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CORAL : CO llaborative trial in R elapsed A ggressive L ymphoma

CORAL : CO llaborative trial in R elapsed A ggressive L ymphoma. 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,

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CORAL : CO llaborative trial in R elapsed A ggressive L ymphoma

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  1. CORAL:COllaborative trial in Relapsed AggressiveLymphoma 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.

  2. 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?

  3. CORAL Trial of RICE v DHAP AB SE CA TM • Which salvage regimen is the best? R A N D O M I Z E SD/POD → Off R-ICE x 3 → CD20+ DLBCL Relapsed/Refractory R A N D O M I Z E R x 6 PR/CR → R-DHAP x 3 Obs • Place of immunotherapy post transplantation? N=400 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  4. 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

  5. CORAL Study Primary 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

  6. Patient distribution CORAL Study Germany 113 Australasia 60 France 128 Cesz Republic 36 Belgium 31 Israel 13 US 9 Sweden 13 Switzerland 24 Ireland 4 481 patients 30/6/2008 UK 50 Thank you to all investigators and pathologists Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  7. 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, group ii) Prior treatment with Rituximab during first line iii) Relapse < 12months and Refractory (non achieving CR 1st line treatment) Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  8. 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

  9. WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORAL RESPONSE AT 1ST LINE Tt Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  10. 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 0-1 119 107 S-AaIPI 2-3 75 74 <12 months 89 87 12 months 112 103 P=0.09 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  11. RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR ALL PATIENTS (Intent To Treat) 63 .5 % 62.8 % Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  12. 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%) Platelets Transfusions % pts 35% 57% Toxic deaths 1 3 On induction safety population, in R-ICE arm 90 SAEs and in the R-DHAP arm 120 SAEsduring the whole study, concerning respectively 58 patients (29%) and 69 patients (36%).

  13. 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% <0.0001 Refractory < 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

  14. 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

  15. 56% OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) 56% PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) 45% 42% Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  16. 64% PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) N=160 N=228 31% 62% N=147 PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) N=241 30% Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  17. Failure from diagnosis =>= 12 months Failure from diagnosis > 12 months N= 106 N= 54 N= 41 Failure from diagnosis =< 12 months Standard salvage regimen does not overcome poor prognosis of early relapse N= 187

  18. MULTIVARIATE ANALYSIS FOR SURVIVAL p PFS EFS OS Prior Rituximab 0.0030.0007 0.01 Relapse < 12 months <0.0001 < 0.0001 < 0.0001 sIPI > 1 < 0.0001 < 0.0004 < 0.0001 Treatment Arm 0.10.3 0.07 Prior 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

  19. 140 events are required to conclude. Nowadays: 85 events (43%) Final analysis of maintenance arm 2010 PROGRESSION-FREE SURVIVAL OF PATIENTS SUBMITTED TO ASCT from date of 1st randomization (INDUCTION ITT) R A N D O M I Z E R x 6 N = 102 Randomized in maintenance N = 197 PR/CR → Obs N = 95 58% Progression-Free Survival of maintenance ITT population from date of 2nd randomization N=197 pts Orlando ASCO May 2009 / Coral study C. Gisselbrecht

  20. 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%

  21. Many Thanks againinvestigatorspathologists 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

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