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

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

2 Stratification Stades I -II EORTC/GELA Médiastin/Thorax > aires ganglionnaires B et VS 30 ou A et VS 50 GHSG Médiastin/Thorax > aires ganglionnaires B et VS 30 ou A et VS 50 Age 50 Atteinte extra-nodale Stades III -IV Aucun facteur: Favorable Facteur 1+: Défavorable LH avancé Aucun facteur: Favorable Facteur 1+: Intermédiaire Exclus: Stades IIB [M/T>0.33, AEN] + Stades IIB [M/T>0.33, AEN] LH avancé

3 Lymphome de Hodgkin FORMES AVANCÉES QUELLE CHIMIOTHÉRAPIE?

4 HL : Chemotherapy 1973 ABVD regimen Dose D1 D15 Doxorubicin 25 mg/m 2 (IV) X X Bleomycin 10 mg/m 2 (IV) X X Vinblastine 6 mg/m 2 (IV) X X Dacarbazine 375 mg/m 2 (IV) X X BEACOPPesc regimen Dose D1 D2 D3 D4 D5 D6 D7 D8 Bleomycin 10 mg/m 2 (IV) X D9 to D Etoposide 200 mg/m 2 (IV) X X X Doxorubicin 35 mg/m 2 (IV) X Cyclophosphamide 1250 mg/m 2 (IV) X Vincristine 1,4 mg/m 2 (IV) [2mg max] X Procarbazine 100 mg/m 2 (PO) X X X X X X X Prednisone 40 mg/m 2 (PO) X X X X X X X X X

5 ABVD Contrôle de la maladie insuffisant pour 25 à 30 % des pts n CR 5y-PFS Follow-up Gordon JCO % 74% 77 months Chisesi JCO % 78% 86 months Viviani NEJM % 73% 61 months Federico JCO % 68% 41 months Hoskin JCO % 76% 52 months 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

6 HD9 10-years outcome by treatment arm Probability p = <.001 A B C BEA esc C/ABVD 82% 64% Pts. at Risk years A B C FFTF OS BEA esc 86% Probability C/ABVD 75% p = < A B C Pts. at Risk years A B C Engert A, JCO 2009; 27: 2548

7 BEACOPP vs ABVD Stage IIB- IV BEACOPP [esc x 4 + Baseline x 2] vs ABVD x 6 Median FU = 41 months FFP OS Federico M, JCO,2009

8 BEACOPP vs ABVD Stage IIB- IV BEACOPP [esc x 4 + Baseline x 4] vs ABVD x 6/8 Median FU = 61 months FFP OS P = P = 0.39 Viviani S, NEJM 2011; 365: 203

9 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 5y PFS* 5y OS 8 x ABVD N =77 N =68 8 x BEACOPP R CT scan % 92% 93% 99% Bleomycin J Etoposide J Doxorubicine J Cyclophosphamide J Vincristine J Procarbazine J Prednisone J *p= p= 0.08 Mounier N, Cologne 2013 Abst T002

10 BEACOPP: Toxicité aigue Diehl et al, NEJM, 2003

11 BEACOPPesc : Fertilité Hommes 90% Azoospermie après 8 x BEACOPPesc Sienawski, Ann Oncol, 2008 Femmes: Aménorrhée 4 ans après fin Chimio 6-8 BEACOPPesc 2 BEACOPPesc + 2 ABVD ou 4 ABVD Behringer K, JCO, 2013

12 HD9 Secondary malignancy Secondary AML/MDS Engert A, JCO 2009; 27: 2548

13 HD15 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) 2 nd Neoplasia 13 (1.8) 5 (0.7) Toxicity of salvage treatment 2 (0.3) 2 (0.3) Other 10 (1.4) 9 (1.3) Engert A, Lancet 2012

14 Chimiothérapies de référence en y-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 Quel patient requière du BEACOPPesc?

15 Lymphome de Hodgkin FORMES AVANCÉES PATIENTS REQUÉRANT DU BEACOPP : VERS UNE STRATÉGIE ADAPTÉE

16 Engert A, JCO 2009; 27: 2548 HD9: IPS

17 PFS and DSS according to tumor microenvironment CD68+ cells Steidl C, NEJM 2010; 262: 875

18 Scott D, JCO 2012; 31: 692

19 A 23 Gene expression predictor in formalin-fixed paraffin-embedded tissue Training set Validation set Scott D, JCO 2012; 31: 692

20 PFS according to IL1RA IL6 CD30s signature in stages III & IV Score 0 27% Score % P<.0001 Score 3 10% Casasnovas O, JCO 2007; 25: 1732

21 Early PET PET2- PET2+ Hutchings M, Blood 2006; 107: 52 Gallamini A, JCO 2007; 25: 3746

22 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 % HL Stage III-IV y n = 357 s ABVD x 2 TEP 5PS = 4-5 5PS < 4 BEACOPP esc x 6 n = 55 (17 %) ABVD x 4 n = 277 Median FU = 16 months % PET2-: ABVD PFS 60 % 40 61% PET2+: BEACOPPesc Mois 2y-PFS = 76% Press O, Cologne 2013 Abst T108

23 GITIL/FIL HD0607 ABVD x 2 N = 330 PET2 Negative N = 271 (82%) Positive N = 59 (18%) ABVD x 5 BEACOPP esc x 4 + BEACOPP b x 4 R-BEACOPP esc x 4 + R-BEACOPP b x 4 2y-PFS 85% 61% Median FU = 32 months Gallamini A, Cologne 2013 Abst P006

24 LYSA: AHL 2011 Standard Arm R Experimental Arm BEACOPP esc x 2 BEACOPP esc x 2 PET2 Neg / Pos Pos Neg BEACOPP esc x 2 BEACOPP esc x 2 ABVD x 2 PET4 Neg Pos Neg Pos Neg BEACOPP esc x 2 Salvage therapy BEACOPP esc x 2 Salvage therapy ABVD x 2 Non inferiority of the experimental arm

25 GHSG: HD18 BEACOPP esc x 2 PET2 Positive Negative BEACOPP esc x 4 BEACOPP esc x 4 BEACOPP esc x 2 End of therapy AND residual nodes > 2.5 cm: PET positive: PET negative: Rx Follow up

26 Lymphome de Hodgkin FORMES AVANCÉES CHIMIOTHERAPIE + ANTICORPS

27 MAb + ABVD in advanced HL n RC 5y-PFS Median FU ABVD Gordon JCO % 74% 77 months ABVD Chisesi JCO % 78% 86 months ABVD Viviani NEJM % 73% 61 months R-ABVD Younes Blood % 82% 68 months R-ABVD Kasamon Blood % 83% 33 months BV-ABVD Ansell ASH 2012 / 22 95% - BV-AVD Cologne % -

28 Adcetris combiné à A(B)VD 51 Hodgkin avancés (45% stade IV, 25% IPS>3, 33% Bulk) BV-ABVD BV-AVD Inclus (n) 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%) Aucune DLT observée (Cycle 1)

29 ECHELON 1 Standard Arm Stage III/IV R Experimental Arm ABVD x 2 AVD-A x 2 PET2 5PS = 1-4 5PS = 5 5PS = 1-4 ABVD x 4 Protocol Therapy or Salvage therapy AVD-A x 4 Planned Accrual = 1040 pts Primary endpoint: PFS

30 Targeted BEACOPP Drug Day 6x BEACOPP escalated 6x BrECADD ( experimental ) 6x BrECAPP ( standard ) Bleomycin 8 10 Etoposide 1-3(2-4) Adriamycin 1(2) Cyclophosphamide Vincristine Brentuximab vedotin Procarbazine 1-7 (2-8) Prednisone 1-14(2-15) Dacarbazine 2-3 2x 250 Dexamethasone

31 Acute Toxicities BrECADD (n=29) Type of Toxicity NCIC-CTC Grade none I II III IV III/IV HD18* III/IV (n=447) Hematological 0% 2 (7%) 1 (3%) 2 (7%) 24 (83%) 26 (90%) 404 (90.4%) Organs 14 (48%) 10 (34%) 5 (17%) 0% 0% 0% 64 (14.3%) No severe neuropathy in > 250 cycles 31

32 Treatment outcome after chemotherapy (primary endpoint) Treatment Outcome BrECAPP N = 16 BrECADD N = 16 Total N = 32 CR or PET negative* PR Less than PR or PET positive* 14 (87,5%) 16 (100%) 30 (93,75%) 2 (12,5%) 0 (0%) 2 (6,25%) *PET above liver (Deauville 4) is regarded positive 32

33 INTERET D UNE INTENSIFICATION DE PREMIÈRE LIGNE?

34 Stage IIIB-IV, < 55 y HD-01 trial EBMT/SFGM/GELA 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

35 HD-01 trial EBMT/SFGM/GELA 8 x ABVD 4 x ABVD ASCT n IPS(%) y FFS y OS Median FU 50 months Federico M, JCO 2003; 21: 2320

36 HD-01 trial EBMT/SFGM/GELA Federico M, JCO 2003; 21: 2320

37 Stage IIB,III, IV; y High risk: M / T 0.45 H97-HR GOELAMS ( ) Stage IV 2 extranodal site 5 nodal area involvement R ABVD x 4 + ASCT (BEAM) VABEM x 3 + Radiotherapy 20Gy + Boost

38 H97-HR GOELAMS ( ) n = % 75% 87% 86% Arakelyan N, Cancer 2008; 113: 3323

39 Lymphome de Hodgkin FORMES AVANCÉES PLACE DE LA RADIOTHÉRAPIE

40 H89 8x ABVPP 6x ABVPP +STNI 6x MOPP/ABV +STNI 8x MOPP/ABV n CR (%) y-EFS (%) y-OS (%) Ferme C, et al. Blood 2006; 107: 4636

41 Advanced HL in first CR after 6-8 MOPP/ABV Aleman B, et al. NEJM 2003;348: 2396

42 Advanced HL (stage III-IV) after 6-8 MOPP/ABV Aleman B, et al. NEJM 2003;348: 2396

43 HD12 Residual disease after chemo Initial bulk without residual disease after chemo Borchmann P, et al. JCO 2011;29: 4234

44 HD15: study 1788 pts Dose density and reduction of toxicity A B C 8 x BEACOPP escalated Randomization 6 x BEACOPP escalated 8 x BEACOPP 14 ( baseline) Residual tumor mass? Yes PET positive: RT 30 Gy 15% of all pts! (>2.5 cm) PET-study PET negative: follow up No follow up

45 HD 15 Trial 8 vs 6 BEAesc vs 8 BEA patients randomized and evaluable for outcome PET after end of chemotherapy for >2,5cm rests: Patients with rests >2,5 cm: n = (78,8%) PET neg: no RT: 244 4,1% relapses 66 (21,2%) PET pos: IF-RT: 62 15,3% relapses

46 Conclusions Pas de bénéfice démontré chez les patients en 1 ère 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?