Marinus van OersProfessor of Hematology/Head of the Department of Clinical Hematology,

Academic Medical Center, University of Amsterdam, The Netherlands

Chairman of the DutchHematology Society

Chairman of the HOVON CLL Group

Co-authored numerous papers in national and international peer-reviewed scientific journals

Principal investigator of theEORTC 20981 study

Prior Chairman of the Lymphoma Group of the Dutch Cancer Society

Prior board member of the Dutch Hemato-oncology Group

Academic Medical Center

Maintenance treatment in follicular lymphoma (FL): indications

and considerations

Marinus van OersAcademic Medical Center,

University of Amsterdam, The Netherlands

Rituximab maintenance therapy in FL: objectives

Natural history of FL Relapsing/remitting course Duration of response (DR) to subsequent therapy

diminishes

Rituximab maintenance therapy in FL: objectives

Natural history of FL Relapsing/remitting course Duration of response (DR) to subsequent therapy

diminishes

Objectives of rituximab maintenance therapy Maintain remission, because prolonged remission predicts

for improved overall survival (OS)1–3

Improve response quality over time (partial response [PR] complete response [CR])

Eradicate minimal residual disease (MRD), thereby potentially increasing OS

1Gallagher C, et al. J Clin Oncol 1986;4:1470–802Weisdorf D, et al. J Clin Oncol 1992;10:942–7

3Montoto S, et al. Ann Oncol 2002;13:523–30

Rituximab maintenance in follicular non-Hodgkin’s lymphoma (NHL): rationale

Maintenance treatment with cytotoxic agents or interferon alpha does not improve OS, but has considerable side effects and long term toxicity1

Rituximab has minimal acute toxicity2

There is no known cumulative toxicity2

The CD20 persists on residual or recurrent lymphoma3

Long half-life allows infrequent therapy while maintaining long-term exposure (in contrast to chemotherapy)3

1Rohatiner A, et al. Br J Cancer 2001;85:29–352Kimby E, et al. Cancer Treat Rev 2005;31:456–73

3Berinstein N, et al. Ann Oncol 1998;9:995–1001

Rituximab maintenance studies in FL

Maintenance after induction with single agent rituximab SAKK 35/981

Minnie Pearl2

Maintenance after induction with chemotherapy ECOG 14963

Maintenance after induction with rituximab +chemotherapy EORTC 209814

GLSG51Ghielmini M, et al. Blood 2004;103:4416–23

2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–953Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

4van Oers MHJ, et al. Blood 2006;108:3295–3015Forstpointner R, et al. Blood 2006;108:4003–8

Rituximab 375mg/m² every 2 months x 4

n=151

PD off study

n=202

Prolongedtreatment

Rituximab375mg/m²weekly x 4

Observation

R

SD, PR, CR

SAKK 35/98: study design Phase III trial of rituximab maintenance therapy

202 patients with previously untreated (n=64) or relapsed/refractory FL; 151 (51 previously untreated) patients randomised

Ghielmini M, et al. Blood 2004;103:4416–23 R = rituximab SD = stable disease; PD = progressive disease

SAKK 35/98 results 52% response to induction rituximab

No increase in toxicity with rituximab maintenance versus observation

Median EFS (months)* Observation

Rituximabmaintenance p value

All patients 11.8 23.2 0.024

Previously untreated 19.0 36.0 0.009

*Patients randomised

Ghielmini M, et al. Blood 2004;103:4416–23EFS = event-free survival

ECOG 1496 study: rituximab maintenance after first line treatment of indolent NHL

Phase III trial of CVP ± rituximab maintenance therapy 401 patients with previously untreated indolent NHL

– 322 randomised– 237 (78%) with follicular histology

Hochster HS, et al.Blood 2005;106:106a (Abstract 349)

Observation

Rituximab maintenance therapy

• 375mg/m2 weekly x 4• every 6 months x 4

RANDOMISE

PR, CR or stable

CVP 6–8 cycles

ECOG = Eastern Cooperative Oncology GroupCVP = cyclophosphamide/vincristine/prednisone

ECOG 1496: progression-free survival (PFS) in FL

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6

Years from maintenance randomisation

MR (120)

Observation (117)

Log-rank one-sided p=0.0000003HR: 0.4 (0.3–0.6)

Pro

bab

ilit

y

HR = hazard ratioMR = rituximab maintenance therapy Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

Median PFS: 61 months vs 15 months

ECOG 1496: PFS at 3 years from randomisation

Characteristic MR Observation p valueHR

(95% CI)

All patients (n=237) (%) 62 36 0.0000003 0.4 (0.3–0.6)

FLIPI score (%)

0–2 (n=118)

3–5 (n=68)

59

58

36

35

0.002

0.004

0.5 (0.3–0.8)

0.4 (0.2–0.8)

Tumour burden (%)

Low (n=85)

High (n=152)

65

59

51

28

0.025

<0.0001

0.5 (0.3–1.0)

0.4 (0.2–0.6)

Residual disease (%)

MRD (n=170)

Gross (n=134)

73

48

41

30

<0.001

0.005

0.3 (0.2–0.5)

0.5 (0.3–0.9)

Total events 42 74 – –

Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

CI = confidence interval; FLIPI = Follicular Lymphoma International Prognostic Index

ECOG 1496: OS in FL

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6

MR (120)

Observation (117)

Log-rank one-sided p=0.03HR: 0.5 (0.3–1.1)

Pro

bab

ilit

y

Years from maintenance randomisation

OS at 42 months from randomisation: 91% vs 75%

Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

ECOG 1496: conclusions

After successful induction, MR – delays disease progression, with more than half of

patients remaining disease-free more than 4 years after completion of CVP

– shows a strong trend towards improved OS for rituximab maintenance over observation at a median 3-year follow-up after randomisation

Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

EORTC 20981: trial design Phase III trial of CHOP ± rituximab, with or without MR 465* patients with relapsed or refractory FL 334 randomised to maintenance versus observation

CHOP x 6

R-CHOP x 6

Observation

MR 375mg/m2

Every 3 months to relapse or for 2 years

RANDOMISE

van Oers MHJ, et al. Blood 2006;108:3295–301

RANDOMISE

*474 patients randomised; nine excluded due to missing consent forms

CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone

EORTC 20981: patient characteristics at second randomisation (n=334)

Observation

(n=167) MR

(n=167)

Induction (%) CHOP R-CHOP

41 59

45 55

Induction response (%) CR PR

29 71

29 71

FLIPI 2 (%) 70 66

van Oers MHJ, et al. Blood 2006;108:3295–301

EORTC 20981: rituximab maintenance prolongs PFS by more than 3 years

Overall log-rank test: p<0.001HR: 0.40

100

80

60

40

20 0

0 1 2 3 4 5Years

MRMedian 51.5 months

ObservationMedian 14.9 months

PF

S (

%)

van Oers MHJ, et al. Blood 2006;108:3295–301

Rituximab maintenance prolongs PFS irrespective of induction therapy

PFS after CHOP (n=145)

Overall log-rank test: p<0.001; HR: 0.30

100

90

80

70

60

50

40

30

20

10

0

Years

0 1 2 3 4 5

Overall log-rank test: p=0.004; HR: 0.54

PFS after R-CHOP (n=189)

Years

MRMedian 42.2 months

ObservationMedian 11.6 months

ObservationMedian 23.0 months

MRMedian 51.8 months

PF

S (

%)

PF

S (

%)

van Oers MHJ, et al. Blood 2006;108:3295–301

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5

MR significantly prolongs OS

Overall log-rank test: p=0.011HR: 0.52

100

90

80

70

60

50

40

30

20

10

0

Years0 1 2 3 4 5 6

MR 3 years 85.1%

Observation 3 years 77.1%

OS

(%

)

van Oers MHJ, et al. Blood 2006;108:3295–301

Rituximab maintenance effect on OS: analysis by induction therapy

OS after CHOP100

90

80

70

60

50

40

30

20

10

0

Years0 1 2 3 4 5 6

Overall log-rank test: p=0.073HR: 0.52

OS

(%

)

OS after R-CHOP

Years

Overall log-rank test: p=0.059HR: 0.49

OS

(%

)

van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation

MR

Observation

MR

Observation

100

90

80

70

60

50

40

30

20

10

00 1 2 3 4 5 6

Adverse events during maintenance: events with >2% reported grade 3-4 events

(World Health Organization)

Per

cen

t

Neutropenia PulmonaryInfection Skin

Observation

Rituximab

Cardiacvan Oers MH, et al. Blood 2006;108:3295–301

*

*p=0.009

10

5

0 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4

EORTC 20981: conclusions

Rituximab maintenance therapy superior to observation for PFS– in the overall population– in subgroups (after R-CHOP/CHOP, after CR/PR)

Rituximab maintenance therapy improves OS– in the overall population– in subgroups longer follow-up required

van Oers MHJ, et al. Blood 2006;108:3295–301van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation

The cost-effectiveness plane: EORTC 20981 analysis

Incremental drug benefit (QALYs)

Incr

emen

tal

cost

s (£

/$ C

AD

)

£/$

£/$

£/$

£/$

Maturi B, et al. Blood 2006;108:106a (Abstract 343)QALY = quality adjusted life years

Cost-effectiveness

threshold

Area of acceptance

Area of rejection

R-maintenance = 17,136/0.839 = $20,428 CAD/QALY gained

1 1.5 20.50

The German Lymphoma Study Group trial: study design

RANDOMISE

4 x FCM

Rituximabplus

4 x FCM

RANDOMISE

MR*

Observation only

Advanced stage relapsed/refractory FL or MCL

Forstpointner R, et al. Blood 2004;104:3064–71

*4 x rituximab (375 mg/m2) at 3 and 9 months after induction

CR/PR

CR/PR

MCL = mantle cell lymphomaFCM = fludarabine/cyclophosphamide/mitoxantrone

MR after R-FCM improves DR in patients with FL and MCL

MR (32/41)Median: not

reached

Observation (21/40)Median: 26 months MR (11/22)

Median: 14 months

Observation (2/25) Median: 12 monthsp=0.035 p=0.049

1.00

0.75

0.50

0.25

0

Years

0 1 2 3 4 5 6

Pro

bab

ilit

y

Years

0 1 2 3 4 5 6

FL MCL

Forstpointner R, et al. Blood 2006;108:4003–8

Pro

bab

ilit

y

1.00

0.75

0.50

0.25

0

Rituximab maintenance versus retreatment upon relapse

Minnie Pearl Cancer Research Network: rituximab maintenance versus retreatment

Phase II randomised trial of MR versus retreatment at disease progression

114 patients with relapsed/refractory indolent NHL following prior chemotherapy, 90 randomised

Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95

Rituximab retreatment• 375mg/m2 qw x 4• Retreat if responsive disease

for 3 months after each course

Rituximab maintenance• 375mg/m2 qw x 4• 6, 12 and 18 months

PR, CR or stable

Rituximab375mg/m2

weekly x 4

RANDOMISE

MR achieves improved outcomes compared with retreatment

Rituximab

OutcomeMaintenance

(n=44)Retreatment

(n=46) p

Overall response rate (%) 52 35 0.14

CR (%) 27 4 0.007

Continuous remission (%) 45 24 0.05

Remaining in CR (%) 23 2 0.03

Median PFS (months) 31.3 7.4 0.007

Median duration of benefit (months)* 31.3 27.4 0.94

Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95

*Subjective primary endpoint

58/106 (55%) still in response at end of

2 years maintenance

19/58 still in remission after

7 years

35/58 progressed 4/58 died while still in remission

Rituximab retreatment after MR

Hainsworth JCO 2002;20:4261

Hainsworth JCO 2005;23:1088

MR versus retreatment: conclusions

The majority of patients who relapse after 2 years of MR remain sensitive to rituximab – can even be given MR again

Retreatment with rituximab, as a single agent, or in combination with chemotherapy, is a reasonable therapeutic option at the time of progression

A ongoing prospective phase III study (RESORT) also addresses quality of life and pharmacoeconomics

Hainsworth JD, et al. Blood 2006;108:263b (Abstract 4723)

MR schedules: all demonstrate significantly improved outcome

Study Schedule Outcomes

Maintenance after induction with single agent rituximab

SAKK 35/981 One dose every 2 months x 4

EFS (median)23.2 vs 11.8 months

Minnie Pearl2 Four doses every 6 months for 2 years

PFS (median)31.3 vs 7.4 months

Maintenance after induction with chemotherapy

ECOG 14963 Four doses every 6 months for 2 years

PFS (median)61.0 vs 15.0 months; OS

Maintenance after induction with rituximab + chemotherapy

EORTC 209814 One dose every 3 months for 2 years

PFS (median)51.5 vs 14.9 months: OS

GLSG5 Four doses at 3 and 9 months

DR (median)NR vs 17.0 months

1Ghielmini M, et al. Blood 2004;103:4416–23; 2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–953Hochster HS, et al. Blood 2005;106:106a (Abstract 349)

4van Oers MHJ, et al. Blood 2006;108:3295–301; 5Forstpointner R, et al. Blood 2006;108:4003–8

MR in FL: open questions

Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study)

MR in FL: open questions

Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study)

Optimal rituximab maintenance regimen– schedule– duration

MR in FL: open questions

Role of rituximab maintenance after R-chemotherapy in first line (PRIMA study)

Optimal rituximab maintenance regimen– schedule– duration

• 2 years? • until relapse?

– long term toxicity?– Ig levels/infections– CD20-negative relapse

Ongoing trials of rituximab maintenance

Study Description

PRIMA* Maintenance versus observation after first-line R-chemotherapy

BNLI* Watch and wait versus rituximab monotherapy versus monotherapy plus maintenance

SAKK* Maintenance (8 months) versus maintenance until progression (maximum 5 years) after first-line rituximab

ECOG(RESORT)†

Rituximab extended schedule or retreatment after first-line R-monotherapy

*One infusion every 2 months †One infusion every 3 months or four infusions at relapse

Rituximab maintenance therapy: conclusions

Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit

Rituximab maintenance therapy: conclusions

Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit

The benefit of rituximab maintenance is observed

– after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy

– in previously untreated and relapsed/refractory patients

– in MCL as well as FL

– in patients with low-, intermediate- and high-risk FL

Rituximab maintenance therapy: conclusions

Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit

The benefit of rituximab maintenance is observed

– after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy

– in previously untreated and relapsed/refractory patients

– in MCL as well as FL

– in patients with low-, intermediate- and high-risk FL

Rituximab maintenance appears to be safe, despite prolonged B-cell depletion

Rituximab maintenance therapy: conclusions

Rituximab + chemotherapy induction and rituximab maintenance therapy is the standard in relapsed/refractory indolent NHL, where it confers a PFS and OS benefit

The benefit of rituximab maintenance is observed

– after rituximab monotherapy, chemotherapy and rituximab immunochemotherapy

– in previously untreated and relapsed/refractory patients

– in MCL as well as FL

– in patients with low-, intermediate- and high-risk FL

Rituximab maintenance appears to be safe, despite prolonged B-cell depletion

Rituximab maintenance therapy is a cost-effective treatment strategy for patients with FL