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Treatment of Diffuse Large B-Cell Lymphoma M. Pfreundschuh German High Grade Non-Hodgkin´s Lymphoma Study Group (DSHNH

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. Update on Clinical Trials . Groups contacted: Australia ALLG +

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Treatment of Diffuse Large B-Cell Lymphoma M. Pfreundschuh German High Grade Non-Hodgkin´s Lymphoma Study Group (DSHNH

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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 SchoolHomburg / Saar, Germany DSHNHL 09-19-00

  2. Update on Clinical Trials Groups contacted: Australia ALLG + France Gela + Europe EORTC + Germany DSHNHL + Netherlands HOVON + Scandinavia Nordic Group + Spain GEATANO + United Kigdom NCRI + USA CALGB + ECOG + SWOG +

  3. Current Randomized Trials IPI=0 No bulk IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Limited Limited Elderly Bulk and /or IPI=1 IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 aaIPI=2,3 U S A (SWOG) Germany France (GELA) U N F I T Ov er 70 U S A (CALBG) U K (NCRI) Japan (JCOG) DSHNHL09/2000

  4. CALGB:50303 Phase III Randomized Study of R-CHOP v. DA-EPOCH-R with Microarray Treatment completed ARM A: R-CHOP C3 C4 C6 C1 C7 C2 C8 C5 Tumor Biopsy Blood Samples Randomization Stage Stage Stage C3 C4 C6 C1 C7 C2 C8 C5 ARM B: DA-EPOCH-R Treatment completed if no change C5 to C7 staging Treatment completed if change C5 to C7 staging Repeat Blood Samples at Staging Proteomics/Pharmacogenomics 6 9 15 0 18 3 21 25 12 Time Line (weeks)

  5. NCRI trial: R-CHOP 14 vs 21 RANDOMISATION R-CHOP 21 CHOP 21  8 cycles Rituximab  8 cycles N=540 Eligible patients Stratified by IPI (0 or 1 vs. 2 vs. 3 vs. 4 or 5) Age <60 vs. 60 Treatment centre R-CHOP 14 CHOP 14  6 cycles Rituximab  8 cycles N=540

  6. Current Randomized Trials IPI=0 No bulk IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Stage I Non-Bulk Limited Limited Elderly Bulk and /or IPI=1 IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 aaIPI=2,3 U S A (SWOG) Germany France (GELA) U N F I T Ov er 70 U S A (CALBG) U K (NCRI) Japan (JCOG) DSHNHL09/2000

  7. Trial Design 6 x CHOP-like + 30–40 Gy (Bulk, E) CD20+ DLBCL 18–60 years IPI 0,1 Stages II-IV, I with bulk Random. 6 x CHOP-like + rituximab + 30–40 Gy (Bulk, E)

  8. Time to Treatment Failure 1.0 median observation time: 34 months 0.9 0.8 0.7 59% 0.6 Probability 0.5 0.4 CHEMO (n=410) 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 M o n t h s Pfreundschuh et al., Lancet Oncology 2006

  9. Time to Treatment Failure 1.0 0.9 79% 0.8 R-CHEMO (n=413) 0.7 59% 0.6 p = 0.000 000 02 Probability 0.5 0.4 CHEMO (n=410) 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 M o n t h s Pfreundschuh et al., Lancet Oncology 2006

  10. Overall Survival

  11. Overall Survival 1.0 0.9 84% 0.8 CHEMO (n=410) 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 M o n t h s Pfreundschuh et al., Lancet Oncology 2006

  12. Overall Survival 93% 1.0 R-CHEMO (n=413) 0.9 p = 0.0001 84% 0.8 CHEMO (n=410) 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 M o n t h s Pfreundschuh et al., Lancet Oncology 2006

  13. Progress in the treatment of Young good-prognosis DLBCL R-CHO(E)P (2004) CHOEP (2001-2003) CHOP-21 (1975-2001) % Surviving 40 20 0 0 1 2 3 4 M O N T H S

  14. Progress in the treatment of Young good-prognosis DLBCL R-CHOP (2005) CHOEP (2001-2003) CHOP-21 (1975-2001) % Surviving 40 20 0 0 1 2 3 4 M O N T H S

  15. Current Randomized Trials IPI=0 No bulk IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Stage I Non-Bulk Limited Limited Elderly Bulk and /or IPI=1 IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 aaIPI=2,3 U S A (SWOG) Germany France (GELA) U N F I T Ov er 70 U S A (CALBG) U K (NCRI) Japan (JCOG) DSHNHL09/2000

  16. SWOG Approach for „Limited Stage“ C H O P C H O P C H O P SWOG    24 12 An alternative for good-prognosis?

  17. SWOG Approach for „Limited Stage“ C H O P C H O P C H O P SWOG    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“ C H O P C H O P C H O P SWOG    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“ C H O P C H O P C H O P SWOG    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“ C H O P C H O P C H O P SWOG    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. Current Randomized Trials IPI=0 Elderly 0/I Elderly aaIPI=0 U N F I T IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 France (GELA) DSHNHL09/2000

  22. MTX MTX IFM - VP16 IFM - VP16 ARA-C ARA-C ACVBP 14 0 2 4 8 12 22 Wks R No CNS prophylaxis 0 2 4 8 12 22 Wks R-ACVBP 14 LNH 03-1B<65 years, aaIPI = 0N. Ketterer, F Reyes Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (83 to 93%) 400 patients required (in 4 years)

  23. Current Randomized Trials IPI=0 Elderly 0/I Elderly aaIPI=0 U N F I T IPI=0 No bulk IPI=1 Elderly Bulky disease and /or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  24. Cox Regression Analysis* Parameter Hazard Ratio (95%-CI) Significance Treatment arm 0.4 p=0.000000003 (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) * for primary endpoint TTF

  25. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 Months C H E M O: T T F R-C H E M O: T T F very favorable 89% 1.0 0.9 0.8 0.7 76% 0.6 Probability less favorable 0.5 0.4 0.3 0.2 0.1 0.0 0 10 20 30 40 50 60 Months 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% 0.0000003

  26. TTF of Prognostic Subgroups Very Favorable (IPI=0, no bulk) Less Favorable (IPI=1 and/or bulk) R-CHOP 97% 1.0 1.0 R-CHOP 78% 0.9 0.9 0.8 87% R-CHOEP 0.8 0.7 76% R-CHOEP 0.7 0.6 Probability 0.6 Probability 0.5 0.5 0.4 0.4 0.3 0.3 p = 0.637 0.2 0.2 p = 0.142 0.1 0.1 0.0 0.0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Months Months Pfreundschuh et al., Lancet Oncology 2006

  27. 93% R-CHOEP (n=130) 1.0 0.9 90% R-CHOP (n=160) 0.8 0.7 0.6 0.5 0.4 0.3 0.2 p = 0.891 0.1 0.0 0 10 20 30 40 50 60 Months Overall Survival Very Favorable (IPI=0, no bulk) Less Favorable (IPI=1 and/or bulk) R-CHOP (n=39) 100% 1.0 0.9 R-CHOEP (n=51) 96% 0.8 0.7 0.6 Probability Probability 0.5 0.4 0.3 0.2 p = 0.173 0.1 0.0 0 10 20 30 40 50 60 Months Pfreundschuh et al., Lancet Oncology 2006

  28. Current Randomized Trials IPI=0 Elderly 0/I Elderly aaIPI=0 U N F I T IPI=0 No bulk IPI=1 Elderly Bulky disease and /or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  29. Current Randomized Trials IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T Cure95% IPI=0 No bulk Cure100% IPI=1 Elderly Bulky disease and /or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  30. 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

  31. Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No bulk IPI=1 Elderly Bulky disease and /or IPI=1 Elderly IPI=1,2,3 aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  32. Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No bulk IPI=1 Elderly Cure90% Bulky disease and /or IPI=1 Elderly IPI=1,2,3 Cure90% aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  33. 0 2 4 6 10 14 24 Wks LNH 03-2B<60 years, aaIPI = 1C. Recher, H. Tilly MTX IFM - VP16 ARA-C R-ACVBP 14 R 4 IT MTX 0 3 6 9 12 15 18 21 Wks R-CHOP 21 Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (75 to 85%) 380 patients required (in 4 years)

  34. Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No bulk IPI=1 Elderly Cure90% Bulky disease and /or IPI=1 Elderly IPI=1,2,3 Cure90% aaIPI=2,3 aaIPI=2,3 France (GELA) Germany DSHNHL09/2000

  35. Treatment for IPI=1 and/or „Bulk“ UNFOLDER (21/14) STUDY DESIGN 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 + / - Radiatio Bulk / E Rando R R R R R R d 1 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

  36. Current Randomized Trials IPI=0 No bulk IPI=0 Elderly aaIPI=0 U N F I T Stage I Non-Bulk I,noBulk Limited Limited Elderly Bulk and /or IPI=1 IPI=1 Elderly II-IV Elderly aaIPI 1,2,3 aaIPI=2,3 aaIPI=2,3 aaIPI=2,3 U S A (SWOG) Germany France (GELA) U N F I T Ov er 70 U S A (CALBG) U K (NCRI) Japan (JCOG) DSHNHL09/2000

  37. Current Randomized Trials IPI=0 No bulk IPI=0 Elderly IPI=0 U N F I T Stage I Non-Bulk I,noBulk Limited Limited Limited Elderly Bulk and /or IPI=1 IPI=1 Elderly II-IV Elderly aaIPI 1,2,3 Cure 60% Cure 60% Cure 60% U S A (SWOG) Germany France (GELA) U N F I T Ov er 70 U S A (CALBG) U K (NCRI) DSHNHL09/2000

  38. HD-Chemotherapy in Primary Aggressive NHL A „foggy“ situation ….

  39. HD-Chemotherapy in Primary Aggressive NHL 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/IIbulky,III/IV all 0.004 n.s. Santini et al., 1998 IIbulky,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 IIbulky,III/IV all n.s. n.s. MISTRAL 2005 IPI >2RD all n.s. n.s. Milpied et al., 2004 <3RF all 0.03 n.s * retrospective subset analysis

  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. HD-Chemotherapy in Primary Aggressive NHL 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/IIbulky,III/IV all 0.004 n.s. Santini et al., 1998 IIbulky,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 IIbulky,III/IV all n.s. n.s. Milpied et al., 2004 <3RF all 0.03 n.s * retrospective subset analysis

  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 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 Rando days 0 20 40 60 80 100 120 140 d 99 B EAM HD-MTX + AraC C E E P 15 C E E P 15

  46. YOUNG HIGH-RISK PATIENTS:SUMMARY/PERSPECTIVES • CHOP-21 = formal standard • CHOP-21 = hard to justify • Conventional high-dose debated • Novel approaches needed

  47. Therapeutic Groups Young Poor-Prognosis • 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 DSHNHL09/2000

  48. DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (60 YRS., AGE-ADJUSTED IPI )2 PBSC PBSC PBSC n=230 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 n=230 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF = rando: + / - Rituximab

  49. DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (60 YRS., AGE-ADJUSTED IPI )2 PBSC PBSC PBSC n=230 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 n=230 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF = rando: + / - Rituximab

  50. 1.0 observation time19 months 1.0 observation time55 months .9 .9 .8 .8 .7 .7 .6 .6 .5 .5 .4 .4 .3 .3 TTF (1y): 73.5% .2 .2 TTF (2y) : 75.0% .1 .1 0.0 0.0 0 5 10 15 20 25 30 0 10 20 30 40 50 60 70 80 Mega-CHOEP Phase II Trials TTF without and with Rituximab R-Mega-CHOEP (n=124) Mega-CHOEP (n=92)

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