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!