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)