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Treatment of Diffuse Large B-Cell Lymphoma M. Pfreundschuh German High Grade Non-Hodgkin´s Lymphoma Study Group (DSHNHL) - PowerPoint PPT Presentation


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: AustraliaALLG+

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

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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 SchoolHomburg / Saar, Germany

DSHNHL 09-19-00


Update on Clinical Trials

Groups contacted:

AustraliaALLG+

FranceGela+

EuropeEORTC+

GermanyDSHNHL+

NetherlandsHOVON+

ScandinaviaNordic Group+

SpainGEATANO+

United KigdomNCRI+

USACALGB+

ECOG+

SWOG+


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


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)


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


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


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)


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


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


Overall Survival


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


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


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


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


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


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?


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“)


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“)


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“)


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“)


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


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)


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


Cox Regression Analysis*

Parameter

Hazard Ratio

(95%-CI)

Significance

Treatment arm0.4p=0.000000003

(0.3;0.6)

Bulky disease1.7p=0.0003

(1.3;2.2)

IPI1.6p=0.0008

(1.2;2.2)

* for primary endpoint TTF


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


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


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


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


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


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


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


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


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)


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


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


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


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


HD-Chemotherapy in Primary Aggressive NHL

A „foggy“ situation ….


HD-Chemotherapy in Primary Aggressive NHL

AuthorPopulationRandoEFS OS

Haioun et al., 19941 RF, BulkCRn.s. n.s.

2000  2 RF CR0.02* 0.04*

Verdonck et al., 1994II-IV<CRn.s. n.s.

Gianni et al., 1997I/IIbulky,III/IVall0.004 n.s.

Santini et al., 1998IIbulky,III/IValln.s. n.s.

2 RF*0.008* n.s.

Kluin-N. et al., 2001allCRn.s. n.s.

Kaiser et al., 2002LDH >UNVCR, PRn.s. n.s.

Gisselbrecht et al., 2002 RFall-0.01 -0.009

Martelli et al., 2003 2 RFCR, PRn.s. n.s.

Sertoli et al., 2003IIbulky,III/IValln.s. n.s.

MISTRAL 2005IPI >2RDalln.s. n.s.

Milpied et al., 2004<3RFall0.03 n.s

* retrospective subset analysis


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

?


HD-Chemotherapy in Primary Aggressive NHL

AuthorPopulationRandoEFS OS

Haioun et al., 19941 RF, BulkCRn.s. n.s.

2000  2 RF CR0.02* 0.04*

Verdonck et al., 1994II-IV<CRn.s. n.s.

Gianni et al., 1997I/IIbulky,III/IVall0.004 n.s.

Santini et al., 1998IIbulky,III/IValln.s. n.s.

2 RF*0.008* n.s.

Kluin-N. et al., 2001allCRn.s. n.s.

Kaiser et al., 2002LDH >UNVCR, PRn.s. n.s.

Gisselbrecht et al., 2002 RFall-0.01 -0.009

Martelli et al., 2003 2 RFCR, PRn.s. n.s.

Sertoli et al., 2003IIbulky,III/IValln.s. n.s.

Milpied et al., 2004<3RFall0.03 n.s

* retrospective subset analysis


The NEW ENGLAND JOURNAL of MEDICINE:

A misleading title …


GOELAMS Trial

CHOP vs. High-Dose in Young IPI=2,3


GOELAMS Trial Design

Suggestive Time S c a l e


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


YOUNG HIGH-RISK PATIENTS:SUMMARY/PERSPECTIVES

  • CHOP-21 = formal standard

  • CHOP-21 = hard to justify

  • Conventional high-dose debated

  • Novel approaches needed


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


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


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


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)


Optimal use of rituximab

Optimal use of rituximab

Rituximab in Young

Poor-Prognosis DLBCL :


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


Optimal use of rituximab

Optimal use of rituximab

Consequence :


Optimal use of rituximab

Optimal use of rituximab

Consequence :

Rituximab should not be combined with chemotherapy regimens other than CHOP outside clinical trials


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


ARM 1:

94 pts

R-MegaCHOP14

x 4

ARM 2b:

94 pts

R-CHOP14

x 4

ARM 1b:

94 pts

R-CHOP14

x 4

ARM 2:

94 pts

R-MegaCHOP14

x 4

R-MAD x 2*

BEAM + ASCT

R-CHOP14 x 4

R-MAD x 2*

BEAM + ASCT

R

E

S

T

A

G

I

N

G

RANDOMI

ZAT

I

ON

RC/RP

CR/PR

NR

Off study

CR/PR

RC/RP

RC/RP

CR/PR

NR

Off study

RC/RP

CR/PR

R-MegaCHOP x 2

IIL-DLCL4: Study Design


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


SWOG/ECOG/CALGB/NCI S9704

CHOP x 5

Evaluation

< PR

CR, PR

ICE Salvage

CHOP x 1

CHOP x 3

Evaluation

Evaluation

ASCT

PR,CRASCT

Cure

Relapse

ASCT

DSHNHL09/2000


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


First line treatment according to

immunohistochemical panel

ABC-like

NC-like

GC-like

CD10-, Bcl-6-,

Bcl-2+, IRF4+;

CD10-,Bcl-6-,

IRF4-,Bcl-2+;

CD10+, Bcl-6+,

Bcl-2-;

CD10-,Bcl-6+,

IRF4+,Bcl-2-;

CD10+, Bcl-6+,

Bcl-2+;

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


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


BEAM

MTX

R-ACVBP 14

0

2

4

6

10

14

Wks

4 IT MTX

PBSC

LNH 03-3B< 60 years, IPIaa = 2-3O. Fitoussi, C. Gisselbrecht

Primary endpoint: CR rate after 4 R-ACVBP

Expected improvement: 10% = 75% RC

120 patients required (in 2 years)


Therapeutic Groups

Young Poor-Prognosis

  • DSHNHL:Mega-CHOEPIII

  • IIL:DLCL-04III

  • SWOG:S9704III

  • Roma-BolognaII

  • G E L A:LNH 03-3BII

  • Nordic Group:LBC-04II

DSHNHL09/2000


Nordic LCB 04

[CHOEP-14 + rituximab] x 6

HD cytarabine x 1

HD Metotrexate x 1

Re-staging 2

PET optional

CR/CRu

PET positive

PR regardless of PET

SD/PD regardless of PET

CR/CRu

PET negative or no PET done

No biopsy

Biopsy inconclusive

Biopsyif possible

Biopsy

not possible

Salvage Therapy

Lymphoma

Normal

Follow-up

Lymphoma

Normal


Treatment of Young Poor-Prognosis DLBCL

A „foggy“ situation ….


Treatment of Young Poor-Prognosis DLBCL

…. to a bright perspective


Current Randomized Trials

IPI=0

No bulk

Elderly aaIPI=0

IPI=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

II-IV

Cure 90%

Cure 90%

Cure 90%

U S A (SWOG)

Germany

France (GELA)

U

N

F

I

T

Ov

er

70

U S A (CALBG)

U K (NCRI)

DSHNHL09/2000


Therapeutic Groups

Elderly Patients (Basic):

  • 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

DSHNHL09/2000


1.0

.9

.8

.7

.6

.5

.4

CHOEP-14 (n=169)

CHOEP-21 (n=170)

CHOP-21 (n=178)

CHOP-14 (n=172)

.3

.2

.1

0.0

0

10

20

30

40

50

60

70

80

90

Survival after dose-dense CHOP-14

(NHL-B2)

69 %

56 %

CHOP-14

vs.

CHOP-21

p < 0.001

49 %

42 %

Months

DSHNHL 15.09.03


NHL-B2: WHO° 3&4 Toxicity

72%

70%

% patients

10%

7%

4%

3%

3%

3%

3%

2.5%


GELA-LNH 98.5 5-year follow-up: overall survival

100

80

60

40

20

0

Rituximab plus

CHOP 58%

Overall survival (%)

CHOP 45%

p<0.007

01 23 4 56 7

Years

Feugier P, et al. J Clin Oncol 2005;23:4117–26


GELA-98.5: WHO° 3&4 Toxicity

% patients

20%

12%

9%

8%

8%

6%

6%

5%


Aggressive Lymphomas:

Progress in Elderly Patients

R-CHO(E)P

(2004)

CHOP-14

(2000)

R-CHOP-21

(2000)

40

CHOP-21

(1975-2000)

20

0

0

1

2

3

4


Treatment of Aggressive NHL in the Elderly

Paris‘ Judgement


Therapeutic Groups

Elderly Patients (Advanced):

  • HOVON: 8 x CHOP-14 vs. 6R-8CHOP-14

  • DSHNHL:6 vs. 8 (R-)CHOP-14

  • GELA:8xR-CHOP-21 vs. 8xR-CHOP-14


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


100

100

90

90

80

80

70

70

60

60

50

50

40

40

30

30

20

20

10

10

0

0

0

5

10

15

20

25

30

35

40

45

0

5

10

15

20

25

30

35

40

45

Time to Treatment Failure

RICOVER-60

6 Cycles vs. 8 Cycles

CHOP-14 vs. R-CHOP-14

p=0.000025 -crit* = 0.031

p=0.23

70%

64%

62%

% failure-free

% failure-free

57%

8 x (R)-CHOP-14

(n=415)

6/8 x R-CHOP-14

(n=414)

6 x (R)-CHOP-14

(n=413)

6/8 x CHOP-14

(n=414)

M o n t h s

M o n t h s


Time to Treatment Failure

RICOVER-60


100

90

80

70

60

% failure-free

50

40

30

20

10

0

0

5

10

15

20

25

30

35

40

45

M o n t h s

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


Optimal use of rituximab

Optimal use of rituximab

Conclusion :


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


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


Event-free survival


EVENT-FREE SURVIVAL CHOP-14

HOVON

DSHNHL

100

100

65%

90

80

75

70

Cumulative percentage

60

50

50

25%

40

30

8 x CHOP-14

(n=100)

25

8 x CHOP-14

(n=204)

20

10

0

0

0

30

0

5

10

15

20

25

30


Cycles given (#)

CHOP14R-CHOP14

#

0 1 -

1 4 3

2 1 3

3 7 7

4 8 1

5 7 4

611 9

7 5 8

85056


1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

0.0

.1

.2

.3

.4

.5

.6

.7

.8

.9

1.0

1.1

1.2

Adherence to Protocol

RICOVER-60

Relative Dose Intensity Cyclophosphamide (median)

6 x CHOP-1499%

6 x R-CHOP-1499%

8 x CHOP-1496%

8 x R-CHOP-1496%


Adherence to Protocol

RICOVER-60

Relative Dose Intensity Cyclophosphamide (median)

6 x CHOP-1499%

6 x R-CHOP-1499%

8 x CHOP-1496%

8 x R-CHOP-1496%

  • „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


  • 100

    90

    80

    70

    60

    % failure-free

    50

    40

    30

    20

    10

    0

    0

    5

    10

    15

    20

    25

    30

    35

    40

    45

    M o n t h s

    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


    Current Randomized Trials

    IPI=0

    No bulk

    IPI=0

    Elderly IPI=0

    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

    aaIPI

    1,2,3

    Cure 90%

    Cure 90%

    Cure 90%

    U S A (SWOG)

    Germany

    France (GELA)

    U

    N

    F

    I

    T

    Ov

    er

    70

    U S A (CALBG)

    U K (NCRI)

    DSHNHL09/2000


    Prophylactic Darbepoietin alfa

    Supportive care

    LNH 03-6B66-80 years, aaIPI = 1,2,3R. Delarue, A. Bosly

    R-CHOP 21

    0

    3

    6

    9

    12

    15

    18

    21

    Wks

    R

    4 IT MTX

    0

    2

    4

    6

    8

    10

    12

    14

    Wks

    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)


    LNH03-6B


    ELDERLY DLBCL : Survival

    Historical Perspective (II): Stages II-IV

    55%*

    % surviving

    8 x CHOP-21*

    n=197

    M o n t h s

    * Feugier et al., JCO 2005


    ELDERLY DLBCL : Survival

    Historical Perspective (II): Stages II-IV

    64%*

    55%*

    % surviving

    8 x R-CHOP-21*

    n=202

    8 x CHOP-21*

    n=197

    M o n t h s

    * Feugier et al., JCO 2005


    ELDERLY DLBCL : Survival

    Historical Perspective (II): Stages II-IV

    74%

    64%*

    55%*

    % surviving

    6/8 x R-CHOP-14

    n=414

    8 x R-CHOP-21*

    n=202

    8 x CHOP-21*

    n=197

    M o n t h s

    * Feugier et al., JCO 2005


    RICOVER-60

    TTF according to IPI

    without Rituximab

    with Rituximab

    M o n t h s

    M o n t h s

    DSHNHL 01.07.05


    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


    Standard for Eldery DLBCL

    Further improvement possible ?


    Standard for Eldery DLBCL

    Further improvement possible ?

    Chemotherapy ?


    Standard for Eldery DLBCL

    Further improvement possible ?

    Chemotherapy ?

     New biologicals


    Standard for Eldery DLBCL

    Further improvement possible ?

    Chemotherapy ?

     New biologicals

    Smarter use of rituximab


    Median Rituximab Serum Level Nadirs

    before next Rituximab Application

    Courtesy of M. Reiser, Cologne


    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

    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

    DENSE-R-CHOP-14

    14

    12


    Median Rituximab Serum Level Nadirs

    before next Rituximab Application

    ?

    ?

    Courtesy of M. Reiser, Cologne


    DENSE-R-CHOP-14: First Results

    Efficacy:

    Patients recruited57

    Chemotherapy complete CR/CRu33/33

    Interim restagingCR/CRu/PR40/40

    Therapy-assoc. deaths 3

    Interstitial pneumonias 7


    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

    CD20+ DLBCL

    Stages I-IV

    61 to 80 years

    Rando-

    mization

    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 = 2 x 400

    Start: 01/07


    Towards the Cure of DLBCL

    „ πάνταρεϊ “

    (everything is in flux)


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