012
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
regimenDose 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
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 ys 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
82%
64%
Engert A, JCO 2009
HD9
Von Treskow, Lancet Hematol 2018
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)
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 ABVDou
4 ABVD
Behringer K, JCO, 2013
HD9Secondary malignancy
Secondary AML/MDS
Engert A, JCO 2009; 27: 2548
BEACOPP vs ABVD
FFP OS
Median FU = 41 months
Federico M, JCO ,2009
Stage IIB- IVBEACOPP [esc x 4 + Baseline x 2] vs ABVD x 6
BEACOPP vs ABVD
PFS OS
Median FU = 61 months
Viviani S, NEJM 2011; 365: 203
Stage IIB- IVBEACOPP [esc x 4 + Baseline x 4] vs ABVD x 6/8
P = 0.004 P = 0.39
Score pronostic international
• Age > 45 ans
• Homme
• Albumine < 40 g/l
• Hb < 10,5 g/100ml
• GB > 15000 /mm3
• Ly < 600 /mm3 < 8%
• Stade IV
Score FFP Survie
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
GELA/EORTC H3-4 TrialIPS <3
Doxorubicine J1 et J15 : 25Bleomycin J1 et J15 : 10 Vinblastine J1 et J15 : 6 DTIC J1 et J15 : 375
Bleomycin J1 10 10Etoposide J1-3 200 100Doxorubicine J1 35 25Cyclophosphamide J1 1250 650Vincristine J8 1.4 1.4Procarbazine J1-7 100 100Prednisone J1-14 40 40
8 x BEACOPP
R
31 2 5 6 74 8
1 2 3 4 5 7 86
CT scan
8 x ABVD
N =77
N =68
5y PFS* 5y OS £
75% 92%
93% 99%
P Carde et al, JCO 2016
*p= 0.008£ p= 0.08
GELA: BEACOPP vs ABVD in pts with IPS 0-2
P = 0.007
Mounier N, Ann Oncol 2014
les enjeux à l’ère de la TEP: formes avancées
• ABVD guérit 70 à 75% des patients
• BEACOPPesc guérit 85% des patients mais toxicités tardives
=> Améliorer le contrôle tumoral en identifiant les pts relevant d’un traitement plus intense?
=> Limiter la toxicité en maintenant le contrôle tumoral?
La TEP précoce
Huchtings M, Blood 2006; 107: 52 Gallamini A, JCO 2007; 25: 3746
PET2-
PET2+
TRAITEMENT DES IMAGES ET INTERPRÉTATION
Analyse visuelleCritères de Deauville
5PS : 2
Echelle semi quantitative à 5 points
1 Pas de fixation
2 Fixation ≤ médiastin
3 Fixation ≤ foie
4 Fixation >> foie, de façon modérée
5 Fixation intense, nouvelles lésions
Prognosis value of early PET interpreted according to 5PS in HL
Biggi, JNM 2013
PET2-
PET2+
p< 0.002
Rossi, JNM 2014
Gallamini A, JCO 2007; 25: 3746
PET2-
PET2+
VPP = 50 - 55%VPN = 80 - 90%
2 approches limitant l’exposition au BEACOPPesc
• Réserver le BEACOPPesc aux mauvais répondeurs
Escalade des pts TEP2+ après ABVD
– Inconvénients:
• Dose intensité insuffisante pour les maladies les plus résistantes / sélection de clones résistants
• VPP < VPN TEP2
– Avantage: tolérance ABVD
• Désescalade des pts TEP2- après BEACOPPesc pour tous– Inconvénient: % TEP2- après BEACOPPesc?
– Avantage: VPN > VPP TEP2
RATHL
PET 2 +ve2 x ABVD
PET 2PET 2 -ve
4 x BEACOPP-14or 3 x BEACOPP-E
PET 3 +ve PET 3 -ve
RT or salvage therapy
2 x BEACOPP-14or 1 x BEACOPP-E (no RT)
Follow-up (No RT)
4 x ABVD 4 x AVD
P. Johnson, NEJM 2016
RATHL: Patients characteristics
N 1 214
Male 55%
Stage II/III/IV 41% / 31% / 28%
B symptoms 61%
Bulky disease 32%
PS 0/1/2/3 74/22/2/1
IPS
- 0-1 34%
- 2-3 48%
- > 3 17%
Deauville score after 2 ABVD
n %
1 114 10
2 493 43
3 347 31
4 145 13
5 38 3
IPS AHL 20110-1 = 14%2-3 = 55%>3 = 31%
P. Johnson, NEJM 2016
Outcome of pts with negative PET2HR : 1.13 (0.81 – 1.57), p = 0.58
3y-PFS, ABVD : 85.7% (IC 95% ; 82.1 – 88.6)
3y-PFS, AVD : 84.4% (IC 95%; 80.7 – 87.5)
P. Johnson, NEJM 2016
Outcome of positive PET2 patientsBEACOPP-14 / BEACOPPesc
16% of positive PET2 patientsP. Johnson, NEJM 2016
3y-PFS = 67.5% 3y-OS = 87.8%
LH IIB-IV B. IPS 0-7
Design de l’étude HD 0607
FIL-GITILEssai HD0607
ABVD x 2
Pas de radiothérapie
ABVD x 4
TEP
TEP
Évaluation de fin de traitementSuivi
Radiothérapie
Non Non Oui
-+
TEP
+ -
R
R
(Biopsie +)
RattrapageBEACOPP-bas. x 4 R-BEACOPP-bas. x 4
Évaluation : Échec (< RP) ?
BEACOPP-esc. x 4 R-BEACOPP-esc. x 4
A. Gallamini et al., JCO 2018
Survie sans échec selon les résultats de la TEP2
0,75
0,50
0,25
0,000 1 2 43
1,00
5
Années
62%66%
81%84%
85%89%
ABVD 1-2 : RDI 100,5 %ABVD 3-6 : RDI 97,6 %(R) BEACOPP : RDI 86,6 %
TOT 86/500 (17,2%)
TEP2 NEG 52/400 (13,0%)
TEP2 POS 33/98 (33,7%)
500* 417 338 37212 1(51) (23) (10) (0)(1) (1)TOT
400 351 290 30186 1(27) (16) (7) (0)(1) (1)TEP2 NEG
98 66 48 726 0(23) (7) (3) (0)(0) (-)TEP2 POS
* 1 patient est décédé à l’évaluation au TEP2 et 1 patient est manquant pour le TEP2
p < 0,001
Patients à risque (evts.)
A. Gallamini et al., JCO 2018TEP2+ = 19,6%
Suivi médian 2,9 ans
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 = 336
TEP
BEACOPP esc x 6
n = 60 (18%)
ABVD x 4
n = 271
5PS = 4-5
Press O, JCO 2016
2y-PFS = 79%Median FU = 39.7 months
82%
64%
AHL 2011
Standard Arm Experimental Arm
Neg / Pos
Salvagetherapy
Pos Neg
PET C4
PET C2
Neg Pos Neg Pos Neg
Salvagetherapy
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 armStandard arm : 85% 5y-PFS ; Experimental arm: 5y-PFS > 75% (HR=1.77)
ABVD x 2BEACOPP esc x 2
BEACOPP esc x 2
AHL2011: PET Review criteria
Local and review interpretations had to follow the 5PS criteria modified as following:
The 5-point scale:
• 1. No uptake.
• 2. Uptake < mediastinum.
• 3. Uptake > mediastinum but < liver.
• 4. Uptake moderately more than liver uptake, at any site.
A moderately uptake more than liver uptake is define as an uptake more or equal than 140% of SUV max liver (assessed on 3 slides on the liver middle region)
• 5. Markedly increased uptake at any site or new sites of disease.
A markedly uptake more than liver uptake is define as an uptake more or equal than 200% of SUV max liver (assessed on 3 slides on the liver middle region)
➢ PET positive is defined by scale level 4 and 5 (as described above)
➢ PET negative is defined by scale level 1, 2 and 3.
33ASCO meeting 2018AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: Characteristics of patients
ASCO meeting 2018
Median age (range)
Male (n - %) 263 64% 253 62% 516 63%
ECOG (n - %) 0 203 49% 193 47% 396 48%
1 177 44% 184 45% 361 45%
2 27 7% 31 8% 58 7%
B symptoms (n - %) 282 68% 278 68% 560 68%
Ann Arbor stage (n - %) I 0 0 2 0.5% 2 0.2%
II 44 11% 52 13% 96 12%
III 114 28% 115 28% 229 28%
IV 255 62% 241 59% 496 60%
Stage IIB (n - %) 42 10% 45 13% 87 11%
M/T≥ 0.33 41 98% 45 100% 86 99%
6 14% 4 9% 10 12%
Bone marrow involved (n - %) 33 8% 32 8% 65 8%
IPS group (n - %) 0-2 160 39% 183 45% 343 42%
≥ 3 250 61% 225 55% 475 58%
30 (16 – 60)
All
N = 823
Extra nodal localization
31 (16 – 60) 29 (16-60)
Standard arm Experimental arm
N = 413 N = 410
AHL 2011
AHL 2011: PET2 results (central review)
ISHL meeting 2018
PET2
Evaluable 398 96% 397 97% 795 97%
Negative 349 88% 346 87% 695 87%
Positive 49 12% 51 13% 100 13%
Standard arm Experimental arm All
n = 413 n = 410 n = 823
In an intent to treat basis, 84% of patients received
2 x BEACOPPesc + 4 x ABVD
in the experimental arm
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: PFS according to treatment arm (Primary endpoint – ITT population)
ISHL meeting 2018
p = 0.68 ; HR = 1.084 (95%CI: 0.73 - 1.59)
4y-PFS = 87.4% ; 5y-PFS = 86.2%
4y-PFS = 87.1% ; 5y-PFS = 85.7%
Median follow-up = 50.4 months
(HR Bound < 1.77)
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
BEACOPP x 6
vs
BEACOPP x 6 (PET2+)
BEACOPP x 2 + ABVD x 4 (PET2-) (84%)
AHL 2011: PFS according to treatment arm (Primary endpoint – per protocol population)
ISHL meeting 2018
(HR Bound < 1.77)
AHL 2011
5y-PFS: 85.4%5y-PFS: 86.7%
P = 0.74; HR=1.144 (95CI%:0.758-1.726)
Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: OS according to treatment arm
38ISHL meeting 2018
p = 0.91; HR = 0.936 (95%CI: 0.42 – 2.05)
4y-OS = 96.9% ; 5y-OS = 95.2%4y-OS = 97.1% ; 5y-OS = 96.4%
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: interim PET results (central review)
ISHL meeting 2018
PET2
Evaluable 398 96% 397 97% 795 97%
Negative 349 88% 346 87% 695 87%
Positive 49 12% 51 13% 100 13%
PET4
Evaluable 383 93% 376 92% 759 92%
Negative 356 93% 360 96% 716 94%
Positive 27 7% 16 4% 43 6%
Standard arm Experimental arm All
n = 413 n = 410 n = 823
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: PFS according to the PET-driven strategy
ISHL meeting 2018
n = 654 (86%)
n = 64 (8%)
n = 43 (6%)
AHL 2011
4y-PFS: 75.4%; 5y-PFS: 75.4% 4y-PFS: 46.5%; 5y-PFS: 46.5%
4y-PFS: 92.5%; 5y-PFS: 90.9%
P< 0.001
Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: Factors influencing PFS
ISHL meeting 2018
n (%)4y-PFS
% (95%CI)HR p HR p
PET2/PET4 PET2-/PET4- 654 (79%) 92.5 (90.1-94.3)
PET2+/PET4- 62 (7.5%) 75.4 (62.5-84.4) 3.588 <0.0001 3.316 <0.0001
PET4+ 43 (5.2%) 46.5 (31.2-60.4) 13.14 <0.0001 12.968 <0.0001
IPS 0-2 343 (42%) 91.9 (88.4-94.4)
≥3 475 (58%) 83.7 (79.9-86.9) 1.915 0.0025 1.6 0.044
Risk factors
Univariate analysis Multivariate analysis
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: OS according to the PET-driven strategy
ISHL meeting 2018AHL 2011
4y-OS: 93.5%; 5y-OS: 93.5%
4y-OS: 98.6%; 5y-OS: 97.1%
4y-OS: 93.6%; 5y-OS: 93.6% P<0.04
Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: Adverse events
ISHL meeting 2018
n % n % p
Patients with AE of any grade 412 100 407 100 NS
Patients with AE Grade ≥3 402 98 394 97 NS
AE grade ≥3
Blood and lymphatic system disorders 400 97 388 95 NS
Anemia 286 69 114 28 <0.001
Leukopenia 381 92 367 9 NS
Neutropenia 359 87 366 9 NS
Febrile neutropenia 145 35 93 23 <0.001
Thrombocytopenia 271 66 163 40 <0.001
Infections and infestations 78 19 43 11 <0.001
Sepsis 29 7 15 4 0.04
Lung infection 12 3 4 1 NS
Other 48 12 28 7 0.02
Gastro-intestinal disorders 41 10 41 10 NS
Standard Arm PET-driven arm
n = 412 n = 407
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: Treatment related SAE
ISHL meeting 2018
n % n % p
Patients with at least 1 related SAE 110 27 71 17 <0.002
Nb of related SAE 192 47 114 28 <0.001
Related SAE leading to death 6 1.3 2 0.5 NS
Standard Arm PET-driven arm
n = 412 n = 407
66% occured during the 2 first cycles
28 patients (6.8%) in the standard arm 4 patients (1%) in the experimental arm
discontinued treatment due to toxicity (p<10-5)
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL 2011: Secondary primary malignancy
ISHL meeting 2018
p
Secondary primary malignancy 10 2.4% 5 1.2% NS
AML 4 1% 1 0.25% NS
B-cell Lymphoma 1 1
T-cell Lymphoma 0 1
Lung cancer 1 0
Renal cancer 0 1
Breast cancer 2 0
Thyroid cancer 0 1
Basal cell skin carcinoma 2 0
Standard arm Experimental arm
n = 412 n = 407
AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
AHL2011: Fertility
• A dedicated study is ongoing ,testing:– Female:
• AMH, inhibin B, 17-beta-oestradiol, FSH, LH levels
– Male
• Spermogram
• FSH, testosterone
– All: • Fertility history including spontaneous pregancy, medical assisted procreation
• Fertility preservation procedure
• To date:– 73 Pregnancies : n=28 (6.8%) in Standard and 45 (11%) in the PET-driven arms (p = 0.036)
– Medical assisted procreation : 6 (21%) vs 6 (7%) in Standard and PET-driven arms respectively
ISHL meeting 2018AHL 2011 Casasnovas et al, Lancet Oncol 2018, in press
GHSG: HD18
Borchmann P, Lancet 2017
PFS PFS in PET2 negative patients
NegativePET2
BEACOPP esc x 2
BEACOPP esc x 2
BEACOPP esc x 4/6
Positive
BEACOPP esc x 4/6
52% DS 1-224% DS 324% DS 4+
HD18: outcome of DS3 patients who received 6 x BEACOPPesc in the santard arm
C Kobe, Blood 2018
HD18: PFS of patients who received 6 cycles of BEACOPPesc in the standard arm according to DS
30% DS 1-270% PET2+
67% DS 1-333% PET2+
C Kobe, Blood 2018
PET guided studies
Study Ann Arbor Stage % IPS>3
Score % 3y-PFS 3y-OS 3y-PFS 3y-OS
RATHL ABVD 1203 II (42%), III (30%), IV (28%) 17.4 4 - 5 16 67.5 87.8 85 97
GITIL/FIL HD 0607 ABVD 782 II (36%), III (32%), IV (32%) 12.5 4 - 5 19.2 60 89 87 99
GITIL ABVD 165 ≥III (46%) 27 (≥ 3) 4 - 5 17 65 (FFS) - 92 (FFS) -
SWOG ABVD 331 II (0%), III (52%), IV (48%) 51 (≥ 3) 4 - 5 18.1 64 (2y) - 82 (2y) -
GHSG HD18 BEACOPPesc 1945 II (14%), III (49%), IV (36%) 16 3 - 5 48 92.5 97.1 93.5 97.3
LYSA AHL2011 BEACOPPesc 823 II (12%), III (28%), IV (60%) 31 4 - 5 12.6 70.7 93.9 91.8 99
Upfront
chemotherapy
Patients
enrolled
Deauville score positivity PET2 positive patients PET2 negative patients
Casasnovas et al, Lancet Oncol 2018, in press
ECHELON 1
Primary endpoint: modified PFS
Scr
ee
nin
gC
T/P
ET
sca
n
1:1
ra
nd
om
iza
tio
n(N
=1
33
4)
ABVD x 6 cycles (n=670)
A+AVD x 6 cycles (n=664)Brentuximab vedotin: 1.2 mg/kg IV infusion
Days 1 & 15
EO
TC
T/P
ET
sca
n
Follow-up
Every 3 months for 36 months,
then every 6 months until study closure
End-of-Cycle-2 PET scan• Deauville 5; could receive alternate therapy per
physician’s choice (not a modified PFS event)
Echelon 1
Echelon 1 : Response
Connors J, NEJM 2018
ECHELON 1: modified PFS
Connors J, NEJM 2018
2y-mPFS: 82.1% vs 77.2%
Modified PFS events per IRF after A+AVD or ABVD were attributed to:
- disease progression (90 vs 102);
- death (18 vs 22)
- receipt of additional anticancer therapy for incomplete response (9 vs 22)
ECHELON 1: PFS
Connors J, NEJM 2018
ECHELON 1: Safety
Connors J, NEJM 2018
ECHELON 1: Safety
Connors J, NEJM 2018
59
Phase II study: brentuximab vedotin as part of targeted BEACOPP in frontline HL (NCT01569204)
Dose: BrECAPP (n=49) and BrECADD (n=52) regimens were administered every 21 days for 6 cycles. Brentuximab vedotin dose was 1.8 mg/kg IV
59
Drug Day
BEACOPP
escalated X6
Cycles
BrECADD x6
CyclesBrECAPPx6 Cycles
Bleomycin (mg/m²) 8 10 – –
Etoposide (mg/m²) 1–3 200 150 200
Doxorubicin (mg/m²) 1 35 40 35
Cyclophosphamide (mg/m²) 1 1250 1250 1250
Vincristine (mg/m²) 8 1.4 – –
Brentuximab vedotin (mg/kg) 1 – 1.8 1.8
Procarbazine (mg/m²) 1–7 100 – 100
Dacarbazine (mg/m²) 2–3 – 250 –Prednisone (mg) 1–14 40 – 40
Dexamethasone (mg) 1–4 – 40 –
Eichenauer D, Lancet Oncol 2017
60
Phase II study: brentuximab vedotin as part of targeted BEACOPP in frontline HL (NCT01569204)
60
*Withdrawal before therapy, n=2 (1 pt: consent withdrawn; 1 pt: acute infection with fever plus inclusion criteria violation [no advanced-stage HL]); †Early treatment termination, n=1
BEACOPP: bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; BrECADD: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone; BrECAPP: brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, procarbazine, prednisone
2 x BrECAPP
4 x BrECAPP 4 x BrECADD
2 x BrECADD
Off study in case of PD
Off study in case of PD
Staging after end of chemotherapy (N=101):†
End of therapy AND residual nodes > 2.5 cm: PET positive: Rx @ 30 GyPET negative: Follow up
RandomizationN=104 patients aged 18-60 y
CS IIB + RF ED or LMM, CS III/IV
Interim Staging (CT-2/PET-2)(N=102)*
Study Design
Eichenauer D, Lancet Oncol 2017
61
Phase II study: brentuximab vedotin as part of targeted BEACOPP in frontline HL (NCT01569204)
Efficacy:
• A total of 101 patients were evaluated;
– In the BrECAPP arm (n=49), 42 (86%) patients achieved a CR or PR (<2.5 cm) or PET-negative PR (≥2.5 cm) and 7 (14%) reached <PR or were PET-positive
– In the BrECADD arm (n=52), 46 (88%) patients achieved a CR or PR (<2.5 cm) or PET-negative PR (≥2.5 cm) and 6 (12%) achieved <PR or were PET-positive (including 1 pt with PD)
– In the HD18 study (N=630), CR or PR (<2.5 cm) or PET-negative PR (≥2.5 cm) was achieved in 88% of patients and <PR or PET-positive in 12% of patients
• PFS at 18 months;
‒ BrECAPP: 95% (85, 100), 2 events
‒ BrECADD: 89% (77, 100), 4 events
61
.
Feasibility, %Pts on full
dose at cycle 6
Pts on baseline dose at cycle 6
BrECAPP 60 17
BrECADD 69 8
BEACOPPesc* 50 15
62
Phase II study: brentuximab vedotin as part of targeted BEACOPP in frontline HL (NCT01569204)
Safety:
• Gr 3 sensory PN was reported in 1 (1%) patient receiving tBEACOPP (n=102) and no Gr 4 sensory PN was observed; 1 ptdeveloped Gr 3 motor PN which resolved completely
• All treatment-related PN events resolved completely
• No severe neurotoxicity reported with BrECADD
• Brentuximab vedotin was reduced/stopped in cycle 5 and/or cycle 6 in 8/102 pts (8%) vs 20% for VCR with BEACOPPesc
62
NCIC-CTC Grade RegimenGrade III
n (%) Grade IV
n (%) Grade III/IV
%
Hematologic
BrECAPP 6 (12) 40 (80) 80
BrECADD 4 (8) 41 (79) 83
BEACOPPesc* – – 93
Organ
BrECAPP 3 (6) 1 (2) 8
BrECADD 1 (2) – 2
BEACOPPesc* – – 15
63
Phase II study: brentuximab vedotin as part of targeted BEACOPP in frontline HL (NCT01569204)
AE of special interest: Gr 4 hematological toxicities
Gr 4 AE BrECAPP (n=50)n (%)
BrECADD (n=52)n (%)
HD18* (n=630)%
Anemia 3 (6) – 10
Thrombocytopenia 20 (40) 15 (29) 47
Infection 1 (2) 1 (2) 2
Total (pts with AE Gr 4) 20 (40) 15 (29) 50
Nivolumab for Newly Diagnosed <br />Advanced-Stage cHL
H89 (GELA)
• Stades IIIB-IV
2 ABVPP
4 ABVPP RP>75: 2 ABVPP
R STNI
4 Hybrid RP>75: 2 Hybrid
2 Hybrid
Fermé C, Blood 2006
H89 (GELA)
ABVPPABVPP
STNI
Hybrid
STNIHybrid
n 116 96 114 92
RC (%) 99 91 95 91
EFS 5 ans (%) 67 75 78 74
OS 5 ans (%) 94 78 88 85
Fermé C, Blood 2006
HD 12
Von Treskow, Lancet Hematol 2018
HD15: Radiotherapy in PET+ residual mass >2.5cm
Engert A, Lancet 2012
Radiation therapy in 12% of patients
GITIL/FIL HD607: radiotherapy in PET2 negativepatients
Gallamini A, JCO 2018
Conclusions• BEACOPPesc upfront > ABVD pour le contrôle de la maladie• Les stratégies TEP guidées permettent d’optimiser la balance efficacité/toxicité• La desescalade après 2 x BEACOPPesc est validée et 4 x A(B)VD doivent être préférés à 2 x
BEACOPPesc– Moindre toxicité hématologique– Meilleure préservation de la fertilité?– Moindre toxicité à long terme?
• La TEP4 apporte de l’information pronostique et permet de dévier les patients vers un traitement de rattrapage précoce
• Les critères de réponse DS4 = résiduel > 140% SUVmax foie et DS5 = résiduel > 200% SUVmax foie doivent etre appliqués pour permettre une bonne stratification des patients et éviter sur ou sous traitement
• L’interet de BV-AVD est limité– Efficacité manifestement inferieure au BEACOPPesc– Toxicité immédiate nettement supérieure à l’ABVD pour un bénéfice clinique modeste– Toxicité à long terme non connue– Cout
• Intérêt du BRECADD et de Nivo-AVD à démontrer• Pas de place pour la radiothérapie de fin de chimiothérapie (stratégie TEP guidée)