Christian Buske Attending 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

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

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

Early treatment with chlorambucil: no impact on survival Ardeshna KM, et al. Lancet 2003;362:516–22 Median follow-up: 16 years Observation (n=151) Chlorambucil (n=158) Cumulative survival (%) Time (years)

Horning SJ. Semin Oncol 1993;20(Suppl. 5):75–88 Survival (n=1,021), 1960–1991 Years – – –1991 Actuarial survival (%) The natural history of indolent NHL: unchanged for more than 30 years

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

CVP ± rituximab in previously untreated FL: study design Follicular NHL (IWF B, C, D) Stage III–IV  18 years No prior treatment Measurable disease Central histology review RANDOMISATIONRANDOMISATION CVP x 4 cycles (every 3 weeks) Rituximab + CVP x 4 cycles (every 3 weeks) RESTAGINGRESTAGING CVP x 4 cycles (every 3 weeks) R + CVP x 4 cycles (every 3 weeks) SD, PD off treatment CR, PR Rituximab 375mg/m 2 i.v. day 1 Cyclophosphamide 750mg/m 2 i.v. day 1 Vincristine 1.4mg/m 2 i.v. day 1 Prednisone 40mg/m 2 p.o. days 1–5 Marcus R, et al. Blood 2005;105:1417–23 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

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

Adding rituximab to first-line CVP prolongs time to treatment failure (TTF) in FL Study month Event-free probability R-CVP: median 27 months CVP: median 7 months p< Patients at risk: CVP R-CVP Median follow-up: 53 months Marcus R, et al. Blood 2006;108:146a (Abstract 481)

Adding rituximab to first-line CVP prolongs time to progression in FL, irrespective of subgroup* Baseline parameterCategory n Lower 95% CLEstimate Upper 95% CL All patients Total BNLI criteria Yes No Age (years)  60 > Extranodal sites >1 0– BM involved (local) Yes No Elevated LDH Yes No Elevated B2M Yes No IPI (CRF validated) 0–1 > B symptoms Yes No Bulky disease Yes No Nodal sites <5 ≥ Haemoglobin (g/dL) >12  FLIPI (prognosis) 0–2 (good) 3–5 (poor) *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; BNLI = British National Lymphoma Intergroup; BM = bone marrow; LDH = lactate dehydrogenase; CRF = chronic renal failure; IPI = International Prognostic Index; FLIPI = Follicular Lymphoma IPI Solal-Celigny P, et al. Blood 2005;106:106a (Abstract 350)

Adding rituximab to first-line CVP prolongs overall survival (OS) in FL 4-year OS estimates: 83% vs 77% R-CVP: median not reached CVP: median not reached Study month Event-free probability p= Patients at risk: CVP R-CVP Median follow-up: 53 months Marcus R, et al. Blood 2006;108:146a (Abstract 481)

6–8 x CHOP 6–8 x CHOP + rituximab CR, PR RANDOMISERANDOMISE PBSCT Standard IFN- maintenance Intensive IFN- maintenance Standard IFN- maintenance Patients <60 years Patients >60 years Hiddemann W, et al. Blood 2005;106:3725–32 CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone PBSCT = peripheral blood stem-cell transplantation IFN = interferon CHOP ± rituximab in previously untreated FL: study design RANDOMISERANDOMISE

Adding rituximab to first-line CHOP prolongs TTF in FL Median observation time: 18 months p<0.001 Hiddemann W, et al. Blood 2005;106:3725– Probability, p Years R-CHOP (195/223) CHOP (144/205)

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

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)

MCP ± rituximab: study design RANDOMISERANDOMISE MCP every 28 days (6 cycles) R-MCP every 28 days (6 cycles) RESTAGINGRESTAGING IFN-  2b maintenance for FL patients in CR/PR 4 weeks after completing induction SD/PD MCP every 28 days (2 cycles) R-MCP every 28 days (2 cycles) CR/PR Off treatment Herold M, et al. J Clin Oncol 2007;25:1986–92MCP = mitoxantrone/chlorambucil/prednisolone

Adding rituximab to first-line MCP improves efficacy in FL Median follow-up: 47 months (overall); 49 months (R-MCP); 42 months (MCP) MCP (n=96)R-MCP (n=105)p value ORR (%) CR (%) Median DR (months)35NR< Median TTNLT (months)29.4NR Median EFS (months)26NR< Median PFS (months)28.8NR< year OS (%) DR = duration of response; NR = not reached; TTNLT = time to next lymphoma treatment EFS = event-free survival Herold M, et al. J Clin Oncol 2007;25:1986–92

Adding rituximab to first-line MCP prolongs PFS in FL Survival distribution function p< R-MCP: median PFS not reached; 4-year PFS 71% MCP: median PFS 28.8 months; 4-year PFS 40% PFS (months) Herold M, et al. J Clin Oncol 2007;25:1986–92

Adding rituximab to first-line MCP prolongs OS in FL R-MCP: median OS not reached; 4-year OS 87% MCP: median OS not reached; 4-year OS 74% p= Survival distribution function OS (months) Herold M, et al. J Clin Oncol 2007;25:1986–92

Staging including CT-scan and bone marrow biopsy CHVP/IFN ± rituximab: FL2000 study design D1 Cyclophosphamide600mg/m 2 D1 Doxorubicin25mg/m 2 D1 Etoposide 100mg/m 2 D1–D5 Prednisone 40mg/m 2 IFN-  2b (Roferon): 4.5MU t.i.w. for 18 months (3MU if aged  70 years) Rituximab: 375mg/m 2 R CHVP/IFN Every month for 6 months (both arms) then every 2 months for CHVP/IFN alone 12 months 6 months Salles G, et al. Blood 2004;104:49a (Abstract 160) Rituximab + CHVP/IFN CHVP = cyclophosphamide/doxorubicin/etoposide/prednisolone

Adding rituximab to first-line CHVP/IFN prolongs EFS and OS in FL 42-month follow-up CHVP/IFN (%) R-CHVP/IFN (%)p value EFS4667< OS EFS subgroup analysis FLIPI 0–2 FLIPI 3–5 Patients with CR/CRu (n=230) Foussard C, et al. J Clin Oncol 2006;24:424s (Abstract 7508)

RANDOMISATIONRANDOMISATION 4 x FCM 4 x FCM + rituximab RANDOMISATIONRANDOMISATION CR, PR CR, PR 4 x rituximab 4 x rituximab Observation only Advanced stage relapsed or refractory FL or MCL F = fludarabine 25mg/m 2 /day days 1  3 C = cyclophosphamide 200mg/m 2 /day days 1  3 M = mitoxantrone 8mg/m 2 /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 R-FCM in relapsed FL and mantle cell lymphoma (MCL): trial design

Adding rituximab to FCM prolongs response duration in relapsed FL and MCL Years after end of initial therapy Rituximab (52/85) Observation (29/91) p= Probability Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

Years after end of initial therapy Rituximab (32/41) Observation (21/40) p=0.035 Adding rituximab to FCM prolongs response duration in relapsed FL Probability Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

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 Schulz H, et al. J Natl Cancer Inst 2007;99:706–14 *Lenz G, et al. J Clin Oncol 2005;23:1984–92; Rivas-Vera S, et al. Blood 2005;106:2431 Marcus 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;106:3725–32 van Oers MHJ, et al. Blood 2006;108:3295–301

R-chemo significantly improved OS compared with chemo alone (all patients) Favours R-chemoFavours chemotherapy R-chemo n/N Chemotherapy n/N HR (95% Cl) Weight (%) HR (95% Cl) Total no. of patients (0.54–0.78) Total no. of events Test for heterogeneity:  2 =4.42, df=6 (p=0.62), I 2 =0% Test for overall effect: Z=4.45 (p<0.001) Forstpointer, 2004*16/6630/ (0.23–0.74) Herold, 2004*37/18151/ (0.40–0.92) Hiddemann, 20056/22317/ (0.40–0.92) Lenz, /6211/ (0.41–2.26) Marcus, /16228/ (0.40–1.23) Rivas-Vera, /666/ (0.32–2.91) van Oers, /23465/ (0.52–1.07) *Includes unpublished data provided by investigators HR = hazard ratio; CI = confidence intervalSchulz H, et al. J Natl Cancer Inst 2007;99:706–14

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

Cost-effectiveness of CVP ± rituximab: total quality-adjusted life years (QALYs) Rituximab generates an additional 1.25 QALYs per patient Lewis G, et al. Blood 2006;108:107a (Abstract 345) 1.25 additional QALYs PFS QALYs Progressed QALYS R-CVPCVP QALYs

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)

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

Single-agent rituximab* achieves a substantial response rate in low tumour burden FL (n=49) ORRCR/CRuPRSDPD Percentage Cheson d78 Best response Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585) *4 x 375mg/m 2

Single-agent rituximab* achieves durable responses in low tumour burden FL: PFS (n=46) Time since beginning of therapy (months) Median PFS = 23.5 months Median follow-up = 83.9 months Percentage Colombat P, et al. Blood 2006;108:147a (Abstract 486) *4 x 375mg/m 2

Single-agent rituximab* in low tumour burden FL: PFS according to clinical response (n=46; Cheson d78) CR/CRu  median PFS = 51.8 months † PR  median PFS = 23 months † Median follow-up = 83.9 months SD/PD  median PFS = 9.5 months † p=0.007 (log-rank) Time since beginning of therapy (months) Percentage *4 x 375mg/m 2 Colombat P, et al. Blood 2006;108:147a (Abstract 486)

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) Time since beginning of therapy (months) Percentage Colombat P, et al. Blood 2006;108:147a (Abstract 486)

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