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  • 1.
    • Treatment of
    • Diffuse Large B-Cell Lymphoma
    • M. Pfreundschuh
    • German High Grade Non-Hodgkin´s Lymphoma Study Group (DSHNHL)
    • Med. Klinik I, Saarland University Medical School Homburg / Saar, Germany
    DSHNHL 09-19-00
  • 2. Groups contacted: Australia ALLG + France Gela + Europe EORTC + Germany DSHNHL + Netherlands HOVON + Scandinavia Nordic Group + Spain GEATANO + United Kigdom NCRI + USA CALGB + ECOG + SWOG + Update on Clinical Trials
  • 3. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Elderly II-IV Elderly 0/I Limited aaIPI=2,3 Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T I,noBulk U N F I T Ov er 70 Japan (JCOG) Elderly IPI=1,2,3 Elderly aaIPI=0 Limited
  • 4. CALGB:50303 Phase III Randomized Study of R-CHOP v. DA-EPOCH-R with Microarray Randomization ARM A: R-CHOP ARM B: DA-EPOCH-R C1 C2 C3 C4 C5 C6 C7 C8 C1 C2 C3 C4 C5 C6 C7 C8 Stage Stage Stage Treatment completed Treatment completed if no change C5 to C7 staging Treatment completed if change C5 to C7 staging 0 3 6 9 12 15 18 21 25 Time Line (weeks) Tumor Biopsy Blood Samples Repeat Blood Samples at Staging Proteomics/Pharmacogenomics
  • 5. NCRI trial: R-CHOP 14 vs 21 Eligible patients RANDOMISATION R-CHOP 21 CHOP 21  8 cycles Rituximab  8 cycles R-CHOP 14 CHOP 14  6 cycles Rituximab  8 cycles N=540 N=540 Stratified by IPI (0 or 1 vs. 2 vs. 3 vs. 4 or 5) Age <60 vs.  60 Treatment centre
  • 6. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Elderly II-IV Elderly 0/I Limited aaIPI=2,3 Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 Japan (JCOG) Elderly IPI=1,2,3 Elderly aaIPI=0 Limited I,noBulk
  • 7. CD20 + DLBCL 18–60 years IPI 0,1 Stages II-IV, I with bulk 6 x CHOP-like + 30–40 Gy (Bulk, E) 6 x CHOP-like + rituximab + 30–40 Gy (Bulk, E) Random. Trial Design
  • 8. Time to Treatment Failure M o n t h s Probability 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 59% CHEMO (n=410) median observation time: 34 months Pfreundschuh et al., Lancet Oncology 2006
  • 9. Time to Treatment Failure M o n t h s Probability 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 79% 59% p = 0.000 000 02 R-CHEMO (n=413) CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  • 10. Overall Survival
  • 11. Overall Survival 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s Probability 84% CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  • 12. Overall Survival 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s Probability 93% 84% p = 0.0001 R-CHEMO (n=413) CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  • 13. 0 20 40 0 1 2 3 4 CHOP-21 (1975-2001) CHOEP (2001-2003) R-CHO(E)P (2004) % Surviving M O N T H S Progress in the treatment of Young good-prognosis DLBCL
  • 14. 0 20 40 0 1 2 3 4 CHOP-21 (1975-2001) CHOEP (2001-2003) R-CHOP (2005) % Surviving M O N T H S Progress in the treatment of Young good-prognosis DLBCL
  • 15. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Elderly II-IV Elderly 0/I Limited aaIPI=2,3 Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 Japan (JCOG) Elderly IPI=1,2,3 Elderly aaIPI=0 Limited I,noBulk
  • 16. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12   
        • An alternative for good-prognosis?
  • 17. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12   
        • An alternative for good-prognosis?
        •  encouraging (short-term) results
        •  published in abstract form only
        •  small number of patients (62)
        •  uncommon population
        • - >60 years, stage I / non-bulk
        • - <60 years: stage I / bulky (or LDH or ECOG >1)
        • - <60 years: stage II / non-bolky („very favorable“)
  • 18. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12   
        • An alternative for good-prognosis?
        •  encouraging (short-term) results
        •  published in abstract form only
        •  small number of patients (62)
        •  uncommon population
        • - >60 years, stage I / non-bulk
        • - <60 years: stage I / bulky (or LDH or ECOG >1)
        • - <60 years: stage II / non-bolky („very favorable“)
  • 19. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12   
        • An alternative for good-prognosis?
        •  encouraging (short-term) results
        •  published in abstract form only
        •  small number of patients (62)
        •  uncommon population
        • - >60 years, stage I / non-bulk
        • - <60 years: stage I / bulky (or LDH or ECOG >1)
        • - <60 years: stage II / non-bolky („very favorable“)
  • 20. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12   
        • An alternative for good-prognosis?
        •  encouraging (short-term) results
        •  published in abstract form only
        •  small number of patients (62)
        •  uncommon population
        • - >60 years, stage I / non-bulk
        • - <60 years: stage I / bulky (or LDH or ECOG >1)
        • - <60 years: stage II / non-bolky („very favorable“)
  • 21. DSHNHL 09/2000 Current Randomized Trials IPI=0 IPI=1 aaIPI=2,3 France (GELA) U N F I T Elderly II-IV Elderly 0/I Elderly IPI=1,2,3 Elderly aaIPI=0
  • 22. LNH 03-1B <65 years, aaIPI = 0 N. Ketterer, F Reyes Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (83 to 93%) 400 patients required (in 4 years) R ACVBP 14 MTX IFM - VP16 ARA-C R-ACVBP 14 MTX IFM - VP16 ARA-C No CNS prophylaxis 0 2 4 8 12 Wks 22 0 2 4 8 12 22 Wks
  • 23. DSHNHL 09/2000 Current Randomized Trials IPI=0 IPI=1 aaIPI=2,3 France (GELA) U N F I T Elderly II-IV Elderly 0/I aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 Germany Elderly IPI=1,2,3 Elderly aaIPI=0
  • 24. Treatment arm 0.4 p=0.000 000 003 (0.3;0.6) Bulky disease 1.7 p=0.0003 (1.3;2.2) IPI 1.6 p=0.0008 (1.2;2.2) Significance Hazard Ratio (95%-CI) Parameter Cox Regression Analysis* * for primary endpoint TTF
  • 25. CHEMO R-CHEMO p IPI = 0 and no Bulk (n=108/101) 78% 89% 0.054 IPI = 0 and Bulk (n=70/73) 61% 78% 0.064 IPI = 1 and no Bulk (n=105/107) 57% 76% 0.034 IPI = 1 and Bulk (n=127/132) 44% 74% 0.000 000 3 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probabilit y Months 89% 76% very favorable less favorable C H E M O: T T F R-C H E M O: T T F 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability Months
  • 26. TTF of Prognostic Subgroups Less Favorable (IPI=1 and/or bulk) Very Favorable (IPI=0, no bulk) 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 97% 87% R-CHOP R-CHOEP Months Probability p = 0.142 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 78% 76% Months Probability R-CHOP R-CHOEP p = 0.637 Pfreundschuh et al., Lancet Oncology 2006
  • 27. Overall Survival Less Favorable (IPI=1 and/or bulk) Very Favorable (IPI=0, no bulk) R-CHOP (n=39) R-CHOEP (n=51) 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 100% 96% Months Probability p = 0.173 Probability Pfreundschuh et al., Lancet Oncology 2006 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 90% 93% Months R-CHOP (n=160) R-CHOEP (n=130) p = 0.891
  • 28. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Germany France (GELA) U N F I T Elderly II-IV Elderly 0/I Elderly IPI=1,2,3 Elderly aaIPI=0
  • 29. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Germany France (GELA) U N F I T Elderly II-IV Elderly 0/I Elderly IPI=1,2,3 Elderly aaIPI=0 Cure  95% Cure  100%
  • 30. 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 C H O P R C H O P C H O P R R R R FLYER (6-6/6-4) STUDY DESIGN C H O P R R Stage I/II aaIPI=0 No Bulk 18-60 years d 1 d 64 d 106
  • 31. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Germany France (GELA) U N F I T Elderly IPI=1,2,3 Elderly aaIPI=0
  • 32. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Germany France (GELA) U N F I T Elderly IPI=1,2,3 Elderly aaIPI=0 Cure  90% Cure  90%
  • 33. LNH 03-2B <60 years, aaIPI = 1 C. Recher, H. Tilly R 6 0 3 12 15 18 9 21 R-ACVBP 14 R-CHOP 21 Wks MTX IFM - VP16 ARA-C 4 IT MTX Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (75 to 85%) 380 patients required (in 4 years) 0 2 4 6 10 14 24 Wks
  • 34. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulky disease and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Germany France (GELA) U N F I T Elderly IPI=1,2,3 Elderly aaIPI=0 Cure  90% Cure  90%
  • 35. 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 R R R R R R C H O P 14 R R R R Rando 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 R R d 1 d 105 d 1 d 75 Treatment for IPI=1 and/or „Bulk“ + / - Radiatio Bulk / E UNFOLDER (21/14) STUDY DESIGN + / - Radiatio Bulk / E
  • 36. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3 IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 aaIPI=2,3 Elderly aaIPI 1,2,3 Elderly aaIPI=0 Limited aaIPI=2,3 Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 Japan (JCOG) I,noBulk Limited
  • 37. DSHNHL 09/2000 Current Randomized Trials Cure  60% IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 Cure  60% Limited Cure  60% Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 Elderly aaIPI 1,2,3 Elderly IPI=0 Limited I,noBulk Limited
  • 38. HD-Chemotherapy in Primary Aggressive NHL A „foggy“ situation ….
  • 39. Author Population Rando EFS OS Haioun et al., 1994  1 RF, Bulk CR n.s. n.s. 2000  2 RF CR 0.02* 0.04* Verdonck et al., 1994 II-IV <CR n.s. n.s. Gianni et al., 1997 I/II bulky ,III/IV all 0.004 n.s. Santini et al., 1998 II bulky ,III/IV all n.s. n.s.  2 RF* 0.008* n.s. Kluin-N. et al., 2001 all CR n.s. n.s. Kaiser et al., 2002 LDH >UNV CR, PR n.s. n.s. Gisselbrecht et al., 2002  RF all -0.01 -0.009 Martelli et al., 2003  2 RF CR, PR n.s. n.s. Sertoli et al., 2003 II bulky, III/IV all n.s. n.s. MISTRAL 2005 IPI >2RD all n.s. n.s. HD-Chemotherapy in Primary Aggressive NHL * retrospective subset analysis Milpied et al., 2004 <3RF all 0.03 n.s
  • 40. HD-Chemotherapy in Primary Aggressive NHL Verdonck et al., 1994 Gianni et al., 1997 Santini et al., 1998 Haioun et al., 1996 / 2000 Kluin-N. et al., 2001 Kaiser et al., 2002 Gisselbrecht et al., 2002 Martelli et al., 2003 Sertoli et al., 2003 Milpied et al., 2002 ?
  • 41. Author Population Rando EFS OS Haioun et al., 1994  1 RF, Bulk CR n.s. n.s. 2000  2 RF CR 0.02* 0.04* Verdonck et al., 1994 II-IV <CR n.s. n.s. Gianni et al., 1997 I/II bulky ,III/IV all 0.004 n.s. Santini et al., 1998 II bulky ,III/IV all n.s. n.s.  2 RF* 0.008* n.s. Kluin-N. et al., 2001 all CR n.s. n.s. Kaiser et al., 2002 LDH >UNV CR, PR n.s. n.s. Gisselbrecht et al., 2002  RF all -0.01 -0.009 Martelli et al., 2003  2 RF CR, PR n.s. n.s. Sertoli et al., 2003 II bulky, III/IV all n.s. n.s. HD-Chemotherapy in Primary Aggressive NHL * retrospective subset analysis Milpied et al., 2004 <3RF all 0.03 n.s
  • 42. The NEW ENGLAND JOURNAL of MEDICINE: A misleading title …
  • 43. GOELAMS Trial CHOP vs. High-Dose in Young IPI=2,3
  • 44. GOELAMS Trial Design Suggestive Time S c a l e
  • 45. GOELAMS Trial Design R e a l t i m e s c a l e C H O P 21 C E E P 15 Rando HD-MTX + AraC C E E P 15 B E A M d 99 20 40 60 80 100 120 140 days 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 C H O P 21 0
  • 46. YOUNG HIGH-RISK PATIENTS: SUMMARY/PERSPECTIVES
    • CHOP-21 = formal standard
    • CHOP-21 = hard to justify
    • Conventional high-dose debated
    • Novel approaches needed
  • 47. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 48. mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 PBSC R 64 PBSC PBSC mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 43 mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 22 1 77 98 days = rando: + / - Rituximab CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (  60 YRS., AGE-ADJUSTED IPI  )2 n=230 n=230
  • 49. mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 PBSC R 64 PBSC PBSC mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 43 mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 22 1 77 98 days = rando: + / - Rituximab CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (  60 YRS., AGE-ADJUSTED IPI  )2 n=230 n=230
  • 50. Mega-CHOEP Phase II Trials TTF without and with Rituximab Mega-CHOEP (n=92) R-Mega-CHOEP (n=124) 80 70 60 50 40 30 20 10 0 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 observation time 55 months TTF (2y) : 75.0% 30 25 20 15 10 5 0 .7 .6 .5 .4 .3 .2 .1 0.0 TTF (1y): 73.5% 1.0 .9 .8 observation time 19 months
  • 51. Optimal use of rituximab Optimal use of rituximab Rituximab in Young Poor-Prognosis DLBCL :
  • 52. Optimal use of rituximab Optimal use of rituximab Rituximab in Young Poor-Prognosis DLBCL : In combination with rituximab myelosuppressive chemotherapy might interfere with rituximab effector mechanisms
  • 53. Optimal use of rituximab Optimal use of rituximab Consequence :
  • 54. Optimal use of rituximab Optimal use of rituximab Consequence : Rituximab should not be combined with chemotherapy regimens other than CHOP outside clinical trials
  • 55. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 56. IIL-DLCL4: Study Design RC/RP RC/RP RC/RP RC/RP NR Off study R-MAD x 2* BEAM + ASCT R-MegaCHOP x 2 NR Off study R-MAD x 2* BEAM + ASCT R-CHOP14 x 4 R E S T A G I N G ARM 1: 94 pts R-MegaCHOP14 x 4 RANDOMI ZAT I ON ARM 1b: 94 pts R-CHOP14 x 4 ARM 2: 94 pts R-MegaCHOP14 x 4 ARM 2b: 94 pts R-CHOP14 x 4 CR/PR CR/PR CR/PR CR/PR
  • 57. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 58. DSHNHL 09/2000 SWOG/ECOG/CALGB/NCI S9704 PR,CR  ASCT ICE Salvage Evaluation CHOP x 1 ASCT CHOP x 3 Evaluation Cure Relapse ASCT CHOP x 5 Evaluation CR, PR < PR
  • 59. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 60. First line treatment according to immunohistochemical panel GC-like NC-like ABC-like CD10+, Bcl-6+, Bcl-2-; CD10-,Bcl-6+, IRF4+,Bcl-2-; CD10+, Bcl-6+, Bcl-2+; CD10-,Bcl-6+, IRF4+,Bcl-2+; CD10-, Bcl-6-, Bcl-2+, IRF4+; CD10-,Bcl-6-, IRF4-,Bcl-2+; R-CHOP x 6 +/- IFRT R-CHOP x 6 + IEV x 1+ ASCT R-CHOP x 6 + IEV x 1+ ASCT Seràgnoli Institute
  • 61. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 62. LNH 03-3B < 60 years, IPIaa = 2-3 O. Fitoussi, C. Gisselbrecht Primary endpoint: CR rate after 4 R-ACVBP Expected improvement: 10% = 75% RC 120 patients required (in 2 years) 0 2 4 6 R-ACVBP 14 10 14 MTX Wks BEAM PBSC 4 IT MTX
  • 63. DSHNHL 09/2000 Therapeutic Groups
    • DSHNHL: Mega-CHOEP III
    • IIL: DLCL-04 III
    • SWOG: S9704 III
    • Roma-Bologna II
    • G E L A: LNH 03-3B II
    • Nordic Group: LBC-04 II
    Young Poor-Prognosis
  • 64. Re-staging 2 PET optional CR/CRu PET negative or no PET done CR/CRu PET positive PR regardless of PET SD/PD regardless of PET Follow-up Biopsy if possible Normal Lymphoma Biopsy not possible Normal Lymphoma HD cytarabine x 1 HD Metotrexate x 1 No biopsy Biopsy inconclusive Salvage Therapy [CHOEP-14 + rituximab] x 6 Nordic LCB 04
  • 65. A „foggy“ situation …. Treatment of Young Poor-Prognosis DLBCL
  • 66. … . to a bright perspective Treatment of Young Poor-Prognosis DLBCL
  • 67. DSHNHL 09/2000 Current Randomized Trials Cure  90% IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 Cure  90% Elderly II-IV Elderly aaIPI=0 Limited Cure  90% Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 I,noBulk Limited
  • 68. DSHNHL 09/2000 Therapeutic Groups
    • GELA 98-5: 8 x CHOP-21 vs. 8 x R-CHOP-21
    • ECOG 4494: CHOP-21 vs. R-CHOP-21
    • DSHNHL: 6xCHO(E)P-21 vs. 6xCHO(E)P-14
    Elderly Patients (Basic):
  • 69. Months DSHNHL 15.09.03 56 % 42 % 69 % 49 % Survival after dose-dense CHOP-14 (NHL-B2) CHOP-14 vs. CHOP-21 p < 0.001 90 80 70 60 50 40 30 20 10 0 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 CHOEP-14 (n=169) CHOEP-21 (n=170) CHOP-21 (n=178) CHOP-14 (n=172)
  • 70. % patients 72% 70% 7% 10% 3% 4% 3% 3% NHL-B2: WHO° 3&4 Toxicity 3% 2.5%
  • 71. GELA-LNH 98.5 5-year follow-up: overall survival p<0.007 Rituximab plus CHOP 58% CHOP 45% 0 1 2 3 4 5 6 7 100 80 60 40 20 0 Overall survival (%) Years Feugier P, et al. J Clin Oncol 2005;23:4117 –26
  • 72. % patients 12% 20% 8% 8% 9% 5% GELA-98.5: WHO° 3&4 Toxicity 6% 6%
  • 73. Aggressive Lymphomas: Progress in Elderly Patients 0 20 40 0 1 2 3 4 R-CHO(E)P (2004) R-CHOP-21 (2000) CHOP-14 (2000) CHOP-21 (1975-2000)
  • 74. Treatment of Aggressive NHL in the Elderly Paris‘ Judgement
  • 75. Therapeutic Groups
    • HOVON: 8 x CHOP-14 vs. 6R-8CHOP-14
    • DSHNHL: 6 vs. 8 (R-)CHOP-14
    • GELA: 8xR-CHOP-21 vs. 8xR-CHOP-14
    Elderly Patients (Advanced):
  • 76. 6 x CHOP-14 + 30-40 Gy (Bulk, E) Random 2x2 Factorial Design 8 x CHOP-14 + 30-40 Gy (Bulk, E) 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab Study Design RICOVER-60 CD20 + DLBCL Stages I-IV 61 to 80 years
  • 77. Time to Treatment Failure RICOVER-60 6 Cycles vs. 8 Cycles CHOP-14 vs. R-CHOP-14 M o n t h s M o n t h s % failure-free % failure-free 6/8 x CHOP-14 (n=414) 6/8 x R-CHOP-14 (n=414) 6 x (R)-CHOP-14 (n=413) 8 x (R)-CHOP-14 (n=415) p=0.000025  - crit* = 0.031 57% 70% 64% 62% p=0.23 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100
  • 78. Time to Treatment Failure RICOVER-60
  • 79. Time to Treatment Failure RICOVER-60 8 x R-CHOP-14 (n=203) 6 x R-CHOP-14 (n=211) 8 x CHOP-14 (n=210) 6 x CHOP-14 (n=204) Median time of observation: 26 months % failure-free M o n t h s 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100
  • 80. Optimal use of rituximab Optimal use of rituximab Conclusion :
  • 81. Optimal use of rituximab Optimal use of rituximab Conclusion : In combination with rituximab 6 cycles of R-CHOP-14 are as good as 8 cycles
  • 82. A randomized phase III study of chimeric anti-CD20 monoclonal antibody (Rituximab) with 2-weekly CHOP chemotherapy (CHOP 14) in elderly patients with intermediate- or high-risk non-Hodgkin's lymphoma . Results of an interim analysis
    • P. Sonneveld, W.L.J. van Putten, P.C. Huijgens,
    • H. Holte, M. Eriksson
    • Dutch-Belgian HOVON group Nordic Lymphoma Group
    NLG
  • 83. Event-free survival
  • 84. Cumulative percentage 0 30 0 25 50 75 100 8 x CHOP-14 (n=100) 0 5 10 15 20 25 30 0 10 20 30 40 50 60 70 80 90 8 x CHOP-14 (n=204) EVENT-FREE SURVIVAL CHOP-14 HOVON DSHNHL 100 25% 65%
  • 85. Cycles given (#)
    • CHOP14 R-CHOP14
    • #
    • 0 1 -
    • 1 4 3
    • 2 1 3
    • 3 7 7
    • 4 8 1
    • 5 7 4
    • 6 11 9
    • 7 5 8
    • 8 50 56
  • 86. Adherence to Protocol RICOVER-60 6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96% Relative Dose Intensity Cyclophosphamide (median) 1.2 1.1 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0
  • 87. Adherence to Protocol RICOVER-60 Relative Dose Intensity Cyclophosphamide (median) 6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96%
      • „ Prephase“ treatment obligatory:
          • 1 mg vincristine d-7
          • 100 mg prednisone d-7 to d-1
      • No dose reduction unless delay >7 days
      • Strict adherence to G-CSF schedule
  • 88. Time to Treatment Failure RICOVER-60 8 x R-CHOP-14 (n=203) 6 x R-CHOP-14 (n=211) 8 x CHOP-14 (n=210) 6 x CHOP-14 (n=204) Median time of observation: 26 months % failure-free M o n t h s 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100
  • 89. DSHNHL 09/2000 Current Randomized Trials Cure  90% IPI=0 No bulk Elderly Bulk and /or IPI=1 IPI=0 IPI=1 Cure  90% Limited Cure  90% Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T Stage I Non-Bulk U N F I T Ov er 70 Elderly aaIPI 1,2,3 Elderly IPI=0 Limited I,noBulk
  • 90. LNH 03-6B 66-80 years, aaIPI = 1,2,3 R. Delarue, A. Bosly 4 IT MTX R R-CHOP 21 0 3 6 9 Wks 12 15 18 21 0 2 4 6 10 14 Wks 8 12 R-CHOP 14 Primary endpoint: EFS Expected improvement: 10% at 3 years with R-CHOP 14 (55 to 65%) 600 patients required (over 4 years) Prophylactic Darbepoietin alfa Supportive care
  • 91. LNH03-6B
  • 92. M o n t h s % surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV 8 x CHOP-21* n=197 55%* * Feugier et al., JCO 2005
  • 93. M o n t h s % surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV 8 x CHOP-21* n=197 8 x R-CHOP-21* n=202 55%* 64%* * Feugier et al., JCO 2005
  • 94. M o n t h s % surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV * Feugier et al., JCO 2005 8 x CHOP-21* n=197 8 x R-CHOP-21* n=202 6/8 x R-CHOP-14 n=414 74% 55%* 64%*
  • 95. DSHNHL 01.07.05 RICOVER-60 TTF according to IPI without Rituximab with Rituximab M o n t h s M o n t h s
  • 96. Optimal use of rituximab Optimal use of rituximab Conclusion : R-CHOP-14 appears to be superior to R-CHOP-21, particularly in high-risk patients
  • 97. Standard for Eldery DLBCL Further improvement possible ?
  • 98. Standard for Eldery DLBCL Further improvement possible ?  Chemotherapy ?
  • 99. Standard for Eldery DLBCL Further improvement possible ?  Chemotherapy ?  New biologicals
  • 100. Standard for Eldery DLBCL Further improvement possible ?  Chemotherapy ?  New biologicals  Smarter use of rituximab
  • 101. Courtesy of M. Reiser, Cologne Median Rituximab Serum Level Nadirs before next Rituximab Application 
  • 102. Optimal use of rituximab C H O P C H O P C H O P C H O P C H O P C H O P DENSE-R-CHOP-14 12 14 C H O P C H O P C H O P C H O P C H O P C H O P 12 14 R-CHOP-14
  • 103. Median Rituximab Serum Level Nadirs before next Rituximab Application Courtesy of M. Reiser, Cologne   ? ?
  • 104. DENSE-R-CHOP-14: First Results Efficacy: Patients recruited 57 Chemotherapy complete CR/CRu 33/33 Interim restaging CR/CRu/PR 40/40 Therapy-assoc. deaths 3 Interstitial pneumonias 7
  • 105. DENSE-R-CHOP-14: Phase-III 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 C H O P C H O P C H O P C H O P C H O P C H O P Rando- mization CD20 + DLBCL Stages I-IV 61 to 80 years n = 2 x 400 Start: 01/07
  • 106. „ πάντα ρεϊ “ (everything is in flux) Towards the Cure of DLBCL