1. What is the optimal management of an asymptomatic 62 year old with low tumor burden, stage IV, grade 1-2 FL? Answer: R-chemotherapy
Peter Martin, M.D.
The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology
Director of Lymphoma Clinical Research
Assistant Professor of Medicine

2. Phase 3 trial of chlorambucil vs. observation: Overall survival
Ardeshna et al. Lancet. 2003;362:516

3. How long do patients on “watch and wait” go before being treated?
Median time to treatment in indolent NHL observation studies (all risk groups)
31 months (Portlock, 1979)
3 years (Horning, 1984)
2.6 years (shorter in age < 70) (Ardeshna, 2003)

4. Johnson, et al (St. Barts) – 1995
212 pts, newly diagnosed follicular lymphoma over 20 years
Treated generally with chlorambucil, CVP, CHOP
Median
Response Survival
Duration From Response
(months) (years)
1st Line nd Line
3rd Line
4th Line
Johnson PWM et al. J Clin Oncol. 1995; 13(1):

5. OS by era of diagnosis.
Tan D et al. Blood 2013;122:

6. Rituximab is standard front-line therapy of indolent B-cell non-Hodgkin lymphoma
Study
Treatment N
1o outcome
2o outcome
Witzig
R x 4 36
ORR 72%
TTP 2.2 y
Herold
MCP +/- R
358
ORR 92% vs. 75%
4-y OS 87% vs. 74%
Buske
CHOP +/- R
552
5-y TTF 65% vs. 32%
5-y OS 90% vs. 84%
Marcus
CVP +/- R
321
TTF 27 vs. 7 mo.
4-yOS 83% vs. 77%
Salles
CHVP+I +/-R
360
5-y EFS 53% vs. 37%
5-y OS 84% vs. 79%
All p values < 0.05 except OS in the Salles trial
Witzig et al. J Clin Oncol 2005;23:1103
Herold et al. J Clin Oncol 2007;25:1986
Buske et al. Blood 2008;112:2599
Marcus et al. J Clin Oncol 2008;26:4579
Salles et al. Blood 2008;112:4824

7. EFS after first treatment course by era of diagnosis.
Tan D et al. Blood 2013;122:

8. Goals of management of any disease
Cure
Prolong survival
Improve symptoms

9. CHOP ± Rituximab in Previously Untreated FL
Pts ≥ 60 years
Intensive IFN maintenance R A N D O M I Z E R A N D O M I Z E
Standard IFN maintenance
Untreated pts with advanced stage III/IV FL (N=428)
R-CHOP × 6-8
Pts < 60 years
CHOP × 6-8
PBSCT (n=79)
IFN maintenance (n=131)
Hiddemann et al. Blood. 2005;106:3725.

10. CHOP ± Rituximab in Previously Untreated FL: TTF1 2 3 4
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
P <0.001
CHOP (144/205)
R-CHOP (195/223)
Probability progression-free
Years
Hiddemann et al. Blood. 2005;106:3725.

11. Prognosis According to FLIPI in Patients With Advanced Stage FL Treated With R-CHOP Frontline: TTF
TTF According to Risk Groups
Survival probability
2-y TTF
92%*
90%*
67% 1 2 3 4 5
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 LR IR HR
Years
FLIPI
* P= vs HR.
Buske et al. Blood Epub ahead of print.

12. A Phase III Intergroup Trial of CHOP + Rituximab vs CHOP  Tositumomab/ 131Iodine-Tositumomab for Previously Untreated Follicular Lymphoma
SWOG S0016
CALGB 50102

13. Progression Free Survival
100%
80%
CHOP-RIT
60%
Median FU 4.9 yr
CHOP-R
40%
CHOP -RIT
CHOP-R
At Risk
265
267
Relapse
or Death 86
106
2-Year
Estimate
80%
76%
2-sided, multivariate p = .11
20% 0% 2 4 6 8 10
Years from Registration
S0016

14. PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)
1.0
Median (months)
B-R n. y. r.
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.56 (95% CI )
p =
0.1
0.0
months 2 2

15. Prognostic impact of post-induction PET-CT on PFS
Trotman J et al. JCO 2011;29:

16. Goals of management of any disease
Cure
True cure is unlikely but a functional cure is feasible.
Prolong survival
Improve symptoms

17. Examining the Effectiveness of Watchful Waiting (WW) Among US Patients with Advanced Stage Follicular Lymphoma (FL)
Sinha R, Byrtek M, Dejoubner N, Taylor M, Nooka A, Ziemiecki R, Friedberg J, Link B, Cerhan J, Hirata J, Flowers C on behalf of the National LymphoCare Study (NLCS)

18. Watchful waiting (WW) vs. active treatment (AT): Patient flow
2,727 patients with newly diagnosed FL enrolled into NLCS
1,822 Stage III/IV
59 patients excluded*
31 patients excluded*
AT group n = 1,462
WW group
n = 270
R-monotherapy n = 232
R-chemotherapy n = 1,019
Other† n = 211
* Patients having disease progression, death, or discontinuation of the study within 90 days after the diagnosis of follicular NHL were excluded
† Investigational treatment (n = 129), chemotherapy (n = 48), radiation/BMT/others (n = 34)

19. Endpoints for analysisWW AT
PD1
PFS
TTNT
AT1
PD2
AT2
PFS2
PFS-Active
Primary endpoint
Overall survival
Secondary endpoints
Progression-free survival (PFS)
Time to next treatment (TTNT)*
Time to first chemotherapy (TTchemo)
(Comparing WW and R- monotherapy)
PFS-Active
PFS2
* For WW strategy, this is time to first active treatment

20. No differences in overall survival at 5 years of follow-upWW
(n = 270)
R-mono
(n = 232)
R-chemo
(n = 1,019)
Other
(n = 211)
Median follow-up time, months 60 57 59 62
Median OS
Not reached
Deaths, % 18 25 20 HR
1.00
(0.64–1.56)
0.76
(0.52–1.10)
(0.46–1.26)

21. Risk of progression after first AT was lower if AT was received directly after diagnosis
PFS after 1st active treatment (PFS-Active):
HR* = 0.70 for AT vs WW (p = )
Time (months)
Survival probability
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 12 24 36 48 60 72 84
First active treatment at diagnosis
First active treatment after WW
* Adjusted for sex, treatment setting (academic/community), histology grade, and FLIPI components (age, # nodal sites, LDH, Hgb) at initiation of active treatment

22. Time to second progression was delayed in patients who had initially received AT
Time to PD after 2nd management strategy (PFS2):
HR* = 0.66 for AT vs WW (p = )
Active treatments
Watchful waiting
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 12 24 36 48 60 72 84
Survival probability
Time (months)
* Adjusted for sex, treatment setting (academic/community), histology grade, and FLIPI components (age, # nodal sites, LDH, Hgb) at diagnosis
Patients were excluded if they had disease progression, death, or discontinued the study within 90 days of diagnosis

23. Goals of management of any disease
Cure
True cure is unlikely but a functional cure is feasible.
Prolong survival
?trend to improved survival
Improve symptoms
Prolong PFS with 1st and 2nd line therapy

24. My conclusion
R-chemo at diagnosis may result in durable remissions exceeding 6-8 years
R-chemo at diagnosis may impact survival
R-chemo at diagnosis may be more effective than R-chemo after W&W