Management of Follicular Lymphoma

F Morschhauser

Centre Hospitalier Universitaire de Lille, France

When are we going to starta cytotoxic treatment ?

GELA criteria BNLI criteria

Rapid disease progression in the preceding 3 months

Life threatening organ involvement

Renal or liver infiltration Bone lesions

Systemic symptoms or pruritus Hb<10 g/dL or WBC< 3.0×109/L

or Plat.<100×109/L ; related to marrow involvement

High tumor bulk defined by either:- a tumor > 7 cm- 3 nodes in 3 distinct areas

each > 3 cm- symptomatic splenic enlargement- organ compression- ascites or pleural effusion

Presence of systemic symptoms

Serum LDH or β2-microglobulin above normal values

Management of Follicular lymphoma

Low tumor burden

Compulsory CT scan

Compulsory CT scan

CT scan only if

clinical CR

Bone marrow for histology and MRD only if CT shows cCR

RANDOMISATION

ARM AWatch and Wait

ARM BRituximab Induction

ARM CRituximab Induction

& maintenance

Continued follow up

Progressive disease requiring therapystops protocol

treatment

Clinic visits

RWW Study(Ardeshna et al, ASH 2010)

cc

Proportion of patients

with no new

treatment initiated

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

% not requiring Rx at 3yr W+W=48% R4=80% R4+RM=91%

Time to Initiation of New Therapy

Events Totals

W+W 83 187

R4 19 84

R4 + M

19 192

HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001

HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p<0.001

HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p=0.10

Years from randomisation

Proportion of

patients progression-

free

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years from randomisation0 1 2 3 4 5

Progression-free survival

HR (Rituximab vs W+W) = 0.46, 95%CI = 0.33, 0.65, p<0.001

HR (Rituximab + M vs W+W) = 0.21, 95%CI = 0.15, 0.29, p<0.001

HR (Rituximab + M vs Rituximab) = 0.43, 95%CI = 0.24, 0.72, p=0.001

3yr PFS W+W=33% R4=60% R4+RM=81%

Events Totals

W+W 108 181

R4 33 83

R4 + M

33 189

% of patients

alive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5

Overall survival

3yr OS=95%

Years from randomisation

HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42

HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72

HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75

Events Totals

W+W 9 187

R4 4 84

R4 + M

8 192

375 mg/m² every 2 months x 4

n = 151

PDofftrial

FL n = 202

Prolonged375 mg/m²weekly x 4

Standard

RSD,PR,CR

SAKK 35/98 trial design

Years since start of treatment

Pro

ba

bili

ty

0.0

0.2

0.4

0.6

0.8

1.0

/ / / // / // //// / /// /

/ //

1 2 3 4 5 6 7 8 9 10

Event-free survival in randomized follicular lymphoma patients

ProlongedStandard

P=0.0007 Median FU: 9.4 years

25% still in remissionat 8 years

SAKK 35/98 (Ghielmini et al, ASCO 2011)Effect of schedule on event free survival

P<0.0001P<0.0001

Years since start of treatment

Pro

ba

bility

0.0

0.2

0.4

0.6

0.8

1.0

/ / /

/ ///

/ /

1 2 3 4 5 6 7 8 9 10

Event-free survival in chemo-naive patients with CR/PR at 12 weeks

ProlongedStandard

(p = 0.03)

EFS in chemo-naïve responders (n=38)

45% of chemo-naiveresponders in remission

at 8 years

13

E4402 (RESORT) Schema

Rituximabre-treatment atprogression*375 mg/m2 qw 4

RANDOMIZE

Rituximab375 mg/m2 qw 4

CR or PR

RituximabMaintenance*375 mg/m2 q 3 months

*Continue until treatment failureNo response to retreatment or PD within 6 months of R

Initiation of cytotoxic therapy or Inability to complete rx

Primary Endpoint: Time to Treatment Failure

Time to First Cytotoxic Therapy

LF faible masse tumorale

W&W still valid

Rituximab is an option but optimal duration of maintenance or retreatment to be discussed?

Room for SC rituximab sub? PK?

Redefine Treatment criteria in the post rituximab era?

Management of Follicular Lymphoma

High Tumor Burden

Study name and author Follow-upOverall survival (%)

PControl Rituximab

M3902; Marcus et al.1 4 years 77 83 GLSG; Hiddemann et al.2 5 years 84 90

M39023; Herold et al.3 4 years 75 89

FL2000; Salles et al.4 8 years 79 84

Cochrane analysis:HR = 0.63 [0.51–0.79]Schulz H et al. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003805.

Rituximab + chemotherapy hasimproved overall survival in FL

1. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586. 2. Buske C, et al. Blood 2008; 112:abstract 2599.

3. Herold M, J Clin Oncol 2007; 25:1986–1992.4. Bachy et al, Lugano 2011

R-Bendamustine versus R-CHOPProgression free survival follicular lymphoma

Rummel et al.: Blood 114: 168 (abstr #405), 2009

B-R: not reached vs CHOP-R: 46,7 months (median)

HR = 0.63 (95% CI: 0.42 - 0.95)

p = 0.0281

100

80

60

40

20

0

Pro

bab

ilit

y

0 12 24 36 48 72

Time (months)

60

B-R

CHOP-R

How to consolidate the results after rituximab plus chemotherapy ?

6 – 8 x

R-CVP or R-CHOP

(or R-BENDA)

Maintenance with rituximab ?PRIMA study

Consolidate with ASCT ?

Consolidate with

RIT ?FIT, SWOG study

FIT: OVERALL PFS FOR TREATMENT GROUPS

0

25

50

75

100

Cu

mu

lati

ve P

erce

nta

ge

90Y-ibritumomabControl

207202

110149

N F

PFS From Time of Randomization (months)

90Y-ibritumomab: n = 207Median PFS: 49.3 mo

Control: n = 202 Median PFS: 12.6 mo

The 7-year overall PFS was 23% in the control arm compared with 47% in the 90Y-ibritumomab arm

HR = 2.09 (95% CI: 1.63 – 2.67); P < 0.001

90Y-ibritumomab

Control

207 143

86

102

6389

48

25

14

At risk:

202

0 21 42 63 84

Median follow-up: 75.7 months

Update May 2011Update May 2011

Patients in the 90Y-ibritumomab arm had a greater than 5-year advantage in TTNT compared with patients in the control arm

HR = 2.03 (95% CI: 1.53 – 2.69); P < 0.0001

90Y-ibritumomabControl

At risk:206202

192154

165116

138 92

11978

9960

0

25

50

75

100

0 12 24 36 48 60

Cu

mu

lati

ve P

erce

nta

ge

90Y-ibritumomab: n = 207 Median TTNT: > 99 mo

Control: n = 202 Median TTNT: 35 mo

90Y-ibritumomab90Y-ibritumomabControlControl

206206202202

8282122122

NN FF

TTNT From Time of Randomization (months)

FIT: TIME TO NEXT TREATMENT (TTNT)

PRIMA: study design

PD/SDoff study

Rituximab maintenance375 mg/m2 every 8 weeks for 2 years‡

Observation‡

CR/CRuPR

Random 1:1*

Immunochemotherapy8 x Rituximab+8 x CVP or6 x CHOP or6 x FCM

High tumor burden untreated follicular lymphoma

Induction Maintenance

Registration

* Stratified by response after induction, regimen of chemo, and geographic region‡ Frequency of clinical, biological and CT-scan assessments identical in both armsFive additional years of follow-up

PRIMA additional follow-up: >2/3 of patients are free of progression

Salles G, et al. unpublished data

PF

S

0.8

0.6

0.4

0.2

0.0

1.0

Rituximab maintenance

Observation

Time from randomization (months)0 6 12 18 24 30 36 42 48 54 60

Stratified HR = 0.55(95% CI: 0.44–0.68)p < 0.0001

4 years = 68%

4 years = 50%

Subjects (n)Event n (%)

Censoredn (%)

Median survival (95% CL)

Observation 513 254 (50) 259 (50) 48.36 (41.17–54.21)

Rituximab 506 160 (32) 346 (68) NA (NA –NA)

Consistent benefit in pre-defined subgroups

SubgroupCategory 95% CIsHR*N

1,018 0.44–0.680.55All

< 60≥ 60

FLIPl ≤ 1

FLIPl ≥ 3

R-CHOPR-CVPR-FCM

CR/CRuPR

0 1 2 3

Response to Induction

Induction Chemotherapy

FLIPl Index

Age

All

Favours maintenance Favours observation

Hazard ratio (HR)

768 0.39–0.650.510.45–1.020.13–2.240.54

0.6828222

720 0.44–0.740.570.32–0.72291 0.48

624 0.37–0.650.490.47–0.94394 0.67

216 0.21–0.720.390.30–0.640.51–0.92 431

3700.680.44

FemaleMale

Sex 485 0.45–0.870.630.36–0.64533 0.48

* Non-stratified analysis.

FLIPl = 2

PFS from registrationby induction regimen

R-CHOP 66.5% (63.1–69.6%)

R-FCM 58.9% (43.0–71.8%)

R-CVP 48.9% (42.4–55.0%)

100

80

60

40

20

0

Pat

ien

ts (

%)

0 1 2 3 4 5

Time (years)

42 months

R-CHOP n = 881R-CVP n = 268R-FCM n = 44p < 0.0001

PFS by induction regimen

Time (years)

Rituximab maintenance81.9% (77.6–85.5%)

Observation61.8% (56.7–66.6%)

Maintenance n = 382Observation n = 386

100

80

60

40

20

00 1 2 3 4 5

p = 0.0001 36 months

Pat

ien

ts (

%)

R-CHOPR-CHOP

Rituximab maintenance67.2% (57.3–75.2%)

Observation 54.3% (44.5–63.1%)

Maintenance n = 109Observation n = 113

p = 0.0589 36 months

100

80

60

40

20

0

Pat

ien

ts (

%)

0 1 2 3 4 5

Time (years)

R-CVPR-CVP

Predictive effect of PET-CT in the two study arms

Observation Rituximab maintenance

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48 54 60

Pro

babi

lity

of P

FS

44

15

No. of subjects

PET Negative

PET Positive

34% (15)

73% (11)

Event

66% (29)

27% (4)

Censored

51.81 (43.40–NR)

29.01 (13.17–35.09)

Median PFS (95% Cl)

1.0

0.8

0.6

0.4

0.2

0

0 6 12 18 24 30 36 42 48 54 60

Time (months) Time (months)

38

9

No. of subjects26% (10)

44% (4)

Event

74% (28)

56% (5)

Censored

NR (51.75 NR)

NR (8.74 NR)

Median PFS (95% Cl)

PET negativePET positive

p = 0.0032 p = 0.1687

PET negativePET positive

Trotman J et al., JCO 2011

Rituximab maintenance is safe

Salles et al., Lancet 2011

Rituximab maintenance (n = 501)

Observation (n = 508)

52

37

Any adverseevent

Grade 3/4neutropenia

Grade 3/4infections

Grade ≥2infections

Pat

ien

ts (

%)

100

80

60

40

20

0<1 4 <1 4

23

Grade 3/4adverse events

<1

3522

16

Future Strategies and Next Generation Trials

In Follicular Lymphoma

How to improve on current results in FL?

↑ Affinity↑ PCDTarget

↑ ADCC ↑ CDCFcRnConjugates

Optimizing the mAb itself

Stimulating immune effector cells

Mφ TNK

Optimization of Rituximab’s

efficacy

FcR

CR3

CD20on B-cell surface

Possible effects of anti-CD20 mAb on B- cells

Type I (Rituximab)

Type II (Tositumomab)

Programmed cell death (PCD)

ADCCComplement

FixationCDC

Both Type I and Type II

GA101: A glycoengineered anti-CD20 antibody

Umaña P, et al. Ann Oncol 2008; 19:Abstract 098.Umaña P, et al. Blood 2006; 108:Abstract 229.

Low fucose content

Type II antibody

Elbow hingesubstitution↑ ADCC

Low CDC

↑Cell death

Clone B-Ly1

ADCC = antibody-dependent cellular cytotoxicityCDC = complement-dependent cytotoxicity

GAUGUIN aNHL Phase II: Study design

*GA101 was given on d1, d8 and every 21 days (9 infusions)

Low-dose GA101* (400 mg) x 8 cycles

400 mg

High-dose GA101* (1600/800 mg) x 8 cycles

800 mg1600 mg

R/R iNHL(n = 40)

18 patients

22 patients

RR

GAUGUIN iNHL Phase II: End-of-treatment response by dose cohort

†ORR based on evaluable patientsCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UNK, unknownSalles G, et al. Blood 2010;116:Abstract 2868, taken from poster presentation at ASH, Dec. 201049

Cohort CR PR SD PD UNK ORR†

High dose (n=22)

2 10 6 4 0 55%

Low dose(n=18)

0 3 6 9 0 17%

End of treatment response is defined as 28 days from the last GA101 infusion using Cheson 1999 response criteria

GAUGUIN iNHL Phase II: End-of-treatment response in rituximab-refractory patients (n=24)

†ORR based on evaluable patientsCR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UNK, unknownSalles G, et al. Blood 2010;116:Abstract 2868, taken from poster presentation at ASH, Dec. 201050

Cohort CR PR SD PD UNK ORR†

High dose (n=11)

1 4 3 2 0 50%

Low dose(n=13)

0 1 4 7 0 8%

End of treatment response is defined as 28 days from the last GA101 infusion using Cheson 1999 response criteria

Rituximab refractory defined as patients who had a response of <6 months or who failed to respond to a rituximab-containing regimen (rituximab monotherapy or in combination with chemotherapy)

GALLIUM (BO21223) Phase III: Study design

www.clinicaltrials.gov; NCT01332968

Maintenance rituximab

q2m 2 years

Maintenance GA101 q2m 2 years

Rituximab 375 mg/m2 + chemotherapy* (n=700)

CR/PR

GA101 1000 mg + chemotherapy* (n=700)

Previously untreated advanced indolent

NHL (n=1400)

Experimental arm GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d + CHOP, CVP or cycles 2–6 q28d + bendamustine

Control arm Rituximab 375 mg/m2 on d1 cycles 1-8 q21d + CHOP, CVP or cycles 1-6 q28d + bendamustine

Primary endpoint Investigator-assessed PFS

Extended treatment Patients achieving CR, PR or SD, may continue induction therapy every2 months for up to 2 years

*FL: Each site to choose 1 of 3 chemotherapy regimens (CHOP, CVP, or bendamustine) which will; then be administered to all patientsNon-FL: CHOP, CVP, or bendamustine selected on a patient-by-patient basis

How to improve in FL?

↑ Affinity↑ ApoptosisTarget

↑ ADCC ↑ CDCFcRnConjugates

Optimizing the mAb itself

Stimulating immune effector cells

Mφ TNK

Optimization of Rituximab’s

efficacy

Follicular Lymphoma is a Disease of Immune Suppression

FL cells Directly Immune Suppress the Patient─ By inducing T-cell immunologic synapse dysfunction in CTLs

which render them impotent

Ramsay A G , et. al. Blood 2009;114:4713-4720

Follicular Lymphoma is a Disease of Immune Suppression

Expression of the T-cell Synapse

Cytolytic Effector Molecule in the

Tumor Microenvironment Predicts

Long Term Survival in FL

Ramsay A G , et. al. Blood 2009;114:4713-4720

“The challenge now is, can CTL activity be enhanced or re-engineered by immunomodulatory strategies to tilt the balance away from immunosuppression in the microenvironment and toward potent anti-tumor activity and maximizing the kiss of death in FL.”

63

Ramsay A G , Gribben J G Blood 2011;118:5365-5366

Lenalidomide repairs FL T-cell immunologic synapse dysfunction with autologous tumor cells.

Ramsay A G et al. Blood 2009;114:4713-4720

R2 Study Design

1 2 3 4 5 6

Lenalidomide 20mg Days 1-21 Cycles 1-6*

Rituximab 375mg/M2 Day 1 of Cycles 1-6

If clinical benefit, can proceed to 12

cycles

•Phase II, single institution

•Planned Enrollment•N= 50 Follicular lymphoma (grade I/II)•N=30 Small lymphocytic lymphoma•N=30 Marginal zone lymphoma

•Groups analyzed independently for response and toxicity

R= RESTAGING R

Lenalidomide 20mg Days 1-21 Cycles 7-12*

Rituximab 375mg/M2 Day 1 of Cycles 7-12

R RR

7 8 9 10 11 12

*SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg)

Fowler, N. et al. ICML 2011. Abst#137.

R2 as Frontline Combination for Follicular Lymphoma: Clinical Response

Fowler, N. et al. ICML 2011. Abst#137.

Grade 3/4 AEs* FL (N=49) – R2 Combination therapy in untreated FL

AE N

G3/G4

%

G3&G4

Neutropenia 20 27%

Rash 7 9%

Pain (Muscle) Fatigue 7 9%

Thrombocytopenia 4 5%

Thrombosis 3 4%

Infection 3 4%

Fowler, N. et al. ICML 2011. Abst#137.

Progression Free SurvivalAll Evaluable Patients

0 10 20 300

20

40

60

80

100

PFS (months)

Per

cen

t su

rviv

al

N=9324 mo PFS: 86%

Fowler, N. et al. ICML 2011. Abst#137.

RELEVANCE – Study Design

81

R2 maintenance

(lenalidomide 1 yr + rituximab 2 yrs)

Rituximab maintenance

(2 yrs)

R

24 mos.

R2

R-Chemo

6 mos.

CR, CRu, PR

CR, CRu, PR

1st line

FL

N=1000

• Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v ≤ 60), diameter of largest node (> 6 v ≤ 6 cm)

• R-Chemo arm: Investigator choice of R-CHOP, R-CVP, R-B

RELEVANCE - Results Expected

Two futility analyses• 1st Futility analysis to evaluate the complete

response rate at 6 months of treatment for the first 200 patients Nov 2013

• 2nd Futility analysis to evaluate the complete response rate at 120 weeks for the first 200 patients – July 2015

Surrogate Endpoint Results - 2016 PFS Endpoint Results - 2024

Tumor Tumor nicheniche

FDCFDC

FRCFRC

MSCMSC

Stromal cellsImmune cells

FL

Pre-FL

Normal B cell

TFH

TAM

MRCMRC

Microenvironment in FL

T

TCD8NK

Treg 1 cancer1 cancer2 niches2 niches

Shaffer et al Annu Rev Immunol 2012; 30:565

Nouvelles stratégies dans le traitement du LF

Target TFH (PD-1/PD-L1) Target Treg (CCR4 inhibitors) Target cytotoxic cells (anti-CD137, anti-KIR,

Ac optimisés pour ADCC, agonists T) Target macrophages (anti-CD47 antagonists,

inh CSF1-R) Target stromal cells (AMD3100, pepducins,

PCI-32765)

Conclusions

Next generation trials all include some kind of maintenance and further investigate:

─ Stimulating immune effector cells

─ Optimizing the antibodies

─ Chemosparing strategies compared to R-chemotherapy

Thank You

LNH folliculaire: options en rechute

At relapse Many strategies are applicable:

─ Rituximab alone

─ Radiolabelled antibody

─ Other chemotherapy agents (FCM, DHAP, Bendamustine…)

─ Autologous transplant

─ Allogeneic transplant

─ New agents … New antibodies Proteasome inhibitors (bortezomib), IMiDs BH3 mimetics, BTK inhibitors, PI3K inhibitors??

Monoclonal antibodies

Naked Mab─ GA101 anti-CD20─ Epratuzumab anti-CD22─ Galiximab anti-CD80

MAb + radionucleide─ 90Y ibritumomab tiuxetan anti-CD20─ 131I tositumomab anti-CD20─ 90Y epratuzumab tetraxetan anti-CD22

MAb + toxin ─ CMC-544 (calicheamicin) anti-CD22─ SAR3419 anti-CD19

Progression-free survival dependson first-line treatment

1. Hainsworth JD, et al. J Clin Oncol 2005; 23:1088–1095.2. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586.

3. Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.4. Salles G, et al. Blood 2008; 112:4824–4831.

5. Buske C, et al. Blood 2008; 112:Abstract 2599.

PF

S (

mo

nth

s)

0

20

40

60

80

R + MR1 R-CVP2 CVP+MR3 R-CHVP4 R-CHOP5

Median PFS in patients with FL

Treatment of first relapse in FL

Two philosophies Avoid chemotherapy as long as possible

Try to reach a CR and have a long duration of CR

Rituximab RituximabTositumomab 90Y ibritumomab

Other biologics Combinations Chemotherapy

0 2 3.5 4.5 5.5 7yrs

R-CHOP

0 6–8 12–15

Biologics

yrs

Treatment of relapse/progression in FL

Treatment depends─ Line of relapse: 1st, 2nd, >2nd

─ Time to relapse (from last dose of treatment): cut-off at 12months? 6 months for refractory disease

─ Previous treatment(s)

─ Histological transformation

─ Patient’s age, comorbidities

─ Patient wishes

─ ….

Histological transformation at 1st relapse

Bachy E, et al. J Clin Oncol 2009; in press.Bachy E, et al. J Clin Oncol 2009; in press.

Treatment of first relapse

Objectives─ To achieve the longest survival

─ To reach the longest PFS Try to have a 2nd CR

─ To preserve quality of life Use less toxic regimens even if less CRs ? Obtain a new CR with long PFS ?

─ Try not to use agents with long term toxicity

Chemotherapy

If the patient had already received R-CHOPSalvage regimen

─ With rituximab

─ DHAP, ESHAP, ICE, VIM

─ Followed by high-dose therapy and autologous transplant

(Z-BEAM or BEAM)

─ R-FC, R-FM, R-FCM, R-bendamustine

No study comparing the different regimens

Phase II prospective R-FM study in relapsing FL patients

Morschhauser F, et al., submitted.Morschhauser F, et al., submitted.

Progression-free survival(median = 33 months)Progression-free survival(median = 33 months)

Overall survivalOverall survival

ORR 84%; CR/CRu 68% ORR 84%; CR/CRu 68%

Rituximab plus HDT offers improved survival after relapse in patients with FL

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al p

rob

abil

ity

Survival after first relapse/progression (years)0 5 10 15 20

Log-rank p < 0.0001

Sebban C, et al. J Clin Oncol 2008; 26:3614–20.

No HDT – no rituximab

No HDT – with rituximab

With HDT – no rituximab

With HDT – with rituximab

Overall survival

Arm A (R–)

Arm B (R+)

Event-free survival

60.4 % [45.5% ; 72%] vs 92 % [72% ; 98%]

65 % [46% ; 79%] vs 92 % [56.5% ; 99%]

Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.

Rituximab maintenance in relapse:Meta-analysis of randomised studies

HR (95% CI) HR (95% CI)Weight (%)

0.001 0.1 10 1000

p < 0.0003

van Oers 2006

Forstpointner 2006Ghielmini 2004 Hainsworth 2005 Hochster 2005

Hochster 2007

Subtotal (95% CI)

0.51 (0.31–0.86)

0.49 (0.18–1.30)0.50 (0.27–0.92)

0.86 (0.49–1.49)0.51 (0.25–1.04)4.51 (0.47–43.4)

0.60 (0.45–0.79)

15.2

29.1

8.120.7

25.3

1.5

100

1

Favours rituximab Favours observation

Study

Pool estimates of overall survival