coral: collaborative trial in relapsed aggressive lymphoma r-ice versus r-dhap in relapsed patients...
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CORAL: COllaborative trial in Relapsed Aggressive Lymphoma
R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell
transplantation: CORAL study.
C. Gisselbrecht, B. Glass, N. Mounier, D. Gill, D. C. Linch, M. Trneny,
A. Bosly, O. Shpilberg, H. Hagberg, N. Ketterer, D. Ma, P. Gaulard,
C. Moskowitz, and N. Schmitz.
WHAT TO DO IN RELAPSING DLBLCL
Standard of care in DLBCL, failing first line chemotherapy treatment, is salvage regimen followed in chemosensitive patients with autologous stem cell transplantation (ASCT).
In the Parma study the 7 yr event free survival rate was 41% for ASCT vs 13% for conventional arm.
Before rituximab era: different salvage regimens would provide a response rate between 50% to 68% with mobilization of hematopoetic peripheral stem cell in most situation.
In the rituximab era: What is the best salvage regimen? No randomized
comparison have been made previously What is the place of rituximab after
transplantation?
CORAL Trial of RICE v DHAP
CD20+ DLBCLRelapsed/Refractory
R-ICE x 3
R-DHAP x 3
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
SD/POD → Off
PR/CR →
→A BS EC AT M
R x 6
Obs
N=400
Which salvage regimen is the best?
Place of immunotherapy post transplantation?
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
CORAL StudyNCT 00137995. Eudract N°2004-002103-32
Inclusion Criteria
Diffuse large B Cell Lymphoma, CD 20+: in 1st relapse, partial response to first line treatment ≤ 65 year old Eligible for transplant Previously treated with chemotherapy
regimen containing anthracyclines with or without rituximab
PS 2 Informed consent
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
CORAL StudyPrimary objective : Part I: induction therapy : Overall response rate
(ORR) adjusted with successful mobilization: MARR Target difference in Response Rate 15% with 400
pts randomized Part II: maintenance therapy : Event free survival
(EFS) at 2 years post transplantation Target difference 15% with 240 patients
randomized Secondary objectives: Eligibility for transplant, toxicities with R-ICE and R-DHAP Toxicity Rituximab post transplant Time to progression or relapse Disease-free survival for complete responders overall survival.
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
• Patient distribution
Australasia
60
Germany
113
Cesz Republic
36
France
128
Belgium
31
Israel
13
US
9
Sweden
13
Switzerland
24
481 patients30/6/2008
Ireland
4
UK
50Thank you to all investigators and pathologists
CORAL Study
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
CORAL Study
Report on 400 patients included between July 24, 2003 to September 4, 2007 : First randomization: R-ICE vs R-DHAP
Second randomization : Rituximab vs no further therapy still on going (240 pts)
Stratification for subgroup analysis
i) Center, groupii) Prior treatment with Rituximab during first lineiii) Relapse < 12months and Refractory (non achieving CR 1st line treatment)
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
Patients randomized
N = 400
R-ICE
N = 202
R-DHAP
N = 194
Received study treatment
N = 197
Received study treatment
N = 191
Completed induction phase
N = 169
Completed induction phase
N = 161
Received BEAM+ASCT
N = 101
Received BEAM+ASCT
N = 105
Randomized in maintenance
N = 98
Randomized in maintenance
N = 99
Arm of treatment
AllARM A / R-
ICEARM B / R-
DHAP
N % N % N %
Response after first line
108 54 101 52 209 53COMPLETE RESPONSE
UNCONFIRMED COMPLETE RESPONSE 23 11 24 12 47 12
PARTIAL RESPONSE 40 20 37 19 77 20
STABLE DISEASE 6 3 10 5 16 4
PROGRESSIVE DISEASE 24 12 20 10 44 11
NOT EVALUATED 0 0 1 1 1 0
122 60 122 63 244 62RITUXIMAB
WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORALRESPONSE AT 1ST LINE Tt
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
CORAL PATIENTS ITTMAIN CHARACTERISTICS AT INCLUSION
R-ICE (202) R-DHAP (194)
Median age 54 y 55 y Sex M 125 118 F 77 76
Stage I-II 81 66 Stage III-IV 119 121
ENS > 1 55 64
LDH > Nl 104 94
S-AaIPI 0-1 119 107S-AaIPI 2-3 75 74
<12 months 89 87
12 months 112 103
P=0.09
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
R-ICE R-DHAP
N 197 % N 191
%
Response including deaths
COMPLETE RESPONSE 48 24 53 28
UNCONFIRMED COMPLETE RESPONSE 24 12 22 12
PARTIAL RESPONSE 53 27 45 24
STABLE DISEASE 23 12 22 12
PROGRESSIVE DISEASE 38 19 35 18
DEATH 6 3 10 5
PREMATURE WITHDRAWAL / NOT EVALUATED
4 2 4 2
Total 197 100 191 100
RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR
ALL PATIENTS (Intent To Treat)
63 .5 % 62.8 %
Arm of treatment Nb patients
Nb responders
with successful
mobilization MARR (%)
R-ICE 197 103 52.3
R-DHAP 191 104 54.5Orlando ASCO May 2009 / Coral study C. Gisselbrecht
CORAL TOXICITY R-ICE R-DHAP
Infection with neutropenia
Grade 3-4 Yes 33 (17%) 31 (16%)
Infection without neutropenia
Grade 3-4 Yes 11 (6%) 15 (8%)
Renal
Grade 3-4 Yes 2(1%) 11 (6%)
PlateletsTransfusions % pts 35% 57%
Toxic deaths 1 3
On induction safety population, in R-ICE arm 90 SAEs and in the R-DHAP arm 120 SAEs during the whole study,
concerning respectively 58 patients (29%) and 69 patients (36%).
Response p
Patients CR/Cru/PR
All patients 245 63 %
CR/CRu 147 38%
Prior Rituximab No 122 83% <0.0001
Yes 124 51%
Relapse > 12 months 140 88% <0.0001Refractory < 12 months 106 46%
s IPI < 2 160 71% <0.0002> 1 76 52%
CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS
* No difference between GELA DSHNHL ALLG** More early relapse in prior Rituximab Group
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
Arm of treatmentARM A /
R-ICEARM B / R-DHAP
N % N %Consolidation treatment (BEAM)
101 51 105 55YesNo 96 49 86 45
Total 197 100 191 100Transplantation
CONSOLIDATION – PATIENTS WITH BEAM AND ASCT (INDUCTION ITT)
Main Reasons for premature withdrawals:Progressive lymphoma 53%
Toxicity 7%Collection failure 10% (CD 34/kg < 2.106)
Deaths 4%
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
OVERALL SURVIVAL ACCORDING TO TREATMENT
ARM (INDUCTION ITT)
PROGRESSION-FREE SURVIVAL ACCORDING TO
TREATMENT ARM (INDUCTION ITT)
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
56%
56%
42%
45%
PROGRESSION-FREE SURVIVAL ACCORDING TO
PRIOR RITUXIMAB (INDUCTION ITT)
PROGRESSION-FREE SURVIVAL
ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
N=160
N=228
N=147
N=241
31%
64%
30%
62%
Failure from diagnosis =>= 12 months
EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT
Failure from diagnosis > 12 months
Standard salvage regimen does not overcome poor prognosis of early relapse
Failure from diagnosis =< 12 months
N= 106
N= 54
N= 41
N= 187
MULTIVARIATE ANALYSIS FOR SURVIVAL
p PFS EFS OS
Prior Rituximab 0.003 0.0007 0.01
Relapse < 12 months < 0.0001< 0.0001< 0.0001
sIPI > 1 < 0.0001< 0.0004< 0.0001
Treatment Arm 0.1 0.3
0.07Prior rituximab exposure will be the rule in future study Relapses after rituximab exposure are more severe.Early relapses and failure are the main adverse prognostic factors.
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
PROGRESSION-FREE SURVIVAL OF PATIENTS
SUBMITTED TO ASCT from date of 1st randomization
(INDUCTION ITT)
Progression-Free Survival of maintenance ITT population
from date of 2nd randomization
R
A
N
D
O
M
I
Z
E
PR/CR →
R x 6N = 102
ObsN = 95
Randomized in maintenance
N = 197
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
N=197 pts
58%
140 events are required to conclude.Nowadays:
85 events (43%) Final analysis of
maintenance arm 2010
R-ICE and R-DHAP have similar activity and mobilization ability with less adverse events for R ICE.
Prognostic factors affecting response and survival: relapse < 12 months, secondary IPI>1, prior
rituximab exposure
A new profile of relapses and refractory patients after rituximab will come out from this trial, and will help the design of future study with new drugs.
A bio CORAL program is on going to better understand this population of poor prognosis patients
CORAL CONCLUSION
POOR RESULTS : RESPONSE RATE 50% PFS 30%
GOOD RESULTS : RESPONSE RATE 80% PFS 60%
Many Thanks again
investigatorspathologists
GELA RC
M Fournier/N. Mounier statistics
C.Pitrou/ G Chartier project leaders
L. Gérard, Data management
and all the project managers in the different countries
Thank you for their continous support: Roche, Baxter, Chugai