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

Indolent NHL: a survival benefit with

rituximab-based therapy

Christian BuskeUniversity 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

0 4 8 12 16 20 24

Observation (n=151)Chlorambucil (n=158)

100

80

60

40

20

0

Cu

mu

lati

ve s

urv

ival

(%

)

Time (years)

Horning SJ. Semin Oncol 1993;20(Suppl. 5):75–88

Survival (n=1,021), 1960–1991

Years

100

80

60

40

20

00 6 12 18 24 30 36

1960–19751976–19861987–1991

Act

uar

ial

surv

ival

(%

)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 action1

Good efficacy1

Favourable tolerability2

Non-overlapping toxicity profile with conventional chemotherapy2

1McLaughlin P, et al. Semin Oncol 1999;26(Suppl. 14):79–872Kimby 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

RANDOMISATION

CVP x 4 cycles(every 3 weeks)

Rituximab + CVP x 4 cycles

(every 3 weeks)

RESTAGING

CVP x 4 cycles(every 3 weeks)

R + CVP x 4 cycles

(every 3 weeks)

SD, PD off treatment

CR, PR

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

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

Response

CVP (n=159)

R + CVP (n=162)

p value

ORR (%) 57.2 80.9 <0.0001

CR (%) 7.5 30.2

CRu (%) 2.5 10.5

CR/CRu (%) 10.0 40.7 <0.0001

PR (%) 47.2 40.1

Marcus R, et al. Blood 2005;105:1417–23

ORR = overall response rateCRu = unconfirmed CR

Adding rituximab to first-line CVP prolongs time to treatment failure (TTF) in FL

Study month

Eve

nt-

free

pro

bab

ility

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 monthsp<0.0001

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

0 6 12 18 24 30 36 42 48 54 60 66 72

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 parameter Category 0.1 0.5 0.9 1.2 1.6 n

Lower95% CL Estimate

Upper95% CL

All patients Total 321 0.320 0.422 0.558BNLI criteria Yes

No91

230

0.202

0.315

0.347

0.440

0.596

0.613Age (years) 60

>60236

85

0.333

0.206

0.461

0.372

0.638

0.671Extranodal sites >1

0–156

265

0.351

0.292

0.686

0.399

1.341

0.545BM involved (local) Yes

No205

112

0.332

0.202

0.469

0.332

0.662

0.547Elevated LDH Yes

No78

226

0.240

0.264

0.431

0.375

0.773

0.532Elevated B2M Yes

No140

148

0.279

0.255

0.420

0.397

0.630

0.617IPI (CRF validated) 0–1

>1143

159

0.259

0.298

0.406

0.439

0.636

0.648B symptoms Yes

No116

205

0.314

0.263

0.505

0.377

0.812

0.541Bulky disease Yes

No136

185

0.256

0.318

0.394

0.462

0.608

0.671Nodal sites <5

≥554

267

0.202

0.297

0.459

0.401

1.040

0.543Haemoglobin (g/dL) >12

12251

66

0.255

0.419

0.355

0.748

0.495

1.335FLIPI(prognosis)

0–2 (good) 3–5 (poor)

155

146

0.242

0.323

0.373

0.479

0.577

0.709*Cox regression analysis42-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

Eve

nt-

free

pro

bab

ility

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54 60 66 72

p=0.0290

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

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

CR, PR

RANDOMISE

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/prednisonePBSCT = peripheral blood stem-cell transplantationIFN = interferon

CHOP ± rituximab in previously untreated FL: study design

RANDOMISE

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

Pro

bab

ilit

y, p

0 1 2 3 4Years

R-CHOP (195/223)

CHOP (144/205)

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

00 1 2 3 4

Years

Pro

bab

ilit

y o

f O

S

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

RANDOMISE

MCP every28 days

(6 cycles)

R-MCP every28 days

(6 cycles)

RESTAGING

IFN- 2b maintenance for FL patients in CR/PR

4 weeks after completing induction

SD/PD

MCP every28 days

(2 cycles)

R-MCP every28 days

(2 cycles)

CR/PR

Off treatment

Herold M, et al. J Clin Oncol 2007;25:1986–92 MCP = 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 (%) 75 92 0.0009

CR (%) 25 50 0.0004

Median DR (months) 35 NR <0.0001

Median TTNLT (months) 29.4 NR 0.0002

Median EFS (months) 26 NR <0.0001

Median PFS (months) 28.8 NR <0.0001

4-year OS (%) 74 87 0.0096

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

Adding rituximab to first-line MCP prolongs PFS in FL

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

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)

0 10 20 30 40 50 60

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=0.0096Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

1.00

0.75

0.50

0.25

0

OS (months)

0 10 20 30 40 50 60

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 Cyclophosphamide 600mg/m2

D1 Doxorubicin 25mg/m2 D1 Etoposide 100mg/m2 D1–D5 Prednisone 40mg/m2

IFN- 2b (Roferon): 4.5MU t.i.w. for 18 months (3MU if aged 70 years)

Rituximab: 375mg/m2

R

CHVP/IFN

Every month for 6 months (both arms) then every 2 months for CHVP/IFN alone

12 months6 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

EFS 46 67 <0.0001

OS 84 91 0.029

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)

RANDOMISATION

4 x FCM

4 x FCM +

rituximab

RANDOMISATION

CR,PR

CR,PR

4 xrituximab

4 xrituximab

Observation

only

Advanced stage relapsed or refractory FL or MCL

F = fludarabine 25mg/m2/day days 13 C = cyclophosphamide 200mg/m2/day days 13 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

R-FCM in relapsed FL and mantle cell lymphoma (MCL): trial design

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 therapy0 1 2 3 4 5 6 7

Rituximab (52/85)

Observation (29/91)p=0.0006

Pro

bab

ilit

y

Hiddemann W, et al. Blood 2005;106:270a (Abstract 920)

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 therapy0 1 2 3 4 5 6 7

Rituximab (32/41)

Observation (21/40)p=0.035

Adding rituximab to FCM prolongs response duration in relapsed FL

Pro

bab

ilit

y

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;106:2431Marcus 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

R-chemo significantly improved OS compared with chemo alone (all patients)

Favours R-chemo Favours chemotherapy

R-chemon/N

Chemotherapyn/N

HR(95% Cl)

Weight(%) HR (95% Cl)

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)

0.1 0.2 0.5 1 2 5 10

Forstpointer, 2004* 16/66 30/62 0.42 (0.23–0.74)Herold, 2004* 37/181 51/177 0.60 (0.40–0.92)Hiddemann, 2005 6/223 17/205 0.60 (0.40–0.92)Lenz, 2005 10/62 11/60 0.96 (0.41–2.26)Marcus, 2005 21/162 28/159 0.70 (0.40–1.23)Rivas-Vera, 2005 10/66 6/55 0.96 (0.32–2.91)van Oers, 2006 52/234 65/231 0.74 (0.52–1.07)

*Includes unpublished data provided by investigators

100.00

10.9120.8920.854.98

11.632.97

27.77

HR = hazard ratio; CI = confidence interval Schulz 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

7

6

5

4

3

2

1

0R-CVP CVP

QA

LYs

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)

ORR CR/CRu PR SD PD

100

80

60

40

20

0

Per

cen

tag

e

Cheson d78Best response

74

26

47

20

6

80

49

31

146

Solal-Celigny P, et al. Blood 2004;104:169a (Abstract 585)*4 x 375mg/m2

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

Per

cen

tag

e

100

90

80

70

60

50

40

30

20

10

00 10 20 30 40 50 60 70 80 90 100

Colombat P, et al. Blood 2006;108:147a (Abstract 486)*4 x 375mg/m2

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)

Per

cen

tag

e

100

90

80

70

60

50

40

30

20

10

00 10 20 30 40 50 60 70 80 90 100

*4 x 375mg/m2 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)

Per

cen

tag

e

100908070605040302010

00 10 20 30 40 50 60 70 80 90 100

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