Presentation is loading. Please wait.

Presentation is loading. Please wait.

Christian Buske Attending Physician and Assistant Professor, University Hospital Grosshadern, Munich, Germany Prior posts at the University Hospital Göttingen,

Similar presentations


Presentation on theme: "Christian Buske Attending Physician and Assistant Professor, University Hospital Grosshadern, Munich, Germany Prior posts at the University Hospital Göttingen,"— Presentation transcript:

1 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

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 Ardeshna KM, et al. Lancet 2003;362:516–22 Median follow-up: 16 years 04812162024 Observation (n=151) Chlorambucil (n=158) 100 80 60 40 20 0 Cumulative survival (%) Time (years)

5 Horning SJ. Semin Oncol 1993;20(Suppl. 5):75–88 Survival (n=1,021), 1960–1991 Years 100 80 60 40 20 0 061218243036 1960–1975 1976–1986 1987–1991 Actuarial survival (%) The natural history of indolent NHL: unchanged for more than 30 years

6 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

7 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

8 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

9 Adding rituximab to first-line CVP prolongs time to treatment failure (TTF) in FL Study month Event-free probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 R-CVP: median 27 months CVP: median 7 months p<0.0001 Patients at risk: CVP159 8651343021171410 6 310 R-CVP162123113989376696353371430 061218243036424854606672 Median follow-up: 53 months 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* Baseline parameterCategory0.10.50.9 1.21.6n Lower 95% CLEstimate Upper 95% CL All patients Total3210.3200.4220.558 BNLI criteria Yes No 91 230 0.202 0.315 0.347 0.440 0.596 0.613 Age (years)  60 >60 236 85 0.333 0.206 0.461 0.372 0.638 0.671 Extranodal sites >1 0–1 56 265 0.351 0.292 0.686 0.399 1.341 0.545 BM involved (local) Yes No 205 112 0.332 0.202 0.469 0.332 0.662 0.547 Elevated LDH Yes No 78 226 0.240 0.264 0.431 0.375 0.773 0.532 Elevated B2M Yes No 140 148 0.279 0.255 0.420 0.397 0.630 0.617 IPI (CRF validated) 0–1 >1 143 159 0.259 0.298 0.406 0.439 0.636 0.648 B symptoms Yes No 116 205 0.314 0.263 0.505 0.377 0.812 0.541 Bulky disease Yes No 136 185 0.256 0.318 0.394 0.462 0.608 0.671 Nodal sites <5 ≥5 54 267 0.202 0.297 0.459 0.401 1.040 0.543 Haemoglobin (g/dL) >12  12 251 66 0.255 0.419 0.355 0.748 0.495 1.335 FLIPI (prognosis) 0–2 (good) 3–5 (poor) 155 146 0.242 0.323 0.373 0.479 0.577 0.709 *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)

11 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 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 061218243036424854606672 p=0.0290 Patients at risk: CVP159155151141136132125120111673080 R-CVP162162160155150144142132124814070 Median follow-up: 53 months Marcus R, et al. Blood 2006;108:146a (Abstract 481)

12 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

13 Adding rituximab to first-line CHOP prolongs TTF in FL Median observation time: 18 months p<0.001 Hiddemann W, et al. Blood 2005;106:3725–32 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Probability, p 0123401234 Years R-CHOP (195/223) CHOP (144/205)

14 Adding rituximab to first-line CHOP prolongs OS in FL R-CHOP (217/223) CHOP (188/205) 1.0 0.8 0.6 0.4 0.2 0 0123401234 Years Probability of OS p=0.016 Hiddemann W, et al. Blood 2005;106:3725–32 90% 95% Median observation time: 18 months

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 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

17 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 (%)7592 0.0009 CR (%)2550 0.0004 Median DR (months)35NR<0.0001 Median TTNLT (months)29.4NR 0.0002 Median EFS (months)26NR<0.0001 Median PFS (months)28.8NR<0.0001 4-year OS (%)7487 0.0096 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

18 Adding rituximab to first-line MCP prolongs PFS in FL Survival distribution function 1.00 0.75 0.50 0.25 0 p<0.0001 R-MCP: median PFS not reached; 4-year PFS 71% MCP: median PFS 28.8 months; 4-year PFS 40% PFS (months) 0102030405060 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% MCP: median OS not reached; 4-year OS 74% p=0.0096 Survival distribution function 1.00 0.75 0.50 0.25 0 OS (months) 0102030405060 Herold M, et al. J Clin Oncol 2007;25:1986–92

20 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

21 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<0.0001 OS84910.029 EFS subgroup analysis FLIPI 0–2 FLIPI 3–5 Patients with CR/CRu (n=230) 55 38 62 72 61 81 0.0019 0.0005 0.002 Foussard C, et al. J Clin Oncol 2006;24:424s (Abstract 7508)

22 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

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 Years after end of initial therapy 0123456701234567 Rituximab (52/85) Observation (29/91) p=0.0006 Probability Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

24 10.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Years after end of initial therapy 0123456701234567 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)

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 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

26 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 patients9949490.65 (0.54–0.78) Total no. of events152208 Test for heterogeneity:  2 =4.42, df=6 (p=0.62), I 2 =0% Test for overall effect: Z=4.45 (p<0.001) 0.10.20.512510 Forstpointer, 2004*16/6630/620.42 (0.23–0.74) Herold, 2004*37/18151/1770.60 (0.40–0.92) Hiddemann, 20056/22317/2050.60 (0.40–0.92) Lenz, 200510/6211/600.96 (0.41–2.26) Marcus, 200521/16228/1590.70 (0.40–1.23) Rivas-Vera, 200510/666/550.96 (0.32–2.91) van Oers, 200652/23465/2310.74 (0.52–1.07) *Includes unpublished data provided by investigators 100.00 10.91 20.89 20.85 4.98 11.63 2.97 27.77 HR = hazard ratio; CI = confidence intervalSchulz 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 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 7654321076543210 R-CVPCVP QALYs

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 Single-agent rituximab* achieves a substantial response rate in low tumour burden FL (n=49) ORRCR/CRuPRSDPD 100 80 60 40 20 0 Percentage Cheson d78 Best response 74 26 47 20 6 80 49 31 14 6 Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585) *4 x 375mg/m 2

32 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 100 90 80 70 60 50 40 30 20 10 0 0102030405060708090100 Colombat P, et al. Blood 2006;108:147a (Abstract 486) *4 x 375mg/m 2

33 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 100 90 80 70 60 50 40 30 20 10 0 0102030405060708090100 *4 x 375mg/m 2 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) Time since beginning of therapy (months) Percentage 100 90 80 70 60 50 40 30 20 10 0 0102030405060708090100 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


Download ppt "Christian Buske Attending Physician and Assistant Professor, University Hospital Grosshadern, Munich, Germany Prior posts at the University Hospital Göttingen,"

Similar presentations


Ads by Google