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Rituximab in aggressive NHL: why combination therapy should not be delayed

Rituximab in aggressive NHL: why combination therapy should not be delayed. Bertrand Coiffier. Service d’Hématologie Hospices Civils de Lyon. Pathologie des Cellules Lymphoïdes EA 3737 – Université Claude Bernard. Groupe d’Étude des Lymphomes de l’Adulte.

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Rituximab in aggressive NHL: why combination therapy should not be delayed

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  1. Rituximab in aggressive NHL: why combination therapy should not be delayed Bertrand Coiffier Service d’Hématologie Hospices Civils de Lyon Pathologie des Cellules Lymphoïdes EA 3737 – Université Claude Bernard Groupe d’Étude des Lymphomes de l’Adulte

  2. The benefits of monoclonal antibodies • Combining rituximab and chemotherapy • increases CR rates • prolongs survival • Rituximab plus CHOP (R-CHOP) is the gold standard • No sufficient data for other antibodies CHOP = cyclophosphamide, doxorubicin, vincristine, predrisoneCR = complete response

  3. Major randomised studies R-CHOP as the standard

  4. LNH 98.5 study: design R A N D O M I S A T I ON R-CHOPevery 3 weeks x 8 • DLBCL • Age 60–80 years • No prior treatment • PS 0–2 • Stage II–IV CHOP every 3 weeks x 8 Rituximab: 375mg/m2 on day 1 Cyclophosphamide: 750mg/m2 on day 1 Doxorubicin: 50mg/m2 on day 1 Vincristine: 1.4mg/m2 (up to 2mg/m2) on day 1 Prednisolone: 40mg/m2/day days 1–5 DLBCL = diffuse large B-cell lymphomaPS = performance status Coiffier B, et al. N Engl J Med 2002;346:235

  5. CR PR No response LNH 98.5 study: treatment responses CHOP (n=197) R-CHOP (n=202) p=0.005 PR = partial response Coiffier B, et al. N Engl J Med 2002;346:235

  6. CHOP R-CHOP Median follow-up 7 years 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 EFS PFS CHOP R-CHOP CHOP R-CHOP Survival probability Survival probability p<0.0001 p<0.0001 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years DFS OS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 CHOP R-CHOP Survival probability Survival probability p=0.0001 p=0.0004 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years EFS = event-free survival; PFS = progression-free survival DFS = disease-free survival; OS = overall survival Coiffier B, et al. J Clin Oncol2007;25(Suppl. 18):443s (Abstract 8009)

  7. Results according to aaIPI PFS: low risk PFS: high risk 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 CHOP R-CHOP CHOP R-CHOP Survival probability Survival probability p=0.0051 p=0.0022 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years OS: low risk OS: high risk CHOP R-CHOP 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 CHOP R-CHOP Survival probability Survival probability p=0.0030 p=0.0213 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Years Years Coiffier B, et al. J Clin Oncol2007;25(Suppl. 18):443s (Abstract 8009) aaIPI = age adjusted International Prognostic Index

  8. R-CHOP: a consistent clinical benefit MInT study1 British Columbia2 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 R-chemotherapy Post-rituximab Survival Probability Chemotherapy Pre-rituximab p=0.000000007 p=0.0001 0 5 10 15 20 25 30 35 40 45 50 0 1 2 3 4 Months Years RiCOVER study4 ECOG study3 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 R-CHOP-14 Maintenance FFS TTF CHOP-14 Observation CHOP R-CHOP p=0.000025 0 5 10 15 20 25 30 35 40 45 0 1 2 3 4 5 Months Years MInT = MabThera International TrialECOG = Eastern Cooperative Oncology Group TTF = time-to-treatment failure FFS = failure-free survival 1Pfreundschuh M, et al. Lancet Oncol 2006;7:379–912Sehn LH, et al. J Clin Oncol 2005;23:5027–333Habermann T, et al. J Clin Oncol 2006;24:3121–74Pfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of print

  9. GELA R-CHOP study 1.0 0.8 0.6 0.4 0.2 0 R-CHOP Survival CHOP P=0.007 0 1 2 3 4 5 6 Years Feugier P, et al. J Clin Oncol 2005 23:4117–26

  10. Intergroup study of CHOP or R-CHOP  rituximab as maintenance therapy 1 2 3 4 5 6 7 8 No further treatment R PR CR R SD Rituximab four infusions every 6 months for 2 years Standard CHOP Rituximab 375mg/m2 Habermann T, et al. J Clin Oncol 2006;24:3121–7 SD = stable disease

  11. Induction therapy: TTF 1.0 0.8 0.6 0.4 0.2 0 R-CHOP ( rituximab maintenance) Probability CHOP ( maintenance) HR=0.78 p=0.04 0 1 2 3 4 5 Years from study entry Evaluable patients n=546 Habermann T, et al. J Clin Oncol 2006;24:3121–7

  12. ECOG 4494: effect of rituximab maintenance on FFS according to induction regimen CHOP induction R-CHOP induction 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Rituximab maintenance Observation Rituximab maintenance Probability Probability Observation p=0.81 p=0.0004 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Habermann T, et al. J Clin Oncol 2006;24:3121–7

  13. MInT: trial design 6 x CHOP-like + 30–40 Gy (Bulk, E) CD20+ DLBCL 18–60 years IPI 0, 1 stages II–IV, I with bulk Randomisation 6 x CHOP-like + rituximab + 30–40 Gy (Bulk, E) CHOP-21 (n=396) CHOEP-21 (n=362) MACOP-B (n=33) PMitCEBO (n=32) Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

  14. MInT study EFS PFS OS R-chemotherapy 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 R-chemotherapy R-chemotherapy Chemotherapy Chemotherapy Chemotherapy EFS (%) PFS (%) OS (%) Log-rank p<0.0001 Log-rank p<0.0001 Log-rank p=0.0001 0 12 24 36 48 60 0 12 24 36 48 60 0 12 24 36 48 60 Months Months Months N at risk R-chemotherapy 413 296 256 156 37 0 Chemotherapy 410 229 194 101 28 1 413 313 266 151 37 0 413 364 318 184 51 2 410 253 205 104 27 1 410 349 283 150 44 1 Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

  15. RiCOVER-60: trial design Only 80% with DLBCL 60% IPI 0–2 All patients received a pre-phase 6 x CHOP-14 + 36 Gy (Bulk, E) 8 x CHOP-14 + 36 Gy (Bulk, E) CD20+ DLBCL stages I–IV 61–80 years Random 2 x 2 factorial design 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x rituximab Eight doses of rituximab regardless ofnumber of cycles of chemotherapy Pfreundschuh M, et al. Blood 2006;108:64a (Abstract 205) Pfreundschuh M, et al. Lancet Oncol 2008. In press

  16. RiCOVER-60 OS EFS 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 8 x CHOP-14 + 8 x rituximab 6 x CHOP-14 + 8 x rituximab 6 x CHOP-14 + 8 x rituximab 8 x CHOP-14 + 8 x rituximab 8 x CHOP-14 Proportion Proportion 8 x CHOP-14 6 x CHOP-14 6 x CHOP-14 0 10 20 30 40 50 60 70 80 0 10 20 30 40 50 60 70 80 Months Months Pfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of print

  17. Questions Question 1: R-CHOP-21 or R-CHOP-14?

  18. R-CHOP-14 or -21? • No randomised study published • Tolerability is good but pre-phase and six cycles in German study • Other phases II seemed to find a poorer tolerability • Probability that R-CHOP-14 can be superior to R-CHOP-21 is low • Equivalent results if eight rituximab infusions

  19. LNH 03-6B: 66–80 years, aaIPI = 1,2,3(R Delarue, A Bosly) Abstract 2436 R-CHOP-21 0 3 6 9 12 15 18 21 Weeks Prophylactic darbepoietin alfa 4 IT MTX R Supportive care 0 2 4 6 8 10 12 14 Weeks R-CHOP-14 Primary endpoint: EFS Expected improvement: 10% at 3 years with R-CHOP-14 (55–65%)600 patients required (4 years)IT = intrathecalMTX =methotrexate Delarue R, et al.

  20. Questions Question 2: dose-dense/dose-intense regimens?

  21. ACVB plus sequential consolidation Induction Consolidation MTX IFM 1,500mg/m² VP16 300mg/m² Ara-C S.C. ACVB I II III IV Week 0 2 4 6 10 12 14 16 18 20 22 26 Response Response Doxorubicin 75mg/m² day 1 Cyclophosphamide 1,200mg/m² day 1 Vindesine 2mg/m² day 1, day 5 Bleomycin 10mg day 1, day 5 Prednisone 60mg/m² day 1–5 IT MTX 15mg day 2 G-CSF 5µg/kg day 6–13 MTX 3g/m² Ara-C 100mg/m²/day x 4 days ACVB = adriamycin, cyclophosphamide, vindesine, bleomycin G-CSF = granulocyte-colony stimulating factor; IFM = ifosfamide; MTX = methotrexate

  22. Survival with ACVB in LNH regimens 1.0 0.8 0.6 0.4 0.2 0 LNH-93 LNH-87 LNH-80 Survival probability LNH-84 0 5 10 15 20 Years NHL = non-Hodgkin’s lymphoma

  23. ACVBP regimen versus CHOP in advanced aggressive lymphoma ACVBP MTX IFM – VP16 Ara-C Week 0 3 6 9 13 15 17 19 21 23 25 27 R 0 3 6 9 12 15 18 21 Week CHOP DFS Survival 100 80 60 40 20 0 100 80 60 40 20 0 Survival (%) Survival (%) ACVBP ACVBP CHOP CHOP p=0.03 p=0.005 0 2 4 6 8 10 0 2 4 6 8 10 Years Year ACVBP = adviamycin, cyclophosphamide, viudesine, bleomycin, prednisone Tilly H, et al. Blood 2003;102:4284–9

  24. LNH 03-2B: <60 years, aaIPI = 1(C Recher, H Tilly) IFM – VP16 MTX ARA-C R-ACVBP-14 0 2 4 6 10 14 24 Weeks R 4 x IT MTX 0 3 6 9 12 15 18 21 Weeks R-CHOP-21 Primary endpoint = EFS Expected improvement: 10% at 2 years with R-ACVBP (75–85%) 380 patients required (in 4 years)

  25. Questions Question 3: high-dose therapy and autotransplant?

  26. Benefit of HDT with ASCT in first CR RANDOMISATION Sequential consolidation MTX/IFM – VP16/L-Aspa/Ara-C Induction phase ACVBfour cycles CR IPI 2–3: n=236 MTX/CBV + ABMT DFS Survival 100 80 60 40 20 0 100 80 60 40 20 0 Survival (%) Survival (%) p=0.04 p=0.02 0 24 48 72 96 120 144 0 24 48 72 96 120 144 Months Months ASCT = autologous stem cell transplantation; CBV = cytarabine, BCNU, etoposide; HDT = high-dose therapy

  27. Interim PET scanning as a prognostic tool in DLBCL Pretreatment Mid-treatment PET = positron emission tomography

  28. EFS according to PET status after two cycles PET negative (n=49) 2 years EFS = 80% 1.00 0.75 0.50 0.25 0 Probability PET positive (n=32) 2 years EFS = 46% p=0.0003 0 1 2 3 4 5 Years

  29. R LNH07-3B study: patients with aaIPI >2 and <61 years TEP 0 TEP C2 TEP C4 Sequential consolidation Negative Negative 2 x R-ACVBP-14 2 x R-ACVBP-14 Positive Z-BEAM Negative Salvage CORAL study if biopsy Positive Salvage CORAL study if biopsy Positive Positive Z-BEAM Negative 2 x R-CHOP14 2 x R-CHOP-14 Negative Negative 4 x R-CHOP-14 Z-BEAM = 90Y ibritumomab, BCNU, ara-c, etoposide, melphalan Athens, February 2007

  30. Questions Question 4: which ways to improve these results?

  31. Rituximab PK: trough serum levels 200 180 160 140 120 100 80 60 40 20 0 R-CHOP-14 Serum levels (mg/ml) 1 9 17 25 33 41 49 57 65 73 81 89 97 105 113 Day of treatment PK = pharmacokinetics Courtesy of Reiser M, Cologne

  32. PK model R-CHOP-14 versus R-CHOP-21 300 225 150 75 0 R-CHOP-14 R-CHOP-21 mg/mL 09.00 PK model based on median values of PK parameters for KELM, V1 (l/kgLBMc), K12, and K21 of 20 patients treated with R-CHOP-14 according to a two-compartment model. Model was then calculated for 21 days interval

  33. Rituximab schedules for DLBCL C H O P C H O P C H O P C H O P C H O P C H O P R-CHOP-14 (8 x R) 12 14 C H O P C H O P C H O P C H O P C H O P C H O P Dense-R-CHOP-14(12 x R) 12 14

  34. Rituximab PK: trough serum levels 200 180 160 140 120 100 80 60 40 20 0 Dense-R-CHOP-14 R-CHOP-14 Serum level (mg/mL) 1 9 17 25 33 41 49 57 65 73 81 89 97 105 113 Day of treatment

  35. Dense-R-CHOP-14 (n=47)versus R-CHOP-14 (n=306) 1.0 0.8 0.6 0.4 0.2 0 Percentage Dense-R-CHOP-14: IPI=1–2 Dense-R-CHOP-14: IPI=3–5 R-CHOP-14: IPI=1–2 R-CHOP-14: IPI=3-5 0 2 4 6 8 10 12 Months

  36. Potential applications of RIT in DLBCL • Is there a role for RIT rather than radiotherapy in localised disease? • Is there a role of RIT as ‘consolidation’ therapy to improve the quality of response? • What is the optimal way to incorporate RIT into R-CHOP regimens? RIT = radioimmunotherapy

  37. Can RIT improve the quality of response after R-CHOP in those failing to achieve CR? • Numerous mature phase II trials in follicular lymphoma showing improvements in quality of response (conversion from PR to CR 60–90%) • Single agent phase II data 90Y-ibritumomab demonstrating high response rate in chemotherapy refractory DLBCL • Emerging phase II data all confirm feasibility of integrating RIT with R-chemotherapy in DLBCL • RIT toxicity mainly haematological, predictable and manageable, otherwise non-overlapping

  38. Studies combining chemotherapy and RIT for untreated DLBCL IFXRT = involved-field external radiation therapy; MSKCC = Memorial Sloan-Kettering Cancer Center; SWOG = Southwest Oncology Group

  39. New molecules? • New monoclonal antibodies • same antigen • different antigens: CD19, CD22, CD80 • conjugated, toxine, isotope • bispecific antibodies • Bortezomib, revlimid • Bevacizumab • SAHA, HDACi

  40. Questions Question 5: at time of relapse

  41. Relapse/refractory/PR • Relapse: PD after CR • PR: response but incomplete • presence of persisting lymphoma cells • tumour fixing with PET scan • Refractory: PD during treatment or just after the end of treatment Highly different outcome PD = progressive disease

  42. Management of aggressive NHL Induction chemotherapy Responsive Primary refractory Relapse Second-line therapy Second-line therapy NR CR/PR CR/PR NR HDT with ASCT NR = no response

  43. Second-line therapy for aggressive NHL • Ideal second-line therapy • provides effective cytoreduction to achieve an optimal response • results in minimal non-haematological toxicity • is not stem-cell toxic • effectively mobilises stem cells into the peripheral blood

  44. Rituximab significantly improves outcomes when combined with HDT and ASCT Historical comparison 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 Rituximab (n=67) Rituximab (n=67) OS DFS No rituximab (n=30) No rituximab (n=30) p=0.004 p=0.002 0 3 6 9 12 15 18 21 27 42 30 0 3 6 9 12 15 18 21 27 42 30 Months post-transplant Months post-transplant Khouri IF, et al. J Clin Oncol 2005;23:2240–7

  45. CORAL study: R-ICE versus R-DHAP followed by ASCT ± maintenance R1 400 patients needed Recruitment complete R-DHAP R-ICE R-DHAP R-ICE OFF Clinical evaluation R-DHAP R-ICE PD/SD Clinicalevaluation Rituximab 375mg/m² every 8 weeks for 12 months PBPC CR/PR BEAM ASCT R2 *With lenograstim 150µg/m²R-ICE = rituximab, ifosfamide, carboplatin, etoposideR-DHAP = rituximab, dexamethasone, ara-c, cisplatinPBPC = peripheral blood progenitor cell Observation Hagberg H, et al. Ann Oncol 2006;17(Suppl. 4):iv31–iv32

  46. CORAL toxicity

  47. CORAL efficacy Cru = unconfirmed CRORR = overall response rateMARR = mobilization adjusted response rate

  48. Response rate prognostic factors CR/CRu/PR: logistic model

  49. Efficacy analysis: secondary criteriaEFS – ITT 1.0 0.8 0.6 0.4 0.2 0 Survival probability Arm A/R-ICEArm B/R-DHAP Log-rank p=0.4589 0 10 20 30 40 EFS (months) No. of subjects Event Censored Median survival (95% CI) Arm A/R-ICE 100 49% (49) 51% (51) 20.96 (9.26 NYR)Arm B/R-DHAP 94 44% (41) 56% (53) NA (8.51 NYR) NYR = not yet reached; CI = confidence interval; ITT = intent to treat GELA data on file

  50. Prognostic factors failure EFS 1.0 0.8 0.6 0.4 0.2 0 Survival probability <12 months12 months Log-rank p<0.0001 0 10 20 30 40 EFS (months) No. of subjects Event Censored Median survival (95% CI) <12 months 108 60% (65) 40% (51) 5.45 (3.61 10.15)12 months 86 29% (25) 71% (53) NA (27.47 NA) GELA data on file

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