1. Rituximab maintenance for the treatment of indolent NHL Dr Christian Buske

2. Rationale for rituximab maintenance therapy in indolent NHL Natural history of indolent NHL –relapsing remitting course due to presence of residual lymphoma cells –rituximab is capable of eradicating residual lymphoma cells –potential long-term disease control with rituximab maintenance Rituximab has a good safety/tolerability profile –patients can enjoy extended disease-free survival without chemotherapy-associated toxicities

3. Is rituximab maintenance therapy better than retreatment?

4. Rituximab maintenance versus retreatment: protocol Retreatment at time of disease progression (identical to induction course) Randomise CR PR SD Maintenance therapy (identical to induction course) every 6 months (months 6, 12, 18) Restage Induction therapy (Rituximab 375mg/m 2 i.v. weekly x 4) Week 6Weeks 1–4 No response Off study Hainsworth JD, et al. Blood 2005;102:69a (Abstract 231)

5. Rituximab maintenance versus retreatment: progression-free survival 100 80 60 40 20 0 01224364860 Months Progression-free survival (%) Maintenance Retreatment p=0.0066 Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95

6. Randomised studies of rituximab maintenance in indolent NHL

7. RANDOMISEDRANDOMISED CHOP every 21 days maximum 6 cycles Rituximab + CHOP every 21 days maximum 6 cycles EORTC 20981: (R)-CHOP followed by rituximab maintenance vs observation RANDOMISEDRANDOMISED Observation Rituximab maintenance* *375mg/m 2 every 3 months for 2 years or until relapse CR PR van Oers M, et al. Blood 2005;106:107a (Abstract 353)

8. EORTC 20981: eligibility criteria Relapsed/resistant follicular lymphoma, grades 1–3 Ann Arbor stage III–IV (at initial diagnosis) Maximum of 2 non-anthracycline-containing systemic regimens –CR, PR, SD or PD after first or second regimen –prior treatment at least 2 months of single-agent therapy and/or at least two consecutive cycles of polychemotherapy or purine analogues Age  18 years CD20 + van Oers M, et al. Blood 2005;106:107a (Abstract 353)

9. EORTC 20981: patient characteristics (n=465) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

10. EORTC 20981: adverse events* during induction *Events with >5% reported grade 3–4 (WHO) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

11. EORTC 20981: r esponse to induction therapy *p<0.0001 (Mantzel Haenszel test for trend) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

12. EORTC 20981: PFS from first randomisation Overall log-rank test: p=0.0003 ONNumber of patients at risk : 1492311458041144CHOP 100 90 80 70 60 50 40 30 20 10 0 01234560123456 Years 12223418610968243R-CHOP Treatment Progression-free survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

13. Overall log-rank test: p=0.096 Hazard ratio: 0.74 ONNumber of patients at risk : 6523120715496409CHOP 100 90 80 70 60 50 40 30 20 10 0 01234560123456 Years 50234218167114447R-CHOP Treatment EORTC 20981: overall survival from first randomisation R-CHOP 3 yrs 82.5% CHOP 3 yrs 71.9% Overall survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

14. EORTC 20981: patient characteristics at second randomisation (n=334) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

15. EORTC 20981: adverse events* during maintenance *Events with >2% reported grade 3–4 events (mod. WHO) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

16. EORTC 20981: PFS from second randomisation – all patients Overall log-rank test: p<0.0001 Hazard ratio: 0.40 ONNumber of patients at risk 1101679042175Observation 66167126864712Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 012345012345 Years Rituximab maintenance median: 51.6 months Observation median: 15.0 months Progression-free survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

17. EORTC 20981: PFS from second randomisation – by induction regimen Progression-free survival after CHOP Overall log-rank test: p<0.0001; HR: 0.30 ONNumber of patients at risk : 5569311141Observation 32766138204Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 Years 012345012345 Overall log-rank test: p=0.004; HR: 0.54 Progression-free survival after R-CHOP ONNumber of patients at risk : 55985931134Observation 34916548278Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 Years 012345012345 Subgroups according to induction treatment Median 42.0 months Median 11.6 months Median 23.1 months Median 51.9 months Progression-free survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

18. EORTC 20981: overall survival from second randomisation Overall log-rank test: p=0.011 HR: 0.52 ON 39167 Observation 23167Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 Years 01234560123456 Number of patients at risk : 1489950142 15511269194 Rituximab maintenance 3 yrs 85.1% Observation 3 yrs 77.1% Overall survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

19. Overall survival after CHOP ONNumber of patients at risk : 19696142237Observation 12767549308Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 Years01234560123456 2 2 Overall log-rank test: p=0.073 EORTC 20981: overall survival from second randomisation – by induction Overall survival (%) Overall survival after R-CHOP ONNumber of patients at risk : 20988757277Observation 119180633911Rituximab Treatment 100 90 80 70 60 50 40 30 20 10 0 Years01234560123456 0 2 Overall log-rank test: p=0.059 Overall survival (%) van Oers M, et al. Blood 2005;106:107a (Abstract 353)

20. ECOG 1496 rituximab maintenance after CVP in untreated indolent NHL: protocol CCyclophosphamide 1,000mg/m 2 i.v. day 1 VVincristine 1.4mg/m 2 (max = 2) i.v. day 1 PPrednisone 100mg/m 2 p.o. days 1–5 Repeat every 21 days; best response + 2 cycles (6–8) Rituximab maintenance 375mg/m 2 weekly x 4, start 4 weeks after CVP; every 6 months for 2 years Observation Rituximab maintenance CVP R A N D O M IS E RESTAGERESTAGE CR, PR, SD Stratify: histology, residual disease Hochster H, et al. Blood 2005;106;10a(Abstract 349)

21. ECOG1496: follicular lymphoma patient characteristics MR (n=120) Obs (n=117) Age >60 years4534 Nodal sites ≥5*3848 LDH abnormal2923 Haemoglobin <121316 Stage IV6664 FLIPI high risk*3835 High tumour burden6267 Minimal residual disease5857 *Data available in 79% of patients Hochster H, et al. Blood 2005;106;10a(Abstract 349)

22. ECOG 1496: median PFS from randomisation in follicular lymphoma patients 1.0 0.8 0.6 0.4 0.2 0 01234560123456 Years from maintenance randomization MR (120) OBS (117) Log-rank one-sided p=0.0000003 HR 0.4 (0.3–0.6) Probability HR = hazard ratio; MR = maintenance rituximab; OBS = observation Hochster H, et al. Blood 2005;106;10a(Abstract 349) Median: 61 months Median: 15 months

23. CVP ± maintenance rituximab: PFS by FLIPI risk group post randomisation 2-yr PFS (%) after randomisation Risk group (n) MR (95% Cl) OBS (95% Cl) p Low (50) 77 (56, 97) 35 (3, 67) 0.11 Intermediate (68) 70 (53, 88) 41 (21, 61) 0.09 High (67) 62 (40, 84) 27 (3, 51) 0.08 Colocci N, et al. Proc Am Soc Clin Oncol 2005;23:566s (Abstract 6526)

24. CVP ± maintenance rituximab (E1496): FLIPI analysis conclusions ECOG 1496 patients disproportionately FLIPI high risk –(47% vs 20% in Solal-Celigny et al.) Lower CVP response in FLIPI high risk group Lower PFS and OS in FLIPI high risk group compared to low risk patients after CVP PFS higher for rituximab maintenance in all FLIPI risk groups Colocci N, et al. Proc Am Soc Clin Oncol 2005;23:566s (Abstract 6526)

25. RandomizationRandomization 4 x FCM 4 x FCM + Rituximab RandomizationRandomization CR,P R 4 x Rituximab 4 x Rituximab Observation only Advanced stage relapsed or refractory FL or MCL F=fludarabine 25mg/m2/d days 1  3 C=cyclophosphamide 200mg/m2/d days 1  3 M=mitoxantrone 8mg/m2/d 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 and all presented data relates to maintenance after R-FCM only Rituximab maintenance after FCM + rituximab in relapsed FL and MCL: study design Hiddemann W et al., Blood 2005;270a (Abstract 920)

26. Rituximab ± FCM ± maintenance: response in FL 100 75 50 25 0 Responders (%) ORRCR 94% 70% 40% 23% p=0.011 p<0.05 Rituximab + FCM FCM Forstpointner R, et al. Blood 2004;104:3064–71

27. Rituximab ± FCM ± maintenance: overall survival (all patients) Forstpointner R, et al. Blood 2004;104:3064–71 1 0.75 0.5 0.25 0 Probability 0123401234 Years R-FCM (50/86) FCM (32/62)

28. Rituximab maintenance after FCM + rituximab in relapsed FL and MCL: 2005 update 174 patients evaluable for the second randomization, 136 of whom had received R-FCM induction In these patients –median DR not reached in the R-maintenance arm vs 17 months for observation (p=0.0024). –benefit for rituximab maintenance demonstrated for both FL and MCL Hiddemann W et al., Blood 2005;270a (Abstract 920)

29. Rituximab maintenance after R-FCM in relapsed FL and MCL: response duration – all patients 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:Abstract 920. Poster update

30. 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 Rituximab maintenance after R-FCM: response duration in FL patients Probability Hiddemann W, et al. Blood 2005; 106:Abstract 920. Poster update

31. Rituximab 375mg/m² every 2 months x 4 n=151 PD off study n=202* Prolonged treatment Rituximab 375mg/m² weekly x 4 Observation R SD, PR, CR Rituximab maintenance versus observation (SAKK35/98): study design Ghielmini M, et al. Blood 2004;103:4416–23 *previously untreated/relapsed indolent NHL

32. Rituximab maintenance versus observation (SAKK35/98): event-free survival 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 24 30 36 42 4854 Months since start of treatment Probability p=0.024 Prolonged treatment (n=73): median 23.2 months Observation (n=78): median 11.8 months Ghielmini M, et al. Blood 2004;103:4416–23

33. Rituximab maintenance for the treatment of indolent NHL: conclusions Rituximab maintenance therapy significantly improves the duration of remission in patients with indolent NHL Rituximab maintenance results in significantly improved overall survival in patients treated with either CHOP or rituximab plus CHOP induction chemotherapy