1. Wilmot Cancer Institute University of Rochester Medical Center
Recurrent Follicular Lymphoma With a Short First Remission: How Aggressive Should We Be?
Carla Casulo, MD
Wilmot Cancer Institute
University of Rochester Medical Center
Rochester, New York
Lymphoma & Myeloma 2014: An International Congress on Hematologic Malignancies
October 25th, 2014

2. No Disclosures

3. Case Presentation 63 year old woman with grade 2-3 FL, stage IV
No other significant PMH
Treated with R-CHOP
18 months later developed enlarged 3 cm neck mass
PET scan showed widespread disease
Otherwise feels well
What is her prognosis?
How aggressive should you be?

4. Introduction
Follicular lymphoma (FL) represents the most common indolent non-Hodgkin lymphoma (NHL) in the world
Gains in overall (OS) and progression-free survival (PFS) have been made in FL with aggressive treatment strategies and maintenance rituximab
Most patients live many years with minimal impact of disease, but a subset will have aggressive course and short survival
Zelenetz et al. J Natl Compr Canc Netw Swenson et al. J Clin Oncol, 2005

5. Recurrent FL and Risk of Death
Contributors to relapse:
Biologic risk factors:
BCL6 rearrangement, MYC abnormalities, modification of histones
Changes in microenvironment; gene expression profiling
Clinical risk factors
FLIPI score – predicts PFS
Time to progression?
Smith, Hematology, 2013

6. Progression-free survival (%)
20% of Patients With FL Experience Disease Progression Within 24 Months of First Line Chemoimmunotherapy
Press et al. J Clin Oncol (SWOG S0016) 60
R-CHOP
100 80 40 20 2 4 30 36 42 8 54 6 12 18
Time (months)
Progression-free survival (%)
Probability
1.0
0.8
0.6
0.4
0.2
0.0
Rummel el al. Lancet
B-R
R-CHOP
Time (months) 6 12 18 24 30 36 42 48 54 60
1.0
Event-free rate
Salles et al. Lancet (PRIMA)
Rituximab maintenance
0.8
0.6
0.4
0.2
0.0 6 12 18 24 30 36 42 48 54 60
Time (months)
This suggests a high-risk group of patients who will relapse early despite different treatment approaches; maintenance

7. Does Short 1st Remission Predict for Poor Overall Survival in FL?
Given that 20% of FL patients have early relapse, The National LymphoCare Study (NLCS) conducted study to determine whether early PD defines patients at high risk for death
What is the clinical significance of early progression after treatment in FL?
Is early progression a marker of short OS in FL?
Casulo et al, Proc ASH 2013, Abstract 510

8. National LymphoCare Study Sites and Enrollment
The National LymphoCare Study (NLCS) is a multicenter, prospective observational study of 2,727 newly diagnosed patients with FL from 2004 to 2007 at 265 sites in the US
Evaluable patients
for this subset
analysis:
No mixed/ transformed FL
Stage II-IV
Treatment with
1st line R-CHOP
Friedberg et al. J Clin Oncol

9. NLCS Participant Selection and Classification
Evaluable patients in the NLCS with newly diagnosed FL (N=2,655)
Stage I or unknown
(n=487)
Stage II, III, lV
(n=2,168)
Watchful waiting or other treatment
(n=1,579)
First-line R-CHOP
(n=588)
Early progressor:
Relapse or death within 2 years of R-CHOP
n=122
Reference group:
NO relapse or death within 2 years of R-CHOP
n=420

10. Distribution of Characteristics by Group
Early Progressor
Reference Group
Significance*
Grade 3 histology
34%
40%
P=.50
High risk FLIPI
57%
P=.01
Elevated LDH
43%
28%
Low Hgb
35%
22%
≥ 2 nodal sites
25%
Poor ECOG PS
16% 4%
P<.01
*X2

11. Poor Survival in FL Relapsing Within 2 Years of 1st line R-CHOP (“Early PD”)
122 patients with early progression
(n=110 PD and n=12 non-PD death within 2 years)
1.0
5 year OS 95%
0.8
Reference Group
0.6
Early Progressor
Survival probability
0.4
Two-year OS (95% CI) was 71% (61.5–78.0)
Five-year OS (95% CI) was 50% (40.3–58.8)
0.2
0.0 1 2 3 4 5 6 7 8 9 10
Patients at risk:
Early =
122
101 78 69 58 49 45 33 14 6
420
407
387
363
344
252
144 33
Reference=
Time (years)

12. NLCS: Outcomes for Early Progressors
Similar to other studies:
21% of patients relapsed early after treatment
Early PD associated with significantly poor OS:
Hazard ratio (HR)=13.3 (95% CI: 7.94–22.4)
After adjusting for FLIPI score, early PD associated with an increased risk of death:
HR=15.4 (95% CI: 9.6–24.7)

13. Replication/Validation Study
NLCS outcomes replicated at the University of Iowa/Mayo Clinic
Cohort: 103 patients with FL treated with R-CHOP in first line setting
Characteristics well matched, except more grade 3 FL in UI/Mayo cohort than NLCS (62% vs 38%; p<0.01)
20% (N=21) had early progression/death, similar to NLCS

14. UI/Mayo Validation Set: Poor Outcomes in Early Relapsed FL After 1st Line R-CHOP (“Early PD”)
Median follow up: 6 years
0.0
0.2
0.4
0.6
0.8
1.0
Two-year OS (95% CI) was 57% (40–83)
Five-year OS (95% CI) was 32% (17–60)
Unadjusted HR=24.2 (95% CI: 8.6–67.8)
FLIPI adjusted HR=23 (95% CI: 7.9–64.3)
Survival probability 1 2 3 4 5 6 7 8 9 10
Years from diagnosis

15. NLCS Conclusions Relapsed FL is a heterogeneous entity
Variable outcomes
PD within 2 years of R-CHOP uniquely defines a group of patients at a substantially greater risk of death
Patients with short remission following chemo- immunotherapy are a high-risk group warranting further exploration in clinical trials

16. How Aggressive Should We Be With Early Relapse after Treatment in FL?
Can we reverse the poor outcomes associated with early relapse in FL?
What are outcomes with second line treatments?
Standard chemotherapies vs. targeted therapies
Role of stem cell transplant
Is there hope for long term disease control?
No consensus on risk stratification, prognostic tools at relapse

17. Conventional Treatment Options in Relapsed FL
Overall Response Rate
Remission Duration/
PFS
Rituximab
40%
18 months
Bendamustine + Rituximab
90-94%
24 months
R-CHOP
85%
33 months
Davis et al. J Clin Oncol 2000; Rummel et al. J Clin Oncol 2005; Robinson et al. J Clin Oncol 2008; vanOers et al.

18. Intensification of Treatment in Relapsed FL: Role for ASCT
SHOULD you refer and WHEN ?
no OS benefit in first remission
high response rates, ? plateau in survival
Toxicity considerations; secondary risks
Myelodysplasia following ASCT (up to 20% at 10 years, especially with TBI regimens)
Laport. Hematology 2013; Khabori et al. JNCI 2011; Rohatiner J Clin Oncol 2007

19. The CUP Trial: ASCT in Relapsed FL
CHOP x 3  if response, randomization:
ASCT with/without purged marrow OR
3 more cycles CHOP
89 patients randomized:
Trial closed prematurely due to poor accrual
Median follow-up 69 months
No rituximab in induction or maintenance
Schouten et al, J Clin Oncol, 2003

20. CUP Trial Outcomes: ASCT vs. Chemo in Relapsed FL
ASCT arms
Standard chemo
PFS:
Superior for ASCT
4 yr OS: 46%; 71%; 77%
(p=0.071):
Schouten et al, J Clin Oncol 2003

21. Timing of ASCT in Relapsed FL?
Survival impacted by number prior regimens
Vose et al. Biol Bld Mar Trans, 2008; Rohatiner J Clin Oncol 2007

22. Remission Duration following ASCT in Relapsed FL Can be Durable:
Median fu 13 years
5 yr OS 71%
10 yr OS 54%
Median fu 8 years
10 yr OS 66, 75%
Rohatiner et al J Clin Oncol 2007
Pettengel et al. J Clin Oncol. 2013

23. ASCT vs. allo for Relapsed FL in the Rituximab Era: NCCN analysis
184 patients with relapsed/refractory FL following rituximab containing treatment
ASCT, N=136
alloSCT, N= 48
Median 3 prior treatments
Most chemo-sensitive at transplant
ASCT 3 yr OS 87%
alloSCT 3 yr OS 63%
No difference FFS
Higher toxicity, NRM allo
Evens et al, Cancer 2013

24. NCCN Risk Factors: ASCT for Relapsed FL
Multivariate Analysis
Older age, more treatment: adverse predictors
At 3 years OS
0 factors: 96%
1 factor: 82%
2 factors 62%
Prognostic Score: Age > 60; > 3 Prior Therapies
No Factors
1 Factor
2 Factors
Evens et al, Cancer 2013

25. Non myeloablative alloSCT for Relapsed FL: MD Anderson Experience
47 patients
9 year follow up
Khouri et al. Blood 2012

26. Conclusions: NCCN Study on ASCT vs. allo in Relapsed FL
ASCT has excellent outcome in the rituximab era
5 yr OS > 80%
ASCT, alloSCT have equivalent FFS in relapsed FL
Late deaths in allo group (several > 5 yrs after transplant) limit OS
mainly from complications
ASCT should be considered the transplant option for relapsed follicular lymphoma

27. What about Novel Agents?
Idelalisib
Phase II, 72 FL
Combinations
+ lenalidomide
+ bendamustine + rituximab
Ibrutinib
Phase I, 16 FL
Lenalidomide
Phase II, 16 FL
Combinations
+ rituximab
GDC-0199
Phase I, 11 FL
+ bendamustine + rituximab
Gopal et al. NEJM 2014; Fowler et al. Proc ASH 2012, abstract 156; Advani et al J Clin Oncol 2012; Witzig et al. J Clin Oncol 2009; Wang et al. Leukemia 2013; Davids Proc ASCO 2014

28. Back to our patient….
63 year old woman with FL, stage IV, relapsed 18 months from R-CHOP
What is her prognosis? 5 yr OS 30-50%
How aggressive should you be?
Standard treatments: median PFS ~18-24 months
Investigational treatments: median PFS ~ 12 months
ASCT: 3 year OS ~ 85%
Earlier may be better, non TBI regimen
For an otherwise healthy patient, good PS, may consider aggressive strategies

29. Conclusions FL with short first remission has a poor prognosis
Consider intensive second line treatments
ASCT associated with durable long term remissions, possible cure?
Combinatorial, novel targeted agents may pave the way for improved outcomes

30. Acknowledgments
Mentor Jonathan Friedberg Funding Sources -ASH Clinical Research Training Institute -University of Rochester SPORE Career Development Award in Lymphoma Research