1. Clinical Considerations and Strategies for Managing Patients With DLBCL Richard I. Fisher, MD Samuel E. Durand Professor of Medicine Director, James P. Wilmot Cancer Center Director, University of Rochester Medical Faculty Group Senior Associate Dean for Clinical Affairs Vice President, University of Rochester Medical Center Rochester, New York This program is supported by an educational grant from

2. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent.  These slides may not be published or posted online without permission from Clinical Care Options –Contact: permissions@clinicaloptions.com Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Diffuse Large B-Cell Lymphoma  Most common NHL, peak incidence 6th decade  Large cells with loss of follicular architecture of node  May present as extranodal disease (stomach, CNS, testis, skin)  Curable in 50% or more of the cases  Median survival, wks to months if not treated Fisher RI, et al. Hematology Am Soc Hematology Educ Program. 2004:221-236. Photo available at: http://www.wjgnet.com/images/english/V10/ksh-1b.jpg. Photo available at: http://www.nhlcyberfamily.org/images/diffuse.jpg.

4. Comparison of a Standard Regimen (CHOP) With 3 Intensive Chemotherapy Regimens for Advanced Non-Hodgkin’s Lymphoma Results of the National High Priority Lymphoma Study Fisher RI, Gaynor ER, Dahlberg S, et al. N Engl J Med. 1993;328:1002-1006.

5. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma OS by Arm, S8516 100 80 60 40 20 0 0510152025 Yrs From Registration ProMACE-CytaBOM m-BACOD CHOP MACOP-B 233 173 37 223 164 35 225 175 34 218 170 32 At Risk Events, n 10-Yr Estimate, % Patients (%) Fisher RI, et al. N Engl J Med. 1993;328:1002-1006.

6. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma International Index for NHL Staging  Adverse risk factors –Older than 60 yrs of age –Stage III or IV –> 2 extranodal sites  Risk category –Low –Low intermediate –High intermediate –High –Performance score > 2 –LDH > normal  No. of risk factors –0, 1 –2 –3 –4, 5 N Engl J Med. 1993;329:987-994.

7. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma International Index (Patients of All Ages) N Engl J Med. 1993;329:987-994. Copyright © [1993] Massachusetts Medical Society. All rights reserved. *Score 0 or 1 for each factor: 0 = absent; 1= present. Factors: older than 60 yrs of age, LDH > normal, performance score > 1, stage III/IV, extranodal involvement > 1 site. Risk Group*Risk Factors, n Distribution of Cases, % CR Rate, % Survival Rate, % 2 Yrs5 Yrs Low0, 135878473 Low Intermediate227676651 High Intermediate322555443 High4, 516443426

8. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Lymphoma Biopsies Genes Diffuse Large B- Cell Lymphoma Three Different Categories of Aggressive Lymphoma Activated B-cell–like diffuse large B-cell lymphoma Germinal center B-cell– like diffuse large B-cell lymphoma Primary mediastinal B-cell lymphoma

9. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma OS (Yrs) Probability Diffuse Large B- Cell Lymphoma PMBL64% GCB59% DLBCL 5-Yr Survival Survival Rates in Different Genetic Groups 1.0 0.8 0.6 0.4 0.2 0 0246810 ABC30% DLBCL

10. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Diffuse Large B- Cell Lymphoma c-rel Amplification BCL-2 Translocation Gain Chromosome 3q Gain/amp Chromosome 9p24 Constitutive NF-  B Activation Dissecting a Cancer Into Molecularly and Clinically Distinct Subgroups GCB DLBCL ABC DLBCL PMBL 16%025% 45%018% 024%5% 06%43% -++

11. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma GELA Phase III Trial: Elderly DLBCL: CHOP ± Rituximab Protocol RANDOMIZERANDOMIZE Patients Stratified by risk factors (0-1 vs 2-3) 12345671421 Days Repeat cycle (8 cycles total) RituximabPrednisone Cyclophosphamide Doxorubicin Vincristine Coiffier B, et al. N Engl J Med. 2002;346:235-242.

12. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma 12/2004 7/2000: Interim analysis (ASH 2000) 5/2001: Update of interim analysis (EHA 2001) 9/2001: Analysis at end of study (NEJM 2002) 12/2002: 3-yr follow-up analysis 12/2004: 5-yr analysis (Feugier JCO. 2005;23:4117-4216) 9/2001 5/2001 7/2000 12/2002 Yrs 1.0 01234567 0 0.2 0.4 0.6 0.8 LNH-98.5: Event-Free Survival

13. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CD20 + DLBCL 18-60 yrs IPI 0,1 Stages II-IV, I with bulk 6 x CHOP-like + 30-40 Gy (Bulk, E) 6 x CHOP-like + Rituximab + 30-40 Gy (Bulk, E) Randomize Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391. MInT Trial: Study Design  MabThera International Trial

14. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391. MInT Trial: Time to Treatment Failure  The addition of rituximab to chemotherapy, primarily R-CHOP, produced significantly better survival compared with chemotherapy alone (79.9% vs 60.8%)  Median observation time: 22 mos

15. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma MInT Trial: Overall Survival Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.  An OS advantage was observed in the group receiving rituximab vs chemotherapy alone (95% vs 86%, respectively; P =.002)

16. CHOP-Rituximab Is Standard Initial Therapy for All Patients With Advanced-Stage, Diffuse Large B-Cell Lymphoma

17. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Lenz G, et al. N Engl J Med. 2008;359:2313-2323. Copyright © [2008] Massachusetts Medical Society. All rights reserved. The Distinction Between the GCB and ABC Subtypes of DLBCL CHOP-Rituximab OS 1.0 0.8 0.6 0.4 0.2 0 Probability 0123456 Yrs P = 4 x 10 -3 CHOP-Rituximab PFS CHOP OS 1.0 0.8 0.6 0.4 0.2 0 0123456 Yrs P = 1 x 10 -4 1.0 0.8 0.6 0.4 0.2 0 012345 Yrs 6 P = 8 x 10 -6 GCB DLBCLABC DLBCL

18. What Is the Role for Dose Intensification for Patients With DLBCL?

19. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Chemotherapy in Older Patients With DLBCL (German Study) Pfreundschuh M, et al. Blood. 2004;104:634-641. RANDOMIZERANDOMIZE CHOP-14 q2w x 6 (n = 172) CHOP-21 q3w x 6 (n = 178) ASSESSASSESS Older, treatment-naive patients with DLBCL (N = 689) CHOEP-14 q2w x 6 (n = 169) CHOEP-21 q3w x 6 (n = 170)

20. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP Chemotherapy in Older Patients With DLBCL (German Study): OS This research was originally published in Blood. Pfreundschuh M, et al. Blood. 2004;104:634-641. © The American Society of Hematology. Alive (%) 0 100 80 60 40 20 0 908070605040302010 Mos CHOP-21 (n = 178) 40.6% CHOP-14 (n = 172) 53.3% 5-Yr OS

21. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial) Pfreundschuh M, et al. Blood. 2005;106:9a. Abstract 13. Primary endpoint: FFTF Radiotherapy was planned for patients with initial bulky disease or extranodal involvement. FFTF is defined as additional therapy, failure to achieve CR, progressive disease, relapse, or death. CHOP-14 x 6 (n = 204) RANDOMIZERANDOMIZE Patients with CD20+ DLBCL, aged 61-80 yrs, stages I-IV (N = 1330) CHOP-14 x 8 + Rituximab q2w x 8 (n = 203) CHOP-14 x 6 + Rituximab q2w x 8 (n = 211) CHOP-14 x 8 (n = 210)

22. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP-14 vs R-CHOP-14 CHOP-14 ± Rituximab in Elderly Patients With DLBCL (RICOVER-60 Trial): TTF by Regimen Pfreundschuh M, et al. Blood. 2005;106:9a. Abstract 13. P =.000025 57% 70% FFS (%) 6/8 × CHOP-14 + R × 8 (n = 414) 6/8 × CHOP-14 (n = 414) Mos 100 80 60 40 20 0 045510152025303540

23. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R R-CHOP-21 0369 Wks 12151821 02461014Wks812 Prophylactic darbepoetin alfa Supportive care R-CHOP-14 Primary endpoint: EFS Expected improvement: 10% at 3 yrs with R-CHOP-14 (55% to 65%) 600 patients required (over 4 yrs) LNH 03-6B: Study Design ClinicalTrials.gov. NCT00144755. 66-80 yrs of age, aaIPI = 1,2,3

24. R-CHOP-14 Compared to R-CHOP-21 in Elderly Patients With Diffuse Large B-Cell Lymphoma: Results of the Interim Analysis of the LNH03-6B GELA Study Delarue R, Tilly H, MD, Salles G, et al. ASH 2009. Abstract 406.

25. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R-CHOP-14 Compared With R-CHOP-21 in Elderly Patients With DLBCL: Interim Results  202 patients randomized; R-CHOP-14: 103; R-CHOP-21: 98  Median follow-up: 24 mos  90% of R-CHOP-14 patients received G-CSF; only 66% of R- CHOP-21 patients received G-CSF  Response rate (CR + CRu): 67% in R-CHOP-14 vs 75% in R-CHOP-21 arm (P = NS)  2-yr EFS: 48% in R-CHOP-14 arm vs 61% in R-CHOP-21 (P = NS)  2-yr PFS (49% vs 63%), 2-yr DFS (57% vs 70%) and 2-yr OS (67% vs 70%) trended similarly (P = NS for all).  Conclusions: interim analysis favors R-CHOP-21

26. A Phase III Trial Comparing R-CHOP-14 and R-CHOP-21 for the Treatment of Newly Diagnosed DLBCL Results from a UK NCRI Lymphoma Group Study Cunningham D, Smith P, Mouncey P, et al. ASCO 2009. Abstract 8506.

27. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Overall Response Rates Based on End of Treatment Scan (N = 831) R-CHOP-21, % (n = 405) R-CHO-14, % (n = 426) CR4940 CRu1418 PR2432 SD65 PD/relapse64 CR/CRu (P =.183)6358 CR/CRu/PR (P =.139)8891 249 patients not evaluable or data missing Cunningham D, et al. ASCO 2009. Abstract 8506.

28. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Should Older DLBCL Patients Receive Dose-Escalated CHOP (CHOP-14)? Answer: not at this time

29. Phase II Study of Dose-Adjusted EPOCH-R in Untreated CD20+ Diffuse Large B-Cell Lymphoma: CALGB 50103 Wilson WH, Porcu P, Hurd D, et al. ASCO 2009. Abstract 6530.

30. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Wilson WH, et al. J Clin Oncol. 2005;23(16s). Abstract 6530. CALGB 50103 Phase II Study: Responses Study Population Patients, nCR/CRu, n (%) PR, n (%)Total, n (%) All patients7149 (69)22 (31)71 (100) Relapsed117 (14)4 (18)11 (15)

31. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Wilson WH, et al. J Clin Oncol. 2005;23(16s). Abstract 6530. CALGB 50103 Phase II Study: PFS  With a very short median follow-up, PFS at 1.5 yrs was 83%  According to the IPI, the low-, low-intermediate–, and high- intermediate–risk groups did well in terms of PFS; the high-risk group did not do well  To date in the poorest risk group, where progress is most needed, there is no evidence that the use of dose- adjusted EPOCH-R has a significant benefit

32. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Randomization Arm A: R-CHOP Arm B: DA-EPOCH-R C1 C2 C3 C4 C5 C6 C1 C2 C3 C4 C5 C6 StageStage/PET/CT Treatment completed 03 6 9 12 15 1821 25 Time Line (Wks) PET/CTBiopsy ClinicalTria\s.gov NCT00118209. Treatment Flow Chart of CALGB 50303

33. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Is There a Role for Maintenance Rituximab Therapy in DLBCL? Answer: not at this time

34. Maintenance Rituximab vs Observation After R-CHOP or CHOP in Older DLBCL Patients An Intergroup E4494/C9793 Update Morrison VA, Weller EA, Habermann TM, et al. ASCO 2007. Abstract 8011.

35. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Probability Yrs From Second Randomization R-CHOP P =.834 0 0.2 0.4 0.6 0.8 1.0 012345 MR Obs 01234 5 P =.0008 MR Obs CHOP Yrs From Second Randomization Morrison VA, et al. J Clin Oncol. 2007;25(18s).Abstract 8011. 4-Arm Analysis: TTF—Evaluable CR/PR Patients N = 352 Probability 0 0.2 0.4 0.6 0.8 1.0

36. What Is the Role of Autologous Stem Cell Transplantation for Patients With Advanced-Stage DLBCL?

37. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma The PARMA Study: Objectives and Design  Evaluation of efficacy of ABMT vs conventional chemotherapy in relapsed NHL Hagenbeek,et al. Blood. 1995;86(suppl 1);Abstract 458a. DHAPDHAP DHAPDHAP N = 216 1st or 2nd relapse Bone marrow harvest Sensitive (n = 109) Resistant (n = 90) n = 55 n = 54 BEAC ± RT DHAP ± RT ABMT Salvage Tx ABMT

38. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma PARMA Randomized Trial: OS Philip T, et al. N Engl J Med. 1995;333:1540-1545. Copyright © [1995] Massachusetts Medical Society. All rights reserved. Mos From Randomization 100 Survival (%) ABMT 53% DHAP 32% ITT analysis P =.038 90 80 70 60 50 40 30 20 10 0 0304560751590

39. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Auto Transplantation in Poor-Risk DLBCL: Results of Randomized Trials Haioun C, et al. J Clin Oncol. 1997;15:1131-1137. Martelli M, et al. J Clin Oncol. 2003;21:1255- 1262. Kaiser U, et al. J Clin Oncol. 2002;20:4413-4419. First AuthorInitial Induction Therapy Treatment Arm Favored TransplantConventionalNo Difference Retrospective Subset Analyses HaiounFull courseDFS,OS SantiniFull courseDFS, PFS Prospective Trials ReyesAbbreviatedEFS,OS MartelliAbbreviatedEFS,OS KaiserAbbreviatedEFS,OS

40. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma CHOP/CHOP- R x 5 PR or CR < PR Off protocol therapy CHOP/CHOP- R x 1 + Transplant CHOP/CHOP- R x 3 Closed: 12/15/07 with 276 randomized patients ClinicalTrials.gov. NCT00004031. RANDOMIZEDRANDOMIZED REGISTERREGISTER SWOG, ECOG, CALGB, NCIC-S9704 Study: Early vs Delayed High-Dose Therapy

41. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Expression of Angiogenesis Factors in Non-Hodgkin’s Lymphoma Low Grade (SWOG 8809) High Grade (SWOG 8516) 2/9 9/11 11/20 0/9 9/11 9/20 0/9 5/11 5/20 VEGFFlt-1KDR

42. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma SWOG-0515 Phase II Trial: R-CHOP Plus Bevacizumab in Advanced-Stage DLBCL  Objective: to determine the CR rate and 2-yr FFS  Eligibility: older than 18 yrs of age; DLBCL; stage bulky II, III, IV  Projected accrual: N = 80  Therapy: R-CHOP plus bevacizumab x 8  Closed 9/15/08 with 71 patients accrued Available at: http://www.swog.org/Visitors/ViewProtocolDetails.asp?ProtocolID=1979. Accessed 9/1/08.

43. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Targets Identified by Transcriptional Profiling of DLBCLs  PKC beta signaling pathway  Phosphodiesterase 4B/cAMP signaling pathways

44. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Enzastaurin in Relapsed/Refractory DLBCL Duration: ≥ 1 cycle≥ 2 cycles ≥ 4 cycles ≥ 12 cycles 42 12 9 4 4 patients progression free at 15+, 16+, 21+, and 37+ mos Robertson MJ, et al. Blood. 2005;106:275a.

45. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Courtesy of L. Staudt Lymphoma Biopsy Samples NF-  B Is Overexpressed in ABC DLBCL and Is a Potential Target Activated B cell-like DLBCL Germinal Center B cell-like DLBCL NF-kB Target Gene P Value

46. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma T  B kinase  inhibitor Validation of the NF-  B Pathway as a Therapeutic Target in DLBCL

47. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Dunleavy K, et al Blood. 2009;113:6069-6076. Median survival: 10.8 mos Median survival: 3.4 mos Dose-Adjusted R-EPOCH Plus Bortezomib ABC DLBCL GCB DLBCL P =.0026 OS Following Bortezomib/EPOCH (Yrs) 01234 1.0 0.8 0.6 0.4 0.2 0 Probability SubtypeTotal, N CR, n (%)PR, n (%)No Response, n (%) P Value ABC DLBCL125 (41.7) 2 (17.0).0004 GCB DLBCL151 (6.5) 13 (87.0)

48. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma BCR Signaling in NHL: A Rational Therapeutic Target?  BCR is maintained on most lymphoma cells  Tonic signaling through BCR maintains lymphoma survival in vitro Syk (spleen tyrosine kinase) amplifies BCR signal and initiates downstream events mlgM Igα/β Igβ/α IP3R DAG Ca 2+ PKC RAS LYN Syk BTK PLC- γ2 BLNK mlgM Kraus M, et al. Cell. 2004;117:787-800.

49. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Syk Is a Rational Therapeutic Target in NHL  Tamatinib fosdium (fostamatinib disodium, R788/R406) –Potent and specific inhibitor of Syk –In vitro activity against NHL –DLBCL –MCL –Human experience –Safety demonstrated in healthy human subjects –Activity demonstrated in phase II trials –Rheumatoid arthritis –ITP

50. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma R788 in DLBCL: Efficacy—ORR: 21% (5/21 Patients) Friedberg J, et al. Ann Oncol. 2008;19(suppl 4).Abstract 102 and oral presentation at ICML X. PatientCategoryDuration (Mos) 94-02PR7.4+ 95-06PR5.7+ 95-02PR5.1 91-16PR4.7 95-03PR2.8 92-03SD4.8+

51. What Is Standard Initial Therapy for Patients With Early-Stage DLBCL?

52. Chemotherapy Alone Compared With Chemotherapy Plus Radiotherapy for Localized Intermediate- and High- Grade Non-Hodgkin’s Lymphoma Miller TP, Dahlberg S, Cassady R, et al. N Engl J Med. 1998;339:21-26.

53. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma S8736: OS for DLBCL Yrs After Registration OS (%) 100 80 60 40 20 0 036912 5-Yr Estimate, % 82 71 Death, n 53 61 N 152 149 CHOP + RT CHOP Miller TP, et al. N Engl J Med. 1998;339:21-26.

54. Effect of Adding Rituximab to Three Cycles of CHOP, Plus Involved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma Southwest Oncology Group Study 0014 Persky DO, Unger J, Spier CM, et al. J Clin Oncol. 2008;26:2258-2263.

55. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma Persky D, et al. J Clin Oncol. 2008;26:2258-2263. Effect of Adding Rituximab to 3 Cycles of CHOP + Involved-Field Radiotherapy for Limited-Stage Aggressive DLBCL: Results  In a comparison of studies, poor-risk patients experienced a PFS benefit with the addition of rituximab to CHOP  Similarly, OS was also improved with the addition of rituximab to CHOP  Despite the lack of prospective randomized data, R-CHOP has become the standard of care for these patients

56. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma New Agents With Activity in DLBCL  Proteosome inhibitors –Bortezomib –Carfilzomib  IMiDs –Lenalidomide –Pomalidomide  Antibodies –RO5072759—a humanized engineered anti CD20 monoclonal antibody –Blinatumomab—anti-CD19 monoclonal antibody –Inotuzumab ozogamicin—anti-CD2 monoclonal antibody attached to calicheamicin –Milatuzumab—anti-CD74 monoclonal antibody –Galiximab—anti-CD80 monoclonal antibody –Dacetuzumab—anti-CD40 monoclonal antibody

57. clinicaloptions.com/oncology Clinical Advances and Practical Applications in Lymphoma New Agents With Activity in DLBCL  Histone deacetylase inhibitors –Vorinostat –LBH589 –MS-275 –Romidespin  Inhibitor of apoptosis proteins –YM155—survivin protein inhibitor  Small molecule inhibitors –BI2536—targets Polo-like kinase-1 –PS1145—kappaB kinase inhibitor –PX478—inhibits HIF1a transcription factor that regulates cellular response to hypoxia –TW-37—small-molecule inhibitor of Bcl-2  Heat shock protein inhibitors –IPI-504

58. For more information on this important clinical topic, go online: 2 CE-certified didactic educational modules 4 CME-certified Interactive Virtual Presentations clinicaloptions.com/Lymphoma09