1. May 30, 2008 Chicago, Illinois Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment This program is supported by educational grants from

2. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors, 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.  Users are encouraged to include these slides in their own 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  These slides may not be published or posted online or used for any other commercial purpose without written permission from Clinical Care Options.  We are grateful to Andre Goy, MD, MPH, who aided in the preparation of this slideset. About These Slides

3. Advances in Targeted Therapies for the Treatment of Non-Hodgkin’s Lymphomas Andre Goy, MD, MPH Cancer Center Deputy Director Lymphoma Division Chief Director of the Tumor Bank HUMC Cancer Center Hackensack, New Jersey

4. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment NHL: Background  NHL refers to at least 30 different diseases –Most common hematologic malignant neoplasm in adults –Presentation ranges from smoldering/indolent to rapidly proliferating and aggressive  Overall 5- and 10-year relative survival has increased –Due to advent of monoclonal antibodies, combined with chemotherapy  First-line gold-standard therapy: rituximab  No consensus on optimal treatment of relapsed/refractory NHL –Encouraging new agents on horizon

5. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Survival in NHL Increased From 1990-1992 to 2002-2004 (SEER Data) Pulte D, et al. Arch Intern Med. 2008;168:469-476.  Higher survival rates among women vs men in 15-44 year age group –No difference in patients 75 years of age or older Relative Survival, %Low-Grade NHLHigh-Grade NHL 1990-19922002-20041990-19922002-2004 5-yr survival 70.784.942.157.8 10-yr survival 52.271.535.249.9 P <.001 for all.

6. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Treatment Options in NHL  First-line standard therapy: rituximab –Anti-CD20 monoclonal antibody  No consensus on optimal treatment of relapsed/refractory disease

7. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Treatment Options in NHL (cont’d)  Targeted agents under evaluation as monotherapy and in combinations with chemotherapy –Epratuzumab, galiximab, 90 Y-ibritumomab (monoclonal antibodies) –Bortezomib (proteasome inhibitor) –Bendamustine (alkylator hybrid and purine analogue) –Lenalidomide (immunomodulatory agent) –Temsirolimus, everolimus (mTOR inhibitors)

8. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Indolent NHL: FL  FL is the most prevalent indolent lymphoma –Represents 35% of adult NHL in United States, 22% worldwide [1]  Outcomes, including OS, improved in recent years largely due to introduction of rituximab [2]  Retrospective analysis conducted of patients with stage IV FL (1972-2002) showed improvements in outcomes [3] –5-year OS improved from 64% to 95% –FFS improved from 29% to 60% –“Plateau” in FFS curve after 8-10 years of treatment –Suggests cure is possible 1. Ganti AK, et al. Oncology (Williston park). 2005;19:213-228. 2. Pulte D, et al. Arch Intern Med. 2008;168:469-476. 3. Liu Q, et al. J Clin Oncol. 2006;24:1582-1589.

9. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Standard First-Line Treatment of FL: Rituximab  Rituximab, anti-CD20 monoclonal antibody, recommended as monotherapy and in combinations –Preferred for elderly or infirm patients  First-line rituximab plus chemotherapy increases –ORR –Response duration –PFS –OS NCCN clinical practice guidelines. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

10. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Maintenance Rituximab Improves PFS and OS in Relapsed/Refractory FL PFSOS Patients (%) Yrs Rituximab Observation This research was originally published in Blood. van Oers MH, et al. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood © American Society of Hematology.  Randomized, open-label phase III study of 334 patients who achieved CR or PR following induction therapy with CHOP or R-CHOP P <.001P =.011 0 10 20 30 40 50 60 70 80 90 100 012345 Patients (%) 0 10 20 30 40 50 60 70 80 90 100 0 12345 6

11. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment First-Line Galiximab + Rituximab in FL: CALGB Phase II Study 1. Czuczman M, et al. ICML 2008. Abstract. 2. ClinicalTrials.gov. NCT00363636.  Galiximab: anti-CD80 monoclonal antibody  Phase II study (N = 61) of galiximab + rituximab in untreated CD20-positive FL [1] –CR: 44% –PR: 26% –Grade 3 adverse events in 13% of patients –No grade 4 toxicities reported  Phase III study initiated: galiximab + rituximab vs rituximab alone in relapsed/refractory FL [2]

12. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment First-Line Phase III RIT in Advanced FL: 90 Y-Ibritumomab (FIT Trial)  90 Y-ibritumomab: anti-CD20 IgG 1 monoclonal antibody conjugated with radioactive yttrium-90 –Indications: relapsed/refractory, low-grade, or follicular B-cell NHL Radford JA, et al. EHA 2008. Abstract 433. All Patients 90 Y-Ibritumomab (n = 208) Observation (n = 206) P Value Median PFS, mos3713<.001 CR after induction29.76.3<.0001 Partial responders5429.5.0154 FLIPI scores  High risk246.5.0789  Intermediate risk5411<.0001  Low riskNot reached24.0502

13. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Diffuse Large B-Cell Lymphoma: Treatment Options  Standard first-line induction therapy: R-CHOP –Locoregional radiotherapy as well if bulky disease or adverse risk factors present –Clinical trial preferred for stage III/IV disease  CR: follow-up/observation  PR or no response: second-line high-dose chemotherapy with ASCT ± rituximab –If not a candidate for high-dose therapy: clinical trial or second-line chemotherapy ± rituximab NCCN clinical practice guidelines. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

14. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment  Primary endpoint: EFS  Secondary endpoints: OS, RR Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126. R-CHOP every 3 weeks for 8 cycles (n = 202) CHOP every 3 weeks for 8 cycles (n = 197) Untreated elderly patients with stage II-IV DLBCL (N = 399) Stratified by risk factors (0-1 vs 2-3) Assessment CHOP ± Rituximab in DLBCL: GELA LNH-98.5 Phase III Study

15. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study) Permission granted by author to print. Coiffier B, et al. ASCO 2007. Abstract 8009. OS (N = 399) Parameter, % Low Risk High Risk Age, < 70 vs ≥ 70 years58.049.0 LDH, NI vs > NI69.045.0* Stage, I/II vs III/IV67.050.0 Bone marrow, yes vs no60.034.5* Tumor size, < 10 vs ≥ 10 cm60.036.5 β 2 -microglobulin, NI vs > NI64.539.0* Serum albumin, ≥ 35 vs < 35 g/L60.040.0 *P <.05 (multivariate analysis). Survival Probability Yrs 0 0.2 0.4 0.6 0.8 1 0 1357 8 24 6 CHOP R-CHOP P =.0004

16. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Epratuzumab and Rituximab + CHOP in First-Line DLBCL (Phase II Study) Micallef IN, et al. ASCO 2008. Abstract 8500.  Epratuzumab added to rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone (ER-CHOP) active in patients with previously untreated diffuse large B-cell lymphoma –85% EFS at 12 months compared with 67% to 79% EFS and PFS at 12 months in R-CHOP trials –95% ORR –62% CR/unconfirmed CR –33% PR  ER-CHOP similar toxicity profile as R-CHOP  Results provide rationale for phase III study to compare R-CHOP with ER-CHOP

17. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment First-Line CHOP + 90 Y-Ibritumomab in Elderly DLBCL Patients (Phase II)  N = 20 patients (median age: 68) –IPI score ≥ 2: 75%  ORR: 100%  2-year PFS: 75%  2-year OS: 95%  Toxicity: moderate, with no evidence of cumulative effects –Grade 3/4 hematologic adverse events: 12 (60%), primarily neutropenia –Nonhematologic adverse events: “practically absent” Zinzani PL, et al. Ann Oncol. 2008;19:769-773. 0 10 20 30 40 50 60 70 80 90 100 Before CHOPAfter CHOP + 90 Y-Ibritumomab CR PR

18. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Treatment Options in MCL  Chemotherapy –R-CHOP –Hyper-CVAD –Fludarabine (with cyclophosphamide/mitoxantrone) –Clofarabine, cladribine  Targeted therapy –Rituximab –Bortezomib –Temsirolimus

19. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment  Primary endpoint: PFS  Secondary endpoints: OS, ORR, safety Temsirolimus 175 mg 3x weekly then 75 mg weekly (n = 54) Temsirolimus 175 mg 3x weekly then 25 mg weekly (n = 54) Patients with relapsed/refractory MCL (N = 162) Treatment until PD, death, or unacceptable toxicity Temsirolimus in Relapsed/Refractory MCL: Phase III Study Hess G, et al. ASCO 2008. Abstract 8513. Investigator’s choice single agent (n = 54)

20. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Temsirolimus vs Investigator’s Choice Therapy in Relapsed/Refractory MCL  Phase III study (N = 162)  2 doses of temsirolimus compared with investigator’s choice therapy* –175 mg thrice weekly then either 75 mg or 25 mg weekly  ORR –175/75: 22% (1 CR, 11 PRs) –175/25: 6% (0 CR, 3 PRs) –Investigator’s choice: 2% Permission granted by author to print. Hess G, et al. ASCO 2008. Abstract 8513. *Single agents, primarily gemcitabine and fludarabine. Probability of PFS Mos 0.00 0.25 0.50 0.75 1.00 0 102025 515 P =.0004 Median PFS 175/75: 4.8 months 175/25: 3.4 months Investigator’s choice: 1.9 months

21. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Bortezomib Therapy in Lymphoma: Phase II Data  Relapsed/refractory B-cell NHL [1] –MCL: 41% ORR, including 6 CRs, 6 PRs –Other B-cell lymphomas: 19% ORR, including 2 CRs, 2 PRs –Primary grade 3/4 adverse events: nausea, fatigue, thrombocytopenia  Indolent NHL and MCL [2] –ORR: 58%, including 2 CRs, 4 PRs, 4 SDs –Most common grade 3 adverse events: lymphopenia, thrombocytopenia  Phase II study of bortezomib plus bendamustine and rituximab in relapsed/refractory FL is under way [3] 1. Goy A, et al. J Clin Oncol. 2005;23:667-675. 2. O’Connor OA, et al. J Clin Oncol. 2005;23:676-684. 3. ClinicalTrials.gov. NCT00636792.

22. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL Goy A, et al. ASH 2007. Abstract 125.  Open-label, prospective, international, multicenter, phase II trial  Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 of 21-day cycle –Upon CR/unconfirmed CR –Treatment continued for 4 additional cycles –If no CR/unconfirmed CR –Treatment continued up to 17 cycles or until disease progression or toxicity Characteristic Patients (N = 155) Median age, years (range) 65 (42-89) Median time from diagnosis, yrs (range) 2.3 (0.2-11.2) Median previous therapies, n1 Stage IV MCL, %77 IPI score ≥ 3, %44 KPS < 90%, %29 LDH > upper limit of normal, %36 Bone marrow involvement, %55

23. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL (cont’d) Goy A, et al. ASH 2007. Abstract 125. Overall response CR/unconfirmed CR 0 20 40 60 80 100 Previous High- Intensity Therapy (n = 52) 32 29 25 8 6 10 Refractory MCL (n = 51) Evaluable (n = 141) Responses by Patient Subgroups Patients (%)

24. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment  N = 29 eligible patients with newly diagnosed or relapsed MCL –13 (44.8%) with no previous chemotherapy –Median age: 67 years (range: 48-79)  Treatment: bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 of 21-day cycle  Median duration of response with unconfirmed CR: 24.2 months Belch A, et al. Ann Oncol. 2007;18:116-121. Response, n (%)All Patients (n = 28) Previous Treatment (n = 15) No Previous Treatment (n = 13) ORR13 (46.4)7 (46.7)6 (46.2)  CRu1 (3.5)1 (6.6)0 (0)  PR12 (42.9)6 (40.0)6 (46.2)  SD12 (42.3)6 (40.0)6 (46.2)  PD3 (10.72 (13.3)1 (7.6) Bortezomib in MCL: NCIC CTG IND.150 Study (Phase II)

25. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Lenalidomide in Relapsed/Refractory NHL: NHL-003 Study (Phase II)  Preliminary analysis of first 83 of planned 200 patients –96% with previous rituximab treatment  Treatment: lenalidomide PO 25 mg/day  ORR: 29% –CR/unconfirmed CR: 6% –PR: 23%  Grade 3/4 adverse events: neutropenia (27%), thrombocytopenia (15%), anemia (8%) Czuczman MS, et al. ASCO 2008. Abstract 8509.

26. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Everolimus in Relapsed, Aggressive NHL: MC048G Study (Phase II)  N = 37 patients with DLBCL (54%), MCL (38%), grade 3 FL, or Burkitt’s lymphoma –Median age: 72 years  Treatment: everolimus orally 10 mg/day (up to twelve 28-day cycles)  ORR: 32.4% –CR: 2.7% –PR: 29.7%  Median TTP: 3.1 months (95% CI: 2.0-4.7) –5 patients progression free at 6+ months Reeder CB, et al. ASH 2007. Abstract 121.

27. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment  Primary endpoint: PFS  Secondary endpoints: OS, RR Bendamustine 90 mg/m 2 on Days 1 and 2 every 28 days + Rituximab 375 mg/qm on Day 1 (n = 166) CHOP on Day 1 every 21 days + Rituximab 375 mg/qm on Day 1 (n = 149) Patients with CD20- positive lymphoma (N = 315) 6 cycles max Rummel MJ, et al. ASH 2007. Abstract 385. Median observation: 18 months First-Line Bendamustine + Rituximab vs R-CHOP in NHL: StiL Study (Phase III)

28. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment  N = 315 patients with CD20+ stage III/IV lymphoma 0 20 40 60 80 100 Response to Treatment (%) 93 88 93 47 3 ORRCR Bendamustine + rituximab (n = 166) CHOP + rituximab (n = 149) 42 44 SD Primary Refractory 3 Rummel MJ, et al. ASH 2007. Abstract 385. First-Line Bendamustine + Rituximab vs R-CHOP in NHL: StiL Study (Phase III)

29. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment First-Line Hyper-CVAD + Rituximab in Burkitt’s Lymphoma or ALL (Phase II)  N = 31 –Median age: 46 years –29% ≥ 60 years of age  CR: 86%  3-year OS: 89%  3-year EFS: 80%  3-year DFS: 88% Permission to reprint granted by Wiley. Thomas DA, et al. Cancer. 2006;106:1569-1580. OS For elderly patients, significant decrease observed in induction mortality vs hyper-CVAD alone (P =.04) and significant improvements noted in 3-year OS, DFS, and EFS Probability of Survival Mos 0.0 0.2 0.4 0.6 0.8 1.0 0 4896 144 2472120 Hyper-CVAD plus rituximab Hyper-CVAD alone (historical) P =.002 4825 313 No. No. Fail

30. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Chemoimmunotherapy in Burkitt’s Lymphoma ± HIV Infection  N = 36 consecutive patients with advanced Burkitt’s lymphoma –HIV infected: 19 (53%)  Treatment: 6 cycles intensive chemotherapy, including 8 doses rituximab  No significant differences in OS, DFS, or CR rates seen between HIV-negative and HIV-positive patients –No AIDS-characteristic opportunistic infections observed in HIV-positive patients Oriol A, et al. Cancer. 2008;[E-pub ahead of print]. 0 10 20 30 40 50 60 70 80 90 100 OSDFSCR HIV positive HIV negative

31. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Conclusions  First-line gold standard therapy for NHL: rituximab –Typically used in combinations  No consensus on optimal treatment of relapsed/refractory NHL  Survival has increased in NHL, primarily due to advent of monoclonal antibodies –Rituximab, galiximab, epratuzumab, 90 Y-ibritumomab

32. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Conclusions (cont’d)  Bortezomib approved for treatment of MCL in patients who have received at least 1 previous therapy –Approval based on PINNACLE trial  Bortezomib currently demonstrating activity as single agent and as combination therapy with various forms of NHL subtypes, including FL, MCL, small lymphocytic lymphoma, and marginal zone lymphoma  Radioimmunotherapy benefits patients with advanced follicular lymphoma, particularly if CR achieved after induction therapy

33. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment Conclusions (cont’d)  R-CHOP standard induction therapy for DLBCL  Bendamustine + rituximab equivalent to R-CHOP in NHL  Lenalidomide shows activity in relapsed/refractory NHL  mTOR inhibitors effective in relapsed/refractory NHL –Temsirolimus, everolimus

34. clinicaloptions.com/oncology Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment More Hematology/Oncology Available Online  Medical Meeting Coverage: key data plus Expert Analysis panel discussions exploring clinical implications  Treatment Updates: comprehensive programs covering the most important new concepts  Interactive Cases: test your ability to manage patients clinicaloptions.com/oncology