glsg/osho study group - · pdf fileglsg/osho study group study concepts • follicular...
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Supported byDeutsche Krebshilfe
GLSG/OSHO Study Group
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GLSG/OSHO Study Group
Study Concepts
• Follicular Lymphomas
• Mantel Cell Lymphomas
• Waldenstroem´s Disease
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Palliationof Symptomes
Prolongation of Life
Cure
Key Steps in Improving Treatment for Follicular Lymphoma
until mid 1990ies
Cytostatic DrugsRadiation
since mid 1990ies
AntibodiesASCT
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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
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Time to Treatment Failure
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Comparison of Two Consecutive Study Generations of the GLSG
Overall Survival
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Future Strategies in Follicular Lymphomas
Induction Therapy in Remission
Rituximab Maintenance
=> Lymphoma Control=> Lymphoma Reduction
Chemotherapy plus Rituximab
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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
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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
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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
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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
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GALLIUM Global RecruitmentFebruary 2013
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GALLIUM Recruitment per CountryFebruary 2013
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GALLIUM - Lymphoma SubtypesFebruary 2013
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GALLIUM - Chemotherapy chosen by Center for FL
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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
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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
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LenalidomideMechanism of Action
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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
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Folie 19
M.S.1 It may be good to include the median follow-up time...Marianna Shafarenko; 14.06.2011
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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)
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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
Funktioneller Status
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
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Therapy of follicular Lymphomas: GLSG/OSHO/StiL
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
Funktioneller Status
Lebenserwartung
Komorbidität
Toxizitätsrisiko
„Go go“
Intensive Chemotherapie
=> anhaltende Remissionen
„Slow go“
Weniger belastende Chemotherapie
=> Zurückdrängen des Lymphoms
„No go“
„supportive“ Therapie=> Syptomkontrolle
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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
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GLSG/OSHO Study Group
Study Concepts
• Follicular Lymphomas
• Mantel Cell Lymphomas
• Waldenstroem´s Disease
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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)
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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
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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
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MCL youngerTime to Treatment Failure
Hermine, ASH 2012
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MCL youngerOverall Survival
Hermine, ASH 2012
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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)
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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
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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
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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
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R-CHOP
R-FC
MCL Elderly Overall survival
Kluin-Nelemans, NEJM 2012
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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
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MCL Elderly Remission Duration
Kluin-Nelemans, NEJM 2012
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MCL ElderlyResponse Duration
After R-CHOP After R-FC
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MCL Elderly: Overall Survival
After R-CHOP After R-FC
p=0.055 for interaction of induction and maintenanceKluin-Nelemans, NEJM 2012
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< 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
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GLSG/OSHO Study Group• Follicular Lymphomas
• Mantel Cell Lymphomas
• Waldenstroem´s Disease