Traitement de première lignedu Lymphome folliculaire

F MorschhauserCentre Hospitalier Universitaire de Lille, France

What do I say to a newly What do I say to a newly diagnosed FL patient ?

Until the end of the 20th century: FL was considered as incurable

� Until the end of the 90’s, FL natural history was thought not

to be influenced by any therapeutic strategy 1, 2, 3

Pro

babili

ty (

%)

1960–1976 (195)

1976–1987 (513)

1987–1992 (314)80

100

Pro

babili

ty (

%)

1993–1999 (5,601)

1986–1999 (4,714)

1978–1985 (4,249)80

100

1. Horning SJ. Semin Oncol 1993; 20 (Suppl. 5):75–88.2. Swenson WT et al., J Clin Oncol 2005; 23:5019-5026.

3. Lister TA, J Clin Oncol, 2005; 25:4830-31.

Pro

babili

ty (

%)

Years

60

40

0

0 5 10 15 20 25

20

30

Pro

babili

ty (

%)

Months following diagnosis

60

40

0

0 50 100 150 200 250

20

300

Log-rankP=.006

Log-rankP=.047

After 2000, a new hope for FL patients

• Improved overall survival with anti-CD20 antibodies:

─ Multiple randomized trials and series1, plus 1 meta-analysis2

─ Epidemiological surveys: substantial OS improvement3

5-year 10-year CHOP + antibody100

Ove

rall

su

rviv

al

%

1. Fisher RI et al, J Clin Oncol 2005;23:8447–522. Schulz H et al., Cochrane Database of Systematic Reviews 2007; 4:CD003805.

3. Pulte D et al; Arch Intern Med. 2008;168:469-476.

Observation period

5-year

survival

Probability

(SD)

10-year

Survival

Probability

(SD)

1992-1994 70.7 (1.3) 52.2 (1.6)

2002-2004 84.9 (0.9) 71.5 (1.4)

CHOP + antibody

ProMACE

CHOP

0 2 4 6 8 10

p <0.0001

0

20

40

60

80

100

Ove

rall

su

rviv

al

%

Years

When and how to decideWhen and how to decideinduction treatment ?

When are we going to starta cytotoxic treatment ?

GELA criteria BNLI criteria

� Rapid disease progression in the preceding 3 months

Life threatening organ

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

each > 3 cm � 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

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

� Presence of systemic symptoms

� Serum LDH or β2-microglobulin above normal values

Critères du GELF

GELF86 GELF 94 FL2000 PRIMA

B symptoms + + + +

PS > 1 + +

LDH > N + + +LDH > N + + +

β2-micro > N > 3 mg/L > 3 mg/L > N

Compression, effusion, spleen + + + +

Cytopenia +

Tumor diameter > 7 cm + + + +

3+ lymph nodes > 3 cm + + +

Tumor

P=0.003

0.6

0.8

1.0

Critères du GELF

Tumor Burden

Low

High

0.0

0.2

0.4

0.6

Years0 4 8 12

Traitement du Lymphome folliculaire

Faible masse tumorale

RANDOMI

ARM AWatch and Wait

ARM BRituximab Induction

Continued follow up

Clinic visits

RWW Study(Ardeshna et al, ASH 2010)

� cc

Compulsory CT scan

Compulsory CT scan

CT scan only if

clinical CR

Bone marrow for histology and MRD only if CT shows cCR

SATION

ARM CRituximab Induction

& maintenance

Progressive disease

requiring therapy

stops protocol

treatment

n = 151FL n = 202 Standard

R

SAKK 35/98 trial design

375 mg/m² every 2 months x 4

PDofftrial

Prolonged375 mg/m²weekly x 4

SD,PR,CR

0.8

1.0

Event-free survival in randomized follicular lymphoma patients

P=0.0007 Median FU: 9.4 years

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

Years since start of treatment

Pro

babili

ty

0.0

0.2

0.4

0.6

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

/ //

1 2 3 4 5 6 7 8 9 10

ProlongedStandard

25% still in remissionat 8 years

P<0.0001P<0.0001

0.8

1.0

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

(p = 0.03)

EFS in chemo-naïve responders (n=38)

45% of chemo-naive

responders in remission

Years since start of treatment

Pro

ba

bili

ty

0.0

0.2

0.4

0.6

/ / /

/ // /

/ /

1 2 3 4 5 6 7 8 9 10

ProlongedStandard

responders in remission

at 8 years

E4402 (RESORT) Schema

RANDO

Rituximab375 mg/m2 qw CR or PR

RituximabMaintenance*375 mg/m2

q 3 months

14

Rituximabre-treatment atprogression*375 mg/m2 qw × 4

OMIZE

375 mg/m qw

× 4

CR or PR

*Continue until treatment failure

No response to retreatment or PD within 6 months of RInitiation of cytotoxic therapy or Inability to complete rx

RESORT Conclusions

� Both strategies appear to delay time to chemotherapy compared to historical controls

� How to interpret?

� Given the excellent outcomes with RR

� 86% chemotherapy free at 3 years� 86% chemotherapy free at 3 years

� Given the lack of QOL difference

� Given fewer AE failures

� Given fewer R doses required with RR

� Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FL

LF faible masse tumorale

� W&W toujours défendable

� Le rituximab est une option mais la maintenance de 2ans est discutable

� Place du rituximab sous cutané avec dosage selon PK?

� Redéfinir les critères GELF à l’ère post rituximab?

Traitement du Lymphome folliculaire

Forte masse tumorale

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 ����

Rituximab + chemotherapy hasimproved overall survival in FL

M39023; Herold et al.3 4 years 75 89 ����

FL2000; Bachy et al.4 8 years 70 78 ����

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

What is the best induction What is the best induction regimen?

Conclusions

� R-CHOP and R-FM are both superior to R-CVP in terms of TTF (Primary endpoint of the study)

� R-CHOP and R-FM have similar anti-lymphoma activity

� R-CHOP and R-CVP are less toxic than R-FM

� R-CHOP is associated with the best efficacy/toxicity ratio but don’’’’t forget R-BENDAMUSTIN! (Rummel et al. ASCO 2012)

R-Bendamustine versus R-CHOPProgression free survival follicular lymphoma

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

Pro

bab

ilit

y B-R

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

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

Consolidate with

ASCT ?

6 – 8 x

R-CVP or R-CHOP

(or R-BENDA)

Maintenance with rituximab ?PRIMA study

Consolidate with

RIT ?FIT, SWOG study

Maintenance in Follicular Lymphoma:current practice

What are the argumentsWhat are the argumentsfavoring the use of anti-CD20

based maintenance ?

Rationale for anti-CD20 Ab maintenance

� Maintenance therapy applied in patients responding to induction treatment is effective in hematological malignancies

─ It may also help to improve response status

� Long half life and good safety profile of rituximab

� Immunological-mediated actions of anti-CD20 antibodies (e.g. ADCC) may be more effective at a period distinct from chemotherapy administration 1-3

1. Cartron G, et al. Blood 2004; 104:2635–2642. 2. Hilchey P, et al. Blood 2009; 113:3809–3812. 3. Abes, at al, Blood. 2010;116(6):926-934)

Rationale for anti-CD20 Ab maintenance: optimal schedule

� Previous clinical experiences indicate that 25 µg/L may be considered as the optimal rituximab through level to achieve the best therapeutic activity:

─ At 3 months after rituximab administration, median serum level was 25.4 µg/L in responders versus 5.9 µg/L in 42 non responders 1.responders 1.

─ Recent data from Austrian investigators obtained in the context of rituximab maintenance further support these data 2.

� This optimal serum level may be optimally achieved when rituximab infusions are administered every 2 months:

─ A PK based administration schedule as well as ECOG data both suggest that every 2 months is optimal 3,4

1. Berinstein NL, et al. Ann Oncol 9:995-1001, 1998. 2. Jäger U, et al. Hematologica 2012, on line. 3. Gordan LN, et al. J Clin Oncol 2005; 23:1096–1102. 4. Kahl B, et al. Blood 2007; 110:Abstract 3420.

Maintenance in Follicular Lymphoma:current practice

How was the clinical benefit of rituximab maintenance of rituximab maintenance

in patients responding to rituximab plus chemotherapy established ?

PRIMA: study design

Rituximab maintenance375 mg/m2

every 8 weeks for 2 years‡Immunochemotherapy

8 x RituximabHigh

Induction Maintenance

Registration

PD/SDoff study

Observation‡

CR/CRuPR

Random 1:1*

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

High tumor burden untreated follicular lymphoma

* 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

R-CHOPN = 885

* 15 pts in 3 sites closed

prematurely Patients evaluable (N = 1202)*

R-CVPN = 272

Patients registered: N = 1217

R-FCMN = 45

Induction

� 9 pts did not receive

chemo

Patient disposition

N = 885

RandomizedN = 769

N = 272 N = 45

RandomizedN = 222

RandomizedN = 28

ObservationN = 513

RituximabN = 505

‡ 1 pt died during the

randomization process

Main

tenance

chemo

� 147 pts withdrew during

or at the end of induction

(failure to respond;

toxicity)

� 28 pts failed to be

randomized

Patients randomized: N = 1018‡

Pati

en

ts (

%)

Patient demographics and tumour characteristics

51

5658

53 5456

40

60

333236

32 3234

Observation n = 513 Rituximab maintenance n = 505

3134

49

45

Pati

en

ts (

%)

0

20

40

Median age(years)

Male(%)

BMpositive

%

3033

2832 32

B symptoms

(%)

ECOGPS > 0

(%)

β2m≥≥≥≥ 3 mg/L

(%)

LDH> ULN

(%)

32

19

34

20

Hb < 12 g/dL

(%)

3134

≥ 3 nodalsites(%)

Bulkydisease

(%)

Salles G, et al. Lancet 2011; 377:42–51.

Primary endpoint (PFS): 36 months follow-up

Even

t-fr

ee r

ate

0.8

0.6

0.4

1.0

Rituximab maintenance75%

58%

Salles et al., Lancet 2011

Even

t

0.4

0.2

0.0

Observation

0

Time (months)

6 12 18 24 30 36 42 48 54 60

505513

Patients at risk

472469

445415

423367

404334

307247

207161

8470

1716 0

0––

Stratified HR = 0.5595% CI: 0.44–0.68p < 0.0001

58%

Response rates at the end of maintenance

80%

Observation (n=491)75

CR/Cru after 2 years

80%

Observation (n=152)

Conversion from PR to CR/CRu

Salles et al., Lancet 2011

0%

20%

40%

60%

CR/Cru endof

maintenance

Maintenance (n=482)55

0%

20%

40%

60%

Conversion from PRto CR/Cru

Maintenance (n=13952

30

Consistent benefit in pre-defined subgroups

SubgroupCategory 95% CIsHR*N

1,018 0.44–0.680.55All

< 60

≥ 60Age

All

Hazard ratio (HR)

624 0.37–0.650.49

0.47–0.94394 0.67

Female

MaleSex

485 0.45–0.870.63

0.36–0.64533 0.48

FLIPl ≤ 1

FLIPl ≥ 3

R-CHOP

R-CVP

R-FCM

CR/CRuPR

0 1 2 3

Response to Induction

Induction Chemotherapy

FLIPl Index

Favours maintenance Favours observation

768 0.39–0.650.51

0.45–1.02

0.13–2.240.54

0.68

28

222

720 0.44–0.740.570.32–0.72291 0.48

216 0.21–0.720.39

0.30–0.64

0.51–0.92 431

370

0.68

0.44

Male 0.36–0.64533 0.48

* Non-stratified analysis.

FLIPl = 2

Maintenance in Follicular Lymphoma:current practice

What are the adverse affects that might be related to the administration be related to the administration

of rituximab maintenance ?

During the 24 months of treatment (completed by all patients)

Safety during rituximab maintenance (cont.)

Grade 3/4 AEs

Observation (n) Rituximab maintenance (n)

TotalResulting in withdrawal

TotalResulting in withdrawal

Neoplasia 17 6 20 5

NeutropeniaNeutropenia(incl. febrile)

7 - 19 1

Infection 5 - 22 4

Cardiac disorder 5 - 11 1

Pregnancy NA 2 NA 3

Other* 13 - 10 5

TOTAL 84 (17%) 8 (2%) 121 (24%) 19 (4%)

* One each of pyrexia, fulminant hepatitis, hypersensitivity, post-procedural fistula and lung disorder

PRIMA : Infections during maintenance or observation

� The most common adverse events reported were grade 2–4 infections in 197 (39%) and 123 (24%) patients, respectively (estimated difference 15·1%; 95% CI 9·4–20·8%, P<0·0001).

� Grades 3-4 infections in respectively 22 (4%) and 5 (1%) patients

� The five most common infections reported in the rituximab and observation arms were

─ bronchitis, )

─ upper respiratory tract infections, ) in aggregate 114 and 61 cases

─ sinusitis, ) respectively

─ nasopharyngitis )

─ and urinary tract infections (14 and 9, respectively)

� The cumulative number of Herpes viruses-related infections were 19 and 12, respectively

Immunoglobulin levels during maintenance / observation

IgG IgA

Imm

un

og

lob

uli

n G

(G

/L)

12

10

8

6

Imm

un

og

lob

uli

n A

(G

/L)

6

3

0

Salles et al., Lancet 2011

IgM

Imm

un

og

lob

uli

n G

(G

/L)

4

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

Imm

un

og

lob

uli

n A

(G

/L)

-3

Imm

un

og

lob

uli

n M

(G

/L)

0.0

0.3

0.6

0.9

1.2

1.5

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

Baseline Visit 3 Visit 6 Visit 12 Assess end trt

60

80

100

120

Me

an

to

tal sco

re

FACT-G

60

80

100

120

Rituximab maintenance does not adversely affect quality of life

EORTC QLQ-C30

0

20

40

Baseline After

induction

1Y 2Y 3Y

Induction Maintenance Follow up

Rituximab maintenance Observation

Me

an

to

tal sco

re

n = 375n = 384

331334

168213

160219

5496

0

20

40

Baseline After

induction

1Y 2Y 3Y

Induction Maintenance Follow up

n = 374n = 394

341343

166217

158224

5693

Salles et al., Lancet 2

FDG PET-CT IMAGING IN THE PRIMA STUDY

J Trotman, M Fournier, T Lamy, J Estell, A Sonet,A Janikova, H Tilly, D Decaudin, J Gabarre,JF Seymour, C Forsyth, E Garin, M Fulham,

T Vander Borght, O Shpilberg, G SallesASH 2010 Abstract 855

JCO in press

PRIMA:Prognostic impact of conventional response assessment on progression-free survival (PFS) in 122

patients.

Trotman J et al. JCO 2011;29:3194-3200

©2011 by American Society of Clinical Oncology

Progression-free survival(from study registration)

Post-treatment PET-CT based assessment

74%

Pro

babili

ty o

f P

FS 0.8

0.6

1.0

PET negative

PET positive

HR = 3.5 (95% CI 2.0-6.1)p < 0.0001

32%Pro

babili

ty o

f P

FS

0.4

0.2

0.0

0

Time (months)

6 12 18 24 30 36 42 48 54 60

91

33

No. of subjects31% (28)

67% (22)

Event69% (63)

33% (11)

Censored

NR19

Median PFS (months)PET negativePET positive

PRIMA:Prognostic impact of postinduction positron emission tomography–computed tomography (PET-CT) on overall survival (OS)

in 122 patients.

Trotman J et al. JCO 2011;29:3194-3200

PRIMA: Summary

� Rituximab maintenance for 2 years significantly improved PFS for patients with previously untreated FL who responded to induction with chemotherapy plus rituximab

� Benefits of rituximab maintenance were seen in all major subgroupsmajor subgroups

� Consistent improvements in secondary endpoints, including EFS, TNLT, TNCT, ORR and CR rate at the end of maintenance

� no new or unexpected safety findings

� Additional follow-up will allow evaluation of a possible effect on overall survival

RADIO-IMMUNOTHERAPY CONSOLIDATION IN FIRST REMISSION

FOLLICULAR NON-HODGKIN’’’’S FOLLICULAR NON-HODGKIN’’’’S LYMPHOMA.

FIT Study Schema

First-line therapy with chlorambucil, CVP,CHOP, CHOP-like, fludarabine

90Y-ibritumomab (n = 207)Rituximab 250 mg/m2 IV on day −7 and day 0 +90Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg) on day 0

CONSOLIDATION

RANDOM

Start Start of studyof study

66--12 weeks after 12 weeks after last dose of inductionlast dose of induction

Patients with previously Patients with previously untreated follicular lymphomauntreated follicular lymphoma

CHOP-like, fludarabine combination, or rituximab combination

INDUCTION

CONSOLIDATION

NRPD

CR/CRu or PR

NOT ELIGIBLENOT ELIGIBLENOT ELIGIBLENOT ELIGIBLENOT ELIGIBLENOT ELIGIBLENOT ELIGIBLENOT ELIGIBLE

MIZATION

No further treatment(n = 202)

CONTROL

CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide, vincristine, prednisone; NR = no response; PD = progressive disease.Morschhauser et al. J Clin Oncol. 2008;26:5156-5164.

last dose of inductionlast dose of induction

Rituximab or Zevalin – Efficacy trial of Therapeutic Alternatives (RoZetta/ ZAR2007)

R-CHOP

Rituximab maintenance1 dose / 8 weeks ( 24 months)

Responseevaluation

InformedConsentobtained

CR/PR

R-CHOP R-CVP

R-B

Zevalin Consolidation + observation (24 months)

SD/PDIneligible

Randomization

Primary objective: PFS-Non inferiority study

484 untreated FL

TREATMENT STRATEGY IN FOLLICULAR NHL: COMBINED FORCES !

Induction:R-chemo

RIT

/SC

T?

Co

nso

lid

ati

on

RIT

R-maintenance

Tumor load reduction

Convert PR ����CR

Eliminate MRD

CURE ?

Future Strategies and Next Generation TrialsGeneration Trials

In Follicular Lymphoma

FDCFDC

FRCFRC

MSCMSC

Stromal cellsImmune cells

T

MRCMRC

Microenvironment in FL

Tγδ

TCD8

NK

Treg 1 cancer1 cancer2 niches2 niches

Tumor nicheTumor niche

FL

Pre-FL

Normal B cell

TFH

TAM

Shaffer et al Annu Rev Immunol 2012; 30:565

How to improve on current results?

↑ Affinity

↑ PCD

Target

↑ ADCC

↑ CDC

Optimizing the mAb itself

Optimization of ↑ CDC

FcRn

Conjugates

Stimulating immune effector cells

Mφ TNK

Optimization of Rituximab’’’’s

efficacy

GA101: A glycoengineered anti-CD20 antibody

Type II antibody

Low CDC

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

Low fucose content

Elbow hingesubstitution↑ ADCC

↑ Cell death

Clone B-Ly1

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

Optimization of Rituximab’’’’s efficacy

↑ Affinity

↑ Apoptosis

Target

↑ ADCC

↑ CDC

Optimizing the mAb itself

Optimization of ↑ CDC

FcRn

Conjugates

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 ─ By inducing T-cell immunologic synapse dysfunction in CTLs

which render them impotent

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

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

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

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

*SLL patients: Dose escalation of lenalidomide

starting with cycle 1: (10mg, 15mg, 20mg)

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

RELEVANCE – Study Design

R2 maintenance(lenalidomide 1 yr + rituximab 2 yrs)

Rituximab maintenance

R

R2

R-Chemo

CR, CRu, PR

CR, CRu, PR

1st line

FL

N=1000

57

maintenance(2 yrs)

24 mos.

R-Chemo

6 mos.

• 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

Thank you!