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Klinikum Grosshadern

Christian Buske Attending Physician and Assistant Professor, University Hospital Grosshadern, Munich, Germany. Prior posts at the University Hospital G ö ttingen, Germany, and the British Columbia Cancer Agency, Vancouver, Canada

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Klinikum Grosshadern

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  1. Christian BuskeAttending Physician and Assistant Professor,University Hospital Grosshadern, Munich, Germany • Prior posts at the University Hospital Göttingen, Germany, and the British Columbia Cancer Agency, Vancouver, Canada • Recipient of the Young Investigator Award at the 29th Annual Meeting of the International Society for Experimental Hematology and the Canadian Research Award • Study coordinator of international trials led by the German Low Grade Lymphoma Study Group • Principal Investigator of the Clinical Cooperative Group ‘Leukaemia’, GSF Research Institute, Munich, Germany • Published work in numerous internationally recognised haematological journals Klinikum Grosshadern

  2. Indolent NHL: a survival benefit with rituximab-based therapy Christian Buske University Hospital Grosshadern, Munich, Germany

  3. Introduction • Indolent non-Hodgkin’s lymphoma (NHL) follows a relapsing/remitting course and has traditionally been considered as an incurable disease • Goals of conventional therapy • keep patients in remission for as long as possible • maintain quality of life

  4. Early treatment with chlorambucil:no impact on survival 100 80 60 40 20 0 Observation (n=151) Chlorambucil (n=158) Cumulative survival (%) 0 4 8 12 16 20 24 Time (years) Ardeshna KM, et al. Lancet 2003;362:516–22 Median follow-up: 16 years

  5. The natural history of indolent NHL: unchanged for more than 30 years Survival (n=1,021), 1960–1991 100 80 60 40 20 0 1960–1975 1976–1986 1987–1991 Actuarial survival (%) 0 6 12 18 24 30 36 Years Horning SJ. Semin Oncol 1993;20(Suppl. 5):75–88

  6. Rituximab in indolent NHL: rationale The use of rituximab in indolent NHL is supported by • Targeted action1 • Good efficacy1 • Favourable tolerability2 • Non-overlapping toxicity profile with conventional chemotherapy2 1McLaughlin P, et al. Semin Oncol 1999;26(Suppl. 14):79–87 2Kimby E, et al. Cancer Treat Rev 2005;31:456–73

  7. CVP ± rituximab in previously untreated FL: study design R A N D O M I S ATION • Follicular NHL (IWF B, C, D) • Stage III–IV • ³18 years • No prior treatment • Measurable disease • Central histology review R ESTAGING CVP x 4 cycles (every 3 weeks) CVP x 4 cycles (every 3 weeks) CR, PR Rituximab + CVP x 4 cycles (every 3 weeks) R + CVP x 4 cycles (every 3 weeks) Rituximab 375mg/m2 i.v. day 1 Cyclophosphamide 750mg/m2 i.v. day 1 Vincristine 1.4mg/m2 i.v. day 1 Prednisone 40mg/m2 p.o. days 1–5 SD, PD off treatment FL = follicular lymphoma; R-CVP = rituximab + cyclophosphamide/vincristine/prednisone; CR = complete response PR = partial response; SD = stable disease; PD = progressive disease i.v = intravenous; p.o. = oral Marcus R, et al.Blood 2005;105:1417–23

  8. Adding rituximab to first-line CVP improves response rates in FL ORR = overall response rate CRu = unconfirmed CR Marcus R, et al. Blood 2005;105:1417–23

  9. Adding rituximab to first-line CVP prolongs time to treatment failure (TTF) in FL 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Median follow-up: 53 months Event-free probability R-CVP: median 27 months CVP: median 7 months p<0.0001 0 6 12 18 24 30 36 42 48 54 60 66 72 Study month Patients at risk:CVP 159 86 51 34 30 21 17 14 10 6 3 1 0R-CVP 162 123 113 98 93 76 69 63 53 37 14 3 0 Marcus R, et al. Blood 2006;108:146a (Abstract 481)

  10. Adding rituximab to first-line CVP prolongs time to progression in FL, irrespective of subgroup* *Cox regression analysis 42-month follow-up; CL = confidence limit; Vertical line = risk ratio estimate for all patients;Horizontal bars = 95% CLs for relevant category. Model includes stratification by centre pool; Solal-Celigny P, et al.Blood 2005;106:106a (Abstract 350) BNLI = British National Lymphoma Intergroup; BM = bone marrow; LDH = lactate dehydrogenase; CRF = chronic renal failure; IPI = International Prognostic Index; FLIPI = Follicular Lymphoma IPI

  11. Adding rituximab to first-line CVP prolongs overall survival (OS) in FL Median follow-up: 53 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 R-CVP: median not reached CVP: median not reached Event-free probability p=0.0290 4-year OS estimates: 83% vs 77% 0 6 12 18 24 30 36 42 48 54 60 66 72 Study month Patients at risk:CVP 159 155 151 141 136 132 125 120 111 67 30 8 0R-CVP 162 162 160 155 150 144 142 132 124 81 40 7 0 Marcus R, et al. Blood 2006;108:146a (Abstract 481)

  12. CHOP ± rituximab in previously untreated FL: study design Patients <60 years PBSCT 6–8 x CHOP + rituximab CR, PR R A N D O M I S E R A N D O M I S E Standard IFN-maintenance Patients >60 years Intensive IFN-maintenance 6–8 x CHOP CR, PR Standard IFN-maintenance CHOP = cyclophosphamide/doxorubicin/vincristine/prednisonePBSCT = peripheral blood stem-cell transplantationIFN = interferon Hiddemann W, et al. Blood 2005;106:3725–32

  13. Adding rituximab to first-line CHOP prolongs TTF in FL Median observation time: 18 months 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 R-CHOP (195/223) CHOP (144/205) Probability, p p<0.001 0 1 2 3 4 Years Hiddemann W, et al. Blood 2005;106:3725–32

  14. Adding rituximab to first-line CHOP prolongs OS in FL Median observation time: 18 months 95% R-CHOP (217/223) 1.0 0.8 0.6 0.4 0.2 0 CHOP (188/205) 90% Probability of OS p=0.016 0 1 2 3 4 Years Hiddemann W, et al. Blood 2005;106:3725–32

  15. Adding rituximab to first-line CHOP improves outcome in elderly patients with FL R-CHOP resulted in significantly improved: • TTF (median 5.0 vs 2.1 years, p<0.0001) • Progression-free survival (PFS) (4-years PFS 62.2% vs 27.9%, p<0.0001) • OS (4-year OS 90% vs 81%, p=0.039) Buske C, et al. Blood 2006;108:146a (Abstract 482)

  16. MCP ± rituximab: study design R A N D O M I S E MCP every28 days(6 cycles) R ESTAG I NG MCP every28 days(2 cycles) CR/PR R-MCP every28 days(6 cycles) R-MCP every28 days(2 cycles) IFN-a 2b maintenance for FL patients in CR/PR 4 weeks after completing induction SD/PD Off treatment MCP = mitoxantrone/chlorambucil/prednisolone Herold M, et al. J Clin Oncol 2007;25:1986–92

  17. Adding rituximab to first-line MCP improves efficacy in FL Median follow-up: 47 months (overall); 49 months (R-MCP); 42 months (MCP) DR = duration of response; NR = not reached; TTNLT = time to next lymphoma treatmentEFS = event-free survival Herold M, et al. J Clin Oncol 2007;25:1986–92

  18. Adding rituximab to first-line MCP prolongs PFS in FL 1.00 0.75 0.50 0.25 0 R-MCP: median PFS not reached; 4-year PFS 71% Survival distribution function MCP: median PFS 28.8 months; 4-year PFS 40% p<0.0001 0 10 20 30 40 50 60 PFS (months) Herold M, et al. J Clin Oncol 2007;25:1986–92

  19. Adding rituximab to first-line MCP prolongs OS in FL R-MCP: median OS not reached; 4-year OS 87% 1.00 0.75 0.50 0.25 0 MCP: median OS not reached; 4-year OS 74% Survival distribution function p=0.0096 0 10 20 30 40 50 60 OS (months) Herold M, et al. J Clin Oncol 2007;25:1986–92

  20. CHVP/IFN ± rituximab: FL2000 study design CHVP/IFN 12 months 6 months R Staging including CT-scan and bone marrow biopsy Rituximab +CHVP/IFN IFN-a 2b (Roferon): 4.5MU t.i.w. for 18 months (3MU if aged 70 years) D1 Cyclophosphamide 600mg/m2 D1 Doxorubicin 25mg/m2 D1 Etoposide 100mg/m2 D1–D5 Prednisone 40mg/m2 Rituximab: 375mg/m2 Every month for 6 months (both arms) then every 2 months for CHVP/IFN alone Salles G, et al. Blood 2004;104:49a (Abstract 160) CHVP = cyclophosphamide/doxorubicin/etoposide/prednisolone

  21. Adding rituximab to first-line CHVP/IFN prolongs EFS and OS in FL • 42-month follow-up Foussard C, et al. J Clin Oncol 2006;24:424s (Abstract 7508)

  22. R-FCM in relapsed FL and mantle cell lymphoma (MCL): trial design * 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 4 x FCM + rituximab 4 x rituximab 4 x rituximab Advanced stage relapsed or refractory FL or MCL CR, PR Observation only 4 x FCM CR, PR F = fludarabine 25mg/m2/day days 13 C = cyclophosphamide 200mg/m2/day days 13 M = mitoxantrone 8mg/m2/day day 1 *Randomisation stopped after 147 patients when a significant improvement in OS was observed for the R-FCM therapy; all subsequent patients received R-FCM Dreyling MH, et al. J Clin Oncol 2005;23:567s (Abstract 6528)Forstpointner R, et al. Blood 2004;105:3064–71

  23. Adding rituximab to FCM prolongs response duration in relapsed FL and MCL 10.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Rituximab (52/85) Probability Observation (29/91) p=0.0006 0 1 2 3 4 5 6 7 Years after end of initial therapy Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

  24. Adding rituximab to FCM prolongs response duration in relapsed FL 10.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Rituximab (32/41) Probability Observation (21/40) p=0.035 0 1 2 3 4 5 6 7 Years after end of initial therapy Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

  25. Adding rituximab to chemotherapy: Cochrane meta-analysis of survival • Systematic review and meta-analysis of data from seven* randomised studies of rituximab plus chemotherapy versus chemotherapy • Patients (n=1,943) had previously untreated or relapsed/refractory advanced indolent lymphoma (1,683) or MCL (260) • The aim of this meta-analysis was to evaluate the impact of adding rituximab to chemotherapy on • OS (primary endpoint) • disease control • ORR and CR • toxicity *Lenz G, et al. J Clin Oncol 2005;23:1984–92; Rivas-Vera S, et al. Blood 2005;106:2431Marcus R, et al. Blood 2005;105:1417–23; Forstpointner R, et al. Blood 2004;104:3064–71 Herold M, et al. Blood 2004;104:584; Hiddemann W, et al. Blood 2005;106:3725–32van Oers MHJ, et al. Blood 2006;108:3295–301 Schulz H, et al. J Natl Cancer Inst 2007;99:706–14

  26. R-chemo significantly improved OS compared with chemo alone (all patients) R-chemo n/N Chemotherapy n/N HR (95% Cl) Weight (%) HR (95% Cl) 10.91 Forstpointer, 2004* 16/66 30/62 0.42 (0.23–0.74) 20.89 Herold, 2004* 37/181 51/177 0.60 (0.40–0.92) 20.85 Hiddemann, 2005 6/223 17/205 0.60 (0.40–0.92) 4.98 Lenz, 2005 10/62 11/60 0.96 (0.41–2.26) 11.63 Marcus, 2005 21/162 28/159 0.70 (0.40–1.23) 2.97 Rivas-Vera, 2005 10/66 6/55 0.96 (0.32–2.91) 27.77 van Oers, 2006 52/234 65/231 0.74 (0.52–1.07) 100.00 Total no. of patients 994 949 0.65 (0.54–0.78) Total no. of events 152 208 Test for heterogeneity: 2=4.42, df=6 (p=0.62), I2=0% Test for overall effect: Z=4.45 (p<0.001) *Includes unpublished data provided by investigators 0.1 0.2 0.5 1 2 5 10 Favours R-chemo Favours chemotherapy HR = hazard ratio; CI = confidence interval Schulz H, et al. J Natl Cancer Inst 2007;99:706–14

  27. Cochrane meta-analysis: summary • Addition of rituximab to chemotherapy significantly improved ORR, disease control and OS • response rate (RR) of tumour response: 1.21 (95% CI: 1.16–1.27); p<0.001 • RR of complete response: 2.03 (95% CI: 1.71–2.40); p<0.001 • HR for disease event: 0.62 (95% CI: 0.55–0.71); p<0.001 • HR for mortality: 0.65 (95% CI: 0.54–0.78); p<0.001 • Subanalyses demonstrated that the addition of rituximab to chemotherapy significantly improved ORR and OS in • FL • RR for tumour response: 1.19 (95% CI: 1.13–1.24); p<0.001 • HR for mortality: 0.63 (95% CI: 0.51–0.79); p<0.001 • MCL • RR for tumour response: 1.22 (95% CI: 1.05–1.42); p=0.009 • HR for mortality: 0.60 (95% CI: 0.37–0.98); p=0.04 • Addition of rituximab to chemotherapy increased the risk of fever and leukocytopenia, but this was not associated with an increased risk of infections Schulz H, et al. J Natl Cancer Inst 2007;99:706–14

  28. PFS QALYs Progressed QALYS Cost-effectiveness of CVP ± rituximab: total quality-adjusted life years (QALYs) 7 6 5 4 3 2 1 0 • Rituximab generates an additional 1.25 QALYs per patient QALYs 1.25 additional QALYs R-CVP CVP Lewis G, et al. Blood 2006;108:107a (Abstract 345)

  29. R-CVP has a cost per QALY well below commonly accepted thresholds • Costs • £20,347 (R-CVP) vs £9,977 (CVP) • QALYs • 5.7 (R-CVP) vs 4.5 (CVP) • Cost per QALY = £10,370/1.25 = £8,290 • Hence, each additional QALY generated by rituximab costs the health service an additional £8,290 Lewis G, et al. Blood 2006;108:107a (Abstract 345)

  30. Rituximab plus chemotherapy in indolent NHL: conclusions • The addition of rituximab to chemotherapy significantly improves outcome in patients with FL and MCL • The addition of rituximab to chemotherapy does not significantly increase the toxicity burden of chemotherapy • the majority of adverse events relating to rituximab were • related to the first infusion • mild to moderate • transient

  31. Cheson d78 Best response Single-agent rituximab* achieves a substantial response rate in low tumour burden FL (n=49) 100 80 60 40 20 0 80 74 49 Percentage 47 31 26 20 14 6 6 ORR CR/CRu PR SD PD *4 x 375mg/m2 Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585)

  32. Single-agent rituximab* achieves durable responses in low tumour burden FL: PFS (n=46) 100 90 80 70 60 50 40 30 20 10 0 Median follow-up = 83.9 months Median PFS = 23.5 months Percentage 0 10 20 30 40 50 60 70 80 90 100 Time since beginning of therapy (months) *4 x 375mg/m2 Colombat P, et al. Blood 2006;108:147a (Abstract 486)

  33. Single-agent rituximab* in low tumour burden FL: PFS according to clinical response (n=46; Cheson d78) 100 90 80 70 60 50 40 30 20 10 0 Median follow-up = 83.9 months CR/CRu  median PFS = 51.8 months† PR  median PFS = 23 months† SD/PD  median PFS = 9.5 months Percentage †p=0.007 (log-rank) 0 10 20 30 40 50 60 70 80 90 100 Time since beginning of therapy (months) *4 x 375mg/m2 Colombat P, et al. Blood 2006;108:147a (Abstract 486)

  34. 4 x single-agent rituximab in low tumour burden FL: OS Seven years after therapy, four deaths out of 46 (one myelodysplasia, two evolution of NHL, one urothelial carcinoma) 100 90 80 70 60 50 40 30 20 10 0 Percentage 0 10 20 30 40 50 60 70 80 90 100 Time since beginning of therapy (months) Colombat P, et al. Blood 2006;108:147a (Abstract 486)

  35. Rituximab in indolent NHL: conclusions • Rituximab is the first targeted therapy for indolent lymphoma • In untreated and relapsed/refractory FL and MCL, the addition of rituximab to chemotherapy achieves significant improvements in • CRs and ORRs • disease control • OS • Rituximab dose not add substantially to the toxicity burden of chemotherapy • Single-agent rituximab • is well tolerated • achieves durable responses in a substantial proportion of patients with low tumour burden

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