1. Asymptomatic Follicular Lymphoma
To Treat or not to Treat?
9th European Congress on Hematologic Malignancies
Feb 23, 2013
Marinus van Oers
Academic Medical Center
Amsterdam, The Netherlands

2. Case 1
A lawyer, age 55, notices a swelling in his neck. He feels perfectly well.
Diagnostic work up reveals a grade 2 follicular lymphoma
Hb and LDH : normal
2 involved sites: neck and groin, max. diameter 2 cm
Positive bone marrow
Conclusion : asymptomatic FL, FLIPI 1 2

3. GELF criteria for low tumour burden FL
Largest (extra)nodal mass < 7cm
≤ 3 nodal sites with a diameter > 3cm
< 5 x 109/l circulating tumour cells
HB > 10g/dl, ANC > 1.5 x 109/l,
platelets > 100 x 109/l
No serous effusions
No risk of organ compression/ compromise
Spleen <16 cm (CT scan)

4. Case 2
A lawyer, age 62, notices a swelling in his neck. He feels perfectly well.
Diagnostic work up reveals a grade 2 follicular lymphoma
Hb and LDH : normal
6 involved sites, 3 with max. diameter 5 cm
Positive bone marrow
Conclusion : asymptomatic FL, FLIPI 3 4

5. THE asymptomatic FL patient does not exist!
There is considerable heterogeneity within lymphoma subgroups as to
Clinical presentation and course
Molecular biology
Thus: individualized approach is required

6. What is the evidence to justify watchful waiting in case 2?
The old days

7. Watch and wait in Follicular Lymphoma
% Not
Treated
TTT
(months)
% ORR CR OS
(yrs)
Portlock 1 ww 44 43 31 NA
10.1
Horning 2 83
38 * 36 11
O’Brien3 56 21 33
6.3
Young 4
PromaceMopp/TNI 60
17# -- 34
NA/43
NA/78
Both
83 % (4yrs)
Brice 5
Prmust/IF 66
127 20 24 70
78/70
78 %
(5yrs)
70/84 %
Ardeshna 6
Chloramb
151
158 19
(at 10yrs )
31.2
76/27
90/63
6.7
5.9
1 Portlock et al. Ann Intern Med Young et al. Semin Hematol.1988
2 Horning et al. N.Engl.J.Med Brice et al. J Clin Oncol 1997
3 O’Brien et al. Q J Med Ardeshna et al. Lancet 2003
* Including 23%
Spont. remissions

8. Follicular Lymphoma: the past
100 80 60 40 20
1987–1996 (n=668)
1976–1987 (n=513)
1960–1976 (n=195)
An incurable disease??
Overall survival (%)
Years
Horning S. Semin Oncol 1993;20(Suppl. 5):75–88

9. Cochrane meta-analysis rituximab and overall survival FL
R + Chemo
n/N
Chemo
n/N
Peto OR (IPD)
95% CI
Weight %
Peto OR (IPD)
[95% CI]
Study
FL subgroup
Forstpointner 04
4/35
8/30
3.24
0.38 [0.12, 1.18]
Herold 2005
14/105
24/96
10.31
0.45 [0.24, 0.85]
Hiddemann 2005
6/223
17/205
23.89
0.60 [0.40, 0.92]
Marcus 2005
21/162
28/159
13.33
0.70 [0.40, 1.23]
van Oers 2006
52/234
65/231
31.82
0.74 [0.52, 1.07]
P <
Subtotal
759
721
82.59
0.63 [0.51, 0.79]
0.1
0.2
0.5 1 2 5 10
Favours R-Chemo
Favours Chemo
Schulz JNCI 2007 9

10. What is the evidence to justify watchful waiting in case 2?
Data in the rituximab era 10

11. An Intergroup Randomised Trial of Rituximab vs a Watch & Wait Approach in Patients with Advanced Stage, Asymptomatic, non-Bulky FL
Kirit M Ardeshna, et al.
Ardeshna K. ASH 2010 11

12. R A N D O M I S A T I O N ARM A Watch and Wait N=181 Clinic visits
R R R R R R R R R R R R
Rx4
months
Compulsory
CT scan
only if
clinical CR
Bone marrow for histology and MRD only if CT shows CR
Clinic visits
ARM B
Rituximab Induction
N=83
Continued
follow up
ARM C
Rituximab Induction
& maintenance
N=189
ARM B CLOSED
Progressive disease
requiring therapy
stops protocol
treatment 12

13. Time to New Therapy (TTNT)
PFS
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 1 2 3 4 5
W&W R4
R4+M
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 1 2 3 4 5
3yr OS=95%
TTnT
3yr %
PFS
W&W 48 33 R4 80 60
R4+M 91 81
More relevant question:
FL, low tumor burden
Immediate R vs R when symptomatic  time to next CHEMOtherapy
Years from randomisation
Ardeshna K. ASH 2010 13

14. Preliminary QOL results of Intergroup study W&W vs rituximab
FACT-G, HADS, AC (concerns as to disease becoming more aggressive, treatment requirement, inability to support themselves/family, planning future)
RESULTS
At baseline QOL similar or superior to general population, except emotional WB (73)
Emotional WB and AC improved most in RM arm
At month 13 anxiety only improved in RM arm (29%→14%; p=0.0005) WAIT AND WORRY

15. Watchful waiting in FL in the rituximab era: results of the F2 database
Prospective collection of clinical, pathologic and therapeutic parameters to prospectively validate FLIPI
1093 treatment-naive FL patients
107 initially WW; compared with 242 good prognosis patients initially treated with R-based regimens
Median follow up 64 months
First treatment in WW group not considered as event!
In 50% of WW patients therapy was started. Median TLT 14 months. Significantly correlated with > 4 nodal sites
Solal-Céligny P et al. JCO 2012;30:

16. FFTF in the W&W cohort and the subgroup of initially treated good prognosis patients
Freedom from treatment failure of the watch and wait (W&W) cohort (n = 107) and the subgroup of initially treated patients with good prognosis characteristics (n = 242).
Solal-Céligny P et al. JCO 2012;30:

17. Watchful waiting in FL in the rituximab era: results of the F2 database
No randomized comparison
Initiation of treatment: physicians preference
No detailed information on first line treatment in both groups (“R-based”). Only minority R mono
5 yrs OS similar in both groups (88% vs. 87%)
No information on subsequent treatment
Solal-Céligny P et al. JCO 2012;30:

18. US National Lymphocare Study
1737 advanced stage FL
237 initially WW;1500 immediate (variable!) therapy
In 146 initially WW patients treatment was given (R-mono , R-chemo)
On R mono no difference in PFS
On R-chemo: PFS in WW group 37 months; in immediate treatment group 71 months
No difference in OS
Sinha R. et al. Blood 118:21,2011 (abstr 775)

19. Are these data relevant for case 2?
NO: they relate to a highly selected, small group of low-tumour burden FL patients
F2 database: 107/1093 patients (9.8 %); 50% started treatment within 14 months!
US Lymphocare: 237/1737 (13.6%)

20. The relevant trial has not yet been done! Rituximab maintenance
R-Chemo
Watch and Wait
Rituximab maintenance
R-Chemo +
R-maintenance 20

21. The proposed trial is also relevant for low tumour burden FL
R-monotherapy disregards a potential curative option in these patients
Ideal setting to obtain CR, eradication of MRD and cure

22. Quality of response predicts overall survival in FL
Long-term results of the GELF-86 trials
1.0
0.8
Complete response
0.6
Survival probability
0.4
A long-term follow-up study of 536 FL patients treated in trials by the GELF group (Groupe d’Etudes des Lymphomes Folliculaires) showed that achieving a CR after first-line therapy translated into significantly improved overall survival.
This shows that the depth of remission has a direct impact on overall survival, and again supports giving the most effective therapies first-line, to improve chances of a CR.
Strengths of this analysis include the large number of patients and the long follow-up (median 14.9 years, which is well beyond the median overall survival).
However, results from retrospective studies such as this can be difficult to interpret, and one possibility is that CR may be acting as a surrogate marker for a group of patients with a favourable prognosis.
Partial response
0.2
p < 0.001
0.0 5 10 15 20
Time (years)
Bachy E, et al. J Clin Oncol 2010; 28:822–829. 22

23. FFR of CHOP+R treated patients according to PCR in BM at the end of the molecular follow-up.
FFR of patients treated with rituximab according to the PCR status.The molecular analysis was performed on BM cells at the end of the molecular follow-up. PCR neg indicates PCR negativity, PCR pos; PCR positivity.
Rambaldi A et al. Blood 2002;99:

24. The proposed trial is also relevant for low tumour burden FL
Ideal setting to obtain CR, eradication of MRD and cure
Counterargument: exposure to toxicity from CT
However
Almost all will need CT in future (TTNCT)
QOL: reduction of anxiety
Novel targeted drugs much less toxic

25. New drugs: targeted therapy
targets
Phase
ABT-263; ABT-199; survivin; XIAP inhibitor
Apoptosis
I/II I
Fostamatinib
BCR-Syk II
PCI32765
BTK-inh.
II/III
Belino-; panobino-;vorinostat
HDAC inh
CAL101
PI3kδ
Evero/temsirolimus
mTOR
SAR245409
PI3k/mTOR 25

26. The relevant trial has not yet been done!
MoAb + novel drug
Watch and Wait
Moab maintenance
MoAb + novel drug
Moab maintenance 26

27. Conclusion
It is not correct to state that WW is appropriate for all asymptomatic advanced stage FL patients
Still an urgent need for relevant clinical trials
In the meantime: individualized approach