Part VII – Non-Hodgkin Lymphoma/ Chronic Lymphocytic Leukemia Tuesday, July 26, :30 PM – 8:30 PM ET RTP TV: An 8-Part Live CME Webcast Series

Stephanie A Gregory, MD The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center Chicago, Illinois John P Leonard, MD Richard T Silver Distinguished Professor of Hematology and Medical Oncology Professor of Medicine, Weill Cornell Medical College New York, New York Neil Love, MD Research To Practice Miami, Florida

Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Allos Therapeutics, Amgen Inc, Astellas Pharma Global Development Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, ImClone Systems, a wholly owned subsidiary of Eli Lilly and Company, Lilly USA LLC, Millennium: The Takeda Oncology Company, Mundipharma International Limited, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle Genetics

Disclosures for Stephanie A Gregory, MD Advisory Committee Amgen Inc, Cephalon Inc, Genentech BioOncology, Novartis Pharmaceuticals Corporation, Spectrum Pharmaceuticals Inc Speakers BureauCephalon Inc

Disclosures for John P Leonard, MD Consulting Agreements Biogen Idec, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, EMD Serono Inc, Genentech BioOncology, GlaxoSmithKline, Millennium: The Takeda Oncology Company, Novartis Pharmaceuticals Corporation, Pfizer Inc, Sanofi

Agenda — Non-Hodgkin Lymphoma/ Chronic Lymphocytic Leukemia Module 1: Follicular Lymphoma (FL) Module 2: Chronic Lymphocytic Leukemia (CLL) Module 3: Mantle-Cell Lymphoma (MCL) Module 4: Diffuse Large B-Cell Lymphoma (DLBCL) Questions and answers

Dr Gregory (Case A): Follicular Lymphoma 6/2004: 54 yo man with diffuse supraclavicular, bilateral axillary and inguinal and intra-abdominal adenopathy, largest 2.8 cm Lab results: All normal, including LDH Inguinal node bx: Follicular lymphoma Grade II/III BM bx: Positive for lymphoma (20%) FLIPI score: 2

Inguinal Node Biopsy Results: Follicular Lymphoma Grade /hpf

1. If this patient presented to you now in 2011, which first-line therapy would you generally recommend?

Baseline CT of abdomen June 11, 2004 Multiple intra-abdominal nodes CT scan 12 weeks after 4 weeks of rituximab induction Markedly decreased adenopathy in all areas

Induction rituximab 375 mg/m 2 weekly x 4 Restage- week 12 End study treatment <PR or PD ≥PR/CR Rituximab re-treatment at progression Single 375 mg/m 2 IV q4wk Continue to rituximab failure Rituximab maintenance Single 375 mg/m 2 IV q12wk Continue to rituximab failure Primary endpoint is time to rituximab failure RANDOMIZERANDOMIZE N = 600+ patients – closed REGISTERREGISTER ECOG 4402 RESORT Trial

Dr Gregory (Case A): Follicular Lymphoma 6/21/2011: Remains asymptomatic in complete remission Labs: Normal except for mildly decreased IgG (794), IgA (144) and IgM (21) Patient has had no infections CT scans every 6 months – no evidence of disease Remains on clinical trial w/o Rx interruption

Ardeshna KM et al. Proc ASH 2010;Abstract 6. An Intergroup Randomised Trial of Rituximab vs a Watch & Wait Approach in Patients with Advanced Stage, Asymptomatic, Non-Bulky Follicular Lymphoma Kirit M Ardeshna, Paul Smith, Wendi Qian, June Warden, Lindsey Stevens, Christopher FE Pocock, Fiona Miall, David Cunningham, John Davies, Andrew Jack, Jan Walewski, A Burhan Ferhanoglu, Ken Bradstock and David C Linch

Rituximab (R) vs a Watch and Wait Strategy in Patients with Stage II-IV Asymptomatic, Nonbulky FL Ardeshna K et al. Proc ASH 2010;Abstract 6. Improved PFS in R arms (P < 0.001) Time to initiation of new treatment in the R arms: –33 mo vs not reached at 4 yr (P < 0.001) No difference in OS (P > 0.5) Quality of life no worse Arm AArm BArm C InterventionObserveR x 4 wk Maintenance——R q2m x 2 yr Number CR/PR (%)2/343/3054/33 3-yr progression-free survival33%60%81% Time to next treatment33 moNR

With permission from Ardeshna KM et al. Proc ASH 2010;Abstract 6. Proportion of patients with no new treatment initiated % requiring Rx at 3 yr Watch and wait = 52% Rituximab = 20% Rituximab and maintenance rituximab = 9% Years from randomisation Time to Initiation of New Therapy

Preliminary Results of Quality of Life (QOL) Analyses from the Intergroup Phase III Randomised Trial of Rituximab vs a Watch and Wait Approach in Patients with Advanced Stage, Asymptomatic, Non-Bulky Follicular Lymphoma (FL) Ardeshna KM et al. International Conference on Malignant Lymphoma 2011.

Salles G et al. Lancet 2011;377(9759): PRIMA: Rituximab Maintenance After R-Chemo Two years of treatment: Every 8 weeks Three-year progression-free survival R maintenance: 75%Control: 58% Gr 3-4 infection R maintenance: 24%Control: 17% Treatment discontinued R maintenance: 4%Control: 2%

PRIMA: Progression-Free Survival Salles G et al. Lancet 2011;377(9759): Rituximab maintenanceObservationHRp-value Progression-free survival 74.9%57.6%0.55< Median follow-up of 36 months

PRIMA: Quality of Life Salles G et al. Lancet 2011;377(9759): EORTC QLQ-C30 global health status mean scores in rituximab maintenance vs observation: –75.5 (95% CI ) vs 75.2 (95% CI ), p-value = 0.89 Mean adjusted FACT-G total scores at the end of treatment in rituximab maintenance vs observation: –86.6 (95% CI ) vs 87.2 (95% CI ), p-value = 0.68

FIT Study Schema Not eligible Start of study 6-12 weeks after last dose of induction Patients with previously untreated FL Hagenbeek A et al. Proc ASH 2010;Abstract Y-ibritumomab (n = 207) Rituximab 250 mg/m 2 IV on day −7 and day Y-ibritumomab 14.8 MBq/kg (0.4 mCi/kg) [max 1184 MBq (32 mCi)] on day 0 CONSOLIDATION No further treatment (n = 202) CONTROL First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combination or rituximab combination INDUCTION CR/CRu or PR NR PD RANDOMIZATIONRANDOMIZATION

Cumulative Percentage 90 Y-ibritumomab Control N F PFS from Time of Randomization (Months) Overall PFS for Treatment Groups 90 Y-ibritumomab: n = 207 Median PFS: 49 mo Control: n = 202 Median PFS: 15 mo The 5-year overall PFS was 29% in the control arm compared to 47% in the 90 Y-ibritumomab arm HR = 1.95 (95% CI: 1.52 – 2.50); P < With permission from Hagenbeek A et al. Proc ASH 2010;Abstract 594.

N = 676 Rituximab (n = 340) vs bortezomib/rituximab (n = 336) Progression-free survival: 11.0 vs 12.8 months, HR = 0.82, p-value = ≥Gr 3 AEs: 21% vs 46% Serious AEs: 11% vs 18%

Eligibility High-risk FL with high tumor burden Stage II-IV disease Grade 1-3a disease FLIPI-1 score of 3, 4 or 5 Arm 1 BR q28d x 6 Rituximab d1, 4 wks after completion of induction, q8wk x 2 yrs ECOG-E2408: A Phase II Trial of BR Followed by Rituximab vs Bortezomib-BR (VBR) Followed by Rituximab vs BR Followed by Lenalidomide/Rituximab Target Accrual = 250 (open) July R Arm 2 VBR q28d x 6 Rituximab as in Arm 1 Arm 3 BR q28d x 6 Lenalidomide q28d x 13 immediately after induction Rituximab as in Arm 1 B = bendamustine, V = bortezomib, R = rituximab

Dr Leonard (Case B): Follicular Lymphoma 8/2006: Currently 61 yo otherwise healthy female artist w/2-cm groin node; asymptomatic Bx: Follicular Grade II/III Imaging: Diffuse lymphadenopathy (LAN) 2-3 cm range Observed 3 years, slowly progressive disease Imaging: Mass over 12 cm Labs remain normal including LDH

58-year-old75-year-old R-CHOP 32%5% R-bendamustine 36%34% R-CVP 26%32% Rituximab monotherapy 1%24% What is currently your usual preferred regimen for a patient with FL who requires initial treatment? Patterns of Care in Medical Oncology: Management of NHL and CLL 2010.

Dr Leonard (Case B): Follicular Lymphoma Bendamustine/rituximab therapy is initiated Excellent response, 75% LAN reduction, no symptoms Tolerated well but dose reduction in last 2 cycles –Mild cytopenias, fatigue, nausea, IV hydration needed 9/2010: R maintenance initiated every 2 months Patient doing well

Before BR After BR

RAPID-FIRE QUESTIONS

59 yo man with bulky follicular lymphoma but minimally symptomatic. What is the optimal regimen? After bendamustine fails, what is the next step? Does rituximab change the natural history of follicular lymphoma? Patient with poor performance status whose FL progressed on rituximab monotherapy Follicular Lymphoma

Dr Leonard (Case C): CLL Currently 75 yo married businessman presents with mild lymphoadenopathy and lymphocytosis PMH: Diabetes, hyperlipidemia Followed off therapy Develops progressive lymphocytosis (70k) anemia, splenomegaly, fatigue Trisomy 12 (intermediate risk)

2. Which first-line therapy would you generally recommend for this patient?

National Patterns of Care Among Clinical Investigators (N = 25): Preferred Initial Treatment for Younger and Older Patients with CLL (Normal Cytogenetics) Patterns of Care in Medical Oncology: Management of NHL and CLL yo75 yo FCR68%12% FR17%33% BR8%29%

Dr Leonard (Case C): CLL F-R x 6 cycles (delayed cycle 6) Tolerated well, mild cytopenias Patient is active with minimal symptoms

Informative for Prognosis or Therapy Decision- Making? Cytogenetics and/or FISH – t(11;14) – t(11q;v) – +12 – del(13q) – del(17p) Molecular Genetic Analysis – Immunoglobulin heavy chain variable gene (IgHV) mutation status Flow Cytometry or Immunohistochemistry – CD38 – Zap 70

CLL-8: Progression-Free Survival with FC versus FCR Hallek M et al. Lancet 2010;376: ChemoimmunotherapyChemotherapyp-value Progression-free survival 51.8 mos32.8 mos<0.0001

Hallek M et al. Lancet 2010;376(9747): FCR (n = 408) FC (n = 409) Hazard ratiop-value 3-year PFS65%45%0.56< year OS87%83% Impact of FC versus FCR on Progression-Free and Overall Survival in CLL

Eligibility Untreated Binet C CLL or Binet B or A with ≥ one of B-symptoms, progressive lymphocytosis, marrow failure; massive, progressive or painful splenomegaly; or massive lymph nodes or nodal clusters No 17p deletion by FISH FCR BR Phase III Trial of Combined Immunochemotherapy with FCR versus BR in Previously Untreated CLL Target Accrual = 550 (open) April R German CLL Study Group

RAPID-FIRE QUESTIONS

FCR versus BR for up-front therapy: Which agents, when and for whom? What is the recommended dose of bendamustine for elderly patients? Is there still a role for single-agent chlorambucil? Chronic Lymphocytic Leukemia

What is the optimal use of alemtuzumab in CLL? Role of bone marrow biopsy in CLL Guidelines regarding re-treatment with rituximab: Role of ofatumumab Chronic Lymphocytic Leukemia

Dr Gregory (Case D): Mantle-Cell Lymphoma 2/2008: 61 yo male w/progressive asymptomatic lymphadenopathy in left neck and right groin 8/2008: Lymph node bx = MCL –Staging workup –CT CAP: Diffuse cervical, axillary, inguinal and mesenteric adenopathy, largest 4.7 cm in the inguinal area –Labs: Normal including LDH and beta2 microglobulin –BM bx: 10% involvement by lymphoma

Low Power Cross Sectional Lymph Node Biopsy Showing Replacement by MCL

High Power Showing MCL

Immunohistochemistry CD5 CD20 CYCLIN D1 KI-67

Bone Marrow Biopsy Showing Involvement by Lymphoma

Initial Staging CT Scan: 8/2008 Mesenteric LN: 4.5 x 3.1 cmInguinal LN 4.7 x 3.2 cm

3. Which treatment would you generally recommend for this patient as first-line therapy? R-CHOP R-CHOP  ASCT R-hyper-CVAD or other Ara-C-containing regimen BR Other

8/ /2009: Patient treated on ECOG-E1405 – 8/ /2009: Randomized to VcR-CVAD – Randomized to SCT w/o rituximab maintenance 4/2011: Patient remains in CR as of last office visit Dr Gregory (Case D): Mantle-Cell Lymphoma

E1405: A Phase II Study of VcR-CVAD Induction Followed by Maintenance Rituximab for Untreated MCL REGISTERREGISTER SD, PR, CR Rituximab Maintenance Rituximab: 375 mg/m 2 IV weekly over 4 consecutive weeks. To begin 4-6 weeks after chemo q6m for a total of 4 courses. Autologous Stem Cell Transplantation This treatment arm is optional. Transplant-eligible pts may be consolidated with ASCT using the institution’s local guidelines. Patients will be monitored for PFS and OS. Patients receiving maintenance rituximab may have stem cells harvested (for possible future use). Patients who come off protocol therapy to receive ASCT may have stem cells harvested according to local institutional guidelines. Accrual Goal = 72 VcR-CVAD induction

Inguinal LN Smaller: 2.8 x 1.4 cm Restaging Scan After 4 Cycles: 12/2008

No abnormal inguinal adenopathyNo abnormal intra-abdominal adenopathy Restaging Scan After 6 Cycles: 1/2009 No abnormal intra-abdominal adenopathy

Rituximab Maintenance Significantly Prolongs Duration of Remission in Elderly Patients with Mantle Cell Lymphoma. First Results of a Randomized Trial of the European MCL Network Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.

European MCL Maintenance Study >60 yo with Stage II-IV MCL Not eligible for HDT Eligibility CR/CRu or PR RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION R-CHOP R-FC RANDOMIZATIONRANDOMIZATION RANDOMIZATIONRANDOMIZATION R maintenance 375 mg/m 2 q2m IFN maintenance Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium.

Efficacy (N = 223 evaluable)RituximabIFN Hazard ratiop-value Remission duration – All pts 51 mos24 mos Overall survival – All pts 3-yr OS – CHOP-R induction NR 85% NR 70% NR — NS Gr 3/4 Adverse Events Leukocytopenia 17%36%—— Thrombocytopenia 7%16%—— Infection 7% —— Outcomes of Maintenance Therapy in Elderly Patients (Median: 70 yo) with MCL (Median F/U: 30 Months) Kluin-Nelemans J et al. European Hematology Association 2011;Presidential Symposium. “Rituximab maintenance after R-CHOP induction should be considered the new standard for elderly patients with MCL.”

Treatment Chemo-Immunotherapy and ASCT Bortezomib D1,8,15,22 every 56 days x 10 Bortezomib D1,4,8,11 every 21 days x 4 A Randomized Phase II Trial of Maintenance vs Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and ASCT for Previously Untreated MCL Target Accrual = 150 (active, not recruiting) April Protocol ID: CALGB R

Dr Leonard (Case E): Mantle-Cell Lymphoma Currently 66 yo married female teacher –1998: Presents with lymphocytosis, splenomegaly, originally CLL suspected 2007: Dx of MCL on positive FISH for t(11;14) Watched for 9 years 2/2010: Increased lymphocytosis, splenomegaly, anemia

Dr Leonard (Case E): Mantle-Cell Lymphoma 2/2010: CHOP-R x 3 cycles, minimal response  progression Oral PEP-C x 2 months  progression BR x 6 cycles, excellent response for 4 months –Progresses 7/2010 Part B R-hyper-CVAD (methotrexate/ARA-C) x 1 cycle, not tolerated well 3/2011: Btk inhibitor (PCI-32765) on study –Excellent response for past 3 months

Before Btk InhibitorAfter Btk Inhibitor

The Btk Inhibitor, PCI-32765, Induces Durable Responses with Minimal Toxicity in Patients with Relapsed/Refractory B-Cell Malignancies: Results from a Phase I Study Fowler N et al. Proc ASH 2010;Abstract 964.

Response with PCI in Relapsed/Refractory B-Cell Malignancies in a Phase IA Study Fowler N et al. Proc ASH 2010;Abstract % 80% 60% 40% 20% 0% Best Response, % MCLCLL/SLLDLBCLFL 7/9 78% 9/13 69% 2/7 29% 4/13 31% CR PR

Dr Gregory (Case F): DLBCL 1999: 20 yo male college student with DLBCL –No B symptoms, no PMH –Positive for CD20, CD10 and CD45 –IPI Score: 1 5/2000: Completes CHOP x 8 Restaging CT after 4 cycles: 50%  in mass size, negative Gallium scan 6/2000: Restaging PET scan high SUV in mediastinum Biopsy: DLBCL 8/2000: ESHAP salvage therapy, BEAM, autoSCT Post-transplant consolidative RT to mediastinum Repeat CT scans: Negative for 5 years Patient lost to follow-up

Dr Gregory (Case F): DLBCL 8/2009 (9 years later): Negative CTs 1/2010: Bilateral inguinal adenopathy found on PE, largest 3.7 cm left inguinal area CT CAP: 2.9 x 3.7 cm, left inguinal lymph node, enlarged left para-aortic nodes and mass around rectal area PET/CT: Consistent with abdominal lesion involving retroperitoneal lymph nodes, abdominal lymph nodes; celiac and pelvic lesion consistent with neoplasm, presumably lymphoma –Enlarged metabolically active lesion rectal region MUGA: LVEF — 52%

PET Scan at Relapse: 2010

Dr Gregory (Case F): DLBCL Colonoscopy: Rectal erythema, edematous folds, friability and an aphthous ulcer; biopsy negative for DLBCL BM bx: Negative LN bx: DLBCL Flow cytometry: Bright CD45, CD20, CD19, CD10 and monoclonal kappa Labs: Normal, LDH 280 Patient received 2 cycles of R-ICE and repeat auto transplant Presently in complete remission one year post-transplant

IPI = 1 –A = Age of 30 –P = Performance Status - 1 –L = LDH: 280 –E = Extra Nodal -1 –S = Stage - IIE? (Was mass arising from rectum? Or was this a nodal mass pushing in on rectum?) Dr Gregory (Case F): DLBCL

Maintenance with Rituximab After Autologous Stem Cell Transplantation in Relapsed Patients with CD20 Diffuse Large B-cell Lymphoma (DLBCL): CORAL Final Analysis Gisselbrecht C et al. Proc ASCO 2011;Abstract 8004.

CORAL: EFS by Post-ASCT Maintenance Rituximab versus Observation Gisselbrecht C et al. Proc ASCO 2011;Abstract PFS and OS also did not differ between post-ASCT maintenance rituximab and observation. Rituximab (n = 122) Observation (n = 120)p-value Event-free survival 45%47%0.7435

4. Do you order specific screening tests for hepatitis for patients who are about to initiate treatment with rituximab and who have no history of or risk factors for hepatitis?

NCCN Clinical Practice Guidelines in Oncology, Non-Hodgkin Lymphomas, v Hepatitis B Screening in Patients Receiving Anti-CD20 Antibody (Rituximab) No risk factors: –Hepatitis B surface antigen and core antibody Risk factors or prior history of hepatitis B: –Add e-antigen If positive, check viral load and consult with gastroenterologist

R-CHOP 2 cycles R-ICE 4 cycles July Eligibility Criteria Bulky Stage II or Stage III/IV DLBCL Target Accrual: 99 ECOG-E3404: Response-Adapted Therapy for Aggressive NHL Based on Early PET Scanning R-CHOP 4 Cycles PET SCAN + -

Interim Positron Emission Tomography Scans in Diffuse Large B-cell Lymphoma: An Independent Expert Nuclear Medicine Evaluation of the Eastern Cooperative Oncology Group E3404 Study Horning SJ et al. Blood 2010;115(4):775-7.

Interim PET Scans Horning SJ et al. Blood 2010;115(4): PET scans read by three independent reviewers Moderate agreement among readers (68% by ECOG criterion) Proportion of positive PET scans relatively low (range 16% to 34%) PET interpretation should be standardized

RAPID-FIRE QUESTIONS

What is the role of maintenance therapy in follicular lymphoma after transformation? Use of bendamustine/rituximab in DLBCL Would you ever consider a transplant at first remission? Is there any clinical benefit to using dose-dense R-CHOP? Diffuse Large B-Cell Lymphoma

Schedule of Events Tuesday, August 2 Chronic Myeloid Leukemia Susan M O’Brien, MD Neil P Shah, MD, PhD