HELIOS – Klinikum Erfurt Immuno-chemotherapy A new standard in the first-line treatment of advanced indolent (follicular) lymphoma? Michael Herold HELIOS – Klinikum Erfurt Germany Kuala-Lumpur, Malaysia 11.3.06

Increase of NHL – German data 2000 1.855 12.561 1990-2000 + 40%

Non-Hodgkin‘s lymphoma: most frequent (important) entities Entity Cases (%) 5-year survival (%) DLBCL 30 46 Follic. lymphoma 22 72 Marginal-Zone B 8 74 (MALT-Type) B-CLL 7 51 Mantle-Cell L. 6 27 Armitage, Blood 1997

Survival of patients with indolent lymphoma: the Stanford experience 1960–1996 1987–1996 1976–1986 1960–1975 100 80 60 40 20 Median survival ~ 11y! Patients (%) 5-year 80% 10-year 60% 15-year 45% Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease.54 0 5 10 15 20 25 30 Years Adapted from Horning. Semin Oncol 1993;20 (5 Suppl. 5):75–88

Expanding treatment options in advanced follicular lymphoma # Watch and wait # Mono-chemotherapy # Combination chemotherapy # New cytotoxic drugs # High-dose-chemotherapy +/- TBI + APBSCT # Biological therapy: monoclonal antibodies +/- chemotherapy

Rationale for combining chemotherapy and rituximab Single agent activity No cross resistance No over-lapping toxicities Synergistic effects in vitro Sensitisation of NHL cell lines by rituximab against cytotoxic drugs in vitro

Rituximab + CHOP in low-grade NHL: efficacy Czuczman M, et al. Blood 2003;102:411a (Abstract 1493),up date 2005

Rituximab + CHOP in low-grade NHL: conclusions from a phase II study Rituximab plus CHOP results in an overall response rate of 100% Time to progression is prolonged Combination therapy is safe and does not cause significant added toxicity Results have to be confirmed in large scale prospective randomized trials Czuczman M, et al. Blood 2003;102:411a (Abstract 1493)

Chemotherapy +/- rituximab first-line M 39021 CVP vs R-CVP GLSG CHOP vs R-CHOP FL 2000 GELA CHVP vs R-CHVP M 39023 (OSHO) MCP vs R-MCP

Rationale/questions of all studies: Can we improve the outcome of patients with advanced indolent NHL/follicular lymphoma by combining chemotherapy with rituximab? End points : # response rates, especially complete responses # time to progression (PFS) and event-free survival (EFS), resp. time to next treatment # is it even possible to prolong survival, is cure possible??

R-CVP x 4 cycles (q 3 weeks) R-CVP x 4 cycles (q 3 weeks) M39021: study design Follicular NHL (IWF B,C, D) Stage III-IV > 18 yrs. No prior Rx Measurable Dz Central histology review R E S T A G I N R A N D O M I Z E CVP x 4 cycles (q 3 weeks) CVP x 4 cycles (q 3 weeks) CR, PR R-CVP x 4 cycles (q 3 weeks) R-CVP x 4 cycles (q 3 weeks) Inclusion criteria CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D) No previous systemic antilymphoma treatment WBC <25 x 109/L No CNS involvement Additional standard inclusion criteria rituximab 375 mg/m2 IV d1 cyclophosphamide 750 mg/m2 IV d1 vincristine 1.4 mg/m2 IV d1 prednisone 40 mg/m2 PO d1–5 SD,PD off treatment R. Marcus, 2005

Patient characteristics CVP (n=159) R-CVP (n=162) Median age (years) 53 52 Stage III−IV (%) 99 Histology − Follicular NHL (%) Grade 1, 2 89 90 Grade 3 8 9 Elevated LDH level (%) 26 Bulky disease (%) 46 39 Extranodal sites > 1 (%) 17 FLIPI 3−5 (poor prognosis) (%) 50 47 FLIPI 2 (intermediate prognosis) (%) 43 40 FLIPI 0−1 (good prognosis) (%) 7 13 Note: central review of pathology performed on 90% of patients, diagnosis of FL confirmed for 95% of patients

CVP ± rituximab in previously untreated FL: response rates CVP R-CVP Last Response CR 12 (7.5 %) 49 (30.2%) Cru 4 (2.5%) 17 (10.5%) PR 75 (47.2%) 65 (40.1%) SD 33 (20.8%) 12 (7.4%) PD 30 (18.9%) 17(10.5%) ORR 91 (57.1%) 131 (80.9%) Not assessable 5 (3.1%) 2 (1.2%) Best Response (either after cycle 4 or 8) CR 13 (8.2%) 49 (30.2%) Cru 5 (3.1%) 17 (10.5%) PR 86 (54.1%) 71 (43.8%) SD 37 (23.3%) 14 (8.6%) PD 13 (8.2%) 9 (5.6%) ORR 104 (65.4%) 137 (84.6%)

Primary endpoint: time to treatment failure median FU 42 months 1.0 0.9 0.8 0.7 0.6 Event-free probability R-CVP: median 27.0 months 0.5 0.4 0.3 0.2 CVP: median 6.6 months p <0.0001 0.1 6 12 18 24 30 36 42 48 54 60 Study month Patients at risk: CVP 159 86 51 34 30 21 16 5 1 R–CVP 162 123 113 98 93 76 66 36 15 5

Time to progression, relapse or death median FU 42 months 1.0 0.9 0.8 0.7 0.6 R-CVP: median 34 months Event-free probability 0.5 0.4 0.3 CVP: median 15 months 0.2 p < 0.0001 0.1 6 12 18 24 30 36 42 48 54 60 Study month Patients at risk: CVP 159 129 87 64 51 39 29 14 5 R–CVP 162 144 132 112 105 84 73 40 16 5

Duration of response median FU 42 months 1.0 0.9 0.8 0.7 R-CVP: median 38 months 0.6 Event-free probability 0.5 0.4 0.3 CVP: median 14 months 0.2 p < 0.0001 0.1 6 12 18 24 30 36 42 48 54 60 Study month Patients at risk: CVP 104 78 53 41 29 25 13 2 R–CVP 137 128 110 100 87 75 54 28 12 1

Disease-free survival median FU 42 months 1.0 0.9 0.8 0.7 R-CVP: median 45 months 0.6 Event-free probability 0.5 0.4 0.3 CVP: median 21 months 0.2 p = 0.0006 0.1 6 12 18 24 30 36 42 48 54 60 Study month Patients at risk: CVP 18 16 14 11 7 6 4 R–CVP 66 65 60 57 47 43 23 8 3

Overall survival median FU 42 months R-CVP: median not reached 1.0 0.9 0.8 0.7 CVP: median not reached 0.6 Event-free probability 0.5 89 % vs 81 % 0.4 0.3 0.2 p = 0.0553 0.1 6 12 18 24 30 36 42 48 54 60 Study month Patients at risk: CVP 159 155 151 141 136 132 122 72 38 7 R–CVP 162 162 160 155 150 144 135 82 43 14

Cox regression analysis: TTP by subgroup 0.5 0.1 0.9 1.2 1.6 Baseline parameter Category n Lower 95% CL Estimate All patients Total 321 0.320 0.422 0.558 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 Extra-nodal sites >1 0–1 56 265 0.351 0.292 0.686 0.399 1.341 0.545 BM involved (local) 205 112 0.332 0.469 0.662 0.547 Elevated LDH 78 226 0.240 0.264 0.431 0.375 0.773 0.532 Elevated B2M 140 148 0.279 0.255 0.420 0.397 0.630 0.617 IPI (CRF validated) 143 159 0.259 0.298 0.406 0.439 0.636 0.648 B-symptoms 116 0.314 0.263 0.505 0.377 0.812 0.541 Bulky disease 136 185 0.256 0.318 0.394 0.462 0.608 Nodal sites <5 ≥5 54 267 0.297 0.459 0.401 1.040 0.543 Haemoglobin (g/dL) >12 12 251 66 0.419 0.355 0.748 0.495 1.335 FLIP index (prognosis) 0–2 (good) 3–5 (poor) 155 146 0.242 0.323 0.373 0.479 0.577 0.709 Upper Note: CL = confidence limit. Vertical line = risk ratio estimate for all patients. Horizontal bars = 95% CLs for relevant category. Model includes stratification by center pool.

Summary of results CVP R-CVP p-value (n=159) (n=162) Median time to treatment failure (months) Median time to progression (months) Median time to new antilymphoma treatment (months) Overall response (%) Median duration of response (months) Estimated 3-year overall survival (%) Complete response (%) 57 81 <0.0001 10 41 <0.0001 7 27 <0.0001 14 34 <0.0001 12 46 <0.0001 14 38 <0.0001 81 89 0.0553

Conclusions The addition of rituximab to each of 8 courses of CVP demonstrates major improvement in all clinical endpoints R-CVP is an effective, short and very low toxicity regimen R-CVP shows superior efficacy to any other chemotherapy regimen published in a large scale clinical trial

R-CHOP versus CHOP in previously untreated follicular NHL and MCL: protocol Peripheral blood stem cell transplant CHOP x 4–6 + rituximab CR, PR <60 years 2 x CHOP (+ MabThera) + standard IFN-maintenance 2 x CHOP (+ MabThera) + intensive IFN-maintenance CHOP x 4–6 CR, PR ≥60 years 2 x CHOP (+ MabThera) + standard IFN-maintenance Hiddemann W, et al. Blood 2004;104:50a (Abstract 161)

R-CHOP versus CHOP in previously untreated follicular NHL: response Hiddemann W, et al. Blood 2005

R-CHOP versus CHOP in previously untreated follicular NHL: TTF 100 80 60 40 20 R-CHOP (231/285) Patients (%) CHOP (164/272) p<0.0001 0 1 2 3 4 5 Years Hiddemann W, et al. Blood 2005

R-CHOP versus CHOP in previously untreated follicular NHL: overall survival 100 80 60 40 20 R-CHOP (272/285) CHOP (249/272) Patients (%) P=0,016 0 1 2 3 4 5 Years Hiddemann W, et al. Blood 2005

Staging including CT-scan and bone marrow biopsy FL2000 study design R Arm A Arm B Staging including CT-scan and bone marrow biopsy 12 months 6 months D1 Cyclophosphamide 600 mg/m2 D1 Doxorubicin 25 mg/m2 D1 Etoposide 100 mg/m2 D1-D5 Prednisone 40 mg/m2 α-IFN 2b (Roferon) : 4.5 MU t. i. w for 18 months (3MU if aged > 70) Rituximab : 375 mg/m2 every month for 6 months (arm A & B) then every 2 months in arm A

FL2000: response at the end of planned therapy (18 months - 358 patients) Arm A (n= 183) Arm B (n=175) p CR + CRu 109 (60%) 132 (75%) .0046 Partial Response 22 (12%) 10 (6%) Stable/PD/Death 52 (28%) 33 (19%) Cheson criteria G. Salles - December 2004 ASH Meeting

FL2000 : event-free survival GS - December 2004 ASH Meeting Median follow-up 31 months Log-Rank P= 0.0031 63% 78% Arm B Arm A Arm B Arm A GS - December 2004 ASH Meeting

R-MCP x 6 cycles (q 4 weeks) R-MCP x 2 cycles (q 4 weeks) M 39023: study design Advanced FL, IC and MCL 18–75 years No prior Rx Central histology review Written informed consent R ESTAGING R A N D O M I Z E MCP x 6 cycles (q 4 weeks) MCP x 2 cycles (q 4 weeks) CR, PR R-MCP x 6 cycles (q 4 weeks) R-MCP x 2 cycles (q 4 weeks) Inclusion criteria CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D) No previous systemic antilymphoma treatment WBC <25 x 109/L No CNS involvement Additional standard inclusion criteria IFN-maintenance for FL SD, PD off treatment MCP ± rituximab Rituximab 375mg/m2 IV d 1 Mitoxantrone 8 mg/m² IV d 3 + 4 Chlorambucil 3 x 3mg/m² PO d 3–7 Prednisolone 25 mg/m² PO d 3–7 ASH, San Diego 12/04 9. ICML, Lugano 6/05

M 39023: rituximab + MCP vs MCP (n=358 ITT) Other (n=29) 8% IC (n=34) 10% R-MCP (n=181) 50.6% FL (n=201) 57% MCL (n=90) 25%

M 39023: demographic characteristics follicular lymphoma R-MCP (105) MCP (96) Age median 60 (33–78) 57 (31–76) Sex m/f 53/52 36/60 FLIPI (low/interm./high) 8/38/59 6/37/53 Median f/u 7/05 43 (37) 31 mo. ECOG (0/1/2/3) 68/29/7/1 54/36/6/0 Stage III/IV 30/75 22/74 Bone marrow 73 71

M 39023 toxicity (all SP patients) R-MCP(n = 183) events/pt. AE total 1.839/180 (98%) SAE total 58/34 (19%) AB-inf.reaction 1/1 (0,5%) (CTC 3) WBC CTC 3+4 457/130 (71%) PLT CTC 3+4 20/19 (11%) Infection CTC 3+4 9/9 (5%) FUO CTC 3 9/14 (8%) MCP(n = 177) events/pt. 1.589/157 (89%) 69/41 (23%) 0/0 (0%) 342/96 (54%) 32/18 (10%) 16/14 (8%) 2/2 (1%)

M 39023: remission rates FL patients (ITT population) R-MCP MCP p n = 105 n = 96 RR (%) CR (%) 92.4 75 0.0009 49.5 25 0.0004

Progression-free survival M39023: progression-free survival FL patients (ITT population) median f/u 37 months 1.00 0.75 0.50 0.25 3y PFS 77.4% Progression-free survival R-MCP: median 54.3 months 3y PFS 44% MCP: median 27.8 months Censored Events 27 vs 54 p<0.0001 0 10 20 30 40 50 60 Time (months)

M39023: overall survival FL patients (ITT population) median f/u 37 months 3y OS 88% 1.00 0.75 0.50 0.25 3y OS 74% Overall survival R-MCP: median not reached MCP: median not reached Censored Events 14 vs 24 P=0.0140 0 10 20 30 40 50 60 Time (months) Cause specific deaths: R-MCP 7 vs MCP 16 p=0.0261

Phase III trials of chemo versus R-chemo in previously untreated advanced follicular NHL Study Treatment, n median FU (mos) ORR (%) CR (%) TTP (median, mos) OS Solal-Celigny et al. [2005] CVP, 159 R-CVP, 162 42 57 81 10 41 14 34 (p<0.0001) 81% 89% (est. 3-yr; p=0.0553) Hiddemann et al. [2005] CHOP, 205 R-CHOP, 223 18 90 96 17* 20* 29 NR (TTF; p<0.001) 90% 95% (est. 2-yr; p=0.016) Herold et al. [2005] MCP, 96 R-MCP, 105 37 75 92 25* 50* 25 54 (TTF;p<0.0001) 74% 88% (36 mos; p=0.014) Salles et al. [2004] CHVP-IFN, 175 R-CHVP-IFN, 184 30 73 84 63 79 62% 78% (EFS; p=0.003) N/A *patients who fulfilled CR criteria but had no evaluable negative BM biopsy defined as PR, not CRu

Antibody based therapy - conclusions New and promising treatment option for NHL including follicular lymphoma, # effective # very well tolerated # but expensive!! ?   Combination of AB with chemotherapy improves the outcome significantly and is a new standard in 2005 Curative potential ?? More, and new, moAB and AB-conjugates will be introduced soon

Treatment costs M 39023 Type MCP R-MCP p-value Active treatment* € 21,500 € 35,600 < 0.01 Observation† € 30,700 € 17,900 Total € 52,200 € 53,500 0.6 * Active treatment includes the cost of managing adverse events. † Observation includes the costs associated with disease progression, complications, new therapies and other costs.

Cumulative treatment costs – per period analyses M 39023 90,000 80,000 MCP 70,000 60,000 Cumulative treatment costs (€) R-MCP 50,000 40,000 30,000 20,000 21 months after end of initial therapy 10,000 obs 1 obs 2 obs 3 obs 4 obs 5 obs 6 obs 7 obs 8 obs 9 obs 10 obs 11 obs 12 obs 13 obs 14 therapy Unpublished data

Antibody based therapy - conclusions New and promising treatment option for NHL including follicular lymphoma, # effective # very well tolerated # but expensive !! ? Combination of AB with chemotherapy improves the outcome significantly and is a new standard in 2006 Curative potential ?? More, and new, moAB and AB-conjugates will be introduced soon European study perspectives   

OSHO # 70 (only G) + PRIMA Study (EU) European Cooperation OSHO # 70 (only G) + PRIMA Study (EU) R A N D O M I Z E OSHO # 70 Study (>65) R–maintenance (SAKK): 375 mg/m² q 2 mo. x 2 y R – MCP x 6 + 2 R R – CHOP x 6 + 2 R R – FCM x 6 + 2 R R A N D O M I Z E CR+PR  ChRx x 6-8 Rituximab x 8 Observation PRIMA = Primary Rituximab and Maintenance

Advanced FL (<65 J.) RI-CHOP M I S T HD-ChRx + APBSCT + Rituximab–maintenance 375 mg/m² q 2 months/2y. R-CHOP x 6 + 2 x R CR, PR Rituximab–maintenance 375 mg/m² q 2 months/2 y.

Perspectives for follicular lymphoma? 1987–1996 1976–1986 1960–1975 100 80 60 40 20 2000 – 2010?? Patients (%) Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease.54 0 5 10 15 20 25 30 Years