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Kompetenznetz Maligne Lymphome Aggressive Non-Hodgkin-Lymphome: Aktuelle Ergebnisse der DSHNHL

Gemeinsame Jahrestagung 2009 der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Onkologie 2. bis 6. Oktober 2009 in Heidelberg / Mannheim . Kompetenznetz Maligne Lymphome Aggressive Non-Hodgkin-Lymphome: Aktuelle Ergebnisse der DSHNHL.

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Kompetenznetz Maligne Lymphome Aggressive Non-Hodgkin-Lymphome: Aktuelle Ergebnisse der DSHNHL

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  1. Gemeinsame Jahrestagung 2009 der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Hämatologie und Onkologie 2. bis 6. Oktober 2009 in Heidelberg / Mannheim Kompetenznetz Maligne Lymphome Aggressive Non-Hodgkin-Lymphome:Aktuelle Ergebnisse der DSHNHL Norbert SchmitzAbteilung Hämatologie und Stammzelltransplantation Asklepios Klinik St. Georg, Hamburg

  2. B-NHL

  3. Derzeitige DSHNHL-Protokolle zur Primärtherapie aggressiver B-Zell-Lymphome FLYER IPI = 0 kein Bulk  RICOVERNachfolge-studie (in Vorbereitung) UNFOLDER IPI = 1 / Bulk  MegaCHOEP Phase III IPI ≥ 2 ≤60 Jahre  >60 Jahre

  4. FLYER (6-6/6-4) STUDY DESIGN C H O P C H O P C H O P C H O P C H O P C H O P R R R R R R Stage I/II aaIPI=0 no Bulk 18-60 years R d 1 d 64 d 106 C H O P C H O P C H O P C H O P R R R R R R

  5. UNFOLDER (21/14) STUDY DESIGN + / - Radiatio Bulk / E C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 IPI = 1 and/or Bulk R R R R R R R d 1 d 75 d 105 C H O P 14 C H O P 14 C H O P 14 C H O P 14 C H O P 14 C H O P 14 + / - Radiatio Bulk / E R R R R R R

  6. DSHNHL 2002-1 „Mega-CHOEP“ study design after amendment 1 for CD20+ B-NHL PBSC PBSC PBSC mCHOEP I mCHOEP II mCHOEP III mCHOEP IV CYC 1500 CYC 4500 CYC 4500 CYC 6000 ADR 70 ADR 70 ADR 70 ADR 70 VCR 2 VCR 2 VCR 2 VCR 2 ETO 600 ETO 960 ETO 960 ETO 1480 PRD 500 PRD 500 PRD 500 PRD 500 1 22 43 64 77 98 days R CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 : Rituximab

  7. Median observation time: 29 months Mega-CHOEP study (phase III) Patients 18 - 60 years, aaIPI 2,3, B-cell (CD20+), ITT (n=185) Event Free Survival (EFS) -- all patients DSHNHL 23.03.09

  8. Mega-CHOEP study (phase III) Patients 18 - 60 years, aaIPI 2,3, B-cell (CD20+), ITT (n=216) EFS* according to Rituximab *event „additional R“ not counted DSHNHL 23.03.09 one patient changed treatment arm to Mega-CHOEP+R after study meeting and is censored

  9. DSHNHL 2002-1 „Mega-CHOEP“ study design after amendment 1 for CD20+ B-NHL PBSC PBSC PBSC mCHOEP I mCHOEP II mCHOEP III mCHOEP IV CYC 1500 CYC 4500 CYC 4500 CYC 6000 ADR 70 ADR 70 ADR 70 ADR 70 VCR 2 VCR 2 VCR 2 VCR 2 ETO 600 ETO 960 ETO 960 ETO 1480 PRD 500 PRD 500 PRD 500 PRD 500 1 22 43 64 77 98 days R CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 : Rituximab

  10. 1 15 29 43 71 99 days CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 : Rituximab DSHNHL 2002-1 „Mega-CHOEP“ study design after the MegaCHOEP arm is closed

  11. Study Design RICOVER-60 6 x CHOP-14 + 30-40 Gy (Bulk, E) CD20+ DLBCL Stages I-IV 61 to 80 years 8 x CHOP-14 + 30-40 Gy (Bulk, E) Random 2x2 Factorial Design 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab

  12. III. Elderly Patients Is further Improvement possible ?

  13. C H O P C H O P C H O P C H O P C H O P C H O P 0 2 4 6 8 10 12 14 W e e k s Study Design DENSE-R-CHOP-14 CD20+ DLBCL Stages I-IV 61 to 80 years

  14. Progression-free Survival* DENSE-R-CHOP-14RICOVER-60 (6xCHOP+8R) IPI 1, 2 IPI 3 - 5 1 1 84% 0.9 0.9 77% 83% 0.8 0.8 p=0.584 0.7 0.7 p=0.064 64% 0.6 0.6 % patients % patients 0.5 0.5 0.4 0.4 0.3 0.3 RICOVER-60 RICOVER-60 (6xCHOP14+8xR; n=123) (6xCHOP-14+8xR; n=183) 0.2 0.2 DENSE-R-CHOP-14 DENSE-R-CHOP-14 0.1 0.1 (6xCHOP-14+12xR; n=72) (6xCHOP-14+12xR; n=52) 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24 Months Months

  15. Study Design DENSE-R-CHO/MP-60 UNFAVORABLE R-CHOP-14 + 36 Gy IN-RT* CD20+ DLBCL IPI 2-4 IPI 1 Bulky 61 to 80 years Random 2x2 Factorial Design DENSE-R-CHOP-14 +36 Gy IN-RT* R-CHMP-14 + 36 Gy IN-RT* DENSE-R-CHMP-14 + 36 Gy IN-RT* * Except Interim-PET-neg.

  16. Involvement of CNS in aggressive NHL  risk factors and prophylaxis  Norbert Schmitz, Volkmar Boehme, Samira Zeynalova, Markus Loeffler and Michael Pfreundschuh GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)

  17. Risk-factors for CNS events in the RICOVER-60 trial multivariate analysis all patients R-treated patients only

  18. CNS events in the RICOVER-60 trial "high-risk" patients with LDH > N, >1 E-lesion, B-symptoms / ECOG >1 all patients ( ) / only patients with R-CHOP-14 ( ) 0.40 0.35 0.30 "high-risk" patients 0.25 0.20 proportion of patients 0.15 0.10 p<0.001 all other patients 0.05 0.00 0 10 20 30 40 50 60 70 80 months

  19. CNS prophylaxis In the RICOVER-60 trial MTX 15mg i.th. 1 5 15 20 d1 d15 d29 d43 d57 d71 d85 d99 In future trials MTX 15mg i.th. d1 d15 d29 d43 d57 d71 d85 d99 2 weeks after last chemo 2 MTX 1.5mg/m² i.v.

  20. T-NHL

  21. A 30 mg A 30 mg A 30 mg A 30 mg A 30 mg A 30 mg C H O P C H O P C H O P C H O P C H O P C H O P DSHNHL 2006-1B Primärtherapie für PTCL bei älteren Patienten (>60 J.) n=150 R C H O P C H O P C H O P C H O P C H O P C H O P n=150 A = Alemtuzumab

  22. 1 0.9 0.8 0.7 0.6 0.5 Proportion 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 80 90 100 110 Months T-cell lymphomas in DSHNHL trials Results from the NHL-B1 trial (≤ 60 years, LDH ≤N, n=98) Event-free survival: role of etoposide 6x CHOEP-14/21 (n=52) 6x CHOP-14/21 (n=46) p=0.010 3-years EFS-rate: with Etoposide: 70.6% (95% CI: 58.1-83.1%) without Etoposide: 49.8% (95% CI: 35.3-64.3%) DSHNHL

  23. HDT / ASCT in T cell lymphoma as part of primary treatment Prospective Phase II Trials [* Non ALK+ ALCL] [+ CR patients only]

  24. allo SCT in pTCL HLA-id donors (n=74) Overall Survival and Progression free survival 43% 39%

  25. DSHNHL 2006-1A: Studiendesign

  26. B-NHL Rezidivtherapie

  27. AB SE CA TM CORAL Trial of RICE v DHAP • Which salvage regimen is the best? R A N D O M I Z E SD/POD → Off R-ICE x 3 → CD20+ DLBCL Relapsed/Refractory R A N D O M I Z E R x 6 PR/CR → R-DHAP x 3 Obs • Place of immunotherapy post transplantation? N=400 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  28. 64% PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) N=160 N=228 31% 62% N=147 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) N=241 30% Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  29. Aggressive B-NHL – RezidiveErgebnisse der allogenen SCT – DSHNHL R3 aNHL, 18-65 y, refractory disease, early relapse HR, relapse after ASCT alloPBSCMRDMUD MMF Tacrolimus R R-ICE R-ICE F25 F25 F25 F25 F25 C60 C60 B4 B4 B4 MMF Tacrolimus R375 R375 R375 R375 R375 R375 R375 R375 w-8 w-5 w3 w4 w5 w6 w25 w26 w27 w28 d-9 d-8 d-7 d-6 d-5 d-4 d-3 Glass et al , Blood 110: ASH abstract #3043

  30. Aggressive B-NHL - RezidiveErgebnisse der allogenen SCT – DSHNHL R3 Progression Free Survival, n=81 DSHNHL 1.0 0.9 0.8 0.7 0.6 Probability of PFS 0.5 0.4 0.3 0.2 0.1 0.0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 Time after Transplant (Years) Glass et al.

  31. Future developments • The addition of Rituximab to conventional chemotherapy (and high-dose chemotherapy?) has significantly improved first-line treatment results of young, high-risk patients with DLBCL. • Increasingly less patients will show chemo-sensitive disease after relapse from R-chemotherapy. •  Results of autografting will deteriorate. • Allogeneic transplantation needs further study.

  32. BACKUP

  33. RICOVER-60 - Event-free Survival - 1 0.9 0.8 6x R-CHOP 14 0.7 8x R-CHOP 14 3-year rates: 66.5% 63.1% 53.0% 47.2% 0.6 8x CHOP 14 Proportion 0.5 1: 6 x CHOP 14 0.4 (n=307) 2: 8 x CHOP 14 0.3 (n=305) 3: 6 x R-CHOP 14 1, 2: p=0.037 6x CHOP 14 0.2 (n=306) 1, 3: p<0.001 4: 8 x R-CHOP 14 1, 4: p<0.001 0.1 (n=304) 3, 4: p=0.561 0 0 10 20 30 40 50 60 70 80 Months Pfreundschuh et al., Lancet Oncol. (2008)

  34. Perspectives of anti-B Cell Antibodies • Optimization of rituximab • Dose-dense rituximab • Combination with IL-21 • 2nd- / 3rd-generation anti-CD20 antibodies • Ofatumomoab • GA 101 • anti-CD19 • anti-CD40 (SGN-40) • anti-CD80 • Radioimmunotherapy • CD20: 90Y-ibritumomab tiuxetan (#8565) • CD22: 90Y-epratumomab (#8502) • Bispecific anti-CD19 antibodies

  35. C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P ECOG (5 x R) 24 C H O P C H O P C H O P C H O P C H O P C H O P DSHNHL (8 x R) 12 Rituximab Schedules forElderly Patients with DLBCL C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P GELA (8 x R) 24

  36. DLBCL at ASH 2008 Novel therapies for (relapsed DLBCL): - Lenalidomide : - ORR 29% (21/73); CR 4% - mTor Inhibitors (Temsirolimus, Everolimus) - ORR 35% ; CR 5% - Fostamatinib (oral Syk-Inhibitor; # 3): - ORR 23% (5/23), CR 5% - preclinical: - IL-21 (# 601) - PU-H71 (purine-scaffold Hsp 90 inhibitor; # 602) - LBH589 (HDAC inhibitor; # 603) - Obatoclax (BH3-mimetic; #605) - MLN4924 (s.-molec. Inhibitor of Nedd8; #606)

  37. RICOVER-60 Trial 61- 80 years, CD20+ B-cell, with Rituximab (n=610) by IPI score IPI 1: 184 (30%);IPI 2: 172 (28%); IPI 3: 155 (26%); IPI 4, 5: 99 (16%)

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