Challenging Cases in Non-Hodgkin Lymphoma: Oncologist and Nurse Investigators Consult on Actual Patients

1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

2. Challenging Cases in Non-Hodgkin Lymphoma Oncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty Thursday, May 1, 2014 12:00 PM – 1:30 PM Faculty Lauren C Pinter-Brown, MD Mitchell R Smith, MD, PhD Amy Goodrich, CRNP-AC Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC ModeratorNeil Love, MD

3. Oncology 6-Part Case Series: Key Themes • Mechanisms of action of novel agents and tissue assays to predict response • Side effects and toxicities of novel agents; dose adjustments • Assessment and management of adherence • Specific goals of therapy and likely outcomes; sequencing of agents in advanced disease • Local and systemic complications of cancer: Fatigue, pain, CNS involvement • Care of older, frail patients and those with comorbidities

4. Oncology 6-Part Case Series: Key Themes • Clinical trials as a means to access new treatments earlier • Management of anxiety and depression • Key determinants of patient satisfaction: What do people with cancer want and need? • Quality, value and cost: Investing resources optimally • End-of-life care and planning • Impact of the cancer experience on family and loved ones, including minor children • Impact of the oncology experience on oncology health professionals

5. Agenda A Patient with Mantle-Cell Lymphoma (MCL) Who Received Multiple Lines of Therapy • 52 yo man with relapsed MCL whose wife is dying of metastatic endometrial cancer (Ms Goodrich) A Patient with Chronic Lymphocytic Leukemia (CLL) in Remission • 69 yo man with CLL currently in remission(Ms Rogers)

6. Agenda Two Patients with Follicular Lymphoma (FL) Who Received Rituximab/Chemotherapy Followed by Rituximab Maintenance • 48 yo man with FL and multiple health problems related to chronic obesity (Ms Goodrich) • 56 yo man with FL and comorbid community-acquired clostridium difficileinfection (Ms Rogers) A Patient with Angioimmunoblastic T-Cell Lymphoma (TCL) and a Patient with ALK-Negative Anaplastic Large Cell Lymphoma (ALCL) • 53 yo man with rapidly progressive disease (Ms Goodrich) • 65 yo man who delayed allogeneic STC and had rapid disease progression (Ms Rogers)

7. Case 1 (from the practice of Ms Goodrich) • A 52-year-old man was diagnosed with Stage IVA MCL in 2009 • He responded to R-CHOP and was considered for autologous stem cell transplant (SCT), but his cardiac ejection fraction was 41% • Eighteen months later, disease progression occurred • He received bendamustine/rituximab (BR) x 2 cycles, then R-ICE x 3 followed by allogeneic SCT • He then developed multiple subcutaneous relapses and underwent treatment with rituximab/radiation therapy and bortezomib/radiation therapy • Most recently, treatment with ibrutinib has been initiated • His wife, who sees the same medical oncologist, is dying of metastatic endometrial cancer

8. Discussion Point Treatment of newly diagnosed MCL in younger and older patients; role of rituximab maintenance

9. Common Induction Regimens for MCL • Aggressive Therapy • CALGB regimen • R-hyper-CVAD • NORDIC regimen • R-CHOP/R-DHAP • Less Aggressive Therapy • Bendamustine/R • R-CHOP • Modified R-hyper-CVAD • Cladribine/R

10. European MCL Maintenance Study R maintenance 375 mg/m2 q2m R-CHOP Eligibility R R CR/CRu or PR • >60 yo with Stage II-IV MCL • Not eligible for HDT R-FC IFN maintenance • Maintenance R reduced the risk of progression or death by 45% • In patients responding to R-CHOP, maintenance R improved overall survival Kluin-Nelemans HC et al. N Engl J Med 2012;367:520-31.

11. Discussion Point Major questions being tested in ongoing up-front trials; bortezomib as part of induction; lenalidomide as maintenance

12. Mechanisms of Action of Proteasome Inhibitors Adapted from Paramore A, Frantz S. Nat Rev Drug Discov 2003;2(8):611-2.

13. Bortezomib • FDA approved for R/R MCL • 1.3 mg/m2 IV days 1, 4, 8, 11 q 21 days • SQ dosing now an option • Phase II PINNACLE trial (n = 155) • ORR: 32% • mDOR: 9.2 months • mTTP: 6.7 months • Peripheral neuropathy main toxicity • 55% (any grade), 13% (Grade ≥3) Fisher RI et al. JCO 2006;24(30):4867-74; Goy A et al. Ann Oncol 2009;20(3):520-5.

14. Lenalidomide:Mechanism of action in lymphoma NK-Cell Effects Immune synapse formation ADCC Direct NK-mediated killing T-Cell Effects Immune synapse formation T-cell activation and proliferation CD8+ T effector cell activity Microenvironmental Effects FGF2 Altered cytokine levels IgG production B-CLL Cell Effects APC function CXCR4 expression

15. Lenalidomide • FDA approved for R/R MCL after 2 prior therapies, one including bortezomib • 25 mg po days 1-21 q 28 days • Phase II EMERGE study (n = 134) • ORR: 28% • mDOR: 16.6 months • mPFS: 4.0 months • Major toxicities • Grade 3/4: Neutropenia (43%); thrombocytopenia (27%) • Any grade: Fatigue (34%), diarrhea (31%), nausea (30%) Goy A et al. JCO 2013;31(29):3688-95.

16. ECOG-E1411 Phase II Study in Older Patients with Untreated MCL Target Accrual: 332 (Active, recruiting) BR  R R BVR  R BR  LR Primary Endpoint: PFS at 2 yrs BVR  LR B = bendamustine V = bortezomib R = rituximab L = lenalidomide www.clinicaltrials.gov, April 2014 ClinicalTrials.gov Identifier: NCT01415752

17. Antigen-Dependent B-Cell Receptor Signaling and Its Targeting by Small-Molecule Inhibitors Adapted from Wiestner A. J Clin Oncol 2013;31:128-30.

18. Ibrutinib • FDA approved for R/R MCL - Nov 2013 • 560 mg po daily • Phase II trial (n = 111) • ORR: 68% • mDOR: 17.5 months • mPFS: 13.9 months • Major toxicities • Grade 3-4: Neutropenia 16%, thrombocytopenia 11% • Any grade: Diarrhea 50%, fatigue 41%, edema 28% Wang ML et al. NEJM 2013;369(6):507-16.

19. Case 2 (from the practice of Ms Rogers) • A 69-year-old retired man diagnosed with CLL in 2006 was observed without medical treatment for several years but used Chinese herbal products for his disease • In 2009 he developed splenomegaly with abdominal discomfort and received single-agent bendamustine70 mg/m2 • He developed a rash that was difficult to treat but resolved when he discontinued use of the herbal products • In 2012 he experienced disease recurrence for which he received bendamustine 90 mg/m2 and rituximab • Currently his disease is in remission and he is being observed

20. Discussion Point Risks, benefits and available data with common induction regimens for younger and older patients requiring treatment

21. Common Induction Regimens in CLL Wierda WG. J Clin Oncol 2012;30(26):3162-4.

22. Toxicity Issues Common Concerns • Prolonged myelosuppression • Treatment-related myeloid neoplasia Fludarabine • F(C)R difficult to tolerate in older patients • Immunosuppression • Renal excretion • Exacerbation of AIHA Bendamustine • Rash • Hypersensitivity

23. German CLL10 Phase III Study Design Target Accrual: 564 (Active, not recruiting) FCR R BR • Median follow-up: 27.9 months FCR BR • Complete response rate: 47.4% 38.1% • 2-year progression-free survival: 85% 78.2% • 2-year overall survival: 94.2% 95.8% www.clinicaltrials.gov, April 2014 Eichhorst B et al. Proc ASH 2013;Abstract 526. ClinicalTrials.gov Identifier: NCT00769522

24. Discussion Point Incidence of various cytogenetic abnormalities (13q and 17p deletions, et cetera) and their impact on therapeutic decision-making

25. Discussion Point Mechanisms of action of Type I and II anti-CD20 monoclonal antibodies; trial of obinutuzumab/chlorambucil

26. Mechanisms of Action of Anti-CD20 Antibodies Complement-mediated lysis C1q binding Rituximab and obinutuzumab binding site MAC CD20 Cell lysis ADCC FCgRIIIa Cell membrane Effector cell B-cell NHL(tumor cell) CD20antigen Direct effects Antibody binding induces antiproliferative signaling, apoptosis and cell-growth inhibition Adapted from Maloney DG. N Engl J Med 2012;366:2008-16.

27. ADCC = antibody-dependent cell-mediated cytotoxicity; DCD = direct cell death. 1. Niederfellner G et al. Blood 2011;118:358-67. 2. Alduaij W et al. Blood 2011;117:4519-29. 3. Mössner E et al. Blood 2010;115:4393-02. 4. Herter S et al. Poster presentation at ASH 2010 (Abstract 3925). Comparison of cell death induced by obinutuzumab and rituximab Type IIanti-CD20 antibody1 GlycoengineeredFc region3 Enhanced DCD vs rituximab2 Up to 100-fold increase in ADCC vs rituximab3,4

28. FDA Approves the Use of Obinutuzumab in Combination with Chlorambucil for CLL “On November 1, 2013, the US Food and Drug Administration (FDA) approved obinutuzumab (GA101) for use in combination with chlorambucil for the treatment of patients with previously untreated CLL, based on demonstration of an improvement in PFS in a randomized open-label multicenter trial that compared obinutuzumab in combination with chlorambucil (GClb) with chlorambucil (Clb) alone in patients with previously untreated CD20-positive CLL.” http://www.cancer.gov/cancertopics/druginfo/fda-obinutuzumab

29. German CLL 11 Phase III Study Target Accrual: 786 (Active, not recruiting) Chlorambucil + Obinutuzumab Chlorambucil + Rituximab R Chlorambucil Primary Endpoint: PFS Final Stage 2 Results: Median PFS: 26.7 mo (chlorambucil/obinutuzumab) vs 15.2 mo (chlorambucil/R) www.clinicaltrials.gov, April 2014 ClinicalTrials.gov Identifier: NCT01010061 Goede V et al. New Eng J Med 2014;370(12):1101-10

30. CLL 11: Obinutuzumab plus Chlorambucil versus Rituximab plus Chlorambucil in Patients with CLL and Coexisting Conditions Grade ≥3 Adverse Events G-Clb R-Clb Infusion-related reactions 20% 4% Neutropenia 33% 28% Infections 12% 14% Goede V et al. N Engl J Med 2014;370:1101-10.

31. FDA Approves the Use of Ofatumumab in Combination with Chlorambucil for CLL “On April 17, 2014, the US Food and Drug Administration (FDA) approved ofatumumab in combination with chlorambucil, for the treatment of previously untreated patients with CLL, for whom fludarabine-based therapy is considered inappropriate, based on results from a Phase III study (COMPLEMENT 1) which demonstrated statistically significant improvement in median PFS in patients who received the combination of ofatumumab and chlorambucil compared to patients who received chlorambucil alone.” • Median Progression-Free Survival: 22.4 vs 13.1 months http://www.cancer.gov/cancertopics/druginfo/fda-ofatumumab

32. Discussion Point Recent FDA approval of ibrutinib; available data and ongoing investigation of lenalidomide and other small-molecule B-cell inhibitors

33. Lenalidomide/Rituximab (R2) Salvage Treatment for Relapsed/Refractory CLL • N = 59 patients with a median of 2 prior treatments (range: 1-9) • Overall response rate 66% • Complete response 12% • Nodular partial response 12% • Time to treatment failure 17.4 months • Estimated survival at 36 months 71% • Most common ≥Grade 3 adverse events: • Neutropenia 73% • Infection or febrile episode 24% Badoux XC et al. J Clin Oncol 2013;31(5):584-91.

34. FDA Approves the Use of Ibrutinib in CLL “On February 12, 2014, the US Food and Drug Administration (FDA) granted accelerated approval to ibrutinib for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, based on the results of a multicenter single-arm trial of 48 patients with previously treated CLL.” • Overall response rate: 71% • Complete response: 2% • Partial response with lymphocytosis: 20% • Byrd JC et al. NEJM 2013;369:32-42. http://www.cancer.gov/cancertopics/druginfo/fda-ibrutinib

35. Discussion Point Novel small molecules under investigation in B-cell cancers: PI3-kinase delta inhibitors (idelalisib), anti-BCL2 inhibitors (ABT-199)

36. Idelalisib (GS-1101, CAL-101): BCR Signaling Inhibitor • Oral inhibitor of PI3Kδ • Rapid and sustained reduction in lymphadenopathy in CLL • Transient lymphocytosis • Bendamustine and/or rituximab + idelalisib in R/R CLL • High ORR: ~80% • 2-yr PFS: 63% • 2-yr OS: 84% • Toxicities • Febrile neutropenia • Pneumonia • Transaminase elevation • Diarrhea • Pyrexia • Ongoing Phase III studies • NCT01539512: GS‑1101/placebo + R • NCT01569295: GS‑1101/placebo + BR Coutre SE et al. Proc ASH 2012;Abstract 191.

37. Mechanism of Action of Idelalisib Idelalisib Adapted from Woyach JA et al. Blood 2012;120(6):1175-84.

38. 220 patients with decreased renal function, previous therapy-induced myelosuppression or major coexisting illnesses with relapsed CLL received R/idelalisib or R/placebo • Median PFS: Not reached vs 5.5 mo • Overall response rate: 81% vs 13% • 12-month overall survival: 92% vs 80%

39. Mechanism of Action of ABT-199 • Many tumors, particularly lymphoid malignancies, are addicted to BCL-2 for survival. • ABT-199 is specific for BCL-2 and induces selective death of BCL-2-dependent tumor cells while sparing platelets, which depend primarily on BCL-XL for survival. Davids MS, Letai A. Cancer Cell 2013;23(2):139-41.

40. ABT-199: A Potent and Selective BCL-2 Inhibitor • Oral, small molecule inhibitor of BCL-2 • Binds with high affinity to BCL-2 and with substantially lower affinity to other BCL-2 proteins (BCL-XL, BCL-W and MCL-1) • Demonstrated preclinical activity as a single agent in a wide range of hematologic cancer • Main toxicities reported in relapsed/refractory NHL: • Primarily Grade 1/2 (minimal Grade 3/4) • Diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, neutropenia, cough • Antitumor activity in multiple NHL histologies, including 100% best response rate in MCL Davids MS et al. Proc ASCO 2013;Abstract 8520.

41. Two Patients with Follicular Lymphoma (FL) Who Received Rituximab/Chemotherapy Followed by Rituximab Maintenance • 48 yo man with FL and multiple health problems related to chronic obesity (Ms Goodrich) • 56 yo man with FL and comorbid community-acquired clostridium difficileinfection (Ms Rogers)

42. Case 3 (from the practice of Ms Goodrich) • A 48-year-old chronically obese man diagnosed with Stage IIIB, Grade I FL in 2007 with dermal involvement and ascites received weekly rituximab x 8 • He experienced some symptomatic response but lost approximately 100 pounds due to his disease • He received R-CVP then R-EPOCH and achieved a PET-negative complete response (CR) • He remained in CR until 2011, when a biopsy-proven recurrence was observed • He received BR followed by 2 years of maintenance rituximab • Currently he is being observed off treatment • He has regained the weight he lost and has multiple health issues related to his obesity

43. Pre-Bendamustine/R: Right Axillary Adenopathy

44. Post-Bendamustine/R: Right Axillary Adenopathy

45. Discussion Point Complications of oncologic care in patients with morbid obesity

46. Discussion Point “Watchful waiting” in FL; role of rituximab monotherapy

47. Discussion Point Commonly used induction regimens for patients receiving active treatment for FL (eg, R-CHOP, bendamustine/R, R-CVP)

48. StiL NHL 1-2003 Phase III Study Bendamustine + Rituximab (BR) R R-CHOP Median PFS: 69.5 mo (BR) vs 31.2 mo (R-CHOP) Rummel MJ et al. Lancet 2013;381;1203-10.

49. Key Findings from StiL NHL 1-2003 • Median follow-up: 45 months • BR vs R-CHOP • Median PFS (all pts): 69.5 vs 31.2 months • Median PFS (FL pts): 39% reduction in risk of progression BR • Erythematous skin reactions R-CHOP • Alopecia • Infections • Peripheral neuropathy • Stomatitis • Hematologic toxicity Rummel MJ et al. Lancet 2013;381;1203-10.

50. BRIGHT Phase III Study Bendamustine +Rituximab (BR) R R-CHOP or R-CVP Complete Response Rate: 31% (BR) vs 25% (R-CHOP or R-CVP) Overall Response Rate: 97% (BR) vs 91% (R-CHOP or R-CVP) Flinn IW et al. Blood 2014;[Epub ahead of print].