1. R-CHOP Recurrent follicular lymphoma: Stem cell transplantation vs
R-CHOP Recurrent follicular lymphoma: Stem cell transplantation vs. novel agents
John P. Leonard, M.D.
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Associate Dean for Clinical Research
Vice Chairman, Department of Medicine

2. Disclosures Consulting advice:
Gilead, Onyx, Teva, Celgene, Medimmune, Genentech, Hospira, Biotest, Pharmacyclics, Dr. Reddy’s Laboratory.

3. Case A
A 63-year-old male presented with follicular, grade 2 NHL with symptomatic diffuse LAN in the 5-cm range. He is treated with R-CHOP x 6 cycles and then observed.
5 years later, he presents with progressive pelvic LAN in the 3-cm range on routine imaging.
Blood counts, chemistries, and LDH are in the normal range. Bone marrow biopsy is negative for evidence of lymphomatous involvement.

4. Case B
A 50-year-old male presented with follicular, grade 2 NHL with symptomatic diffuse LAN in the 5-cm range. He is treated with R-CHOP x 6 cycles and then observed.
1.5 years later, he presents with progressive pelvic LAN in the 3-cm range on routine imaging. He is treated with R-Bendamustine and has a CR.
1 year later he has recurrent, progressive pelvic LAN in the 3 cm range on routine imaging.
Blood counts, chemistries, and LDH are in the normal range. Bone marrow biopsy is negative for evidence of lymphomatous involvement.

5. Issues to consider in selection of therapy for FL
Indications for therapy
Bulk of disease
Comorbidities
Toxicity concerns
Interest in and availability of clinical trials
R/O transformation

6. Caveats from data in this population
Heterogeneous prior therapies
Heterogeneous prior use of rituximab
Heterogeneous prior use of R-CHOP and R-bendamustine
How much these data apply an individual patient today unclear
Expect that with better upfront therapy a “resistant” patient will be “worse” with respect to prognosis, “relapsed” unknown

7. Chemotherapy data for recurrent indolent NHL (until recently)
Regimen N RR
TTF/PFS, Mo
Rituximab monotherapy
166
48% 13
FCM 30
70% 21
Rituximab + FCM 35
94%
Not reached
(median follow-up: 3 years)
CHOP
231
72% 20
R-CHOP
234
85% 33
FCM=fludarabine, cyclophosphamide, mitoxantrone.
McLaughlin. J Clin Oncol. 1998;16:2825; Forstpointner. Blood. 2004;104:3064; Van Oers. Blood. 2006;108:3295; Vose. J Clin Oncol. 2000;18:1316; Witzig. J Clin Oncol. 2002;20:2453; Witzig. J Clin Oncol. 2002;20:3262; Horning. J Clin Oncol. 2005;23:712. 7

8. Bendamustine in rituximab-refractory indolent NHL
100 pts, rituximab-refractory
indolent NHL (no response to R
or response < 6 months)
Median 3 prior regimens
(range 1-10), 47% chemoresistant
Bendamustine 120 mg/m2
ORR 84% (29% CR),
median PFS 9.7 months
Kahl, B, et al, Cancer 2010

9. Key novel agents for recurrent FL
Novel anti-CD20s
Anti-apoptotic agents
Antibody-drug conjugates
Radioimmunotherapy
Lenalidomide
PI3K inhibitors
BTK inhibitors

10. Current RIT for Recurrent Disease
Regimen N RR
TTF/PFS, Mo
131I-tositumomab 45
57%
9.9 (DOR)
Rituximab 70
56% 10
90Y-ibritumomab 73
80% 11
90Y-ibritumomab* 54
74%
6.8
131I-tositumomab* 40
65%
10.4
*Rituximab-refractory patients defined as no response to last course of rituximab or response lasting ≤6 months.
McLaughlin. J Clin Oncol. 1998;16:2825; Forstpointner. Blood. 2004;104:3064; Van Oers. Blood. 2006;108:3295; Vose. J Clin Oncol. 2000;18:1316; Witzig. J Clin Oncol. 2002;20:2453; Witzig. J Clin Oncol. 2002;20:3262; Horning. J Clin Oncol. 2005;23:712. 10

11. Time from treatment, years
Proportion without death
0.0
0.2
0.4
0.6
0.8
1.0 2 4 6 8 10
RIT can induce durable remissions I-131 tositumomab in relapsed indolent or transformed NHL Time to progression (all patients) (N=250)
Study RIT-I-000 L/T, n = 42
Study RIT-II-001, n = 47
Study RIT-II-002 Arm A/Crossover, n = 61
Study RIT-II-004, n = 60
Study CP , n = 40
Fisher, et al, J Clin Oncol (30):

12. Timing of RIT Clearly a useful option for many situations
Elderly can particularly benefit
Benefits vs other options (e.g. chemo/rituximab) remain debatable in early treatment
Offers advantages in “relatively resistant” pts
Long-term effects as well as “acceptance” in practice are an issue
Keep period of cytopenias in mind

13. CALGB 50401 Amended schema Rituximab (n=90) R A N D O M I Z E Relapsed
Follicular NHL
after ≥ 1 rituximab
based regimens
Rituximab +
Lenalidomide (n=45)
Lenalidomide (n=45)
L days 1-21d, q 28d x 12 months, R weekly x 4
Modified September 2007, completed accrual April 2011

14. Key subject characteristics
L (N=45)
L + R (N=44)
Median age
63 (34-85)
62 (36-89)
FLIPI Low
Intermed
High
31.4 %
42.9
25.7
48.5 %
30.3
21.2
TTP since last R dose
1.6 yrs
1.3 yrs
Stage I/II
III/IV
20.0 %
80.0
30.2 %
69.8
LDH > NL
16.3 %
2.4 %
N=89 total (data not reported for 3 pts R alone arm, 3 never treated, 2 insufficient)
Pending data on FLIPI (31 pt), prior R (3 pt), stage (1 pt) and LDH (4 pt)

15. Response and event-free survival
L (N=45)
L + R (N=44)
Overall (ORR)
51.1%
95% CI ( )
72.7%
95% CI ( )
Complete (CR)
13.3%
36.4%
Partial (PR)
37.8%
Median EFS
1.2 yrs
2.0 yrs
2 year EFS
27%
44%
Median F/U 1.7 years (0.1 – 4.1)
Unadjusted EFS HR of L vs L+R is 2.1 (p=0.010)
Adjusted (for FLIPI) EFS HR of L vs L+R is 1.9 (p=0.061)

16. Event-free survival L + R median 2 yrs L median 1.2 yrs
Median F/U 1.7 years (0.1 – 4.1)

17. B-cell receptor signaling and inhibition in B cell malignancies.
Ibrutinib Idelalisib
Fostamatinib
Modified from Stevenson F K et al. Blood 2011;118:

18. g a b d Idelalisib (CAL-101, GS-1101) Class I PI3K Isoform
Expression
Ubiquitous
Leukocytes
EC50 (nM)
>20,000
1,900
3,000 8
Targeted, selective, oral inhibitor of PI3K delta
Inhibits proliferation and homing, induces apoptosis in B-cell malignancies
Active in CLL, FL, MCL
iNHL ORR 48%, DOR 18 mo, CLL ORR 46%, PFS 17 mo
MCL ORR 40%, PFS 3.7 mo
Principal toxicities GI, liver enzymes, fatigue, rash

19. Idelalisib combinations in recurrent indolent NHL Best Overall Response
Rituximab
+ Idelalisib
(N=32)
Bendamustine
+ Idelalisib
(N=33)
Bendamustine
Rituximab
+ Idelalisib
(N=14)
Inevaluable (patients without a follow-up tumor assessment)
a Criterion for response [Cheson 2007]

20. Idelalisib combinations in indolent NHL Best Overall Response
Rituximab
Idelalisib
(N=23/32)
Benda
Idelalisib
(N=28/33) BR
Idelalisib
(N=10/14)
All combinations
+ Idelalisib
(N=61/79)
78%
85%
72%
71%
43% CR
26% CR
27% CR
19% CR
a Criterion for response [Cheson 2007]

21. Selected idelalisib studies ongoing
B-R +/- idelalisib – Ph 3 CLL, Ph 3 iNHL
Rituximab +/- idelalisib – Ph 3 CLL, Ph 3 iNHL
Ofatumomab +/- idelalisib – Ph 3 CLL
Triplets (Alliance)

22. Ibrutinib in Rel/Ref Follicular Lymphoma Efficacy
Efficacy (n=16)
n (%)
1.25 mg/kg/d
(n=4 FL)
≥ 2.5 mg/kg/d
(n=11 FL)
≥ 5.0 mg/kg/d
(n=9 FL)
ORR
7 (44)
25%
55%
56%
CR/CRu
3 (19)
27%
33% PR
4 (25)
22%
Median DOR, mo
12.3 NE
10.3
Median time to first response, mo (range)
4.7 (2-12) −
Median time to first PR, mo (range)
4.6 (2-11)
Median time to first CR, mo (range)
11.5 (5-12)
Median PFS, mo
13.4
19.6
Median OS, mo
No deaths
Median time on treatment = 7 mo (range, 0-29)
Dose of 5 mg/kg/day or higher recommended for phase II studies
Fowler et al. ASH 2012, Abstract 156.

23. Kinase inhibition as a component of chemotherapy-free approaches in FL and MCL
Alliance A (Leonard PI)
Phase I trial of PI3K inhibitor Idelalisib (CAL-101,GS-1101) + lenalidomide and rituximab in recurrent FL
Establish dosing, safety and preliminary activity
Alliance A (Ujjani PI)
Phase I/II trial of Btk inhibitor Ibrutinib + lenalidomide and rituximab in previously untreated FL
Alliance A (Smith PI)
Phase I/randomized II trial of PI3K inhibitor Idelalisib + lenalidomide and rituximab in recurrent MCL

24. Key novel agents for FL Key questions vs. SCT
What fraction of patients, if any, can have durable remissions with these agents?
If comparable, how does QOL (short-term vs. chronic) compare?

25. CUP trial in of AuSCT in relapsed FL
Schouten, et al, JCO 2003, 21(21):

26. CUP trial - PFS
Schouten, et al, JCO 2003, 21(21):

27. CUP trial - OS
Schouten, et al, JCO 2003, 21(21):

28. Remission Duration of Patients Receiving AuSCT for FL in Second or Later Remission
St. Barts and DFCI
Rohatiner et al. J Clin Oncol. 2007;25:

29. 280 enrolled and randomized (purged/non-purged)
Rituximab purging and/or maintenance in R-naive patients with chemosensitive relapsed FL.
280 enrolled and randomized (purged/non-purged)
Approximately 200 transplanted (100 purged/100 non purged)
Approximately 50 maintenance R in each arm
Rituximab naïve, 80% 2 prior regimens, 30% CR, 70% VGPR
Pettengell R et al. JCO 2013;31:

30. Progression-free survival by treatment arm
Pettengell R et al. JCO 2013;31:

31. AuSCT at first relapse after R-CHVP-IFN
PFS and OS
After ASCT vs no ASCT
175 relapsers after FL2000 study
(R-CHVP-I vs CHVP-I)
70 relapsers after R-CHVP-I
Various second line rx (65%
included R)
13 with ASCT
ASCT associated with improved
PFS and OS
Le Gouill S, et al, Haematologica 2011

32. Allo vs. Auto SCT IBMTR Registry data OS DFS N = 904 patients with FL
Transplants between
Probability of improved long-term OS not improved by allo ASCT
Significant heterogeneity in subjects
DFS OS
van Besien K, et al, Blood 102:2003;

33. Allo vs. non-myeloablative SCT in FL
Retrospective, 88 pts (48 allo, 40 miniallo)
Characteristics
Miniallo pts were older and more often had prior autoSCT
Outcomes
Relapse rate 13% (allo) vs 28% (miniallo)
1 year TRM 33% (allo) vs 28% (miniallo)
2 year OS and PFS (allo) 52% and 46%
2 year OS and PFS (miniallo) 53% and 40%
Chemosensitive disease and no prior AutoSCT correlated with outcome
Rodriguez R, et al, Biol Blood Marrow Transplant, 2006;12(12):

34. Late relapse (> 2 yrs or so)
One approach to treat a patient with recurrent FL (post chemoimmunotherapy) needing treatment?
Late relapse (> 2 yrs or so)
Many options, decision based on tolerability/efficacy balance
Early relapse (< 2 yrs or so)
Chemotherapy
RIT
SCT
Novel/investigational agents