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GLSG/OSHO Study Group


Study Concepts

• Follicular Lymphomas

• Mantel Cell Lymphomas

• Waldenstroem´s Disease

[email protected]

Palliationof Symptomes

Prolongation of Life

Cure

Key Steps in Improving Treatment for Follicular Lymphoma

until mid 1990ies

Cytostatic DrugsRadiation

since mid 1990ies

AntibodiesASCT

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 OSRituximab – 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

Follicular LymphomasQuestions 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 activityType II vs. Type I antibody

B cell

Effectorcell

Increased direct cell deathType II vs. Type I antibody

Enhanced ADCCGlycoengineering for increased

affinity to FcγRIIIa

CD20 FcγRIIIa

ComplementGA101

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 every2 months for up to 2 years

Maintenance rituximab

q2m 2 years

Maintenance GA101 q2m 2 years

CR/PRPreviously 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 RecruitmentFebruary 2013

GALLIUM Recruitment per CountryFebruary 2013

GALLIUM - Lymphoma SubtypesFebruary 2013

GALLIUM - Chemotherapy chosen by Center for FL

GALLIUM (BO21223): Timelines for Futility Analysis

FA data availabilityIA data availability

Futility2010 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

Follicular LymphomasQuestions 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

LenalidomideMechanism of Action

SLL (N=24)

Marginal (N=24)*

Follicular(N=45)*

All PatientsEval

(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 RituximabFirst Line Therapy of Follicular Lymphoma

M.S.1

Folie 19

M.S.1 It may be good to include the median follow-up time...Marianna Shafarenko; 14.06.2011

R1st line

FLn = 1000

R2 Maintenance

2 Years Rituximab Maintenance

R2

R-Chemo

CR, CRu, PR

CR, CRu, PR

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

International, multi-centre, randomised study

R2 maintenance2 Years of RituximabMaintenance1 Year of LenalidomideMaintenance

R2 InductionLenalidomide 20 mg d 2-22 for 6 CyclesRitux 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


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

RituximabMaintenance

GA 101 Maintenance

CHOP/Benda-G

RELEVANCE

R- Chemo R- 2

RituximabMaintenance

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 RituximabA

B

R A N D O MI S A T I O N

4x R-Bendamustine

+ 1 x Rituximab

CRPRSD

PD

Re-Staging

Week 16

Rituximab375 mg/m²

every 8 weeksweek 21, 29, 37

Induction

CRPRSD

Rituximab375 mg/m²

every 8 weeksweek 21, 29, 37

Observation

Observation

Study Design – Medically Non-Fit


Study Concepts

• Follicular Lymphomas



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

First line treatmentconventional

immuno-chemotherapy(e.g. R-CHOP)

Rituximab maintenance !radioimmunotherapy ?

watch & wait ?Rituximab monotherapy

ChlorambucilBendamustin

1. relapsehigh tumor load:

immuno-chemotherapy(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

immuno-chemotherapy(e.g. R-FC,

R-Bendamustin)

molecular approaches !autologous PBSCT

radioimmunotherapy ? Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-Bendamustin)

molecular approaches

higher relapsemolecular approaches: Temsirolimus, Bortezomib, Lenalidomide

(preferable in combination)repeat previous therapy (long remissions)

dose-intensifiedimmuno-chemotherapy

(either sequential:R-CHOP/R-DHAP =>PBSCT

or R-Hyper-CVAD)

European MCL NetworkPatients <65 Years

PR, CR!

Cyclo 120mg/kg+ TBI 12 Gray

PBSCT

PR, CR!

3 x R-CHOP3 x R-DHAPalternating

(stem cellmobilization after

course 4)

PBSCT

TBI 10 GrayAra-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 YoungerResponse to Induction

DHAPR-CHOPR-

223

131

89

42

92

6

8

0

2376

94%

55%

38%

18%

39%

3%

3%

0%

3%

p=0.13

p=0.0005

p=0.0040

3%7Abort without staging

213

92

59

33

121

12

12

0

237

90%

39%

25%

14%

51%

5%

5%

0%

CR

CR or CRu

CRu

PR

CR or CRu or PR

SD

PD

ED

Evaluable

MCL youngerTime to Treatment Failure

Hermine, ASH 2012

MCL youngerOverall Survival

Hermine, ASH 2012

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

First line treatmentconventional

immuno-chemotherapy(e.g. R-CHOP)

Rituximab maintenance !radioimmunotherapy ?

watch & wait ?Rituximab monotherapy

ChlorambucilBendamustin

1. relapsehigh tumor load:

immuno-chemotherapy(e.g. R-FC)

allo-transplant ?radioimmunotherapy ?

Rituximab maintenance ?

immuno-chemotherapy(e.g. R-FC,

R-Bendamustin)

molecular approaches !autologous PBSCT

radioimmunotherapy ? Rituximab maintenance ?

immuno-chemotherapy

(e.g. R-Bendamustin)

molecular approaches

higher relapsemolecular approaches: Temsirolimus, Bortezomib, Lenalidomide

(preferable in combination)repeat previous therapy (long remissions)

dose-intensifiedimmuno-chemotherapy

(either sequential:R-CHOP/R-DHAP =>PBSCT

or R-Hyper-CVAD)

European MCL NetworkPatients >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

Rituximabmaintenance(all 2 months)

3 x R-FC

Kluin-Nelemans, NEJM 2012

MCL Elderly: Response to Induction

3%84%12ED

14%366%15PD

28%7337%100PR

AllR-FCR-CHOP

532265267Evaluable

208

135

102

33

13

11276

78%

51%

38%

12%

5%

4%

p=0.15

p=0.30

p=0.15

18550

223

123

86

37

17

7274

84%

46%

32%

14%

6%

3%

CR/CRu/PR

CR/CRu

CR

CRu

SD

Premature stopDocumented

MCL Elderly: Toxicity of Induction

0.004

<0.001

0.097

0.002

0.059p

169474982150481537533175freq

R-CHOP(n 261)

19322110107168421995054160freq

R-FC (n 272)

69191932601959291367% %GradeToxicity

Lymphocytes

Platelets

Granulocytes

Leukocytes

Hemoglobin

3/41/23/41/23/41/23/41/23/41/2

7894140691773182060

R-CHOP

R-FC

MCL Elderly Overall survival


European MCL NetworkPatients >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

Rituximabmaintenance(all 2 months)

3 x R-FC

Kluin-Nelemans, ASH 2011

MCL Elderly Remission Duration


MCL ElderlyResponse 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 maintenanceKluin-Nelemans, NEJM 2012

< 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

BeRTBR-Temsirolimus

Ibrutinib vsTemsirolimus

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• Follicular Lymphomas



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