The Treatment of Hodgkin's Disease (part 2)

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Volker Diehl, M.D., Professor, University of Cologne, Germany Customization: The Treatment of Hodgkin's Disease

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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The Treatment of Hodgkin's Disease (part 2)

  1. 1. Precautions to avoid toxic deathsFor > 45 year old and frail patients (IPS >3)1. First BEA cycle as inpatient2. Mandatory prophylactic cotrim or ciprobay3. Prephase with VCR- Prednison day -74. Age limit for BEA esc 60 years of age
  2. 2. HD12 (5/2006): OS All 4 Arms at 4 Years Med. Obs. Time 1.0 0.8Probability 0.6 0.4 p = 0.753 4xBEA esc. + 4xBEA baseline 4xBEA esc. + 4xBEA baseline + RT 0.2 8xBEA esc. 8xBEA esc. + RT 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 Time [months]
  3. 3. HD15: 1st PET guided study 2050 pats recruited (2004-09) Advanced stage HL 8x BEACOPP 6x BEACOPP 8x BEACOPP Escalated (21) Escalated (21) Baseline (14)EPO vs Placebo EPO vs Placebo EPO vs Placebo Restaging: PR and residual tumor >2,5 cm No YES PET - PET + Rtx 30Gy at Follow up residual tumor
  4. 4. Do we really need RT for ALLpatients with residual disease? CR PR PETneg Is a negative PET predictive for “no-relapse”? The GHSG HD15 study PET+ 8 vs 6 esc BEA vs 8 BEA -14 +RT(10%) ASH 2010: GHSG HD15-PET trial
  5. 5. HD15: PET guided therapyis safe after chemotherapy 1.0 0.9 0.8 80% p = 0.266 Progression-free Survival 70% 70% 0.7 60% 0.6 RADIOTHERAPY HD9 50% 0.5 40% HD15 0.4 30% 20% 0.3 12% HD12 B+D 10% 0.2 0% HD12 A+C 0.1 HD9 HD15 0.0 0 6 12 18 24 Months after Randomisation
  6. 6. Entwicklung von SGN-35 in der GHSGRandomisierte Phase II Studie mit 2 Armen1. innovativ: EAC SGN35 DTIC, Dexa (ECADD-B)2. konservativ: BEAC SGN35 PP (ECAPP-B) “Targeted BEACOPP variants in patients with newly diagnosed advanced classical Hodgkin Lymphoma (HL) – A randomized phase II study” 7
  7. 7. Therapeutic progress in HL:advanced stage disease 100 BEACOPPesc (1993-99) 80 COPP+ABVD 60 (1988-93) COPP 40 Alkylators (1975) (1965) 20 No therapy (1940) 0 0 1 2 3 4 5 years
  8. 8. BEACOPP escalated Proof of Principle in 3 Randomized Prospective Trials in > 500 centers including 220 private oncologists all over Europe > 4500 patients treated: Results : (in comparison with ABVD) Pros: Con:higher CR-rates : >90% more hematoxicity (40-90%)higher tumor cell kill PFS: 90% vs 70%more infertility M: 90% /F: 52% vs 34%Cure rate 11% higher at 10 ys more AML/MDS: 0,8-1,2% vs < 0,5%20% less need for salvage therapy!!
  9. 9. The Principle of BEACOPP:Hit early and hard with the first hit!(Early Intensification)The Principle of most of the ongoingglobal studies: UK, USA, Italy:Start soft and hit hard with the 2nd hit!(Late Intensification)
  10. 10. New Treatment Strategies forAdvanced Hodgkin Lymphoma Ongoing Global Studies soon answering the Question of “Kairos” or “Chronos”
  11. 11. USA- Cooperative Group Trial Advanced Hodgkin Lymphoma IPS: 0-7 Neg ABVD x 4 no RT2 ABVDPET 8-10 weeks duration! Pos BEACOPP esc x 6+IFRTCaveat: BEACOPPesc might be 8 weeks too late!!Better for IPS > 3 RFs: 2 esc BEACOPPPET neg: 6 ABVD  PET pos: 4- 6 BEAesc
  12. 12. Effect of esc BEACOPP: Early or Late Intensification ts - PET vs. IPS 100 1Cumulative failure-free survival 86% 8 esc BEA: early intensification (kairos) PET +: (GHSG, Israel,EORTC) 0,8 Difference 26% 2 ABVDPET + 4 esc BEA+4 base BEA Late intensification: (chronos) (Gallamini et al) IP SandP ET 60% 60% IPS 0-2, P ET2ne 0,6 50 IPS 0-2, P ET2po IPS 3-7, P ET2ne IPS 3-7, P ET2po 0,4 No intensification! 0,2 2 ABVDPET +: 6 ABVD 0 0 log rank, p Gallamini A, Hutchings M, Rigacci L, et al.: JCO 2007, accepted.
  13. 13. Ongoing HD18 trial for advanced stages 843 pats recruited 2009-2010 2 x BEACOPP escalated (esc) PET + PET - (43%) (57%)6xBEACOPPesc 6xR-BEACOPPesc 6xBEACOPPesc 2xBEACOPPesc After chemo: PET; RX to PET+ res nodes >2.5 cm PET-: Follow up
  14. 14. GELA 2011 Stage III/IV and high risk IIB Hodgkin Lymphoma IPS 0-7 R Experimental Arm Standard Arm BEACOPP esc x 2 BEACOPP esc x 2PET2 Neg / Pos Pos Neg BEACOPP esc x 2 BEACOPP esc x 2 ABVD x 2PET4 Neg Pos Neg Pos Neg Salvage Salvage ABVD x 2 BEACOPP esc x 2 BEACOPP esc x 2 therapy therapy Non inferiority of the experimental arm Courtesy of O Casasnovas 810 patients planned to be enrolled over 6 years
  15. 15. H11 advanced stage HL trial: EORTC ® Experimental Arm Standard Arm 1 x ABVD 1 x BEAescPET/CT PET+ PET- PET+/- 3 x BEAesc 3 x ABVD 3 x BEAescCT CR / PR PD/ SD CR / PR PD/ SD* CR / PR PD/ SD 1 x BEAesc Off protocol 4 x ABVD Off protocol 4 x BEAbase Off protocol 3 x BEAbase Post-chemotherapy PET/CT RT 36 Gy to PET-positive residual masses
  16. 16. The Problemof the management of Advanced Hodgkin Lymphoma What is the Goldstandard induction regimen? ABVD or BEACOPP ? Does one size fit all?? Or do we need more differentiated approaches? Thus far the dispute is similar to the fight between the US Democrats and the RepublicanTea Party Lots of emotional arguments, Waiting for robust evidence! Till then: we only should use hard facts and evidence
  17. 17. The new England Journal of Medicine 12july 21, 2011vol. 365no. ABVD versus BEACOPP for Hodgkin’s Lymphoma When High-Dose Salvage Is Planned Simonetta Viviani, M.D., Pier Luigi Zinzani, M.D., Alessandro Rambaldi, M.D., Ercole Brusamolino, M.D., Alessandro Levis, M.D., Valeria Bonfante, M.D., Umberto Vitolo, M.D., Alessandro Pulsoni, M.D., Anna Marina Liberati, M.D., Giorgina Specchia, M.D., Pinuccia Valagussa, B.S., Andrea Rossi, M.D., Francesco Zaja, M.D., Enrico M. Pogliani, M.D., Patrizia Pregno, M.D., Manuel Gotti, M.D., Andrea Gallamini, M.D., Delia Rota Scalabrini, M.D., Gianni Bonadonna, M.D., and Alessandro M. Gianni, M.D., for the Michelangelo Foundation, the Gruppo Italiano di Terapie Innovative nei Linfomi, and the Intergruppo Italiano Linfomi My problem with this paper:“After1.Small number of patients completion of the overall planned treatment, 2.Short follow up including salvage therapy, 3.Statistics full of flaws ,the 7-year rate of freedom fromdifference is concluded, but never was 4.“Non-significance” for survival a second progression wasPFS=88% in the BEACOPP group and investigated. 6%PFS=82% inpatient numbers nor the(P=0.12), 5.Neither the ABVD group primary endpoint is reported correctly 6.With regard to its surprisingly deficient statistical analysis and reportingand the 7-yearmanuscriptoverallamended in large parts to contribute to an quality, the rate of must be survival wasOS= 89% and debate on the5% undesigning treatment of advanced Hodgkin Lymphoma.OS=84%, respectively (P=0.39).Severe adverse events occurred more frequently in the BEACOPP groupthan in the ABVD group”.
  18. 18. The new England Journal of Medicine 12july 21, 2011vol. 365no. ABVD versus BEACOPP for Hodgkin’s Lymphoma When High-Dose Salvage Is PlannedSimonetta Viviani, M.D., Pier Luigi Zinzani, M.D., Alessandro Rambaldi, M.D., Ercole Brusamolino, M.D., Alessandro Levis, M.D., Valeria Bonfante, M.D., Umberto Vitolo, M.D., Alessandro Pulsoni, M.D., Anna Marina Liberati, M.D., Giorgina Specchia, M.D., Pinuccia Valagussa, B.S., Andrea Rossi, M.D., Francesco Zaja, M.D., Enrico M. Pogliani, M.D., Patrizia Pregno, M.D., Manuel Gotti, M.D., Andrea Gallamini, M.D., Delia Rota Scalabrini, M.D., Gianni Bonadonna, M.D., and Alessandro M. Gianni, M.D., for the Michelangelo Foundation, the Gruppo Italiano di Terapie Innovative nei Linfomi, and the Intergruppo Italiano Linfomi...just some personal thoughts to a controversial paper.... At 7 ys: PFS-difference : 12% EFS-difference : 6% OS-difference: 5% HDCT+SCT : 45 pats after ABVD (2x more than with eBEA!) 20 pats after eBEA My Conclusion: USA: 4000 new pats with adv.HL/anno, 5% /4000 young patients = 200 young patients will die unnecessarily! Possibly more since the paper is not powered for OS!!
  19. 19. 11% difference in OS amounts to 440 young patients with adv HL in the USA (4000new cases / anno) who have to die unnecessarily !! 6eB= 95,3% OS ABVD= 84% OSVIVIANI, NEJM 11% GHSG HD15 difference
  20. 20. I think ..we all agree that not faith or myths-but scientific evidence should lead our decisions...for the best of our patients!
  21. 21. My Recommendations: Hodgkin Lymphoma 2011• Early Stages: 2 ABVD + 20 Gy IF-RT 2-4 ABVD no RT: tested in ongoing trials!!• Interm.Stages: 2 esc BEA+2 ABVD + 20 Gy IF-RT or 4 ABVD + 30 Gy IF-RT• Adv.Stages: IPS: 0-2 2 ABVD PET neg + 4 ABVD +/- RT (70% IPS: 3-7 2 escBEAPET neg  4 ABVD+/-RT (30%) PET pos  4esc BEA+/-RT
  22. 22. GHSG Initiatives V• Early favorable Stages: - chemotherapy alone for PET neg pats• Early unfavorable stages: - intensify chemotherapy - no RT for PET neg pats at end of chemo• Advanced Stages: - detoxify BEACOPP, maintain efficacy• Refract/Relapse: - optimize 2nd response with targeted therapy
  23. 23. Future PerspectivesComprehensive Aim:Combine conventionalwith targeted therapy
  24. 24. New Generation of Drugs other than Moabsin Patients with refractory HL (Selection) Drug Type Patients Response (n) (%) ZenaRX1) RIT (anti-CD25) 23 67 SGN-352) IT (anti-CD30) 217 67 MGCD01033) HDAC-Inhibitor 20 40 RAD0014) m-TOR-Inhibitor 14 42 Lenalidomide5) IMID 7 56 1)Waldmann ISHL 2007; 2) Younes et al ISHL 2007; 3)Younes et al ISHL 2007; 4)Johnston et al ISHL 2007; 5)Borchmann et al unpubl 2007
  25. 25. CD30- Antigen in Hodgin RS.cells
  26. 26. „Targeted therapy“ with Antibodiesin Hodgkin Lymphoma Anti-CD30 Antibody WithHodgkin Reed Sternberg Auristatin (a chemical bomb!)cell TRAF3 proteolysis NFkB
  27. 27. Targeted (individualized) Therapy Brentuximab Vedotin (SGN-35)Phase 1, single-agent1- Relapsed CD30-positive lymphomas (45 HL, 2 ALCL, 1 AITL)- Well tolerated: Mostly grade 1 or 2 adverse events—fatigue, fever, diarrhea,nausea, neutropenia, peripheral neuropathy- MTD: 1.8 mg/kg every 3 weeks- Across all dose levels: 44 evaluable patients; 39% objective response(82% responded: 25% CR, 14% PR, 43% SD)- At 1.2 mg/kg and higher: 15/28 patients (54%) objective response Median duration of response: 9.7 monthsPhase 2, pivotal single-agent2- 1.8 mg/kg every 3 weeks for up to 16 doses- 75% objective response- Median duration of response: >6 months- Granted fast track designation by FDA for HL 1) Younes A et al, NEJM 2010;363:1812-1821 2) Chen R et al, ASH 2010
  28. 28. Targeted (individualized) Therapy Lenalidomide (Revlimid) A new principle of targeted therapy in Hodgkin´s lymphoma Interfering with the micro- enviromentMode of Action-Thalidomide analogue- Immune-modulatory properties - down-regulation of pro-survival cytokines (TNF-a, VEGF, Il-8, Il-6) and -interference with the micro-enviroment - stimulation of T-cells and NK-cells- antiangionetic activity- pro-apoptotic effect

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