1. Follicular lymphoma : To treat or not to treat, and if so when ?
11th European Congress on Hematologic Malignancies:
From Clinical Science to Clinical Practice
 13-15 March 2015
Barcelona, Spain
Follicular lymphoma :
To treat or not to treat, and if so when ?
Gilles SALLES
« Pathologie des Cellules Lymphoïdes »
UMR 5239 CNRS – UCB – ENS – HCL
Université de Lyon

2. Gilles SALLES DISCLOSURES OF COMMERCIAL SUPPORT
Name of Company
Research support
Employee
Consultant
Stockholder
Speaker’s Bureau
Advisory Board
Other
Amgen
YES
Celgene
Gilead
Janssen
Mundi-pharma
Roche

3. is an acceptable option in selected patients GELF-86 OVERALL SURVIVAL
Watch and wait
is an acceptable option in selected patients
GELF-86 OVERALL SURVIVAL
P = 0.88
At risk 66 51 29 6 64 48 23 5 63 31 3
Low Tumor Burden
No Treatment
Prednimustine
Interferon a
0.0
0.2
0.4
0.6
0.8
1.0
Years 4 8 12
Proportion
Brice et al., 1997, JCO

4. Therapeutic strategies in asymptomatic follicular lymphoma pts
Watchful waiting strategy has been validated in randomized studies 1
It was challenged with the use of rituximab as single agent 2-4
Young RC et al. Semin Hematol, 1988 ; Brice et al. , JCO 1997 ; Ardeshna KM et a Lancet 2003
Colombat P, Blood. 2001
Ghielmini M, et al. J Clin Oncol. 2005
Witzig TE, J Clin Oncol. 2005

5. Rituximab as single agent summary of phase II studies in first line
Good efficacy :
- about 3 out of 4 patient respond to therapy
Some long term (molecular) responses
Minimal toxicity
Hainsworth 2000 ; Colombat 2001 ; Ghielmini 2004; Witizig 2005

6. Rituximab as single agent summary of phase II studies in first line
Good efficacy :
- about 3 out of 4 patient respond to therapy
Some long term (molecular) responses
Minimal toxicity
But:
short median PFS:
- 20 to 30 months
Costs are high ?
Hainsworth 2000 ; Colombat 2001 ; Ghielmini 2004; Witizig 2005

7. Does rituximab (4 infusions) delay the time to next treatment ?
OBSERVATION
The median time to first systemic treatment was 2·6 years (~ 31 months) for the entire observation group.
Ardeshna et al., 2003, Lancet

8. Does rituximab (4 infusions) delay the time to next treatment ?
OBSERVATION
4 RITUXIMAB INFUSIONS
YEARS
MONTHS
Ardeshna et al., 2003, Lancet
Colombat et al., 2012, Ann Oncol

9. Watch and Wait in the Rituximab era
Time to initiation of lymphoma
therapy (TLT) and OS OS
TLT
Solal Celigny et al, JCO 2012

10. Watch and Wait in the Rituximab era
Time to initiation of lymphoma
therapy (TLT) and OS
Freedom From Treatment Failure
according to initial management OS
W&W
TLT
Rituximab
Solal Celigny et al, JCO 2012

11. Therapeutic strategies in asymptomatic follicular lymphoma pts
Watchful waiting strategy has been validated in randomized studies 1
It was challenged with the use of rituximab as single agent 2-4
Several clinical trials have investigated prolonged rituximab treatment:
RWW, RESORT, SAKK
Young RC et al. Semin Hematol, 1988 ; Brice et al. , JCO 1997 ; Ardeshna KM et a Lancet 2003
Colombat P, Blood. 2001
Ghielmini M, et al. J Clin Oncol. 2005
Witzig TE, J Clin Oncol. 2005

12. Rituximab vs. Watch and wait: Study design
Primary endpoints:
Time to initiation of new therapy (chemotherapy or radiotherapy)
Effect on quality of life R A N D O M I S E
ARM A
Watchful waiting
ARM A
Watchful waiting
ARM B
R-mono 375 mg/m2 weekly x 4 X
ARM B
R-mono 375 mg/m2 weekly x 4
Asymptomatic stage 2, 3 or 4 FL
Grades 1, 2 & 3a
Adequate bone marrow reserve
DISCONTINUED
ARM C
R-mono 375 mg/m2 weekly x 4
+ maintenance
q2mo for 2 years
ARM C
R-mono 375 mg/m2 weekly x 4
+ maintenance
q2mo for 2 years
Total planned enrolment: 360 patients
Ardeshna KM, et al. Blood 2010;116:Abstract 6.

13. Time to Initiation of New Therapy (TTINT)
1.0
0.9
0.8
Proportion
of patients
with
no new
treatment
initiated
0.7
0.6
0.5
0.4
0.3
% not requiring Rx at 3yr
W+W=48%
R4=80%
R4+RM=91%
0.2
Events
Totals
W+W 83
187
0.1 R4 19 84
R4 + M 19
192
0.0 1 2 3 4 5
Years from randomisation
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
Ardeshna KM, et al. Blood 2010;116:Abstract 6.

14. Overall survival % of patients alive 3yr OS=95%
1.0
0.9
0.8
% of
patients
alive
0.7
3yr OS=95%
0.6
0.5
0.4
0.3
0.2
Events
Totals
W+W 9
187
0.1 R4 4 84
R4 + M 8
192
0.0 1 2 3 4 5
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
Ardeshna KM, et al. Blood 2010;116:Abstract 6.

15. Rituximab re-treatment at progression*
E4402 (RESORT) Schema R A N D O M I Z E
Rituximab
Maintenance*
375 mg/m2 q 3 months
Rituximab
375 mg/m2 qw  4
CR or PR
Rituximab re-treatment at progression*
375 mg/m2 qw  4
*Continue until treatment failure
Primary Endpoint: No response to retreatment or PD within 6 months of Rituximab ; Initiation of cytotoxic therapy or inability to complete treatment

16. RESORT Secondary endpoints
PFS
Time to chemo
Kahl et al, JCO 2014.

17. RESORT Primary Endpoint: Time to Treatment Failure
Kahl et al, JCO 2014.

18. Asymptomatic FL patients What is the evidence in 2015 ?
Delaying treatment initiation remains an acceptable option in 2015
The benefit of using a short treatment with rituximab to delay R-chemo is doubtful
The clinical benefit of prolonged rituximab treatment in FL patients is not established

19. Asymptomatic FL patients What is the evidence in 2015 ?
But if treatment needed,
when ?

20. Individuals with > 10-4 IGH-BCL2+ cells in PB have a 23 fold increased risk to develop FL
Roulland et aL., JCO 2014

21. Median time to develop FL according to
IGH-BCL2+ cells in PB
Roulland et aL., JCO 2014,

22. For patients on W&W, “EFS12” is associated with prolonged survival
Maurer et al., ASH 2014

23. How do define asymptomatic patients ?
GELA criteria BNLI criteria
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
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

24. Asymptomatic FL patients Do not treat (immediately) in 2015 !
Delaying treatment initiation remains an acceptable option in 2015
The benefit of using a short treatment with rituximab to delay R-chemo is doubtful
The clinical benefit of prolonged rituximab treatment in FL patients is not established
There is no harm in waiting for clinical progression to start a very efficient treatment
- rituximab plus chemotherapy followed by R maintenance

25. PRIMA 6 years follow-up Progression free survival from randomization
HR= 0.57
P<0001
Median follow-up since randomization : 73 months