Treatment of Diffuse Substantial B-Cell Lymphoma M. Pfreundschuh German High Review Non-Hodgkin's Lymphoma Study Bunch (

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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

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

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Current Randomized Trials IPI=0 No mass IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Limited Elderly Bulk and/or IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV 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) DSHNHL 09/2000

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

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

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Current Randomized Trials IPI=0 No mass IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Stage I Non-Bulk Limited Elderly Bulk and/or IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV 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) DSHNHL 09/2000

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

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Time to Treatment Failure 1.0 middle perception 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

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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

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Overall Survival

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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

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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

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

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

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Current Randomized Trials IPI=0 No mass IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T I,noBulk Stage I Non-Bulk Limited Elderly Bulk and/or IPI=1 Elderly II-IV Elderly IPI=1,2,3 Elderly II-IV 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) DSHNHL 09/2000

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SWOG Approach for „Limited Stage" C H O P C H O P C H O P SWOG  24 12 An option for good-forecast?

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SWOG Approach for „Limited Stage" C H O P C H O P C H O P SWOG  24 12 An option for good-guess?  empowering (short-term) comes about  published in theoretical shape just  small number of patients (62)  uncommon populace - >60 years, organize I/non-mass - <60 years: arrange I/massive (or LDH or ECOG >1) - <60 years: arrange II/non-bolky („very positive")

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SWOG Approach for „Limited Stage" C H O P C H O P C H O P SWOG  24 12 An option for good-visualization?  empowering (short-term) comes about  published in theoretical shape just  small number of patients (62)  uncommon populace - >60 years, organize I/non-mass - <60 years: arrange I/massive (or LDH or ECOG >1) - <60 years: arrange II/non-bolky („very positive")

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SWOG Approach for „Limited Stage" C H O P C H O P C H O P SWOG  24 12 An option for good-visualization?  empowering (short-term) comes about  published in dynamic frame just  small number of patients (62)  uncommon populace - >60 years, organize I/non-mass - <60 years: arrange I/cumbersome (or LDH or ECOG >1) - <60 years: organize II/non-bolky („very ideal")

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SWOG Approach for „Limited Stage" C H O P C H O P C H O P SWOG  24 12 An option for good-anticipation?  empowering (short-term) comes about  published in dynamic frame just  small number of patients (62)  uncommon populace - >60 years, organize I/non-mass - <60 years: arrange I/massive (or LDH or ECOG >1) - <60 years: organize II/non-bolky („very ideal")

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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) DSHNHL 09/2000

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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 = 0 N. Ketterer, F Reyes Primary endpoint: EFS Expected change: 10% at 2 years with R-ACVBP (83 to 93%) 400 patients required (in 4 years)

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Current Randomized Trials IPI=0 Elderly 0/I Elderly aaIPI=0 U N F I T IPI=0 No mass IPI=1 Elderly Bulky sickness and/or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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Cox Regression Analysis* Parameter Hazard Ratio (95%-CI) Significance 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) * for essential endpoint TTF

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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 F R-C H E M O: T F extremely great 89% 1.0 0.9 0.8 0.7 76% 0.6 Probabilit y less good 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% 0.000 000 3

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

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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 mass) Less Favorable (IPI=1 as well as mass) R-CHOP (n=39) 100% 1.0 0.9 R-CHOEP (n=51) 96% 0.8 0.7 0.6 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

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Current Randomized Trials IPI=0 Elderly 0/I Elderly aaIPI=0 U N F I T IPI=0 No mass IPI=1 Elderly Bulky infection and/or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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Current Randomized Trials IPI=0 Elderly aaIPI=0 Elderly 0/I U N F I T Cure  95% IPI=0 No mass Cure  10 0% IPI=1 Elderly Bulky illness and/or IPI=1 Elderly IPI=1,2,3 Elderly II-IV aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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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 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

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Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No mass IPI=1 Elderly Bulky malady and/or IPI=1 Elderly IPI=1,2,3 aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No mass IPI=1 Elderly Cure  90% Bulky ailment and/or IPI=1 Elderly IPI=1,2,3 Cure  90% aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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0 2 4 6 10 14 24 Wks LNH 03-2B <60 years, aaIPI = 1 C. 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 change: 10% at 2 years with R-ACVBP (75 to 85%) 380 patients required (in 4 years)

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Current Randomized Trials IPI=0 Elderly aaIPI=0 U N F I T IPI=0 No mass IPI=1 Elderly Cure  90% Bulky illness and/or IPI=1 Elderly IPI=1,2,3 Cure  90% aaIPI=2,3 France (GELA) Germany DSHNHL 09/2000

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Treatment for IPI=1 as well as „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 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

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Current Randomized Trials IPI=0 No mass IPI=0 Elderly aaIPI=0 U N F I T Stage I Non-Bulk I,noBulk Lim

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