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Relapse in Diffuse Large B-cell Lymphoma Treatments

Relapse in Diffuse Large B-cell Lymphoma Treatments. Corinne HAIOUN Unité Hémopathies Lymphoïdes- CHU Henri Mondor Université Paris Est Créteil Sousse, May 2012. On February 10th, the merging of the GELA and the Goelams lymphoma groups resulted in the birth of the new group Lysa .

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Relapse in Diffuse Large B-cell Lymphoma Treatments

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  1. Relapse in Diffuse Large B-cell LymphomaTreatments Corinne HAIOUN Unité Hémopathies Lymphoïdes- CHU Henri Mondor Université Paris Est Créteil Sousse, May 2012 On February 10th, the merging of the GELA and the Goelams lymphoma groups resulted in the birth of the new group Lysa. Lysa, The Lymphoma Study Association

  2. Rituximab effect • Major breakthrough with the combination of rituximab with chemotherapy • R-CHOP became the standard for the majority of patients • But some patients continue to not respond to or relapse after R-CHOP

  3. CD20+ DLBCL 18–60 years IPI 0,1 Stages II–IV, I with bulk (n = 823) How many patients will relapse? MInT trial low risk Relapse rate 10-20% Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

  4. GELA trials In DLBCL with ASCT < 60 yrs, 2–3 aaIPI factors How many patients will relapse? POOR RISK PATIENTS ACVBP Rituximab HD-MTX 13 LNH98-3B R CBVM 0 2 4 6 Wk Relapse rate 20-30% Observation PBSCT R-ACVBP HD-MTX 13 LNH03-3B BEAM Wk 0 2 4 6 First introduction of rituximab PBSCT

  5. R-CHOP studies > 60y : How many patients will relapse? Relapse rate 40-60% High-risk patients Low-risk patients High-risk patients Low-risk patients Coiffier B, et al. ASCO 2007.

  6. Median follow-up 7 y PFS EFS OS DFS

  7. Registry data also show these improvements BCCA registry1 Czech Republic registry2 1.0 1.0 R-Chemo (n = 120)3-year OS: 88.7% 0.8 0.8 Post-rituximab 0.6 0.6 Chemo (n = 256)3-year OS: 73.2% Probability 0.4 0.4 Pre-rituximab 0.2 0.2 N = 292 p < 0.0001 p = 0.0007 0 0 1 0 12 24 36 48 60 72 84 96 0 2 4 5 6 7 3 Time (years) Time (months) 1. Updated from: J Clin Oncol 2005; 23:5027–5033.2. Blood 2005; 106:Abstract 2444.

  8. LNH-87 LNH-93 LNH-98 LNH-03 Young, aaIPI=0 (F Reyes) CHOP+RT vs. ACVBP Young aaIPI=1 (P Morel) Stratification on bcl-2 protein expression ACVBP + seq. consol. or HDT Young, aaIPI>1 (C Gisselbrecht) ACVBP vs. early HDT Elderly, IPI=0 (G Fillet) CHOP vs. CHOP + RT Elderly, IPI>0 (H Tilly) CHOP vs. ACVBP GELA randomized studies

  9. Four generations of GELA studies Total ACVBP Other arms LNH-87 3114 1381 1733 LNH-93 3830 1268 2562 LNH-98 1377 585 792 LNH-03 592 297 295 All 8913 3531 5382

  10. Overall Survival: All patients 7400 patients, 18-80 years old Coiffier B et al. EHA 2009

  11. Studies with/without rituximab With rituximab Without rituximab Coiffier B et al. EHA 2009

  12. Studies with/without rituximab With rituximab Without rituximab Percentage of patients in each groups Without / With rituximab No relapse 50 61 Late relapse 13 13 PR 8 10 Early relapse 11 8 No response 18 8 Coiffier B et al. EHA 2009

  13. PFS and OS of 87/93/98 studies 7400 patients 18-80 years old 8-9% 7 years: PFS = 47.5% [46-49%]; OS = 56% [54-57%] Coiffier B et al. EHA 2009

  14. Parma study: event-free survival (Updated from JY Blay et al., Blood 1998) 100 80 60 40 20 0 Chemo-sensitive responders:ORR 58%, CR 25% ABMT (n=55) Event-free survival (%) DHAP (n=54) p=0.002 0 15 30 45 60 75 90 months from inclusion

  15. Relapsed aggressive lymphoma (DLBCL)Patients candidates to HDT/ASCT (<60-65y) Accepted strategy • Short salvage chemotherapy • Evaluation of response • HDT/ASCT Questions • 1.- Which optimal salvage chemotherapy regimen? • 2.- Will rituximab combined with salvage chemotherapy be effective if previously used first-line? • 3.- Is rituximab useful as maintenance therapy after HDT/ASCT?

  16. AB SE CA TM CORAL Trial of RICE v DHAP • 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 Gisselbrecht C. J Clin Oncol 2010

  17. 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 Gisselbrecht C et al. JCO 2010;28:4184-4190

  18. PATIENTS ENROLLED IN CORAL STUDY ACCORDING TO RESPONSE TO FIRST LINE TREATMENT Gisselbrecht C et al. asco 2011

  19. PATIENTS CHARACTERISTICS R-ICE (243) R-DHAP (234) Median age 54 y 55 y Sex M 156 147 F 87 87 Stage I-II 93 89 Stage III-IV 149 143 ENS > 1 67 78 LDH > Nl 126 117 S-AaIPI 0-1 142 139 S-AaIPI 2-3 93 88 <12 months 107 106 12 months 133 122 Gisselbrecht C et al. asco 2011

  20. RESPONSE TO INDUCTIVE SALVAGE TREATMENTS 63 .6 % 64.3 % Gisselbrecht C et al. asco 2011

  21. CONSOLIDATION with BEAM • Main Reasons for premature withdrawals: • Progressive lymphoma: 53% • Toxicity: 7% • Collection failure: 7-11% (CD 34/kg < 2.106) • Deaths: 4% Gisselbrecht C et al. asco 2011

  22. EFS and OS by induction treatment 1.0 1.0 R-ICE R-ICE R-DHAP R-DHAP 0.8 0.8 0.6 0.6 Survival probability Survival probability 0.4 0.4 0.2 0.2 p = 0.2672 p = 0.3380 0.0 0.0 0 0 12 12 24 24 36 36 48 48 60 60 72 72 EFS (months) OS (months) 481 patients first randomised from 24 July 2003 to 30 June 2008 245 patients randomised in the second part from 21 October 2003 to 21 October 2008 EFS (induction ITT) OS (induction ITT)

  23. 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%

  24. 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

  25. CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS 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%

  26. TAKE HOME MESSAGESbased on CORAL study • A new profile of relapses and refractory patients after rituximab is seen • Prognostic factors affecting response and survival are: • relapse < 12 months • secondary IPI>1 • prior rituximab exposure • When rituximab has been used during first-line therapy: optimal salvage combination remains to be determined? New drugs mandatory

  27. AB SE CA TM CORAL Trial of RICE v DHAP • 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 Gisselbrecht C. J Clin Oncol 2010

  28. CORAL maintenance: PFS/OS by treatment arm 1.0 1.0 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.0 0.2 0 12 24 36 48 60 72 0.0 0 12 24 36 48 60 72 PFS OS Observation Observation Rituximab Rituximab Survival probability Survival probability p = 0.8314 p = 0.7547 PFS (months) Overall survival (months)

  29. CORAL: Prognostic factors for maintenance post-ASCT – multivariate Cox Model

  30. CORAL maintenance: OS by gender 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 Female Male Survival probability p = 0.0066 OS (months) Gisselbrecht C, et al..

  31. Patients randomized N = 400 MATERIAL : Paraffin blocks Patients analyzed N = 249 (63%) Diagnosis Relapse = CORAL Primary Biopsy N = 189 (47%) Relapse Biopsy N = 147 (37%) Matched pairs N = 87 (22%)

  32. + + _ _ Subclassification of de novo DLBCL (Hans CP et al. Blood. 2004) GCB _ GCB MUM1 CD10 + non-GCB bcl6 5-Year OS non-GCB GCB non-GCB 76% 34%

  33. Progression Free Survival GC Non GC Hans algorithm R-DHAP R-ICE R-ICE (n=61) R-DHAP (n=54). 52% 31% 32% 27% R-ICE (n=56) R-DHAP (n=61) 3 years 3 years p = 0.04 p = NS Thieblemont C et al JCO 2011

  34. C-MYC probe, split-signal Pattern YY YGR

  35. MYC+ DLBCL treated in CORAL study Cuccuini W. et al., Blood 2012

  36. MYC- n=133 MYC+ n=28 MYC+ DLBCL is associated with a poor prognosis PROGRESSION FREE SURVIVAL OVERALL SURVIVAL 62% 42% 29% 18% 4 years 4 years p = 0.0113 p = 0.0322 Cuccuini W. et al Blood 2012

  37. MYC- MYC+ MYC+ DLBCL : No impact of treatment arm OVERALL SURVIVAL R-DHAP R-ICE 26% 31% 3 years 3 years p = .0324 p = .1832 Cuccuini W. et al Blood 2012

  38. TAKE HOME MESSAGES Molecular characteristics are “similar” at diagnosis and relapse. Differential efficacy of non-based anthracycline chemotherapy within molecular subtypes of DLBCL MYC rearrangement is associated with a bad prognosis, independently from the type or treatment or other biological prognostic classification Importance of realizing molecular characterization in DLBCL for a rational development of treatment. Clinical prognostic factors remain very important

  39. Elderly patients (>65y), not eligible for HDT • No standard of care • R- GemOx, R GDP, ESHAP, VIM, Ifosfamide-etoposide…

  40. R - GemOx Protocol • 8 CYCLES DELIVERED EVERY 2 WEEKS • No dose adjustment for hematological toxicity. • Next cycle delayed until recovery ( A N C > 1 x 109 / L and platelets > 100 x 109 / L ). • In case of neurotoxicity, dose reduction was planned for oxaliplatin only. Haioun C et al. ASCO 2010

  41. R - GemOx Study : Study design Consolidation Follow-up 0 Induction C1 C2 C3 C4 C5 C6 C7 C8 E R-GEMOX R-GEMOX R-GEMOX R-GEMOX R-GEMOX R-GEMOX R-GEMOX R-GEMOX W8 W10 W12 W14 W16 W0 W2 W4 W6 Evaluation of response: if CR, CRu or PR, start consolidation Response to treatment E = Enrollment W = Week C = Cycle

  42. Patient Characteristics ( n = 49 )

  43. Response after induction TX (4 cycles) 60.4 % CI : [ 45.3% - 74.2% ]

  44. Response at the end of TX 45.8 % CI : [ 31.4% - 60.8% ]

  45. Progression - Free Survival 1 0.8 Median follow-up: 41 months 0.6 Survivalprobability 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Months

  46. PFS according to delay from last Treatment (< or > 1 year ) 1 0.8 Time last treatment / C1 < 1 year Time last treatment / C1 > 1 year 0.6 p = 0.0166 Survivalprobability 0.4 0.2 0 0 6 12 18 24 30 36 42 48 54 60 Months

  47. PFS according to delay from last TX ( < or > 1 year ) and previous rituximab TX 1 Previous rituximab : No & Time last treatment / C1 < 1 year Previous rituximab : No & Time last treatment / C1 > 1 year Previous rituximab : Yes & Time last treatment / C1 > 1 year Previous rituximab : Yes & Time last treatment / C1 < 1 year 0.8 0.6 Survivalprobability 0.4 0.2 p < 0.0001 0 0 6 12 18 24 30 36 42 48 54 60 Months

  48. TAKE HOME MESSAGES This prospective multicenter trial suggest that R - GemOx regimen is a safe outpatient salvage regimen. The response rate of 60%, after 4 cycles, observed across a wide age range of patients appears similar to the response rate obtained with other salvage regimens (RICE, R-DHAP…) and appears less toxic. The familiarity of practicing oncologists with the GemOx combination for other malignancies will allow it to be largely applied to lymphoma.

  49. A new profile of patients relapsing less than one year after the end of last treatment and previously treated xith rituximab come out from this trial (median PFS: 2 months), and will help the design of future studies with new drugs • This regimen could be considered as a platform for new combinations

  50. Targeted Therapy for Cancer Younes A. (2010) Beyond chemotherapy: new agents for targeted treatment of lymphoma.Nat Rev Clin Oncol. doi:10.1038/nrclinonc.2010.189.

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