Optimal use of rituximab in aggressive NHL Professor Michael Pfreundschuh.

Optimal use of rituximab in aggressive NHL

Professor Michael Pfreundschuh

International Prognostic Index (IPI)

Patients of all ages Risk factors Age >60 yearsPS 2–4LDH level Elevated Extranodal involvement >1 siteStage (Ann Arbor) III-IV

Patients 60 years (age-adjusted)PS 2–4LDH ElevatedStage III-IV

Shipp N Engl J Med 1993;329:987

DLBCL: overall survival

Year

Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.

Pat

ien

ts (

%)

100

60

40

20

0

0 2 5 6 7 83 41

80

IPI 0–1

IPI 2–3

IPI 4–5p<0.001

Rituximab in first-line treatment of aggressive NHL

Rituximab plus CHOP versus CHOP in elderly patients with DLBCL

Cyclophosphamide 750mg/m²Doxorubicin 50mg/m²Vincristine 1.4mg/m²Prednisone 40mg/m²/day x 5 days

3 weeks 8 cycles

R-CHOP 375mg/m²

Coiffier B, et al. N Engl J Med 2002;346:235–43Feugier P, et al. J Clin Oncol 2005 23:4117–26

GELA phase III trial (n=399)

GELA- LNH 98.5 trial planned interim analysis: initial data

R-CHOP CHOP p value (n=169) (n=159)

Median 1-year

EFS (%) 69 49 <0.0005

OS (%) 83 68 <0.01

Coiffier B, et al. Blood 2000;96:223a (Abstract 950)

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

Ove

rall

su

rviv

al (

%)

Years

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

GELA-LNH 98.5 5-year follow-up: progression-free survival

100

80

60

40

20

00 1 2 3 4 5 6 7

Pro

gre

ssio

n-f

ree

surv

ival

(%

)


CHOP 30%

Years

p<0.00001

PFS excludes late deaths not related to lymphoma or treatment


GELA-LNH 98.5: 5-year EFS in low-aaIPI patients (aaIPI 0/1)

100

80

60

40

20

0 1 2 3 4 5 6 7

Eve

nt-

free

su

rviv

al (

%)


CHOP 34%

Years

p=0.0008


GELA-LNH 98.5: 5-year EFS in high-aaIPI patients (aaIPI 2/3)

100

80

60

40

20

00 1 2 3 4 5 67

Eve

nt-

free

su

rviv

al (

%)


CHOP 27%

Years

p=0.004


RANDOMISED

Stratified by IPI(0–1 vs 2–4)

CHOP

1 2 3Cycle 4 5 6 7 8

Rituximab

RANDOMISED

Stratified by IPICR/PR; induction

MR every6 months x

2 years

Observation

(n=632) (n=415)1 2 3Cycle 4 5 6 7 8

ECOG 4494 phase III trial: study design

Habermann T, et al. Blood 2004;104:40a (Abstract 127)

ECOG 4494: R-CHOP versus CHOP weighted analysis to remove the effect of maintenance

HR=0.64p=0.003

R-CHOP

CHOP

HR=0.72p=0.05

R-CHOP

CHOP

Pro

bab

ilit

yP

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Years from induction randomisation

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Years from induction randomisation

OS

FFS

Habermann T, et al. Blood 2004;104:40a (Abstract 127)

Rituximab plus CHOP for DLBCL in British Columbia (BC): study aim

March 1, 2001: BC Cancer Agency implemented a new policy recommending R-CHOP for all patients with advanced stage DLBCL in BC

Population-based retrospective analysis over a 3-year interval (1/9/99 – 31/8/02)

Compare outcomes– 18 months prior to rituximab policy (pre-rituximab)

versus– 18 months following rituximab policy

(post-rituximab)

Sehn LH, et al. J Clin Oncol 2005;23:5027–33

CHOP rituximab in British Columbia: overall survival by treatment era and age (≥60 vs <60 years)

1.0

0.8

0.6

0.4

0.2

0

Post-rituximab

Pre-rituximab

p=0.0003

Pro

bab

ilit

y o

f su

rviv

al

0 1 2 3 4 5 Years Years

1.0

0.8

0.6

0.4

0.2

0

Post-rituximab

Pre-rituximab

p=0.02

Pro

bab

ilit

y o

f su

rviv

al

0 1 2 3 4 5

≥60 years (n=170) <60 years (n=122)

Sehn LH, et al. J Clin Oncol 2005;23:5027–33

RICOVER 60: trial design

CD20+ DLBCL61–80 years

IPI I-V

(n=828)

RANDOMISATION2 x 2 factorial design

6 x CHOP-14+ 36 Gy (Bulk, E)



+ 8 x rituximab


+ 8 x rituximab

Pfreundschuh et al., Blood 2005;106 (Abstract 13)

CHOP-14 R-CHOP-14 p

CR/CRu (%) 73 81 0.008

Progressive disease (%) 9 6 0.102

RICOVER 60: response to therapy

6 Cycles 8 Cycles p

CR/CRu (%) 76 78 0.432

Progressive disease (%) 7 7 0.985


RICOVER 60 interim analysis: freedom from treatment failure (FFTF)


Regimen No. of patients FFTF*

6 x CHOP-14 203 53%

6 x CHOP-14 + 8 x R 211 70%

8 x CHOP-14 210 58%

8 x CHOP-14 + 8 x R 203 70%

*Median 26 months follow-up

CHOP-14 vs R-CHOP-14

Fai

lure

-fre

e su

rviv

al (

%)

8 x (R)-CHOP-14(n=415)

6 x (R)-CHOP-14(n=413)

p=0.000025 -crit* = 0.031

57%

70%64%

62%

p=0.23

Fai

lure

-fre

e su

rviv

al (

%)

100

80

60

40

20

0

100

80

60

40

20

0

6/8 x R-CHOP-14(n=414)

6/8 x CHOP-14(n=414)

0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45

Months Months

6 cycles vs 8 cycles

RICOVER 60: time to treatment failure


p=0.088p=0.284

78%

77%

78%

76%

CHOP-14 vs R-CHOP-14

Su

rviv

ing

(%

)

6 x (R)-CHOP-14(n=415)

8 x (R)-CHOP-14(n=413)

100

80

60

40

20

00 5 10 15 20 25 30 35 40 45

Months

Su

rviv

ing

(%

)

100

80

60

40

20

0

6/8 x R-CHOP-14(n=414)

6/8 x CHOP-14(n=414)

0 5 10 15 20 25 30 35 40 45

Months

6 cycles vs 8 cycles

RICOVER 60: survival


Historical perspective (I): stages I–IV

78%

72%*

58%*

*Pfreundschuh et al., Blood 2004;104:634–41

Su

rviv

ing

(%

)

100

80

60

40

20

0 0 5 10 15 20 25 30 35 4045 Months

8 x R + 6/8 x CHOP-14 (n=414)6 x CHOP-14* (n=172)6 x CHOP-14* (n=176)

Elderly DLBCL: survival


Historical perspective (II): stages II–IV

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

8 x R + 6/8 x CHOP-14n=4148 x R-CHOP-21*n=2028 x CHOP-21*n=197

74%

55%*

64%*

Elderly DLBCL: survival

Su

rviv

ing

(%

)

0 5 10 15 20 25 30 35 40 45 50 55 60

100

90

80

70

60

50

40

30

20

10

0

Months


• R-CHOP-14 superior to CHOP-14

• Trend in favour of 8 x CHOP-14 over 6 x CHOP-14

- disappears after rituximab

• 8 x R+ 6/8 x CHOP-14: best results in elderly to date

• 8 x R + 6 x CHOP-14: reference for future trials

RICOVER 60: conclusions


CD20+ DLBCL18–60 years

IPI 0,1Stages II–IV,I with bulk

(n=823)

6 x CHOP-like+ 30–40 Gy (Bulk, E)

6 x CHOP-like+ rituximab

+ 30–40 Gy (Bulk, E)

Randomisation

MInT: trial design

Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

Median observation time: 22 months

MInT: time to treatment failure

p=0.00 00 00 00 7

R-Chemo

Chemo

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Months

80%

61%

Pro

bab

ilit

y


Lymphoma-associated deaths:Chemo: 42R-Chemo: 13

Median observation time: 23 months

p=0.0002

MInT: overall survival

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Months

Pro

bab

ilit

y

R-Chemo

Chemo

95%

86%


R-CHOP vs CHOP R-CHOEP vs CHOEP

Pro

ba

bil

ity

50454035302520151050

Months

R-CHOEP (n = 181)

CHOEP (n = 180)

80.4%

65.1%

P = 0.0006

R-CHOP (n = 197)

50454035302520151050

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

Months

Pro

ba

bil

ity

CHOP (n = 197)

82.9%

55.3%

P < 0.00000005


1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0


CHOP vs CHOEP R-CHOP vs R-CHOEP

50454035302520151050

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

55.3%

65.1%

P = 0.04

Months

Pro

bab

ility

Months

Pro

bab

ility

50454035302520151050

1.0

.9

.8

.7

.6

.5

.4

.3

.2

.1

0.0

R-CHOEP(n = 181)

80.4%

82.9%

P = 0.67

CHOP(n = 187)

CHOEP(n = 180)

R-CHOP(n = 197)



MInT: overall survival for (R)-CHOP versus (R)-CHOEP

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 40 45 50

Months

Pro

bab

ility

p=0.26

95.1%

100%

R-CHOEP

R-CHOP1.0

0.8

0.6

0.4

0.2

0

Months

Pro

bab

ility

p=0.65

92.8%

95.8% R-CHOP

0 5 10 15 20 25 30 35 40 45 50

R-CHOEP

Very favourable (IPI=0, no bulk)

Less favourable(IPI=1 and/or bulk)


Rituximab in first-line treatment of aggressive NHL: conclusions

8 cycles of rituximab plus chemotherapy is the standard of care for DLBCL patients irrespective of age or risk factors– confirmed in a community-based study

Addition of 8 cycles of rituximab to dose intensified strategies allows a reduction in the number of cycles of CHOP– may reduce toxicity, particularly cardiotoxicity

Rituximab in relapsed/refractory aggressive NHL

Kewalramani T, et al. Blood 2004;103:3684–8

Rituximab plus ICE for relapsed/refractory CD20+ DLBCL

Day

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Rituximab x

Ifosfamide x

Carboplatin x

Etoposide x x x

G-CSF x x x x x x x x

Median days to complete three cycles R-ICE: 45 (35–59) vs 37 with ICE

10/34 (29%) patients completed R-ICE in 35 days

28/34 (83%) sufficient PBPC harvest vs 80/92 (87%) ICE

R-ICE for relapsed/refractory CD20+ DLBCL

Months from ASCT

Pro

po

rtio

n p

rog

ress

ion

-fre

e

p=0.25

ICE (n=92;historical controls)

R-ICE (n=34)

PFS1.0

0.8

0.6

0.4

0.2

0 0 20 40 60 80 100 120

Response rates

R-ICE (%)

ICE (%)

ORR 78 71

Relapsed CR 65 34

Refractory CR 31 19

Kewalramani T, et al. Blood 2004;103:3684–8

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Rituximab + EPOCH in relapsed aggressive NHL: protocol

MabThera 375 mg/m2 i.v. day 1 Doxorubicin 15 mg/m2 c.i.v. days 2–4

Etoposide 65 mg/m2 c.i.v. days 2–4 Vincristine 0.5 mg c.i.v. days 2–4

Cyclophosphamide 750 mg/m2 i.v. day 5 Prednisone 60 mg/m2 p.o. days 1–14

Days

MabThera

Doxorubicin

Vincristine

Etoposide

Cyclophosphamide

Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

Prednisone

Rituximab + EPOCH in relapsed aggressive NHL: response

Patients (%)

(n=50)

ORR 64

CR 26

PR 38

Stem cell harvest in 18 of 27 patients (67%) under 60 years

Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

CORAL trial of R-ICE versus R-DHAP

CD20+ DLBCL

Relapsed/refractory

R-ICE x 3

R-DHAP x 3

R

A

N

D

O

M

I

S

E

R

A

N

D

O

M

I

S

E

SD/PD Off

PR/CR

ASCT

R x 6

Obs

BEAM+

400 patients needed

Stratification:rituximab-naive

versus previousrituximab

Rationale for rituximab in vivo purging and consolidation

Rituximab in vivo purging can eliminate residual lymphoma cells, a major cause of relapse, from stem cell harvests, without adversely affecting the yield or function of stem cells

Rituximab can also be used as consolidation therapy post-transplant to eliminate residual malignant cells and reduce the likelihood of relapse

In vivo purging with rituximab prior to ASCT

B-NHL patients (n=27) received rituximab plus DexaBEAM therapy prior to ASCT

Patients (%)

Remission rate 25 (96)

Complete remission 24 (92)

Partial remission 1 (4)

16 months post HDT: – 95% overall survival– 77% progression-free survival

Flohr T, et al. Bone Marrow Transplant 2002;29:796–75

CY BCNU/VP/CY

Harvest†

Horwitz SM, et al. Blood 2004;103:777–83

Rituximab* Rituximab*

ASCT

*375mg/m2 weekly x 4†CD34-enriched and in-vitro antibody purged

Rituximab after HDT/ASCT

Time6 months

42 days

All patients Recurrent DLBCL

Rituximab after autologous transplantation: event-free survival

120

100

80

60

40

20

00 1 2 3 4 5 0 1 2 3 4 5

Years Years

n=35 n=21

120

100

80

60

40

20

0

Eve

nt-

free

su

rviv

al (

%)

Eve

nt-

free

su

rviv

al (

%)

Horwitz S, et al. Blood 2004;103:777–83

Rituximab for treatment of relapsed/refractory aggressive NHL:

conclusions

Adding rituximab to salvage chemotherapy improves the response to chemotherapy and therefore can improve patient outcome

In vivo purging with rituximab prior to ASCT may impact progression-free and overall survival

Rituximab consolidation post-ASCT may impact event-free survival providing further patient benefit

Optimal use of rituximab in aggressive NHL Professor Michael Pfreundschuh.

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