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Rituximab efficacy in other haematological malignancies

Rituximab efficacy in other haematological malignancies. Christian Buske. CLL. Dose escalation of rituximab for CLL: response in patients with CLL. Response rate (%). (n=39)*. (n=24)*. (n=7)*. (n=9)*. Rituximab (mg /m 2 ). * Evaluable patients.

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Rituximab efficacy in other haematological malignancies

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  1. Rituximab efficacy in other haematological malignancies Christian Buske

  2. CLL

  3. Dose escalation of rituximab for CLL: response in patients with CLL Response rate (%) (n=39)* (n=24)* (n=7)* (n=9)* Rituximab(mg/m2) * Evaluable patients O’Brien et al. J Clin Oncol. 2001;19:2165.

  4. Thrice weekly rituximab:overall response and outcome Evaluable patients(n=33) Complete response Partial response Overall response rate Response (%) 3 42 45 • Median response duration – 10 months • Fludarabine refractory patients – 6 months Byrd J, et al. J Clin Oncol 2001;19:2153–64

  5. Rituximab thrice weekly for CLL: median progression-free survival 100 Responders All patients 80 60 Patients (%) 40 20 0 0 2 4 6 8 10 12 14 16 18 20 Months Adapted from Byrd et al. J Clin Oncol. 2001;19:2153.

  6. Progression-free survival: rituximab plus fludarabine (9712) versus fludarabine arm of 9011 Retrospective analysis 1.0 0.8 0.6 0.4 0.2 0 Rituximab + fludarabine CALGB 9712 Probability of progression-freesurvival Fludarabine CALGB 9011 p<0.0001 0 20 40 60 80 100 120 140 Months Byrd J, et al. Blood 2005;105:49–53

  7. Overall survival: rituximab plus fludarabine (9712) versus fludarabine arm of 9011 Retrospective analysis 1.0 0.8 0.6 0.4 0.2 0 Rituximab + fludarabine CALGB 9712 Probability of progression-freesurvival Fludarabine CALGB 9011 p=0.0006 0 20 40 60 80 100 120 140 Months Byrd J, et al. Blood 2005;105:49–53

  8. Start cycle 2 Cycle 1 1 2 3 4 8 15 22 29 Days Cyclophosphamide 250mg/m2 Cycle repeats Cycles 2–6 1 2 3 8 15 22 29 Days MabThera + fludarabine/cyclophosphamide (FCR) for previously untreated CLL: protocol MabThera 375mg/m2 (cycle 1) or 500mg/m2(cycles 2–6) Fludarabine 25mg/m2 Keating M, et al. Blood 2005;106;599a (Abstract 2118)

  9. FCR for previously untreated CLL: patient characteristics Patient characteristics Male (%) 70.3 Rai stage III-IV (%) 33 Median age (range) 57 (17–86) Hemoglobin (range) 12.5G% (6.1–18.7) White cell count (range) 76 x 103/μl (2.1–620) Platelets (range) 154 x 103/μl (8–406) Splenomegaly (%) 51 Keating M, et al. Blood 2005;106;599a (Abstract 2118)

  10. FCR for previously untreated CLL: response rates Response rate (%) CR 72 nPR 10 PR 12 • The pretreatment characteristic most strongly associated with CR rate was β2-microglobulin level Keating M, et al. Blood 2005;106;599a (Abstract 2118)

  11. FCR for previously untreated CLL: 4-year analysis of previously untreated CLL patients Response Patients (n) Response duration (%) Overall survival (%) CR 217 83* 84* nPR 31 64 84 PR 37 38 50 Overall 300 77 (CR + PR) 83 *p<0.01 • PCR for IgVH and flow responses were independently associated with duration of response Keating M, et al. Blood 2005;106;599a (Abstract 2118)

  12. FCR for previously untreated CLL: toxicity Patients (%) Secondary cancers 17.7 AML 1 Myelodysplastic syndrome 1 AIHA 8.3 Red cell aplasia 2 Keating M, et al. Blood 2005;106;599a (Abstract 2118)

  13. Time to failure by initial treatment:historical comparison of F+P vs FC vs FCR 1.0 0.8 0.6 0.4 0.2 0.0 Proportion Patients Failed Ex 202 185 F ± P 92 63 FC 224 53 FCR p=0.004 p<0.001 0 12 24 36 48 60 72 84 Months Keating M, et al. Proc Am Soc Clin Onc 2004

  14. FCR for previously treated CLL: response by prior therapy Patients (%) Fludarabine Fludarabine sensitive resistant (n=108) (n=37) OR 76 59 CR 31 5 PR 28 43 Nodular PR 17 11 Wierda et al., J Clin Oncol 2005;23:4070–8

  15. Relapsed/refractory CLL: overall survival by treatment regimen Patients Died Protocol Median (months) 251 241 F ± P* 19 111 83 FC* 29 143 55 FC + rituximab 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 Wierda W, et al. Blood 2003;102:110a (Abstract 373)

  16. Pentostatin cyclophosphamide in previously treated CLL patients: response rates 77 74 17 8 Weiss M, et al. J Clin Oncol 2003;21:1278–84

  17. CFAR: doses and schedule Drug Dose Day of course Cyclophosphamide 250mg/m2 3–5 Fludarabine 25mg/m2 3–5 Alemtuzumab 30mg 1, 3, 5 Rituximab 375–500mg/m2 2 (Allopurinol; TMP/SMX; Valacyclovir) Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  18. Patient characteristics: CFAR (n=63) Rai stage (int., high risk) 30, 33 Karyotype (n=53) complex (17p=15; 11q=10) 48% 11q del sole 5% 6q del sole 2% 13q del 5% Diploid 17% +12 8% Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  19. Patient characteristics CFAR (cont.) Median no. prior Rx 3 (1–14) Alk refractory 35 (56%) Flu refractory 28 (44%) Prior FC 11 (17%) Front-line 3 Salvage 8 Prior FCR 32 (51%) Front-line 13 Salvage 19 Prior SCT 4 (6%) Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  20. Response Patients (%) ORR 42 (67) CR 14 (22) nPR 1 (2) PR* 27 (43) NR 17 (27) Early death 3 (5) Not evaluable 1 (2) Response assessment (NCI-WG): CFAR (n=63) *10 PRs due to persistent cytopenia Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  21. Response by patient characteristics:CFAR (n=63) Response (%) Characteristic CR OR Rai Stage I–II (n=30) 27 80 III–IV (n=33) 18 52* Fludarabine sensitive (n=35) 37** 83 Fludarabine resistant (n=28) 4** 46** *p<0.02 **p<0.01 Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  22. Multivariate analysis: FCR and CFAR (n=231) Variable CR TTP OS Flu-Ref <0.001 2M 0.003 <0.001 No. prior Rx <0.001 ALB 0.03 Rai stage <0.001 Cytogenetics <0.01 PLT 0.03 Protocol 0.90 0.27 0.07 p-value Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  23. Haematological toxicities: CFAR Patients (%) CFAR FCR n=63 n=177 Toxicity G3 G4 G3 G4 Neutropenia 17 71 15 66 Thrombopenia 24 35 16 18 Wierda W, et al. Blood 2005;106:213a (Abstract 719)

  24. Waldenström’s macroglobulinaemia

  25. Single-agent rituximab for the treatment of WM *Median follow-up of 20 months 1. Dimopoulos M, et al. J Clin Oncol 2002;20:2327–33 2. Treon S, et al. Blood 2002;100:813a (Abstract 3211)

  26. Rituximab plus chemotherapy for the treatment of WM • Dimopoulos et al. 2004 • previously untreated WM patients (n=34) • treated with dexamethasone, rituximab and cyclophosphamide • mean follow-up of 18 months 90% of pts progression free • Treon et al. 2002 • previously treated WM patients (n=23) • treated with rituximab plus fludarabine • 85.7% of evaluable patients responded Dimopoulos M, et al. Blood 2004;104:215a (Abstract 752) Treon S, et al. Blood 2002;100;211a (Abstract 794)

  27. R-CHOP vs CHOP in previously untreated LP-IC: patients • Patients (n=75) with previously untreated lymphoplasmocytoid/ic immunocytoma (LP-IC) • Lymphoplasmocytic 72% Lymphoplasmocytoid 28% Median age 61 years IPI int/high or high 23% Buske C, et al. Ann Onco 2005l;16:v110 (Abstract 250)

  28. R-CHOP vs CHOP: response in patients with lymphoplasmocytoid/ic immunocytoma (LP-IC) 92* 70* 11* 5* *p=0.035 TTF after 4 years: median not reached (R-CHOP) vs 1.8 years (CHOP); p=0.003 Buske C, et al. Ann Onco 2005l;16:v110 (Abstract 250)

  29. PTLD

  30. PTLD: response rates to single-agent rituximab and R-chemo Choquet S, et al. Blood 2003;102:277a (Abstract 986) Trappe R, et al. Blood 2005;106:274a (Abstract 932)

  31. Front-line rituximab improves overall and event-free survival in patients with PTLD • 108 patients with PTLD enrolled in the study • 33% treated with rituximab • In the whole group • CR: 46% • PR: 13% • Patients treated with rituximab had significantly prolonged OS and EFS compared to the group as a whole (median follow-up of 15.2 months) • OS: 76% vs 21% (p=0.007) • EFS: 70% vs 15% (p=0.02) Gonzalez-Barca E, et al. Blood 2004;104:394a (Abstract 1406)

  32. Rituximab efficacy in other haematological malignancies: conclusions • Rituximab in combination with fludarabine and cyclophosphamide is one of the most active regimens for the treatment of CLL • now being evaluated in phase III trials • Promising response rates in fludarabine refractory CLL patients have been achieved with rituximab containing regimens • Single-agent rituximab and rituximab/chemotherapy combinations have also demonstrated efficacy in LP-IC, WM and PTLD and warrant further investigation

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