glsg/osho study group - kompetenznetz- · pdf fileglsg/osho study group study concepts •...

Supported by

Deutsche Krebshilfe

GLSG/OSHO Study Group


Study Concepts

• Follicular Lymphomas

• Mantel Cell Lymphomas

• Waldenstroem s Disease

[email protected]

Palliation

of Symptomes

Prolongation

of Life

Cure

Key Steps in Improving Treatment for

Follicular Lymphoma

until mid 1990ies

Cytostatic Drugs

Radiation

since mid 1990ies

Antibodies

ASCT

CVP 64 % 14 mo 83 %

R-CVP 87 % (p<0.0001)

38 mo (p<0.001)

89 % (p=0.022)

Marcus et al. 2008

CHOP 90 % 31 mo 90 %

R-CHOP 96 % (p=0.011)

n.r. (p=0.0006)

95 % (p=0.016)

Hiddemann et al. 2005

MCP 75 % 26 mo 74 %

R-MCP 92 % (p=0.0009)

n.r. (p<0.0001)

87 % (p=0.0096)

Herold et al. 2007

CHVP+IFN 72 % 35 mo 79 %

R-CHVP+IFN 81 % (p<0.0001)

n.r. (p<0.0001)

84 % (p=0.029)

Salles et al. 2008

OR PFS OS

Rituximab – Chemotherapy Combinations

Time to Treatment Failure

Comparison of Two Consecutive Study

Generations of the GLSG Overall Survival

[email protected]

Future Strategies in

Follicular Lymphomas

Induction Therapy in Remission

Rituximab Maintenance

=> Lymphoma Control => Lymphoma Reduction

Chemotherapy plus Rituximab


Questions for the Next Steps of Therapy

• Best Chemotherapy to be combined with Rituximab

• Value of Radio-Immuno Therapy

• Value of Stem Cell Transplantation after R Chemo

• Improvement of Rituximab Application

• Improvement of Rituximab Maintenance

• New Antibodies

• New Agents

[email protected]

Adapted from Press. Cancer J Sci Am. 1998;4(suppl 2):S19.

CD22

HLA-DR

CD20

slg

CD19 B Cell

CD37

CD25

CD52

Antibody Therapy for B - Cell Lymphomas

• Targeting agent

– Monoclonal antibody

– Engineered antibody

– Recombinant toxin

• Modifications

– None

– Conjugation

• Radioisotopes

• Drugs

• Toxins

B-Cell

GA101 Mechanisms of Action

*Mössner E, et al. Blood. 2010; June 3; 115:4393-4402; Roche data on file

Lower CDC activity Type II vs. Type I antibody

B cell

Effector

cell

Increased direct cell death Type II vs. Type I antibody

Enhanced ADCC Glycoengineering for increased

affinity to FcγRIIIa

CD20 FcγRIIIa

Complement GA101

10

GALLIUM Phase III - Study Design

Experimental arm GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2–6/8 +

CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m2 d1, d2 q28d

Control arm Rituximab 375 mg/m2 d1 cycles 1-6/8 +

CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m2 d1, d2 q28d

Patient population 1200 fNHL and 200 MZL

Primary endpoint PFS of 1200 fNHL patients

Maintenance treatment Patients achieving CR or PR continue therapy every

2 months for up to 2 years

Maintenance rituximab q2m 2 years

Maintenance GA101 q2m 2 years

CR/PR Previously untreated

indolent NHL (n=1400)

GA101 1000 mg x 6-8 cycles +

CHOP/CVP/Bendamustine x 6-8 cycles

Rituximab 375 mg/m2 x 6-8 cycles +

CHOP/CVP/Bendamustine x 6-8 cycles CR/PR

Source: www.clinicaltrials.gov

GALLIUM Global Recruitment

February 2013

GALLIUM Recruitment per Country

February 2013

GALLIUM - Lymphoma Subtypes

February 2013

GALLIUM - Chemotherapy chosen by Center for FL

GALLIUM (BO21223):

Timelines for Futility Analysis

FA data availability

IA data availability

Futility 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

GALLIUM (BO21223) – Phase III G-chemo vs. R-chemo in 1st line iNHL w/maintenance

L

Futility CR

(Feb ’13)

Futility PFS

(May ’15) (Nov ‘19) IA PFS

(Jan ’17)

FA

(Jun ’18)

Futility analysis based on first 170 patients’ response at end of induction


Questions for the Next Steps of Therapy

• Best Chemotherapy to be combined with Rituximab

• Value of Radio-Immuno therapy

• Value of Stem Cell Transplantation after R Chemo

• Improvement of Rituximab Application

• Improvement of Rituximab Maintenance

• New Antibodies

• New Agents

Lenalidomide

Mechanism of Action

SLL (N=24)

Marginal (N=24)*

Follicular (N=45)*

All Patients

Eval (N=93)

ITT (N=100)

ORR, n (%) 20(83) 21(88) 44(98) 85(91) 85(85)

CR/Cru 6(25) 16(67) 38(85) 60(65) 60(60)

PR 14(59) 5(21) 6(13) 25(27) 25(25)

SD, n (%) 2(8) 3(13) 1(2) 6(6) 6(6)

PD, n (%) 2(8) 0 0 2(2) 2(2)

Fowler, N. et al. ICML 2011. Abst#137.

Lenalidomide plus Rituximab

First Line Therapy of Follicular Lymphoma

R

1st line

FL

n = 1000

R2 Maintenance

2 Years Rituximab Maintenance

R2

R-Chemo

CR, CRu, PR

CR, CRu, PR

R-Chemo

R-CHOP (6x), R-CVP (8x), R-B (6x)

International, multi-centre, randomised study

R2 maintenance

2 Years of Rituximab

Maintenance

1 Year of Lenalidomide

Maintenance

R2 Induction

Lenalidomide 20 mg d 2-22 for 6 Cycles

Ritux 4xCycle 1, 1x Cycles 2-6

RELEVANCE : Phase 3 Study Design (Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001)

Therapy of follicular Lymphomas:

GLSG/OSHO Gruppe 1

„Fit patient“

Organfunktion

Funktioneller

Status

Lebenserwartung

Komorbidität

Toxizitätsrisiko

Gruppe 3

„Frail patient“

Organfunktion

Funktioneller Status

Lebenserwartung

Komorbidität

Toxizitöätsrisiko

Gruppe 2

„Compromised

patient“

Organfunktion


Lebenserwartung

Komorbidität

Toxizitätsrisiko

„Go go“

Intensive

Chemotherapie

=> anhaltende

Remissionen

„Slow go“

Weniger

belastende

Chemotherapie

=> Zurückdrängen

des Lymphoms

„No go“

„supportive“

Therapie

=> Syptomkontrolle

GALLIUM

CHOP/Benda-R

Rituximab

Maintenance

GA 101

Maintenance

CHOP/Benda-G

RELEVANCE

R- Chemo R- 2

Rituximab

Maintenance

R - 2

Maintenance

Therapy of follicular Lymphomas:

GLSG/OSHO/StiL

Gruppe 1

„Fit patient“

Organfunktion


Lebenserwartung

Komorbidität

Toxizitätsrisiko

Gruppe 3

„Frail patient“

Organfunktion


Lebenserwartung

Komorbidität

Toxizitöätsrisiko

Gruppe 2

„Compromised patient“

Organfunktion


Lebenserwartung

Komorbidität

Toxizitätsrisiko

„Go go“

Intensive Chemotherapie

=> anhaltende

Remissionen

„Slow go“

Weniger belastende

Chemotherapie

=> Zurückdrängen des

Lymphoms

„No go“

„supportive“ Therapie

=> Syptomkontrolle

Off study

4 x Rituximab

+ 1x Rituximab

A

B

R

A

N

D

O

M

I

S

A

T

I

O

N

4x R - Bendamustine

+ 1 x Rituximab

CR

PR

SD

PD

Re -

Staging

Week 16

Rituximab

375 mg/m²

every 8 weeks

week 2 1 , 29 , 3 7

Induction

CR

PR

SD

Rituximab

375 mg/m²

every 8 weeks

week 2 1 , 29 , 3 7

Observation

Observation

Study Design – Medically Non-Fit


Study Concepts




Young Patients (<65) Elderly Patients (>65) Compromised Patients

First line treatment

conventional

immuno-chemotherapy

(e.g. R-CHOP)

Rituximab maintenance !

radioimmunotherapy ?

watch & wait ?

Rituximab monotherapy

Chlorambucil

Bendamustin

1. relapse

high tumor load:

immuno-chemotherapy

(e.g. R-FC)

allo-transplant ?


Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-FC,

R-Bendamustin)

molecular approaches !

autologous PBSCT



immuno-

chemotherapy

(e.g.

R-Bendamustin)

molecular approaches

higher relapse

molecular approaches: Temsirolimus, Bortezomib, Lenalidomide

(preferable in combination)

repeat previous therapy (long remissions)

dose-intensified

immuno-chemotherapy (either sequential:

R-CHOP/R-DHAP =>PBSCT

or R-Hyper-CVAD)

European MCL Network

Patients <65 Years

PR, CR!

Cyclo 120mg/kg

+ TBI 12 Gray

PBSCT

PR, CR!

3 x R-CHOP

3 x R-DHAP

alternating

(stem cell

mobilization after

course 4)

PBSCT

TBI 10 Gray

Ara-C 4 x 1.5 g/m2

Melphalan 140 mg/m2

3 x R-CHOP

DexaBEAM (stem cell mobilization)

3 x R-CHOP

Hermine, ASH 2012

MCL Younger

Response to Induction

R- CHOP R- DHAP

Abort without staging 7 3% 6 3%

Evaluable 237 237

ED 0 0% 0 0%

PD 12 5% 8 3%

SD 12 5% 6 3%

PR 121 51% 92 39%

CRu 33 14% 42 18%

CR 59 25% 89 38% p=0.0040

CR or CRu 92 39% 131 55% p=0.0005

CR or CRu or PR 213 90% 223 94% p=0.13

MCL younger

Time to Treatment Failure

Hermine, ASH 2012

MCL younger

Overall Survival

Hermine, ASH 2012

Young Patients (<65) Elderly Patients (>65) Compromised Patients

First line treatment

conventional

immuno-chemotherapy

(e.g. R-CHOP)

Rituximab maintenance !


watch & wait ?

Rituximab monotherapy

Chlorambucil

Bendamustin

1. relapse

high tumor load:

immuno-chemotherapy

(e.g. R-FC)

allo-transplant ?



immuno-chemotherapy

(e.g. R-FC,

R-Bendamustin)

molecular approaches !

autologous PBSCT



immuno-

chemotherapy

(e.g.

R-Bendamustin)

molecular approaches

higher relapse

molecular approaches: Temsirolimus, Bortezomib, Lenalidomide

(preferable in combination)

repeat previous therapy (long remissions)

dose-intensified

immuno-chemotherapy (either sequential:

R-CHOP/R-DHAP =>PBSCT

or R-Hyper-CVAD)


Patients >60 Years

4 x R-CHOP

PR, CR

IFN-α maintenance

(3 x 3 M IU/week)

or Peg-IFN (1mg/kg week)

4 x R-CHOP

PR, CR

3 x R-FC

Rituximab

maintenance (all 2 months)

3 x R-FC

Kluin-Nelemans, NEJM 2012

MCL Elderly: Response to Induction

R-CHOP R-FC All

Documented 274 276 550

Premature stop 7 3% 11 4% 18

Evaluable 267 265 532

ED 12 4% 8 3%

PD 15 6% 36 14%

SD 17 6% 13 5%

PR 100 37% 73 28%

CRu 37 14% 33 12%

CR 86 32% 102 38% p=0.15

CR/CRu 123 46% 135 51% p=0.30

CR/CRu/PR 223 84% 208 78% p=0.15

MCL Elderly: Toxicity of Induction

R-CHOP

(n 261)

R-FC (n

272)

Toxicity p Grade freq % freq %

Hemoglobin 0.059 1/2 175 67 160 60

3/4 33 13 54 20

Leukocytes 0.002 1/2 75 29 50 18

3/4 153 59 199 73

Granulocytes 0.097 1/2 48 19 42 17

3/4 150 60 168 69

Platelets <0.001 1/2 82 32 107 40

3/4 49 19 110 41

Lymphocytes 0.004 1/2 47 19 22 9

3/4 169 69 193 78

R-CHOP

R-FC

MCL Elderly

Overall survival



Patients >60 Years

4 x R-CHOP

PR, CR

IFN-α maintenance

(3 x 3 M IU/week)

or Peg-IFN (1mg/kg week)

4 x R-CHOP

PR, CR

3 x R-FC

Rituximab

maintenance (all 2 months)

3 x R-FC

Kluin-Nelemans, ASH 2011

MCL Elderly

Remission Duration


MCL Elderly

Response Duration

After R-CHOP After R-FC

MCL Elderly:

Overall Survival

After R-CHOP After R-FC

p=0.055 for interaction of induction and maintenance


< 65 years > 65 years

R-HAD +/- Bortezomib

1. Relapse

European MCL Network: new studies 2013

2. Relapse (or not qualifying for R-HAD)

First line

BeRT BR-Temsirolimus

Ibrutinib vs

Temsirolimus

MCL elderly R2:

R-CHOP vs R-CHOP/Ara-C

=> Rituximab M

+/-Lenalidomide

MCL younger:

R-CHOP/DHAP

=> low risk: ASCT vs. I .

high risk: ASCT-> R vs I

MCL elderly I:

BR +/- Ibrutinib

=> Rituximab M

+/- Ibrutinib

glsg/osho study group - kompetenznetz- · pdf fileglsg/osho study group study concepts •...

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