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Please note, these are the actual video-recorded proceedings from the live CME event and

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.

Oncology Grand Rounds Hodgkin and Non-Hodgkin Lymphomas Nurse and Physician Investigators Discuss New Agents,

Oncology Grand Rounds Hodgkin and Non-Hodgkin Lymphomas Nurse and Physician Investigators Discuss New Agents, Novel Therapies and Actual Cases from Practice Wednesday, April 10, 2019 6: 00 PM – 8: 00 PM Faculty Christopher R Flowers, MD, MS Patrick B Johnston, MD, Ph. D Robin Klebig, APRN, CNP, AOCNP Amy Goodrich, CRNP Moderator Neil Love, MD

Oncology Grand Rounds Series

Oncology Grand Rounds Series

Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research

Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abb. Vie Inc, Acerta Pharma — A member of the Astra. Zeneca Group, Adaptive Biotechnologies, Agendia Inc, Agios Pharmaceuticals Inc, Amgen Inc, Ariad Pharmaceuticals Inc, Array Bio. Pharma Inc, Astellas Pharma Global Development Inc, Astra. Zeneca Pharmaceuticals LP, Bayer Health. Care Pharmaceuticals, Biodesix Inc, bio. Theranostics Inc, Boehringer Ingelheim Pharmaceuticals Inc, Boston Biomedical Inc, Bristol-Myers Squibb Company, Celgene Corporation, Clovis Oncology, Daiichi Sankyo Inc, Dendreon Pharmaceuticals Inc, Eisai Inc, Exelixis Inc, Foundation Medicine, Genentech, Genmab, Genomic Health Inc, Gilead Sciences Inc, Guardant Health, Halozyme Inc, Immuno. Gen Inc, Incyte Corporation, Infinity Pharmaceuticals Inc, Ipsen Biopharmaceuticals Inc, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC, Jazz Pharmaceuticals Inc, Kite Pharma Inc, Lexicon Pharmaceuticals Inc, Lilly, Loxo Oncology, Merck, Merrimack Pharmaceuticals Inc, Myriad Genetic Laboratories Inc, Natera Inc, Novartis, Oncopeptides, Pfizer Inc, Pharmacyclics LLC, an Abb. Vie Company, Prometheus Laboratories Inc, Puma Biotechnology Inc, Regeneron Pharmaceuticals Inc, Sandoz Inc, a Novartis Division, Sanofi Genzyme, Seattle Genetics, Sirtex Medical Ltd, Spectrum Pharmaceuticals Inc, Taiho Oncology Inc, Takeda Oncology, Tesaro, Teva Oncology, Tokai Pharmaceuticals Inc and Tolero Pharmaceuticals.

Christopher R Flowers, MD, MS Professor, Hematology and Medical Oncology Director, Emory Lymphoma Program

Christopher R Flowers, MD, MS Professor, Hematology and Medical Oncology Director, Emory Lymphoma Program Scientific Director, Winship Research Informatics Winship Cancer Institute Atlanta, Georgia

Disclosures for Dr Flowers Consulting Agreements Abb. Vie Inc, Bayer Health. Care Pharmaceuticals, Denovo

Disclosures for Dr Flowers Consulting Agreements Abb. Vie Inc, Bayer Health. Care Pharmaceuticals, Denovo Biopharma, Gilead Sciences Inc, Janssen Biotech Inc, Karyopharm Therapeutics, Optum. Rx Inc, Pharmacyclics LLC, an Abb. Vie Company, Spectrum Pharmaceuticals Inc Contracted Research Abb. Vie Inc, Acerta Pharma — A member of the Astra. Zeneca Group, Burroughs Wellcome Fund, Celgene Corporation, Eastern Cooperative Oncology Group, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, National Cancer Institute, Roche Laboratories Inc, Takeda Oncology, TG Therapeutics Inc, V Foundation for Cancer Research Uncompensated Consulting Celgene Corporation, Genentech, Roche Laboratories Inc

Amy Goodrich, CRNP Nurse Practitioner The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Amy Goodrich, CRNP Nurse Practitioner The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine Baltimore, Maryland

Disclosures for Ms Goodrich Advisory Committee Gilead Sciences Inc, Mylan Pharmaceuticals Inc, Sandoz Inc,

Disclosures for Ms Goodrich Advisory Committee Gilead Sciences Inc, Mylan Pharmaceuticals Inc, Sandoz Inc, a Novartis Division

Patrick B Johnston, MD, Ph. D Consultant in Hematology and Blood and Marrow Transplant

Patrick B Johnston, MD, Ph. D Consultant in Hematology and Blood and Marrow Transplant Mayo Clinic Rochester, Minnesota

Disclosures for Dr Johnston No relevant conflicts of interest to disclose

Disclosures for Dr Johnston No relevant conflicts of interest to disclose

Robin Klebig, APRN, CNP, AOCNP Nurse Practitioner Division of Hematology, Lymphoma Group Mayo Clinic

Robin Klebig, APRN, CNP, AOCNP Nurse Practitioner Division of Hematology, Lymphoma Group Mayo Clinic Rochester, Minnesota

Disclosures for Ms Klebig No relevant conflicts of interest to disclose

Disclosures for Ms Klebig No relevant conflicts of interest to disclose

Oncology Grand Rounds 2009 -2019 54 Symposia 218 Faculty

Oncology Grand Rounds 2009 -2019 54 Symposia 218 Faculty

Oncology Grand Rounds 2019 ONS Congress Anaheim, California Symposia Themes Personalized oncology: Implementing an

Oncology Grand Rounds 2019 ONS Congress Anaheim, California Symposia Themes Personalized oncology: Implementing an individualized oncologic strategy • Tumor factors (eg, biomarkers, numeracy) • Biopsychosocial factors (eg, adherence, available family support, comorbidities, mood) Novel agents and treatment strategies • The new-agents revolution (beginning of the end? ) The bond that heals (both ways)

The Core Oncology Triad Developing an Individualized Oncology Strategy

The Core Oncology Triad Developing an Individualized Oncology Strategy

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large B-Cell Lymphoma

Case Presentation (Ms Klebig) Woman in her early 50 s with relapsed Hodgkin lymphoma

Case Presentation (Ms Klebig) Woman in her early 50 s with relapsed Hodgkin lymphoma Treatments received • Brentuximab vedotin + ABVD (on clinical trial) • ICE • Autologous transplant • Nivolumab Other considerations • Patient is single and lives alone • Patient prefers chiropractic/herbal remedies and has concerns over receiving therapy indefinitely

Case Presentation (Ms Klebig) RUSIH? (Are you sure it’s Hodgkin’s? )

Case Presentation (Ms Klebig) RUSIH? (Are you sure it’s Hodgkin’s? )

Mechanism of Action of Brentuximab Vedotin Brentuximab vedotin is an antibody-drug conjugate (ADC) targeted

Mechanism of Action of Brentuximab Vedotin Brentuximab vedotin is an antibody-drug conjugate (ADC) targeted to cells expressing CD 30 on their surface 1 ADC binds to CD 30 and initiates internalization of the ADC-CD 30 complex 2 MMAE is released 3 MMAE binds to tubulin and disrupts the microtubule network 4 Cell cycle arrest 5 Apoptosis (cell death) Courtesy of Julie M Vose, MD, MBA.

Brentuximab Vedotin Mechanism of action • CD 30 -targeted antibody-drug conjugate Indication • Previously

Brentuximab Vedotin Mechanism of action • CD 30 -targeted antibody-drug conjugate Indication • Previously untreated Stage III or IV HL in combination with chemotherapy • HL at high risk of relapse or progression as post-auto-HSCT consolidation • HL after auto-HSCT failure or after 2 multiagent regimens if ineligible for auto-HSCT Administration • IV infusion over 30 minutes – Every 2 weeks with chemotherapy for untreated HL (max 12 doses) – Every 3 weeks as consolidation (max 16 cycles) or for relapsed HL (until progression) Brentuximab vedotin package insert, March 2018.

ECHELON-1 Phase III Study Schema Accrual: 1, 334 patients Eligibility • Stage III/IV classical

ECHELON-1 Phase III Study Schema Accrual: 1, 334 patients Eligibility • Stage III/IV classical Hodgkin lymphoma • Treatment naïve • No sensory or motor peripheral neuropathy www. clinicaltrials. gov; NCT 01712490 (1: 1) R Brentuximab vedotin + AVD Brentuximab vedotin 1. 2 mg/kg doxorubicin 25 mg/m 2 vinblastine 6 mg/m 2 dacarbazine 375 mg/m 2 ABVD Doxorubicin 25 mg/m 2 bleomycin 10 units/m 2 vinblastine 6 mg/m 2 dacarbazine 375 mg/m 2

ECHELON-1: Modified PFS By independent review committee (IRC) 2 -y modified PFS = 82.

ECHELON-1: Modified PFS By independent review committee (IRC) 2 -y modified PFS = 82. 1% 2 -y modified PFS = 77. 2% (n = 664) (n = 670) Hazard ratio for progression, death or modified progression, 0. 77 p = 0. 04 by stratified log-rank test Connors JM et al. N Engl J Med 2018; 378(4): 331 -44.

ECHELON-1: Subsets of Patients Who Benefit from BV-AVD North American Results Patients in North

ECHELON-1: Subsets of Patients Who Benefit from BV-AVD North American Results Patients in North America seemed to preferentially benefit from BV-AVD Activity BV-AVD ABVD 2 -yr modified PFS 84. 3 vs 73. 7% Log-rank test p-value: 0. 012 Hazard ratio: 0. 596 Time (Months) from Randomization Ramchandren R et al. Clin Cancer Res 2019; 25(6): 1718 -26. Kaplan-Meier Plot of Modified PFS per INV Probability of Progression-Free Survival Probability of Modified Progression-Free Survival Kaplan-Meier Plot of Modified PFS per IRF BV-AVD ABVD 2 -yr PFS 88. 1% vs 76. 4% Log-rank test p-value: 0. 002 Hazard ratio: 0. 500 Time (Months) from Randomization

ECHELON-1: Select Adverse Events (AEs) BV + AVD (N = 662) ABVD (N =

ECHELON-1: Select Adverse Events (AEs) BV + AVD (N = 662) ABVD (N = 659) Grade ≥ 3 AEs 83% 66% Serious AEs 43% 27% AE resulting in drug discontinuation 13% 16% Hospitalizations 37% 28% Any grade Grade ≥ 3 Neutropenia 58% 54% 45% 39% Peripheral neuropathy 67% 11% 43% 2% Connors JM et al. N Engl J Med 2018; 378(4): 331 -44.

Case Presentation (Ms Goodrich) Man in his mid-50 s with Stage IIIB nodular sclerosing

Case Presentation (Ms Goodrich) Man in his mid-50 s with Stage IIIB nodular sclerosing Hodgkin lymphoma Treatments received • ABVD • ICE • Autologous and allotransplants • Brentuximab vedotin Other considerations • Management of neuropathy associated with brentuximab vedotin • Graft versus host disease and transplant

Case Presentation (Ms Goodrich) Prior to brentuximab vedotin

Case Presentation (Ms Goodrich) Prior to brentuximab vedotin

AETHERA Phase III Trial: BV Consolidation After Transplant Eligibility (n = 329) • Refractory

AETHERA Phase III Trial: BV Consolidation After Transplant Eligibility (n = 329) • Refractory to front-line Tx • Relapse <12 months after front-line Tx • Relapse ≥ 12 months after front-line Tx with extranodal disease ASCT R CR, PR or SD to salvage therapy BV Placebo • Median PFS update (median 5 years follow-up): • BV: not reached • Placebo: 15. 8 mo • No OS benefit at interim analysis (analysis planned for 2020) Moskowitz CH et al. Lancet 2015; 385(9980): 1853 -62; Sweetenham J et al. Proc ASH 2015; Abstract 3172; Moskowitz CH et al. Blood 2018; 132(25): 2639 -42.

Case Presentation (Ms Klebig) Woman in her early 50 s with relapsed Hodgkin lymphoma

Case Presentation (Ms Klebig) Woman in her early 50 s with relapsed Hodgkin lymphoma Treatments received • Brentuximab vedotin + ABVD (on clinical trial) • ICE • Autologous transplant • Nivolumab Other considerations • Patient is single and lives alone • Patient prefers chiropractic/herbal remedies and has concerns over receiving therapy indefinitely

Case Presentation (Ms Klebig) Before nivolumab Granulomatous vs residual disease?

Case Presentation (Ms Klebig) Before nivolumab Granulomatous vs residual disease?

Targeting the PD-1/PD-L 1 Axis in HL • HL characterized by small number of

Targeting the PD-1/PD-L 1 Axis in HL • HL characterized by small number of malignant Hodgkin Reed-Sternberg cells (HRS) surrounded by normal immune cells • 9 p 24. 1 chromosomal abnormalities frequently observed in HRS • More than 90% of HRS have alterations in PD-L 1 and PD-L 2 loci • Malignant Hodgkin and RS cells overexpress PD-L 1/L 2 ligands (due to cytogenetic events, infection with EBV) Villasboas JC, Ansell SA. Cancer J 2016; 22(1): 17 -22; Roemer MGM et al. J Clin Oncol 2016; 34(23): 2690 -7.

Immune Checkpoint Inhibitors in R/R HL KEYNOTE-087 (pembrolizumab) ORR: 69% Check. Mate 205 (nivolumab)

Immune Checkpoint Inhibitors in R/R HL KEYNOTE-087 (pembrolizumab) ORR: 69% Check. Mate 205 (nivolumab) ORR: 69% Chen R et al. J Clin Oncol 2017; 35(19): 2125 -32; Armand P et al. J Clin Oncol 2018; 36(14): 1428 -39.

Ongoing Phase III Trials Evaluating Immune Checkpoint Inhibitors in HL KEYNOTE-204 Eligibility • R/R

Ongoing Phase III Trials Evaluating Immune Checkpoint Inhibitors in HL KEYNOTE-204 Eligibility • R/R HL • Responded to BV if previously treated with BV • No prior checkpoint inhibitor Pembrolizumab R Brentuximab vedotin Check. Mate 812 Eligibility • R/R HL • Failed to respond to auto-SCT or ineligible for auto-SCT www. clinicaltrials. gov. Accessed April 2019. Nivolumab + brentuximab vedotin R Brentuximab vedotin

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large B-Cell Lymphoma

Case Presentation (Ms Klebig) Man in his late 50 s with relapsed/refractory follicular lymphoma

Case Presentation (Ms Klebig) Man in his late 50 s with relapsed/refractory follicular lymphoma Treatments received • Bendamustine/rituximab (R) • R-CHOP ➔ R maintenance • R-ICE • Idelalisib • Pembrolizumab • Lenalidomide/rituximab (R 2) ➔ R maintenance Other considerations • Busy father of 10 children

Case Presentation (Ms Klebig) Before R 2 2 months – Deauville 2

Case Presentation (Ms Klebig) Before R 2 2 months – Deauville 2

Subcutaneous (Sub. Q) Rituximab Indication • Previously approved indications for rituximab in FL, DLBCL

Subcutaneous (Sub. Q) Rituximab Indication • Previously approved indications for rituximab in FL, DLBCL and CLL Administration • Shortens administration time to 5 to 7 minutes compared to IV (up to several hours) • Flat dosing Efficacy • No significant difference in ORR, PFS, OS between IV and sub. Q Toxicity • No significant difference in AEs, including serious AEs, between IV and sub. Q https: //www. fda. gov/Drugs/Information. On. Drugs/Approved. Drugs/ucm 564235. htm; Rituximab and hyaluronidase human package insert, June 2017; Davies A et al. Lancet Oncol 2017; 4(6): e 272 -e 82.

Obinutuzumab Mechanism of action • Anti-CD 20 monoclonal antibody Indication • Untreated bulky Stage

Obinutuzumab Mechanism of action • Anti-CD 20 monoclonal antibody Indication • Untreated bulky Stage II, III or IV FL with chemotherapy, followed by maintenance • R/R FL after rituximab, with bendamustine, followed by maintenance Administration • 1, 000 mg IV infusion – Start at 50 mg/h (100 mg/h after cycle 1) – Increase by 50 mg/h (100 mg/h after cycle 1) every 30 min to maximum of 400 mg/h if tolerated https: //www. fda. gov/drugs/informationondrugs/approveddrugs/ucm 585660. htm Obinutuzumab package insert, November 2017

Comparison of Cell Death Induced by Obinutuzumab and Rituximab Type II anti-CD 20 antibody

Comparison of Cell Death Induced by Obinutuzumab and Rituximab Type II anti-CD 20 antibody 1 Enhanced DCD vs rituximab 2 DCD = direct cell death; ADCC = antibody-dependent cell-mediated cytotoxicity 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 -402. 4. Herter S et al. Poster presentation at ASH 2010 (Abstract 3925). Glycoengineered Fc region 3 Up to 100 -fold increase in ADCC vs rituximab 3, 4

GALLIUM: Four-Year Results with Obinutuzumab-Based Immunochemotherapy for Previously Untreated FL Probability of survival Progression-free

GALLIUM: Four-Year Results with Obinutuzumab-Based Immunochemotherapy for Previously Untreated FL Probability of survival Progression-free survival HR = 0. 73 p = 0. 0034 + R-chemotherapy (N = 601) G-chemotherapy (N = 601) Censored G-chemo (n = 601) R-chemo (n = 601) Any adverse event (AE) 99. 8% 99. 5% Grade 3 -5 AEs 79. 2% 71. 2% Infections 22. 2% 18. 6% Neutropenia 48. 4% 41. 4% Second cancer 6. 9% 4. 4% G = obinutuzumab; R = rituximab Time (months) • • G-chemo continues to demonstrate clinically meaningful improvements in outcomes relative to R-chemo for patients with previously untreated FL OS data remain immature, with additional follow-up needed to draw conclusions Townsend W et al. Proc ASH 2018; Abstract 1597.

GALLIUM: Safety Summary R-chemo (n = 597) G-chemo (n = 595) Any AE 98%

GALLIUM: Safety Summary R-chemo (n = 597) G-chemo (n = 595) Any AE 98% 100% Grade ≥ 3 AEs (≥ 5% in either arm) 68% 75% Neutropenia 40% 46% Thrombocytopenia 3% 6% Infections 16% 20% Infusion-related reactions 7% 12% Second neoplasms 3% 5% Grade 5 AEs 3% 4% Grade ≥ 3 AEs of special interest Marcus R et al. N Engl J Med 2017; 377(14): 1331 -44.

RELEVANCE: A Phase III Trial of Rituximab with Lenalidomide versus Rituximab with Chemotherapy for

RELEVANCE: A Phase III Trial of Rituximab with Lenalidomide versus Rituximab with Chemotherapy for Patients with Untreated FL Trial identifier: NCT 01476787 (Closed) Rituximab + chemotherapy R-CHOP, R-CVP or BR Eligibility • Grade I-IIIa, Stage II-IV untreated FL • Symptomatic, requiring treatment R Lenalidomide + rituximab Primary endpoints: Complete response rate at 120 weeks and PFS Morschhauser F et al. N Engl J Med 2018; 379(10): 934 -47.

Probability of progression-free survival RELEVANCE: Rituximab + Lenalidomide (R 2) versus Rituximab + Chemotherapy

Probability of progression-free survival RELEVANCE: Rituximab + Lenalidomide (R 2) versus Rituximab + Chemotherapy (R-chemo) in Untreated, Advanced FL R 2 (n = 507) R-chemo (n = 503) Neutropenia 32% 50% Febrile neutropenia 2% 7% Cutaneous reactions 7% 1% Diarrhea 2% 1% Tumor lysis syndrome 1% <1% Grade 3 -4 adverse events R-chemo group R 2 group HR 1. 10, p = 0. 48 Months since randomization • Efficacy results were similar between R 2 and R-chemo in advanced, untreated follicular lymphoma. • The safety profile differed between the 2 groups. Morschhauser F et al. N Engl J Med 2018; 379(10): 934 -47.

Progression-free survival probability (IRC assessment) AUGMENT: R 2 versus Rituximab/Placebo in R/R FL or

Progression-free survival probability (IRC assessment) AUGMENT: R 2 versus Rituximab/Placebo in R/R FL or Marginal Zone Lymphoma Primary Endpoint PFS R 2 Median = 39. 4 mo p < 0. 001 HR = 0. 46 Rituximab + placebo Median = 14. 1 mo Months from randomization Leonard JP et al. J Clin Oncol 2019; [Epub ahead of print]. R 2 (n = 178) R/placebo (n = 180) ORR 78% 53% CR 34% 18% 36. 6 mo 21. 7 mo Median DOR

PI 3 K Activation in B-Cell Lymphomas • PI 3 K/AKT/m. TOR pathway is

PI 3 K Activation in B-Cell Lymphomas • PI 3 K/AKT/m. TOR pathway is frequently activated in human cancer PI 3 K inhibitor • Constitutive activation of the PI 3 K pathway in B-cell lymphomas allows for increased growth and survival of malignant cells • PI 3 K inhibitors idelalisib and copanlisib block PI 3 K activity Lampson BL et al. Expert Opin Investig Drugs 2017; 26(11): 1267 -79; BBMG. net

PI 3 K Inhibitors for FL: Indication and Dosing Idelalisib 1 Copanlisib 2 Duvelisib

PI 3 K Inhibitors for FL: Indication and Dosing Idelalisib 1 Copanlisib 2 Duvelisib 3 Mechanism of action Selective PI 3 Kδ inhibitor Pan-PI 3 K inhibitor Dual inhibitor of PI 3 Kδ, γ Indication Relapsed FL after at least 2 prior systemic therapies R/R FL after at least 2 prior systemic therapies Dosing 150 mg orally, twice daily 1 hour IV infusion weekly (3 weeks on, 1 week off) 25 mg orally, twice daily 1 Gopal AK et al. N Engl J Med 2014; 370(11): 1008 -18; Idelalisib package insert, October 2018. 2 Dreyling M et al. J Clin Oncol 2017; 35(35): 3898 -905; Copanlisib package insert, September 2017. 3 Flinn IW et al. J Clin Oncol 2019; [Epub ahead of print]; Duvelisib package insert, September 2018.

PI 3 K Inhibitors for FL: Activity and Tolerability Idelalisib 1 Activity Tolerability Copanlisib

PI 3 K Inhibitors for FL: Activity and Tolerability Idelalisib 1 Activity Tolerability Copanlisib 2 Duvelisib 3 • ORR: 57% (6% CR) • ORR: 59% (12% CR) • ORR: 42. 2% (1. 2% CR) • Median time to response: 1. 9 mo • Median time to response: 1. 7 mo • Median time to response: 1. 9 mo* • Median Do. R: 12. 5 mo • Median Do. R: 22. 6 mo • Median Do. R: 10 mo* Grade ≥ 3 AEs: 54% Grade ≥ 3 TRAEs: 84% Grade ≥ 3 AEs: 88%* • Neutropenia: 27% • Hyperglycemia: 41% • Neutropenia: 25%* • Diarrhea: 13% • Hypertension: 24% • Diarrhea: 15%* • Increased ALT: 13% • Neutropenia: 24% • Increased AST: 3. 1%* * All patients on study (FL, SLL, marginal zone-B lymphoma) 1 Gopal AK et al. N Engl J Med 2014; 370(11): 1008 -18; Idelalisib package insert, October 2018. 2 Dreyling M et al. J Clin Oncol 2017; 35(35): 3898 -905; Copanlisib package insert, September 2017. 3 Flinn IW et al. J Clin Oncol 2019; 37(11): 912 -22; Zinzani PL et al. Proc EHA 2017; Abstract S 777; Duvelisib package insert, September 2018.

Case Presentation (Ms Goodrich) Man in his late 40 s with relapsed/refractory follicular lymphoma

Case Presentation (Ms Goodrich) Man in his late 40 s with relapsed/refractory follicular lymphoma Treatments received • R monotherapy • R-CHOP ➔ R maintenance • Copanlisib Other considerations • Observation compared to R monotherapy • Side effects associated with copanlisib

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large B-Cell Lymphoma

Gastrointestinal Involvement in MCL Case report: Submucosal lesions in the gastric antrum, duodenal bulb

Gastrointestinal Involvement in MCL Case report: Submucosal lesions in the gastric antrum, duodenal bulb and rectum by endoscopy Li D et al. Medicine 2017; 96: 11(e 6321).

Current Treatment Options for Up-Front and Recurrent MCL Up-Front Treatment (+/- Transplant) Treatment of

Current Treatment Options for Up-Front and Recurrent MCL Up-Front Treatment (+/- Transplant) Treatment of Recurrence • Chemotherapy/rituximab • Ibrutinib – R-CHOP, RDHA(P), NORDIC, Hyper. CVAD • Acalabrutinib • Bendamustine/rituximab • Lenalidomide • Bortezomib/chemo/rituximab (VR-CAP) • Venetoclax • Lenalidomide/rituximab • Bortezomib • Rituximab/bendamustine/cytarabine (RBAC) NCCN Guidelines B-Cell Lymphomas. Version 2. 2019

Ly. Ma: Rituximab Maintenance After Autologous Stem Cell Transplant for MCL HR*0. 46 =

Ly. Ma: Rituximab Maintenance After Autologous Stem Cell Transplant for MCL HR*0. 46 = p = 0. 002 Median EFS R (n = 120) Observation (n = 120) Not reached * Disease progression, relapse, death, rituximab allergy or severe infection • PFS (4 -y): R, 83%; observation, 64% (p < 0. 001) • OS (4 -y): R, 89%; observation, 80% (p = 0. 04) Le Gouill S et al. N Engl J Med 2017; 377(13): 1250 -60.

Case Presentation (Ms Goodrich) Man in his early 80 s with relapsed/refractory mantle cell

Case Presentation (Ms Goodrich) Man in his early 80 s with relapsed/refractory mantle cell lymphoma Treatments received • R monotherapy • Acalabrutinib Other considerations • Initial therapy for older patient with multiple comorbidities and on multiple medications

Mechanism of Action of BTK Inhibitors BCR LYN SYK ┬ Ibrutinib Acalabrutinib PI 3

Mechanism of Action of BTK Inhibitors BCR LYN SYK ┬ Ibrutinib Acalabrutinib PI 3 K delta BTK PLCγ 2 AKT GSK-3 PKC m. TOR p 70 s 6 k Woyach JA et al. Blood 2012; 120(6): 1175 -84. NF-kβ pathway elf 4 E

Ibrutinib Mechanism of action • Selective inhibitor of Bruton tyrosine kinase activity Indication •

Ibrutinib Mechanism of action • Selective inhibitor of Bruton tyrosine kinase activity Indication • For the treatment of adult patients with MCL who have received at least 1 prior therapy Dosing • 560 mg orally, once daily Ibrutinib package insert, January 2019

Ibrutinib Monotherapy in Relapsed/Refractory MCL: Pooled Analysis from 3 Studies • N = 370

Ibrutinib Monotherapy in Relapsed/Refractory MCL: Pooled Analysis from 3 Studies • N = 370 patients with relapsed/refractory MCL in 3 studies (PCYC-1104, SPARK, RAY) • ORR: 66% (CR: 20%, PR: 46%) • Median PFS: 12. 8 mo • Median OS: 25. 0 mo Rule S et al. Haematologica 2018; [Epub ahead of print].

Phase II Trial of Ibrutinib/Rituximab for Relapsed/Refractory MCL Four-Year Follow-Up • N = 50

Phase II Trial of Ibrutinib/Rituximab for Relapsed/Refractory MCL Four-Year Follow-Up • N = 50 patients with relapsed/refractory MCL, treated with ibrutinib/rituximab • Median follow-up: 47 mo • Complete remission: 58% • Median PFS: 43 mo • Mostly Grade 1/2 toxicities (fatigue, diarrhea, nausea, arthralgias, myalgias) Jain P et al. Br J Haematol 2018; 182(3): 404 -411

Acalabrutinib versus Ibrutinib • Acalabrutinib is more selective for BTK with less off-target kinase

Acalabrutinib versus Ibrutinib • Acalabrutinib is more selective for BTK with less off-target kinase inhibition compared to ibrutinib in vitro Acalabrutinib Ibrutinib Kinase selectivity profiling at 1 M Larger red circles represent stronger inhibition Kinase inhibition average IC 50 (n. M) Kinase Acalabrutinib Ibrutinib BTK 5. 1 1. 5 TEC 126. 0 10 ITK >1000 4. 9 BMX 46 0. 8 TXK 368 2. 0 EGFR >1000 5. 3 ERBB 2 ~1000 6. 4 ERBB 4 16 3. 4 BLK >1000 0. 1 JAK 3 >1000 32 BLK = B lymphocyte kinase; BMX = bone marrow tyrosine kinase gene in chromosome X; BTK = Bruton tyrosine kinase; EGFR = epidermal growth factor receptor; ERBB 2 = erb-b 2 receptor tyrosine kinase; ERBB 4 = erb-b 4 receptor tyrosine kinase; IC 50 = inhibitory concentration of 50%; ITK = interleukin-2 -inducible T-cell kinase; JAK 3 = Janus kinase 3; TEC = tyrosine kinase expressed in hepatocellular carcinoma; TXK = T and X cell expressed kinase. Barf T et al. J Pharmacol Exp Ther 2017; 363(2): 240 -52.

Acalabrutinib Mechanism of action • Selective inhibitor of Bruton tyrosine kinase activity Indication •

Acalabrutinib Mechanism of action • Selective inhibitor of Bruton tyrosine kinase activity Indication • For the treatment of adult patients with MCL who have received at least 1 prior therapy Dosing • 100 mg orally, twice daily https: //www. fda. gov/Drugs/Information. On. Drugs/Approved. Drugs/ucm 583106. htm Acalabrutinib package insert, October 2017

ACE-LY-004: Response to Acalabrutinib • The primary endpoint was investigatorassessed ORR according to the

ACE-LY-004: Response to Acalabrutinib • The primary endpoint was investigatorassessed ORR according to the 2014 Lugano Classification • High concordance was observed between investigator- and IRCassessed ORR and CR (91% and 94%, respectively) • IRC-assessed ORR by 2007 IHP criteria (exploratory endpoint) was 75% with a CR rate of 30% Wang M et al. Lancet 2018; 391(10121): 659 -67. ORR using the 2014 Lugano Classification N = 124 Investigator assessed n (%) IRC assessed n (%) ORR (CR + PR) 100 (81) 99 (80) Best response CR PR SD PD Not evaluable 49 (40) 51 (41) 11 (9) 10 (8) 3 (2) 49 (40) 50 (40) 9 (7) 11 (9) 5 (4)

ACE-LY-004 Phase II Trial of Acalabrutinib: Response Maximum change from baseline in the SPD

ACE-LY-004 Phase II Trial of Acalabrutinib: Response Maximum change from baseline in the SPD of target lesions (all patients) Overall response rate by INV assessment = 100 (81%) • CR = 49 (40%) • PR = 51 (41%) • Median time to best response = 1. 9 mo • Median time to CR = 3. 4 mo • Median duration of response = not reached • Median PFS and median OS = not reached Wang M et al. Lancet 2018; 391(10121): 659 -67.

ACE-LY-004: Most Common Adverse Events AEs occurring in ≥ 15% of all patients Headache

ACE-LY-004: Most Common Adverse Events AEs occurring in ≥ 15% of all patients Headache Diarrhea Fatigue Myalgia Cough Nausea Pyrexia 24 12 17 10 19 6 15 5 17 2 3 1 1 2 10 7 11 4 Grade 1 Grade 2 Grade 3 Grade 4 1 Grade ≥ 3 AEs occurring in ≥ 5% of all patients Anemia Neutropenia Pneumonia 12 5 8 1 6 1 5 0 10 20 30 % of Patients Wang M et al. Lancet 2018; 391(10121): 659 -67; Proc ASH 2017; Abstract 155. 40 50 100 60

Case Presentation (Ms Goodrich) Man in his early 60 s with relapsed/refractory mantle cell

Case Presentation (Ms Goodrich) Man in his early 60 s with relapsed/refractory mantle cell lymphoma Treatments received • R-CHOP alternating with R-DHAP • Ibrutinib/rituximab • Clinical trial of onalespib • Lenalidomide/rituximab (R 2) • Venetoclax/rituximab • Allotransplant Other considerations • Allotransplant

Case Presentation (Ms Goodrich) Prior to venetoclax

Case Presentation (Ms Goodrich) Prior to venetoclax

Mechanism of Action of Venetoclax (ABT-199) • Bcl-2 functions to prevent cell death by

Mechanism of Action of Venetoclax (ABT-199) • Bcl-2 functions to prevent cell death by apoptosis ABT-199 Bcl-2 Bcl-XL Tumor cell Platelet Adapted from Davids MS, Letai A. Cancer Cell 2013; 23(2): 139 -41. • Venetoclax is specific for Bcl-2 and inhibits function, thereby removing the block on apoptosis

Venetoclax Monotherapy in Relapsed/Refractory MCL • N = 28 patients with relapsed/refractory MCL received

Venetoclax Monotherapy in Relapsed/Refractory MCL • N = 28 patients with relapsed/refractory MCL received venetoclax (300 -1, 200 mg) • Median follow-up: 27 mo Clinical endpoint Venetoclax (N = 28) Overall response rate (ORR) Complete response rate 75% 21% Median duration of response 16 mo Median PFS 11 mo • Grade 3/4 AEs: neutropenia (14%), anemia (14%), pneumonia (11%), thrombocytopenia (11%) Davids MS et al. Proc ASH 2018; Abstract 2883.

Proposed Stepwise Ramp-up Dosing of Venetoclax for Patients with Mantle Cell Lymphoma Davids MS

Proposed Stepwise Ramp-up Dosing of Venetoclax for Patients with Mantle Cell Lymphoma Davids MS et al. J Clin Oncol 2018; 36(35): 3525 -7. • To minimize tumor lysis syndrome risk, this dosing schedule has a venetoclax starting dose of 20 mg once daily for 7 days followed by a gradual stepwise weekly ramp-up to reach a dose of 400 mg daily by 5 weeks. • For patients with MCL who receive venetoclax monotherapy, we suggest 1 additional ramp-up to 800 mg by 6 weeks, given the possibility of deeper responses observed at this dose compared to lower doses in the Phase I study.

SYMPATICO: A Phase III Trial of Ibrutinib Combined with Venetoclax in Mantle Cell Lymphoma

SYMPATICO: A Phase III Trial of Ibrutinib Combined with Venetoclax in Mantle Cell Lymphoma Trial Identifier: NCT 03112174 (Open) Estimated Enrollment: 287 Eligibility • Pathologically confirmed MCL with overexpression of cyclin D 1 in association with other markers • At least 1, but no more than 5 prior treatments • Failure to achieve PR with or PD after most recent treatment regimen Ibrutinib + venetoclax Until PD or unacceptable toxicity R Ibrutinib + placebo Until PD or unacceptable toxicity Primary Endpoints: Time to occurrence of TLS and occurrence of dose-limiting toxicities (safety run-in period), progression-free survival www. clinicaltrials. gov (Accessed April 2019).

MCL-002 (SPRINT): Phase II Trial of Lenalidomide for Relapsed/Refractory MCL • N = 254

MCL-002 (SPRINT): Phase II Trial of Lenalidomide for Relapsed/Refractory MCL • N = 254 patients with relapsed/refractory MCL, treated with lenalidomide (LEN) versus investigator’s choice of monotherapy (INV) • Median follow-up: 15. 9 mo • Objective response rate: LEN, 40%; INV, 11% (p < 0. 001) • Median PFS: LEN, 8. 7 mo; INV 5. 2 mo (HR 0. 61, p = 0. 004) • Grade 3/4 toxicities: neutropenia, thrombocytopenia, leucopenia, anemia Trněný M et al. Lancet Oncol 2016; 17(3): 319 -31.

First-Line Lenalidomide + Rituximab in MCL: Response Duration and Select Adverse Events Induction Phase

First-Line Lenalidomide + Rituximab in MCL: Response Duration and Select Adverse Events Induction Phase (Select AEs) Events (n = 38) Subjects n = 36 ORR: 92% CR: 64% PR: 28% Any grade Grade ≥ 3 Neutropenia 68% 42% Thrombocytopenia 29% 11% Anemia 47% 8% Febrile neutropenia 3% 3% Upper respiratory tract infection 24% 0% Urinary tract infection 11% 0% Diarrhea 53% 0% Months • At median follow-up of 64 months, the 5 -year PFS and OS were 63. 9% and 77. 4%, respectively. Ruan J et al. Blood 2018; 132(19): 2016 -25.

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large

Hodgkin and Non-Hodgkin Lymphomas: Agenda Hodgkin Lymphoma Follicular Lymphoma Mantle Cell Lymphoma Diffuse Large B-Cell Lymphoma

Case Presentation (Ms Klebig) Woman in her mid-30 s with relapsed/refractory, triple-hit (highgrade) DLBCL

Case Presentation (Ms Klebig) Woman in her mid-30 s with relapsed/refractory, triple-hit (highgrade) DLBCL Treatments received • R-CHOP • DA-R-EPOCH • R-GDP • R-ICE • Axicabtagene ciloleucel Other considerations • Diagnosed in second trimester of pregnancy • CAR T-cell associated CRS

Case Presentation (Ms Klebig) 1 st PET after C-section and 3 cycles of R-CHOP

Case Presentation (Ms Klebig) 1 st PET after C-section and 3 cycles of R-CHOP

Case Presentation (Ms Klebig) Woman in her mid-30 s with DLBCL and metastases to

Case Presentation (Ms Klebig) Woman in her mid-30 s with DLBCL and metastases to the liver, kidney and pancreas Treatments received • CHOP • GDP • DHAP • Venetoclax • ICE Other considerations • Married with a 7 -year-old daughter • Preferred to receive treatment locally when possible to avoid separation from family

Case Presentation (Ms Klebig) Baseline PET/CT After first 3 cycles of CHOP and 1

Case Presentation (Ms Klebig) Baseline PET/CT After first 3 cycles of CHOP and 1 dose of HD-MTX = Deauville 4

Case Presentation (Ms Klebig) 6 weeks after completion of CHOP/HD-MTX Continued progression/refractory

Case Presentation (Ms Klebig) 6 weeks after completion of CHOP/HD-MTX Continued progression/refractory

Case Presentation (Ms Klebig) Renal involvement Creatinine trend

Case Presentation (Ms Klebig) Renal involvement Creatinine trend

Long-Term Follow-Up from a Combined Analysis of 2 Phase II Trials of Lenalidomide with

Long-Term Follow-Up from a Combined Analysis of 2 Phase II Trials of Lenalidomide with R-CHOP for Previously Untreated DLBCL by Cell of Origin Cell of origin Outcome (Hazard ratio; p-value) Non-GCB HR (p-value) 5 -year PFS (n = 41, 47) 64. 5% 52. 8% 1. 54 (0. 1983) 5 -year TTP (n = 41, 47) 69. 6% 61. 6% 1. 33 (0. 4436) 5 -year OS (n = 43, 47) 74. 1% 68. 6% 1. 59 (0. 2375) • Addition of lenalidomide appears to mitigate negative prognosis of non-GCB phenotype • Incidences of therapy-related secondary cancer and late toxicities were low Castellino A et al. Blood Cancer J 2018; 8(11): 108; Proc ASH 2018; Abstract 2962.

ROBUST: A Phase III Trial of Lenalidomide plus R-CHOP versus R-CHOP for Untreated ABC-Type

ROBUST: A Phase III Trial of Lenalidomide plus R-CHOP versus R-CHOP for Untreated ABC-Type DLBCL Trial identifier: NCT 02285062 (Closed) Lenalidomide + R-CHOP Eligibility (570) • Untreated, ABC-type DLBCL R Placebo + R-CHOP Primary endpoint: Progression-free survival www. clinicaltrials. gov. Accessed April 2019.

Mechanism of Action of Polatuzumab Vedotin Polatuzumab vedotin is an antibody-drug conjugate (ADC) consisting

Mechanism of Action of Polatuzumab Vedotin Polatuzumab vedotin is an antibody-drug conjugate (ADC) consisting of monomethyl auristatin E (MMAE) conjugated to anti-CD 22 and CD 79 b monoclonal antibodies via a cleavable linker molecule Antibody with potential conjugation sites for VC-MMAE ( ) ADC binds to receptor ADC in circulation ADC-receptor complex is internalized * VC-MMAE (linker-drug) MC VC PABC MMAE Protease cleavage Morschhauser F et al. Proc ASCO 2014; Abstract 8519. Apoptosis (cell death)

Polatuzumab Vedotin, an Anti-CD 79 b Antibody-Drug Conjugate, in Combination with BR for R/R

Polatuzumab Vedotin, an Anti-CD 79 b Antibody-Drug Conjugate, in Combination with BR for R/R DLBCL Patients with DLBCL BR (n = 40) Pola-BR (n = 40) HR p-value Median PFS 2. 0 mo 7. 6 mo 0. 34 <0. 0001 Median OS 4. 7 mo 12. 4 mo 0. 42 0. 0023 ORR at EOT by IRC 18% 45% — 0. 008 CR 15% 40% — 0. 012 EOT = end of treatment; IRC = independent review committee Sehn LH et al. Proc ASCO 2018; Abstract 7507; Sehn LH et al. Proc ASH 2018; Abstract 1683.

Adverse Events with Polatuzumab Vedotin and BR for R/R DLBCL BR Pola-BR Grade 1

Adverse Events with Polatuzumab Vedotin and BR for R/R DLBCL BR Pola-BR Grade 1 Grade 2 Grade 3 Grade 4 Sehn LH et al. Proc ASCO 2018; Abstract 7507; Sehn LH et al. Proc ASH 2018; Abstract 1683.

POLARIX: An Ongoing Phase III Trial of Polatuzumab Vedotin with R-CHP versus R-CHOP for

POLARIX: An Ongoing Phase III Trial of Polatuzumab Vedotin with R-CHP versus R-CHOP for Patients with Untreated DLBCL Trial identifier: NCT 03274492 (Open) Polatuzumab vedotin + R-CHP Eligibility (Target N = 875) • CD 20 -positive, untreated DLBCL R Placebo + R-CHOP Primary endpoint: Progression-free survival www. clinicaltrials. gov. Accessed April 2019.

Case Presentation (Ms Klebig) Woman in her mid-30 s with relapsed/refractory, triple-hit (highgrade) DLBCL

Case Presentation (Ms Klebig) Woman in her mid-30 s with relapsed/refractory, triple-hit (highgrade) DLBCL Treatments received • R-CHOP • DA-R-EPOCH • R-GDP • R-ICE • Axicabtagene ciloleucel Other considerations • Diagnosed in second trimester of pregnancy • CAR T-cell associated CRS

Case Presentation (Ms Klebig) Before CAR T-cell After CAR T-cell

Case Presentation (Ms Klebig) Before CAR T-cell After CAR T-cell

Case Presentation (Ms Klebig) Abdominal pain 4/5/2019 PET/CT 4/10/2019

Case Presentation (Ms Klebig) Abdominal pain 4/5/2019 PET/CT 4/10/2019

Overview of CAR T-Cell Therapy

Overview of CAR T-Cell Therapy

Variations in CAR Constructs Axicabtagene ciloleucel Lisocabtagene maraleucel (JCAR 017) Tisagenlecleucel sc. FV Hinge

Variations in CAR Constructs Axicabtagene ciloleucel Lisocabtagene maraleucel (JCAR 017) Tisagenlecleucel sc. FV Hinge FMC 63 CD 8 CD 28 4 -1 BB CD 3 zeta sc. FV Spacer 4 -1 BB CD 3 zeta

Three Major CAR T-Cell Products for DLBCL Axicabtagene ciloleucel Tisagenlecleucel Lisocabtagene maraleucel (JCAR 017)

Three Major CAR T-Cell Products for DLBCL Axicabtagene ciloleucel Tisagenlecleucel Lisocabtagene maraleucel (JCAR 017) Anti-CD 19 -CD 28 -CD 3 z Anti-CD 19 -41 BB-CD 3 z Bulk 1: 1 CD 4: CD 8 2 x 106/kg (max 2 x 108) 0. 6 to 6. 0 x 108 DL 1: 0. 5 x 107 DL 2: 1. 0 x 108 None allowed 93% 72% Lymphodepletion Flu/Cy 500/30 x 3 d Flu/Cy 250/25 x 3 d Or BR Flu/Cy 300/30 x 3 d Treatment locale Inpatient only Inpatient or outpatient Construct T cells Dose Bridging tx Approval status FDA approved for DLBCL, FDA approved for pediatric high-grade B-cell lymphoma, ALL, DLBCL, high-grade Btransformed FL, primary cell lymphoma, mediastinal B-cell lymphoma transformed FL Not yet FDA approved

Summary of Pivotal CAR T-Cell Therapy Trials in R/R DLBCL ZUMA-1 (N = 108)

Summary of Pivotal CAR T-Cell Therapy Trials in R/R DLBCL ZUMA-1 (N = 108) JULIET (N = 93) TRANSCEND-NHL-001 (N = 102) Axicabtagene ciloleucel Tisagenlecleucel Lisocabtagene maraleucel NR (1 -5+( 3 (1 -6) 3 (1 -8) ORR 82% 52% 75% CR 58% 40% 55% CR (>6 months) 40% 31% Agent Median prior therapies (range) Borchmann P et al. Proc EHA 2018; Abstract S 799; Abramson JS et al. Proc ASCO 2018; Abstract 7505; Locke FL et al. Proc ASCO 2018; Abstract 3003; Locke FL et al. Proc ASCO 2018; Abstract 3039.

Approved CAR T-Cell Therapy in DLBCL Approval Dates • Axicabtagene ciloleucel (axi-cel): 10/18/17 •

Approved CAR T-Cell Therapy in DLBCL Approval Dates • Axicabtagene ciloleucel (axi-cel): 10/18/17 • Tisagenlecleucel: 5/1/18 Mechanism of action • CD 19 -targeted chimeric antigen receptor (CAR) T-cell immunotherapy Indication • For the treatment of adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including DLBCL not otherwise specified, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma – axi-cel is also approved to treat primary mediastinal large B-cell lymphoma Recommended dose • One infusion of (CAR)-positive viable T cells after lymphodepleting chemotherapy Tisagenlecleucel package insert, May 2018; Axicabtagene ciloleucel package insert, October 2017

Comparison of Axicabtagene Ciloleucel in ZUMA-1 and Treatment in the “Real World” at 17

Comparison of Axicabtagene Ciloleucel in ZUMA-1 and Treatment in the “Real World” at 17 US Centers ZUMA-1 This study 108 165 100% 51% 58 (23 -76) 59 (21 -82) ECOG 0 or 1 100% 84% Prior autologous transplant 23% 31% DLBCL including HGBCL, not t. FL or PMBCL 78% 61% 82%/58% (Best) 79%/50% (Day 30) CRS 13%/NEs 31% CRS 7%/NEs 31% N infused patients Patients meeting ZUMA-1 eligibility criteria Age, median (range) ORR/CR Grade 3 or higher toxicity Nastoupil LJ et al. Proc ASH 2018; Abstract 91

Cytokine Release Syndrome (CRS): Common Symptoms Nausea/vomiting/ anorexia Based on CAR T-cell experience Fatigue

Cytokine Release Syndrome (CRS): Common Symptoms Nausea/vomiting/ anorexia Based on CAR T-cell experience Fatigue Headache Myalgia/ Hypotension arthralgias Dyspnea/ tachypnea/ hypoxia Rigors High fevers CRS Escalating fevers Diagnosis based on clinical symptoms and events

CAR T Cell-Related Encephalopathy Syndrome (CRES) Symptom or sign Neurological assessment score (by CARTOX-10)

CAR T Cell-Related Encephalopathy Syndrome (CRES) Symptom or sign Neurological assessment score (by CARTOX-10) Raised intracranial pressure Seizures or motor weakness Grade 1 Grade 2 7 -9 (mild impairment) 3 -6 (moderate impairment) NA NA Grade 3 Grade 4 0 -2 (severe impairment) Patient in critical condition and/or obtunded and cannot perform assessment tasks NA Stage 3 -5 papilloedema, or CSF Stage 1 -2 papilloedema, or CSF opening pressure ≥ 20 mm. Hg, or opening pressure <20 mm. Hg cerebral edema NA Generalized seizures, or Partial seizure, or nonconvulsive seizures on EEG with status epilepticus, or new motor response to benzodiazepine weakness • Signs and symptoms include — Diminished attention — Language disturbance — Impaired handwriting — Confusion — Disorientation • Typically lasts 2 -4 days but the range is from hours to weeks • Severity can fluctuate rapidly Neelapu SS et al. Nat Rev Clin Oncol 2018; 15(1): 47 -62.

CRES: Timeline of Events CAR-T therapy administered Day 5 Phase 1 (Days 0 -5)

CRES: Timeline of Events CAR-T therapy administered Day 5 Phase 1 (Days 0 -5) • Concurrent with high fever and other CRS symptoms • Typically shorter duration and lower grade (Grade 1 -2) • Anti-IL-6 therapy is effective 3 weeks 5 weeks Delayed events Phase 2 (Day 5 onward) • CRS and fever have subsided • 10% of patients experienced delayed • Typically longer duration and neurotoxic events, higher grade (Grade 3+) including seizures and • Anti-IL-6 therapy is not episodes of confusion, effective; corticosteroids during the 3 rd or 4 th recommended week after treatment Neelapu SS et al. Nat Rev Clin Oncol 2018; 15(1): 47 -62.