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Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival?. Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK. Trial 1: R-CVP versus CVP study design. R A N D O M I S E. Follicular NHL (IWF B, C, D)

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Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

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  1. First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival? Robert MarcusDepartment of Haematology, Addenbrooke’s Hospital, Cambridge, UK

  2. Trial 1: R-CVP versus CVP study design R A N D O M I S E • Follicular NHL (IWF B, C, D) • Stage III−IV •  18 years • No prior Rx • Measurable disease • Central histology review R E S T A G E R-CVP x 4 cycles (q3wk) R-CVP x 4 cycles (q3wk) CR, PR CVP x 4 cycles (q3wk) CVP x 4 cycles (q3wk) SD PD off study Rituximab 375 mg/m2 iv day 1 Cyclophosphamide 750 mg/m2 iv day 1 Vincristine 1.4 mg/m2 iv day 1 Prednisolone 40 mg/m2 po days 1–5 Marcus R, et al. Blood 2005; 105:1417–1423.

  3. Participating sites

  4. Patient characteristics Central review of pathology performed on 90% of patientsFL diagnosis confirmed in 95% of patients Marcus R, et al. Blood 2005; 105:1417–1423.

  5. Response rates* * Response up to 42 days after completion of treatment Marcus R, et al. Blood 2005; 105:1417–1423.

  6. Conclusions • Rituximab plus CVP improved: • Overall and complete response rates • TTP, TTNLT, DFS • Overall survival • Addition of rituximab did not substantially increase regimen toxicity • 8 cycles of R-CVP should be considered as standard treatment for previously untreated FL

  7. CR, PR 6–8 cycles x CHOP plus rituximab CR, PR 6–8 cycles x CHOP Trial 2: R-CHOP versus CHOP study design Patients < 60 years (< 65 years) R A N D O M I S A T I O N R A N D O M I S A T I O N PBSCT Standard IFN-maintenance Patients > 60 years (> 65 years) Intensive IFN-maintenance Standard IFN-maintenance Hiddemann W, et al. Blood 2005; 106:3725–3732.

  8. TTF is significantly improved with rituximab-based induction therapy Patients aged > 60 years 1.0 0.8 R-CHOP (78/112) Median 5 years 0.6 Probability 0.4 CHOP (37/109) Median 2.1 years 0.2 p < 0.0001 0.0 0 1 2 3 4 5 6 Years Buske C, et al.Blood 2006; 108:Abstract 482.

  9. Patients aged > 60 years Overall survival is significantly improved with rituximab-based induction therapy 1.0 R-CHOP (102/112) 0.8 CHOP (89/109) 0.6 Probability 4-year OS R-CHOP: 90% CHOP: 81% 0.4 0.2 p = 0.039 0.0 0 1 2 3 4 5 6 Years Buske C, et al.Blood 2006; 108:Abstract 482.

  10. Survival is significantly improved with R-CHOP in all FLIPI subgroups R-CHOP CHOP 1.0 1.0 Median NR 0.8 0.8 Median 4.1 years Median NR 0.6 0.6 Survival probability Survival probability Median 3.0 years Median 4.0 years 0.4 0.4 0.2 0.2 Median 2.0 years 0 0 0 1 2 3 4 5 6 0 1 2 3 4 5 6 Time (years) Time (years) FLIPI 0–1: Low risk p = 0.0091FLIPI 2: Intermediate prognosis p < 0.0001FLIPI 3–5: Poor prognosis p = 0.0001 Buske C, et al.Blood 2006; 108:Abstract 482 and unpublished data.

  11. Trial 3: R-MCP versus MCP study design R ESTAGING R A N D O M I S E D R-MCP6 cycles(q4wk) R-MCP2 cycles(q4wk) • Advanced FL, IC and MCL • 18–75 years • No prior rituximab • Central histology review • Written informed consent CR, PR MCP6 cycles(q4wk) MCP2 cycles(q4wk) IFN-maintenance for FL SD PD off study • Rituximab 375mg/m2iv d 1 • Mitoxantrone 8 mg/m² iv d 3and 4 • Chlorambucil 3 x 3mg/m² po d 3–7 • Prednisolone 25 mg/m² po d 3–7 Herold M, et al.J Clin Oncol 2007; April 9 (Epub).

  12. Rituximab-based induction therapy significantly improves survival in patients with FL ITT population: Median follow-up 47 months 1.00 R-MCP: Median NR 0.75 MCP: Median NR Survival distribution function 0.50 4-year OS R-MCP: 87% MCP: 74% 0.25 p = 0.0096 0 60 0 10 20 30 40 50 Time (months) Herold M, et al.J Clin Oncol 2007; April 9 (Epub).

  13. PFS is significantly improved with R-MCP in all FLIPI subgroups R-MCP MCP Median NR4-year PFS: 82% 1.0 1.0 Median 36 months 4-year PFS: 43% 0.8 0.8 Median NR 4-year PFS: 61% 0.6 0.6 Survival probability Survival probability 0.4 0.4 Median 26.5 months4-year PFS: 36% 0.2 0.2 0 0 0 10 20 30 40 50 60 0 10 20 30 40 50 60 Time (months) Time (months) FLIPI 2: Intermediate prognosis p = 0.0016 FLIPI 3–5: Poor prognosis p = 0.0011 Herold M, et al.J Clin Oncol 2007; April 9 (Epub) and unpublished data.

  14. αIFN 2b, 4.5 MU tiw for 18 months (3 MU if aged  70 yr) Trial 4: R-CHVP-IFN vs CHVP-IFN study design Arm A 6 months 12 months R Staging including CT-scan and bone marrow biopsy Arm B d1 Cyclophosphamide 600 mg/m2 d1 Doxorubicin 25 mg/m2 d1 Etoposide 100 mg/m2 d1–5 Prednisolone 40 mg/m2 Rituximab: 375 mg/m2 every month for 6 months (arm A & B) then every 2 months in arm A Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

  15. EFS and OS are significantly increased with rituximab-based therapy 100 100 R-CHVP + IFN-(Arm B) R-CHVP + IFN-(Arm B) 91% Event-free survival Ovarall survival 75 75 CHVP + IFN- (Arm A) 84% 67% 50 50 46% CHVP + IFN- (Arm A) 25 25 p < 0.0001 p = 0.029 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Months Months Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

  16. First-line rituximab-based induction therapy improves overall survival 1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 7508. 2. Herold M, et al.J Clin Oncol 2007; April 9 (Epub). 3. Hiddemann W, et al. Blood 2005; 106:3725–3732.4. Marcus R, et al. Blood 2006; 108:Abstract 481.

  17. Rituximab-based induction therapy: Conclusions • R-Chemo yields superior results to chemotherapy in four prospective randomised trials • The FLIPI predicts outcome in all studies • Prognosis was worse with a high FLIPI score • Majority of patients with poor prognosis will relapse within 4–5 years • There does not seem to be a TTP/PFS ‘plateau’ of any subgroup in any trial yet

  18. Overall survival improvement with rituximab in FL 1.0 GLSG study NHL 2000 0.8 0.6 GLSG study NHL 1996 Survival probability 0.4 0.2 p < 0.0001 0.0 0 12 24 36 48 60 72 84 96 108 120 Time (months) Number of patients at risk: NHL 1996 538 485 457 419 386 332 242 125 46 0 NHL 2000 794 621 440 250 108 8 0 Hiddemann W, et al. Blood 2006; 108:Abstract 483.

  19. Rituximab maintenance after CVP in untreated indolent NHL: ECOG 1496 study design • Phase III trial of CVP ± rituximab maintenance • 401 patients with previously untreated indolent NHL, 322 randomised R A N D O M I S E D • Rituximab maintenance • 375 mg/m2 q1wk  4 • q6mo  4 CVP 6–8 cycles PR, CR or SD Observation

  20. Rituximab maintenance therapy significantly prolongs PFS in FL Median PFS from randomisation: 15 mo vs 61 mo 1.0 0.8 Rituximab maintenance (n = 120) 0.6 Probability 0.4 0.2 Observation (n = 117) p = 0.0000003 0.0 0 1 2 3 4 5 6 Years from maintenance randomisation Hochster H, et al. Blood 2005; 106:Abstract 349.

  21. Rituximab monotherapy induction and maintenance in first-line treatment of FL * 375 mg/m2 rituximab once weekly x 4† Follicular lymphoma patients onlyFU = follow-up 1. Hainsworth JD, et al. Blood 2003; 102:Abstract 1496. 2. Ghielmini M, et al. Blood 2004; 103:4416–4423.

  22. SAKK 35/03 study: Efficacy of extended rituximab maintenance therapy in FL Short maintenance Rituximab maintenance q2mo x 4 R Rituximab375 mg/m² weekly x 4 PR, CR Rituximab maintenance q2mo until relapse (maximum 5 years) PD, SD off study Long maintenance

  23. PRIMA study: Efficacy of rituximab-based induction and maintenance in first-line indolent NHL Rituximab maintenance therapy 1 x q8wk for 24 months R A N D O M I SE 8 x rituximab + 8 x CVP or 6 x CHOP or 6 x FCM Indolent NHL stages III–IV, untreated CR, PR Observation SD PD off study

  24. RiCHOP trial: Efficacy of ASCT followed by rituximab maintenance in indolent NHL HDTASCT R A N D O M I SE Rituximab maintenance1 x q8wk for 24 months CR, PR R-CHOP x 6 + R x 2 SD PD off study N > 600 patients with indolent FL (< 65 years old). Study start 2007

  25. A note of caution! Incidence of hepatitis B reactivation with rituximab • Out of 456 patients, 32 were Hep B positive • 14 received rituximab monotherapy • 18 received rituximab plus chemotherapy A total of 5 patients developed liver failure (15%) Hanbali A, et al. Blood 2006; 108:Abstract 2766.

  26. But…prophylactic lamivudine can reduce the incidence of hepatitis during chemotherapy • Non-randomised comparison of lymphoma patients treated with prophylactic lamivudine during chemotherapy with historical controls • 100 mg was administered daily for up to 64 weeks Lamivudine prophylaxis reduced the incidence of hepatitis Li Y, et al. Cancer 2006; 106:1320–1325.

  27. Outstanding questions in first-line therapy for FL • Do more intensive therapies yield superior results than R-CVP? • If so do ALL patients require such therapy, or only poor prognosis patients? • Which component provides superior results? • Anthracycline, interferon or both? • Does maintenance have a role in first-line FL? • PRIMA trial to provide evidence • Do PBSCT or other approaches have a role in first-line therapy?

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