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MabThera ® for Chronic Lymphocytic Leukemia (CLL)

MabThera ® for Chronic Lymphocytic Leukemia (CLL). Chronic Lymphocytic Leukemia. Staging CLL Characteristics Therapy Options MabThera in combination with chemotherapy for CLL MabThera monotherapy for CLL. Stage Criteria 0 I II III IV Lymphocytosis (>15,000/mm 3 )     

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MabThera ® for Chronic Lymphocytic Leukemia (CLL)

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  1. MabThera® forChronic Lymphocytic Leukemia (CLL)

  2. Chronic Lymphocytic Leukemia • Staging • CLL Characteristics • Therapy Options • MabThera in combination with chemotherapy for CLL • MabThera monotherapy for CLL

  3. Stage Criteria 0 I II III IV Lymphocytosis (>15,000/mm3) Lymphadenopathy  Splenomegaly  Hepatomegaly  Anemia (hemoglobin <11 g/dL) Thrombocytopenia (<100,000/mm3) Rai Staging of Chronic Lymphocytic Leukemia  +  +/-

  4. CLL Characteristics B-cell lineage 95% Immunophenotype CD5+ CD19+ CD20+ CD23+ CD52+ Cytogenetic abnormalities Deletions at 13q14 Trisomy 12

  5. Therapeutic Options for CLL • Chemotherapy • Single-agent: chlorambucil, fludarabine® • Combination: FC, CVP • MoAbs • MabThera® • Campath-1H® • SCT • Allogeneic • Mini-allogeneic • Autologous • Radiation (localized)

  6. MabThera in combination with chemotherapy for CLL

  7. MabThera + fludarabine for previously untreated CLL Byrd et al Blood 2003

  8. MabThera + fludarabine for previously untreated CLL: protocol Fludarabine 25mg/m2 MabThera 375mg/m2 Concurrent R A N D O M I S E D Consolidation therapy Patients with CR, PR, or stable disease received MabThera (375mg/m2 weekly x 4) 1 5 9 13 17 21 (2 months) Weeks Sequential 1 5 9 13 17 21 Weeks Byrd JC, et al. Blood 2003;101:6–14

  9. MabThera + fludarabinefor previously untreated CLL: patient characteristics Byrd JC, et al. Blood 2003;101:6–14

  10. MabThera + fludarabinefor previously untreated CLL: response Byrd JC, et al. Blood 2003;101:6–14

  11. MabThera + fludarabine in previously untreated CLL: progression-free survival 100 80 60 40 20 0 Sequential arm Percentageprogression-free survival Concurrent arm 0 10 20 30 40 50 Months Byrd JC, et al. Blood 2003;101:6–14

  12. Sequential arm 100 80 60 40 20 0 Concurrent arm Percentage overall survival 0 10 20 30 40 50 Months MabThera + fludarabine in previously untreated CLL: overall survival Byrd JC, et al. Blood 2003;101:6–14

  13. MabThera + fludarabinefor previously untreated CLL: grade 3/4 adverse events • Consolidation therapy well tolerated in both treatment arms Byrd JC, et al. Blood 2003;101:6–14

  14. MabThera + fludarabine for previously untreated CLL: comparison with fludarabine only Similar patient eligibility criteria * Combined sequential/concurrent arms Byrd JC, et al. Blood 2003;102:73a (Abstract 245)

  15. MabThera + fludarabinefor previously untreated CLL: summary • Higher ORR and CR rate in the concurrent arm (90% and 47%, respectively) than in the sequential arm (77% and 28%, respectively) • Response rates increased after consolidation therapy with MabThera • MabThera consolidation therapy well tolerated • There is a significant advantage for treatment with MabThera + fludarabine compared with fludarabine alone Byrd JC, et al. Blood 2003;101:6–14; Byrd JC, et al. Blood 2003;102:73a (Abstract 245)

  16. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL Wierda et al Ann Oncol 2003

  17. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Protocol Start cycle 2 Cycle 1 MabThera® 375 mg/m2 (cycle 1) or 500 mg/m2(cycles 2–6) 1 2 3 4 8 15 22 29 Days Fludarabine 25 mg/m2 Cyclophosphamide 250 mg/m2 Cycle repeats Cycles 2–6 1 2 3 8 15 22 29 Days Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  18. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Patient Characteristics No. of patients135 Age (y)Median57(range) (24–86) SexMale 67%Female 33% Rai stage0–II 63% III–IV 37% Median b2-microglobulin (mg/dl)3.9 Median WBC (x103/µl)9.2 Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  19. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Response % of Patients(n=135) ORR 95 CR 63 PR 17 Nodular PR 15 No response 4 Early death 1 Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  20. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Response % of Patients MabThera® + FC Fludarabine* FC* (n=135)(n=82)(n=53) ORR 95 85 91 CR 63 35 43 PR 32 50 48 * Historical controls Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  21. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Molecular Response % PCR-negative CR (n=55) 56 PR (n=10) 60 Nodular PR (n=8) 38 Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  22. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Tolerability % of Cycles (n=721) Hematologic (grade 3/4) Neutropenia 60 Thrombocytopenia 7 Non-hematologic (all grades) Nausea 20 Vomiting 6 Infections 14 Tumor lysis 1 Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

  23. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Summary • ORR and CR rate of 95% and 63%, respectively • CRs substantially higher after six versus three courses • MabThera® does not increase apparent toxicity of FC Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008. Keating et al. Blood. 2000;96(suppl 1):514a. Abstract 2214.

  24. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL Wierda et al Blood 2003

  25. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: treatment protocol Allopurinol 300mg/day Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  26. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: response (72) Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  27. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: survival by response 1.0 0.8 0.6 0.4 0.2 0 CR (median not reached) Nodular PR (median not reached) PR (median 41+ months) Proportion surviving No response (median 18 months) Early death (median 2 months) 0 1 2 3 4 Years Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  28. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: response by treatment regimen 59 67 72 * Historical controls Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  29. Patients Died Protocol Median (months) 251 241 F ± P* 19 111 83 FC* 29 143 55 FC + MabThera 42+ 1.0 0.8 0.6 0.4 0.2 0 p<0.01 p<0.04 Proportion surviving 0 1 2 3 4 5 6 7 8 9 10 11 12 Years * Historical controls Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: overall survival by treatment regimen Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  30. Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: conclusions • FC plus MabThera is well tolerated and produces the highest CR rate in previously treated patients to date • Improved survival with FC plus MabThera compared with historical F ± P and FC treated patients Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  31. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL Garcia-Manero et al Blood 2001

  32. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Eligibility Criteria • Performance status 3 • Rai stage I–II with active disease (e.g., weight loss >10%, fever, fatigue) • Rai stage III–IV • Normal organ function Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  33. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Patient Characteristics No. of patients* 136 Age (y) Median 59 (range) (36–81) Stage IV 38% Other 62% Performance status1 79% No. of prior treatments Median 2.5 Prior treatment status Alkylating agents only 15%* Fludarabine sensitive 62%* Fludarabine refractory 23%* * Evaluable patients Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  34. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Response • Median follow-up = 5 months % of Patients (n=136)* ORR 71 CR 21 PR 37 Nodular PR 13 * Evaluable patients Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  35. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Response by Prior Therapy % of Patients Alkylators Fludarabine Fludarabine only sensitive resistant (n=20) (n=85) (n=31) ORR 60 78 56 CR 15 27 6 PR 30 37 41 Nodular PR 15 14 9 Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  36. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Tolerability % of Courses(n=554) HematologicNeutropenia 46 Febrile neutropenia 2 Thrombocytopenia 5 Non-hematologicNausea 19 Vomiting 5 Pneumonia 2 Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  37. 1.0 0.8 0.6 0.4 0.2 0.0 (n=136) Proportion surviving P <0.01 (n=117) Fludarabine ± predisone Fludarabine/cyclophosphamide MabThera® + fludarabine/cyclophosphamide (n=252) 0 6 12 18 24 30 36 41 48 Months MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL:Survival Compared with Historical Controls Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  38. MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Summary • ORR of 71% • 21% CR • 37% PR • 13% nodular PR • Survival advantage of MabThera® +FC versus FC alone demonstrated at 13+ months median follow-up (P<0.01) • MabThera® does not increase the apparent toxicity of FC Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

  39. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL Lamanna et al Blood 2003

  40. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: protocol Fludarabine (25mg/m2/day x 5 days every 4 weeks x 6 cycles) High-dose cyclophosphamide (3g/m2 every 2–3 weeks x 3 cycles) MabThera (375mg/m2/week x 4) Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

  41. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: patient characteristics Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

  42. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: response Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

  43. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: grade 3/4 adverse events There were no treatment-related deaths Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

  44. Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: summary • Consolidation therapy with high-dose cyclophosphamide improves quality of response over induction with fludarabine • A second consolidation with MabThera further improves quality of response in a significant proportion of patients Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

  45. MabThera® + Fludarabine in CLL Schulz et al Blood 2001

  46. MabThera® + Fludarabine in CLL: Protocol MabThera®375 mg/m2/week i.v., weeks 9, 13, 17, 21 Fludarabine 25 mg/m2/day i.v. days 1–5, weeks 1, 5, 9, 13 Week 1 5 9 13 17 21 Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

  47. MabThera® + Fludarabine in CLL:Patient Characteristics No. of patients 30 Age (y) Median 59 (range) (30–70) Sex Male 70% Female 30% Binet stage B 70% C 30% B symptoms 50% Prior therapy None 63% Chlorambucil/prednisone 37% Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

  48. MabThera® + Fludarabine in CLL: Tolerability % of Patients (n=30)Grade 3/4 Hematologic Neutropenia 37 Leukopenia 27 Thrombocytopenia 10 Anemia 10 Non-hematologic Infections* 13 Fever 3 Pain 3 Arrhythmia 3 * Nine patients (30%) experienced grade I/II infections Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

  49. MabThera® + Fludarabine in CLL: Response % of Patients All Untreated Relapsed Stage B Stage C (n=29) (n=18) (n=11) (n=21) (n=8) ORR 90 89 90 91 87 CR 24 22 27 29 12 CRu 10 6 18 14 – PR 55 61 45 48 75 SD 3 – 9 5 – Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

  50. MabThera® + Fludarabine in CLL:Time to Progression 1.0 0.8 0.6 0.4 0.2 0 Five progressions (n=30). Median not reached Rate with progression 0 3 6 9 12 15 18 21 Months Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

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