1. What’s New in Indolent NHL, MCL and PTCL
What’s New in Indolent NHL, MCL and PTCL? ASH 2012 Review March 14, 2013
Myron S. Czuczman, MD
Professor of Medicine and Oncology
Chief, Lymphoma/Myeloma Section
Head, Lymphoma Translational Research Laboratory
Roswell Park Cancer Institute, Buffalo, NY

2. Disclosure of Conflicts of Interest Myron S. Czuczman, MD
Reported a financial interest/relationship or affiliation in the form of participating in Advisory Boards: Celgene Corporation, Genentech BioOncology, Spectrum, Millennium, Onyx Pharmaceuticals Today’s presentation will discuss off-label use of novel agents, many of which are in early clinical development

3. Agenda Frontline Therapy for Follicular Lymphomas
Novel Therapies for Advanced Follicular Lymphoma
The Role of PI3K and BTK Inhibitors
Novel Therapies for MCL
Advances in T-cell Lymphoma Therapy

4. Subanalysis of the StiL NHL-1 Study: Achievement of CR Results in Superior Survival c/w PR
Frontline BR vs CHOP-R (max 6 cycles)
Subanalysis of the impact of response quality on outcome
Subanalysis of responders in NHL1 (StiL) phase III study in indolent lymphoma and MCL
Rummel et al. ASH 2012, Abstract 2724

5. Responder Subanalysis of BR vs CHOP-R in Indolent and MCL (StiL): Subgroup Analysis/ConclusionsCR PR P
Median PFS, mo
All Patients
57.5
43.5
0.0037*
BR Arm NR 57
0.1912
R-CHOP Arm 54 31
0.0215*
OS at 5 y
90%
78%
0.0008*
91%
80%
0.0044*
75%
0.0737
Male vs Female
Male (n=272)
Female (n=242)
CR rates
29%
42%
0.0016*
38.6
51.4
0.0866
Pts in CR c/w PR following 1st-line Rx: significantly longer PFS and OS
Results suggest: association between quality of response vs outcome
*Denotes statistically significant differences
Rummel et al. ASH 2012, Abstract 2724

6. Frontline BR vs R-CHOP/R-CVP in Advanced Indolent NHL (The BRIGHT Study): Study Design
Bendamustine 90 mg/m2 Day 1 and 2 Rituximab 375 mg/m2 on D1 q28d
(6-8 cycles); n=224
Frontline advanced indolent NHL
(Preassignment of chemo arms by investigator)
Primary: Noninferiority of CR for BR vs standard treatment (IWG criteria); independent and investigator review)
R-CHOP and R-CVP: std dosing q21d
(6-8 cycles); n=223
447 randomized; 436 received treatment; 419 evaluable for efficacy
Most patients completed 6 cycles of treatment
Dose delays more common for BR-treated patients (35% vs 19%); dose reductions less common (22% vs 29%)
Flinn et al. ASH 2012, Abstract 902

7. Frontline BR vs R-CVP or R-CHOP in Advanced Indolent NHL (The BRIGHT Study): Efficacy/Conclusions
CR Rates
BR, %
R-CVP/ R-CHOP, %
Ratio (95% CI)
P value
Evaluable, IRC 31 25
1.25 ( )
0.0225a
Randomized, IRC 23
1.34 ( )
0.0084a
In NHL 27
1.16 ( )
0.1289a
In MCL 51 24
1.95 ( )
0.0180b
Randomized, Investigator 18
1.60 ( )
0.0013b
IRC, independent review committee. aTest for noninferiority; bTest for superiority
High ORRs were attained in both groups (94% BR vs 84% R-CVP/R-CHOP)
BR shows CR rate that is non-inferior to that of R-CHOP/R-CVP
MCL: BR produced significantly higher CR rate
AE profile of BR was distinct from R-CHOP/R-CVP
Flinn et al. ASH 2012, Abstract 902

8. Responses (1999 IWG) assessed every 3 cycles
Phase II Study of Lenalidomide and Rituximab (L+R) in Untreated iNHL: Final Results Study Design/Patient Characteristics
Responses (1999 IWG) assessed every 3 cycles
Phase II
Advanced stage, untreated iNHL; measurable disease (>1.5 cm) (N=110)
LEN 20 mg, days
Rituximab 375 mg/m2 day 1, q28d x 6 cycles (responders up to 12 cycles)
Fowler et al. ASH 2012, Abstract 901

9. Phase II Study of L+R in Untreated iNHL: Final Results Conclusions
The combo of L+R is active and tolerable in pts with untreated iNHL
All patients: 90% ORR (64% CR)
FL: 98% ORR (87% CR)
SLL: 80% ORR (27% CR)
MZL: 89% ORR (67% CR)
High CR rates with durable remissions were observed in FL patients
2-year PFS = 83% for all patients; 89% for FL
Randomized studies comparing this regimen with traditional combination chemotherapy regimens are underway
Ongoing RELEVANCE study
Fowler et al. ASH 2012, Abstract 901

10. B-cell Receptor Signaling Pathway
Kersh, Gilbert J(Sep 2007) Lymphocyte Activation Signals: Transduction. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: / a pub2]

11. BCR pathway members as potential targets in the treatment of NHL
Friedberg J W Clin Cancer Res 2011;17:
©2011 by American Association for Cancer Research

12. Targeted Therapy, Novel Agents Being Tested in FL
Btk inhibition in B-cell malignancies
Ibrutinib shows clinical benefit with single-agent PO dosing1
52% ORR in 48 evaluable pts
78% in MCL; 29-33% in FL, DLBCL, MZL, MALT
Well tolerated, minimal toxicities at <12.5 mg/kg/day
Idelalisib: Oral PI3K inhibitor
Clinical benefit in pts with r/r indolent NHL, MCL, and CLL2
Well tolerated with minimal hematologic toxicity
Most frequent AE: reversible increase in ALT/AST
55% ORR in indolent NHL (n=24); 62% in MCL (N=16)
1Fowler KH et al. ASH 2010 Abst 964
2Kahl B et al. ASH 2010 Abst 1777

13. The BTKi Ibrutinib (PCI-32765) in Relapsed FL Study Design
Ibrutinib induces apoptosis and inhibits cellular migration and adhesion in neoplastic B-cells
Phase I
Rel/ref B-cell lymphoma (FL); ECOG ≤1, 1-4 prior therapies, measurable disease
Ibrutinib PO dose escalation
Intermittent: 1.25–12.5 mg/kg
Continuous: 8.3 mg/kg and 560-mg fixed dose QD
Efficacy for doses ≥2.5 mg/kg (ie, full BTK occupancy)
Response measured every 2 mo (2007 IWG)
Primary objectives: safety and MTD
Dosing
1.25, 2.5, 5.0, 9.3, 12.5 mg/kg/d PO Cycle = 28 days on/7d off: intermittent dosing
2 continuous dosing cohorts (cycle = 35 days)
8.3 mg/kg /d PO
560 mg/d PO (fixed dose)
Fowler et al. ASH 2012, Abstract 156

14. Ibrutinib in Relapsed FL: 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 DR, 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); Well-tolerated
Dose of 5 mg/kg/day or higher recommended for phase II studies
No cumulative toxicity with extended dosing
Response improved with continued treatment in some pts
Fowler et al. ASH 2012, Abstract 156

15. GS-1101+R vs GS-1101+B vs GS-1101+BR in iNHL: Results/Conclusions
Lack of overlapping toxicities allows the oral PI3Kδ inhibitor, GS-1101, to be delivered at the full single-agent starting dose (150 mg BID) when co-administered with BR in heavily pretreated indolent NHL patients
Highly active and generally well tolerated in hard-to-treat patients, inducing
Profound reductions in lymphadenopathy ; (ORR 71%-88%; CR 20%-29%)
Durable clinical benefit with median DR and PFS not yet reached
Phase 3 trials should be pursued evaluating these 3 regimens
Fowler et al. ASH 2012, Abstract 3645

16. Interim Results of Phase I Study of ABT-199 in r/r NHL: Study Design/Results
Rel/ref NHL; median 3 prior therapies, 35% bulky adenopathy
ABT-199, 50 to 200 mg;
Daily dosing targets 200 mg (n=3), 300 mg (n=3), 400 mg (n=4), and 600 mg (n=7)
Safety (NCI CTCAE V4); Responses (2007 IWG)
First in human phase I open-label, dose escalation, multicenter study; n=30
ABT-199: oral, second-generation BH3 mimetic that inhibits BCL-2
Overall best response rate (CR + PR) = 11/23 patients (48%)
Laboratory TLS seen in one MCL patient at 200 mg dose
ABT-199 was active with an acceptable safety profile with daily dosing, particularly in MCL (7/7 PR)
Activity also observed in DLBCL (1/4 CR) and WM (2/2 PR)
No evidence of dose-related thrombocytopenia; consistent with BCL-2 selectivity
Dose escalation continues to id the optimal dosing regimen and MTD of ABT-199 in NHL
Davids et al. ASH 2012, Abstract 304

17. Phase II Study 0f CT-011 + R in Relapsed FL
Rituximab-sensitive, grade 1-2 FL, relapsed after 1-4 prior therapies, measurable disease, adequate organ function, ALC ≥0.6x109/L
CT mg/kg IV every 4 wks X 4 + Rituximab 375 mg/m2/wk IV X 4 starting 2 wks after CT-011 (Responders could receive additional 8 infusions CT-011 [total 12])
Primary: ORR CT +/- PET after 2 and 4 infusions CT-011 and q 3 mo for ≤2 y;
BM biopsy needed to confirm CR
PD-1: an inhibitory receptor belonging to the B7-receptor family
Presence of PD-1/PDL-1 on tumors: poor prognosis and immune suppression
CT-011 (pidilizumab) is a humanized anti-PD-1 monoclonal antibody
CT-011 blocks the interaction between PD-1 and its ligand, PDL-1
Leads to enhancing the anti-tumor function of both T-cells and NK cells
Westin et al. ASH 2012, Abstract 793

18. Phase II Study 0f CT-011 + R in Relapsed FL: Results/Conclusions
Efficacy (n=29)
n (%)
ORR
19 (66) CR
15 (52) PR
4 (14)
Measurable tumor regression
25 (86)
Median time to response, d 88
Median PFS, mo
In responders (n=19)
Pts with tumor regression (n=25)
21.1 NR
Subgroup analysis for clinical response: No association with FLIPI, FLIPI2, prior chemo, # of prior rituximab doses, or duration of response to prior therapy
The ORR of 66% and CR of 52% compare favorably with the previously reported ORR of 40% and CR rate of 11% with rituximab retreatment in relapsed FL
These data support further evaluation of PD-1 targeted therapy in FL
Westin et al. ASH 2012, Abstract 793

19. Lenalidomide Post-Bortezomib in Rel/Ref MCL (MCL-001); Study Design
Phase II global, multicenter, single-arm, open-label study
MCL patients relapsed, progressed, or refractory to bortezomib (N = 134)
Follow-Up
CT every 90 days
Treatment Phase*
Lenalidomide 25 mg days 1-21, q28d; CT every 2 cycles
PD or toxicity
Primary endpoints†: ORR and DOR
Secondary endpoints: CR, PFS, TTP, OS and safety
*Aspirin or low molecular weight heparin prophylaxis provided for high-risk patients.
†Based on independent central review per modified International Working Group criteria.1-3
1. Cheson et al. J Clin Oncol. 1999;17: Kane et al. Clin Cancer Res. 2007;13: Fisher et al. J Clin Oncol. 2006;24: Goy et al. ASH 2012, Abstract 905.

20. Lenalidomide Post-Bortezomib in Rel/Ref MCL (MCL-001): Conclusions
EMERGE trial confirmed lenalidomide efficacy with an ORR of 28% (CR/CRu 8%); median DR 16.6 months
Heavily pretreated MCL population
Subgroup analyses for efficacy (ORR and DR) based on baseline characteristics/demographics were similar
Safety profile was manageable and consistent with other studies of lenalidomide in NHL
Lenalidomide demonstrated rapid (median TTR, 2 months) and durable efficacy in MCL patients who failed prior therapies that included bortezomib

21. Ibrutinib in Bortezomib-Naive or -Exposed MCL
Phase II: Rel/ref MCL; phase II study of bortezomib-naive and bortezomib-exposed patients with MCL
Ibrutinib 560 mg/d PO; continuous 28-day cycles until PD
Primary: ORR (every 2 cycles)
Secondary: DOR, PFS, OS, and safety
Median DR, PFS, and OS not yet reached
Median (range) time to PR: 1.9 (1.4 – 8.3) months
Median (range) time to CR: 3.9 (1.7 – 11.2) months
Efficacy
Bort-Naive (n=63)
Bort- Exposed (n=46)
All Patients
(n = 109)
65%
72%
68%
CR/CRu
21%
23%
22% PR
44%
49%
46%
Efficacy
ASH 2011 (n=51)
ASH 2012 (n=51)
Median time on study treatment, mo
3.8 mo
11.3 mo
ORR
69%
75% CR
16%
35%
Treatment-emergent adverse events were consistent with previous reports (11% neutropenia, 5% anemia, 5% thrombocytopenia)
A pivotal study in R/R MCL previously treated with bortezomib has been initiated
Wang et al. ASH 2012, Abstract 904

22. Phase I/II Trial of Vorinostat + Cladribine + R (VCR) in Previously untreated MCL
Epigenetic modifications have been identified in MCL
Cladribine: Cytotoxic plus has hypomethylating properties
Vorinostat: HDAC inhibitor
Phase II dosing
V (400 mg po D+1 to 14); C (5 mg/m2 IV D+1 to +5); R (wkly x 4, then q month)
Responders may receive MR
n=28 previously untreated MCL
n=26 evaluable (completed >2 cycles)
ORR = 100% (69% CR)
None of the CR pts has relapsed (med F/U = 14.7 m)
Worse outcomes seen in blastoid MCL
Toxicities: include marrow suppression, fatigue, anorexia, and dehydration
Conclusions:
“VCR” has significant activity and epigenetic activity in prev untreated MCL
Initial F/U results are promising in non-blastoid MCL who continue MR
Spurgeon et al. ASH 2012, Abstract 3675

23. Brentuximab Vedotin in Rel/Ref CD30+ Heme Malignancies Rothe (German Hodgkin Study Group) et al
Retrospective analysis of CD30+ refractory or relapsed HL or relapsed ALCL without prior high-dose chemotherapy (HDCT) and autologous SCT (German Hodgkin Study Group)
Response (revised IWG) OS – time from initiation of therapy to death from any cause PFS – time from initiation to progression, relapse, or death
Brentuximab vedotin 1.8mg/kg body weight; 30-min infusion; every 3 weeks
Retrospective analysis supports previously reported therapeutic efficacy of brentuximab vedotin in patients with heavily pretreated CD30+ malignancies
69% ORR (31% CR); 22% PFS and 68% OS at 12 months
Presents the first data indicating therapeutic efficacy of brentuximab vedotin as reinduction therapy in chemotherapy-refractory HL and ALCL patients before HDCT and ASCT
Broadens spectrum of reinduction treatment that can be used before HDCT/ASCT in primary refractory HL and ALCL patients who may be ineligible
Rothe et al. ASH 2012, Abstract 2743

24. Frontline Romidepsin + CHOP in PTCL (Ro-CHOP):
Romidepsin: Starting dose 10 mg/m2 days 1 and 8
+ CHOP:
Cyclophosphamide 750 mg/m2 day 1 Doxorubicin 50 mg/m2 day 1
Vincristine 1,4 mg/m2 day 1
Prednisone 40 mg/m2 days 1 – 5
Phase Ib
Previously untreated, biopsy-proven PTCL (N=18)
3 + 3 design; DLT considered in first 2 cycles
Safety, efficacy, tolerability
Romidepsin can be combined with CHOP with manageable heme toxicity
Some cardiovascular events were observed but the relationship with romidepsin was questionable
Romidepsin dose of 12 mg/m2 on days 1 and 8 currently under evaluation in phase II extension of the study (close to accrual)
Response rates seemed promising (78% ORR; 57% CR), but longer follow-up is needed
Dupuis et al. ASH 2012, Abstract 1617

25. Phase II Study of Mogamulizumab in CTCL/PTCL
Mogumulizumab (KW-0761): humanized anti-CCR4 mAb (potent ADCC)
Phase I in CCR4-positive T-cell malignancies: well-tolerated; encouraging efficacy
Phase II in CCR4-positive ATLL: 50% ORR (approved for Rx of ATLL in Japan in 2012)
Phase I/IIa prev Rx’d CTCL (US): 37% ORR
Current study: Phase II study for relapsed CCR4-positive CTCL and PTCL (Japan)
Multicenter; primary end-point = ORR; 8 weekly infusions
Results: See Table; n=37 assessable; severe AE’s: 14 (in 7 pts); polymyositis, CMV retinitis
Conclusion: Mogamulizumab mono Rx has promising antitumor activity in r/r PTCL/CTCL
Ishida et al. ASH 2012, Abstract 795

26. New directions in the treatment of NHL in 2013
The successful use of novel targeted agents in NHL is inducing a paradigm shift in attitudes toward treatment:
Therapeutic goals are moving from palliation of indolent NHL to Rx approaches that result in durable CRs
Therapeutic principles are changing and novel targeted agents are being incorporated into upfront and salvage settings and yielding improved outcomes (esp in poor-risk patients)
Continued development and testing of novel targeted agents will result in higher cure rates of NHL in the foreseeable future 26