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Hodgkin Lymphoma Management:       State of the Art 2011             Volker Diehl                for the       German Hodg...
Hodgkin´s Disease 1865                Hodgkin Lymphoma 1991                A malignant Lymphoma with features of an      ...
The German Hodgkin Study    Group Experience             1978–2010  6 Generations of Hodgkin            Trials  20.000 pa...
How to personalize therapy?              ..until we have the right targets...Use:1.Risk Factor Prediction (IPS, GHSG-EORTC...
GHSG Iniative I       Personalize Therapy1. Search for the molecular target2. Specify the role of the microenvironment3. F...
GHSG Initiatives II• Early favorable Stages:      - chemotherapy alone for PET neg pats• Early unfavorable stages:      - ...
Early Favorable Stage :             GHSG: HD10- Trial           CS I–II without risk factors ABVD           ABVD          ...
HD10: Early Stage HL                                                     Overall Survival                                 ...
Early Favorable Group            Current GHSG Study HD13                    (985 patients recruited!)                     ...
HD16:   GHSG-Study for Early favorable Stages                        CS I/II ohne RF*         Standard                    ...
Early Favorable Stages              Ongoing Studies•   GHSG     HD16:      2 ABVD  PET neg Nil•   UK- RAPID Trial :   3 A...
Hodgkin Lymphoma: Risk Adaptation           in the GHSG             Early          favourable           Early        Advan...
GHSG Initiatives III• Early favorable Stages:      - chemotherapy alone for PET neg pats• Early unfavorable stages:      -...
HD14 study (GHSG)          for early unfavorable HL              Stages I, IIA with RF a-d; IIB with RF c,d               ...
HD-14:         FFTF           median observation time = 42 months           1.0           0.9           0.8           0.7 ...
Progression and RelapseMedian observation time = 42 months                                  Arm A                   Arm B ...
Progress in        Intermediate stages             GHSG dataTrial   Chemotherapy          Failure RateHD 8    4 C/ABVD    ...
Pregnancy, offspring, orammenorrhea after therapy Only women up to 40 y from the ongoing HD14 fertility survey project    ...
Next GHSG trialfor early unfavorable (HD17)                     Early unfavorable HL                      2xBEACOPP esc + ...
GHSG Initiatives IV• Early favorable Stages:      - chemotherapy alone for PET neg pats• Early unfavorable stages:      - ...
What is the best     Induction Therapy             forAdvanced Hodgkin Lymphoma?
ABVD compared with BEACOPPin advanced stage HL trials (% of pts)    Source           Chemotherapy        5-y FFS     5-y O...
Fourth-Generation Regimens:              Are They Superior to ABVD??1. ABVD + RITUXIMAB (YOUNES . ET AL, ASH 2007)2. STANF...
Advanced HL     Is Stanford V superior to ABVD?                                                   Stanford V in the UK stu...
SummaryAre the fourth generation regimen better than ABVD             ABVD + Ritux > ABVD???    not yet evaluable, needs c...
The BEACOPP Schedule                Basis Escalated              [mg/m2] [mg/m2]1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22B Bl...
Advanced HL:        De-escalation of BEACOPP and RT                        in             5 Generations of Trials         ...
HD9 – 10 Yrs FFTF by Treatment Arm                    1.0                    0.9                                          ...
HD9 – 10 Yrs OS by Treatment Arm                    1.0                    0.9                                            ...
Salvagebility: Survival after Relapse at 10 ys                    1.0                    0.9                    0.8       ...
HD12 Trial Design       CS IIB with large mediastinal mass / E-lesions;                 CS III and IV (1590 pats)         ...
HD12 (5/2006): Acute Hematological                                     Toxicity Per Chemotherapy Cycle Per Arm            ...
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The Treatment of Hodgkin's Disease (Part 1)

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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 1)

  1. 1. Hodgkin Lymphoma Management: State of the Art 2011 Volker Diehl for the German Hodgkin Study Group (GHSG) Hackensack, New York 3.November 2011
  2. 2. Hodgkin´s Disease 1865  Hodgkin Lymphoma 1991 A malignant Lymphoma with features of an innate immunity driven tumor - a chimera between Infection- Inflammation and Tumor EBV: yes Tuberculosis: no Syphilis: noMonoclonal B-cell- Active Innate Immunity-Lymphoma Microenvironment
  3. 3. The German Hodgkin Study Group Experience 1978–2010 6 Generations of Hodgkin Trials 20.000 pats documented since 1978  400 centers recruiting 220 private hem-oncologists In Germany, Austria, Switzerland, Tschechia, Holland
  4. 4. How to personalize therapy? ..until we have the right targets...Use:1.Risk Factor Prediction (IPS, GHSG-EORTC- Criteria)2.Response Adaptation (FDG-PET)3.Molecular-Genetic Markers f.e. CD68+ macrophages: Steidl et al, NEJM, 2010 9
  5. 5. GHSG Iniative I Personalize Therapy1. Search for the molecular target2. Specify the role of the microenvironment3. Find molecular- genetic risk/prognostic markers f.e. CD68+ macrophages (Steidl et al NEJM) Host- Tumor ImmuneResponse/ Microenvironment Targeted Therapy
  6. 6. GHSG Initiatives II• 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
  7. 7. Early Favorable Stage : GHSG: HD10- Trial CS I–II without risk factors ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD30 Gy IF 20 Gy IF 30 Gy IF 20 Gy IF 2003: 1375 patients recruited. Trial closed 1/2003.
  8. 8. HD10: Early Stage HL Overall Survival Median observation time = 91 months 1.0 0.9 0.8 0.7 No difference for Overall Survival 0.6 0.5 2 ABVD vs 4 ABVD 0.4 and 0.3 0.2 20 vs 30 GY 0.1 30 Gy RT 20 Gy RT 0.0 0 12 24 36 48 60 72 84 96 108 120 Time [months] Pts. at Risk 30 Gy RT 575 570 561 556 551 534 468 351 227 124 32 20 Gy RT 589 584 576 569 561 539 467 346 232 131 25GHSG 2009 – HD10
  9. 9. Early Favorable Group Current GHSG Study HD13 (985 patients recruited!) Stages I, II without RF A B C DABVD ABV AVD AVABVD ABV AVD AV 203 pats200 pats 204 pats 201 pats30 Gy 30 Gy 30 Gy 30 GyIF-RT IF-RT IF-RT IF-RT30 Gy because of the reduction of chemotherapy!
  10. 10. HD16: GHSG-Study for Early favorable Stages CS I/II ohne RF* Standard Experimental Arm Arms 2 x ABVD 2 x ABVD 2 x ABVD PET (+/-) PET- PET+ 20 Gy IF Follow up 20 Gy IF*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
  11. 11. Early Favorable Stages Ongoing Studies• GHSG HD16: 2 ABVD  PET neg Nil• UK- RAPID Trial : 3 ABVD  PET neg Nil• EORTC HD10: 4 ABVD  PET neg Nil• USA-Intergroup: 4 ABVD  PET neg Nil
  12. 12. Hodgkin Lymphoma: Risk Adaptation in the GHSG Early favourable Early Advanced unfavor Advanced Stages stages -able
  13. 13. GHSG Initiatives III• 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
  14. 14. HD14 study (GHSG) for early unfavorable HL Stages I, IIA with RF a-d; IIB with RF c,d BEACOPP escalated ABVD BEACOPP escalated ABVD ABVD ABVD ABVD ABVD 30 Gy IF 30 Gy IF*a) large mediastinal mass; b) extranodal disease; c) high ERS; d) 3 or more areas
  15. 15. HD-14: FFTF median observation time = 42 months 1.0 0.9 0.8 0.7 P < 0.001 0.6 5-year FFTF 95%CI FFTF 0.5 Arm A 87,3% [83,8% - 90,2%] 0.4 Arm B 95,0% [93,0% - 96,4%] 0.3 difference 7,6% [4,0% - 11,3%] 0.2 0.1 A B 0.0 0 12 24 36 48 60Pts. at Risk Time [months]A 761 723 698 637 557 466 388 306 238 184 103B 758 722 695 653 561 490 413 331 259 199 127 15
  16. 16. Progression and RelapseMedian observation time = 42 months Arm A Arm B ITT analysis set (ABVD) (“2+2”) N=818 N=805 Type of event N % N % progression 24 2.9 7 0.9 Early relapse 23 2.8 7 0.9 Late relapse 19 2.3 7 0.9 Ʃ 66 8,1 21 2,6 GHSG HD14 - Final Analysis July 16 2010 - V.2.0 (October 2010)
  17. 17. Progress in Intermediate stages GHSG dataTrial Chemotherapy Failure RateHD 8 4 C/ABVD 18%HD11 4 BEACOPP or 4 ABVD 16%HD14 2 BEAesc + 2 ABVD 3%
  18. 18. Pregnancy, offspring, orammenorrhea after therapy Only women up to 40 y from the ongoing HD14 fertility survey project fertility status 4x ABVD „2+2“ > 1y AFTER therapy (arm A) (arm B) N % N % pregnancy/child: NO 114 89 93 82 pregnancy/child: 14 11 21 18 YES amenorrhea: NO 119 87.5 109 83.8 amenorrhea: YES 17 12,5 21 16,2 Men: fathered 12% 5%
  19. 19. Next GHSG trialfor early unfavorable (HD17) Early unfavorable HL 2xBEACOPP esc + 2xABVD PET - PET + 30 Gy IF No Rx 30 Gy IF 30 Gy IN Follow-up GHSG 2010
  20. 20. GHSG Initiatives IV• 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
  21. 21. What is the best Induction Therapy forAdvanced Hodgkin Lymphoma?
  22. 22. ABVD compared with BEACOPPin advanced stage HL trials (% of pts) Source Chemotherapy 5-y FFS 5-y OS Canellos 6-8 ABVD 61 73 Duggan 2003 8-10 ABVD 63 82 8 ABVD 73 (7ys) 82 (7ys) Viviani 2011 8 x 4+4 e/b BEA 85(7ys) 88 (7ys) Diehl 2003 HD9 4 (COPP+ABVD) 68 83 8 BEACOPP esc. 88 92 GHSG 2011 HD15 6 BEACOPP esc 90,3 95,3
  23. 23. Fourth-Generation Regimens: Are They Superior to ABVD??1. ABVD + RITUXIMAB (YOUNES . ET AL, ASH 2007)2. STANFORD V (HORNING ET AL, ASH 2007)3. COPP-EBV-CAD (GOBBI, JCO 2005; FEDERICO, COLOGNE 2007)4. ABVD dd-di ( RUSSO ET AL,2009)5. BEACOPP (DIEHL ET AL, 1998)
  24. 24. Advanced HL Is Stanford V superior to ABVD? Stanford V in the UK study: PFS @ 5 years 74% 53% stage I/II 73% irradiated Stanford V in the US study: PFS @ 5 years 72% stage I/IIA includedThe UK Study ISRCTN 64141244, Hoskin et al., J Clin Oncol 27:5390-5396. 2009The US Study ECOG E2496, Gordon et al., ASH, 2010
  25. 25. SummaryAre the fourth generation regimen better than ABVD ABVD + Ritux > ABVD??? not yet evaluable, needs confirmation in large trials Stanford V = ABVD. needs 90% RT ! Coop-trial results: ABVD vs Stf V: no difference COPP-EBV-CAD = ABVD: more toxic, more costly ABVD-dd-di few patients, needs confirmation in larger trial, cardio-tox! BEACOPP what is it´s impact???
  26. 26. The BEACOPP Schedule Basis Escalated [mg/m2] [mg/m2]1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 22B Bleomycin 10 10 restartE Etoposide 100 200A Doxorubicin 25 35C Cyclophos. 650 1250O Vincristine 1.4 1.4P Procarbazin. 100 100P Prednisone 40 40 G-CSF sc
  27. 27. Advanced HL: De-escalation of BEACOPP and RT in 5 Generations of Trials 1992-2013• HD- 9 8 esc BEA + 70% RT• HD- 12 4+4 esc+ base BEA + 36% RT• HD- 15 6 esc BEA + 12% RT• HD- 18 2+2 (PET-) esc BEA + 12% RT• HD- 21 6 new BEA (BRECADD) + ?? RT
  28. 28. HD9 – 10 Yrs FFTF by Treatment Arm 1.0 0.9 BEA esc 0.8 0.7 0.6 Probability 0.5 C/ABVD 0.4 Log-rank tests: 0.3 A v B v C p < 0.0001 0.2 p = <.001 AvB p = 0.040 BvC p < 0.0001 0.1 A B C AvC p < 0.0001 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 yearsPts. at RiskA 261 194 173 146 110 75 19 0B 469 378 332 282 222 106 26 0C 466 412 384 321 234 92 14 0
  29. 29. HD9 – 10 Yrs OS by Treatment Arm 1.0 0.9 BEA esc 0.8 11% 0.7 C/ABVD 0.6 Probability 0.5 Log-rank tests: 0.4 A v B v C p = 0.0005 0.3 AvB p = 0.19 0.2 p = <.001 BvC p = 0.0053 0.1 AvC p < 0.0001 A B C 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Pts. at Risk yearsA 261 238 218 196 147 107 30 0B 469 436 392 344 272 134 36 0C 466 441 412 357 270 113 18 0GHSG. 2007. HD9.
  30. 30. Salvagebility: Survival after Relapse at 10 ys 1.0 0.9 0.8 0.7 0.6 Probability 0.5 C/ABVD 0.4 BEAesc 0.3 p = 0.235 BEA base 0.2 0.1 A B C 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 yearsPts. at RiskA 42 34 25 20 13 4 0B 47 40 29 15 8 1 0C 25 17 12 7 5 1 0
  31. 31. HD12 Trial Design CS IIB with large mediastinal mass / E-lesions; CS III and IV (1590 pats) randomisation Arm A Arm B Arm C Arm D 4 x B esc 4 x B esc8 x B esc 8 x B esc + + 4 x B bas 4 x B bas central diagnostic panel 30 Gy 30 Gy (initial bulk, „no RT“ (initial bulk, „no RT“ residual) residual)
  32. 32. HD12 (5/2006): Acute Hematological Toxicity Per Chemotherapy Cycle Per Arm Leukopenia 8 Besc 4+4 Thrombopenia 70 70 AnaemiaPatients With WHO Grade III-IV (%) Infection 60 60 50 50 40 40 30 30 20 20 10 10 0 0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Cycle Cycle

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