Follicular and Low-Grade Non-Hodgkin (Indolent Lymphomas)

Stefan K Barta, M.D., M.S.

Associate Professor of Medicine Leader, Program Perelman Center for Advanced Medicine Facts and Figures: Non-Hodgkin Lymphomas

• Most common blood cancer • 7th most common cancer in the US3 • 71,850 new cases in the US in 20151 • 19,790 died of NHL in 20151 • About 549,625 people are living with a history of NHL (2012)1 • 85% of all NHLs are B-cell lymphomas2 • = 2nd most common type, ~25% of all NHLs4

1 http://seer.cancer.gov/statfacts/html/nhl.html. 2 ACS. Detailed Guide (revised January 21, 2000): Non-Hodgkin’s Lymphoma. 3 http://www.cancer.gov/cancertopics/types/commoncancers 4 Blood 89: 3909, 1997 The

T- CELLS B- CELLS

Cellular immunity: Humoral immunity: helper + cytotoxic T-cells antibodies Lymphatic System Lymph Node Anatomy Lymph Node: Microscopic View

: Microscopic View Causes

Possible cause(s): • chemical exposures (pesticides, fertilizers or solvents) • individuals with compromised immune systems • heredity • infections (e.g. H. pylori, Hep C, chlamydia trachomatis) • most patients have no clear risk factors • IN MOST CASES, THE EXACT CAUSE IS UNKNOWN Cellular Origins of Lymphomas &

PLEURIPOTENT STEM CELL ACUTE LEUKEMIAS

LYMPHOID STEM CELL ACUTE LYMPHOBLASTIC LEUKEMIAS

PRECURSOR T - CELL PRECURSOR B - CELL LYMPHOBLASTIC LYMPHOMAS / LEUKEMIAS

MATURE T - CELL MATURE B - CELL NON-HODGKIN LYMPHOMAS / CHRONIC LYMPHOCYTIC

LYMPH NODES, EXTRANODAL TISSUES Normal Life Cycle and Related Lymphoid Malignancy

Bone Marrow Peripheral Tissues Lymph Node

Germinal Center

Memory B Cell

Pluripotent Lymphoid Pre-B Cell B Cell Activated Stem Cell Stem Cell B Cell CD19 CD20 CD20 Antigen Expression CD22 CD22 +/-CD30

Precursor B-Cell B cell non-lymphomas, Myeloma Acute Leukemias Hodgkin, CLL Normal T-Cell Life Cycle and Related Lymphoid Malignancy

Bone Marrow Thymus Peripheral Tissues

Helper T-Cell

Pluripotent Lymphoid Thymocytes Cytotoxic T-Cell Stem Cell Stem Cell

Antigen Expression: CD4 CD4 TdT CD3 + or CD8 CD8

Precursor T-Cell T-Cell Lymphoblastic Peripheral T-Cell Acute Leukemias Lymphoma Lymphomas Classification of Lymphomas: the First 50 Years

1956 1974 1975 1982 1994 2001 2008 2016

RAPPAPORT LUKES-COLLINS

KIEL

NCI

REAL CLASSIFICATION

WHO CLASSIFICATION Diagnosis and Classification of Lymphomas

LYMPH NODE OR TISSUE BIOPSY FOR EVALUATION OF:

- HISTOLOGY (tumor cell size, pattern of tumor cell distribution)

- IMMUNOPHENOTYPING (tumor cell-specific proteins)

- GENOTYPING (tumor cell-specific genetic changes) Biopsy (excisional or incisional vs. aspiration)

Histology: microscopic appearance of tumor cell size and distribution

Diffuse large B-cell lymphoma Small lymphocytic lymphoma

IMAGES FROM: http://pleiad.umdnj.edu/~dweiss/default.html Follicular Lymphoma Biopsy

low magnification: high magnification: tumor cell distribution tumor cell size

https://www.moffitt.usf.edu/pubs/ccj/v3n2/dept3.html Immunophenotyping: Follicular Lymphoma immunophenotyping: tumor cell-specific proteins

http://path.upmc.edu/cases/case25/images/micro8.jpg

IMMUNOPHENOTYPE: CD5-, CD10+, CD19/20+, CD23-, SIg+ Genotyping: Follicular Lymphoma t(14;18)

Genotyping: identifying tumor cell-specific genetic changes

www.pathologyoutlines.com/chromosomes.html Non-Hodgkin Lymphomas (NHL): Clinical Groups

• “INDOLENT” - untreated survival measured in years

• “AGGRESSIVE” – untreated survival measured in months

• “HIGHLY AGGRESSIVE” – untreated survival measured in weeks Non-Hodgkin Lymphomas: WHO Classification

MATURE (PERIPHERAL) B-CELL NEOPLASMS MATURE (PERIPHERAL) T-CELL NEOPLASMS

• T-CELL PROLYMPHOCYTIC LEUKEMIA • B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA / SMALL LYMPHOCYTIC LYMPHOMA • T-CELL GRANULAR LYMPHOCYTIC LEUKEMIA • B-CELL PROLYMPHOCYTIC LEUKEMIA • AGGRESSIVE NK-CELL LEUKEMIA • LYMPHOPLASMACYTIC LYMPHOMA (WALDENSTROM’S) • ADULT T-CELL LYMPHOMA / LEUKEMIA (HTLV I +) • SPLENIC B-CELL LYMPHOMA (+/- VILLOUS • EXTRANODAL NK/T-CELL LYMPHOMA NASAL TYPE ) • ENTEROPATHY-TYPE T-CELL LYMPHOMA • • HEPATOSPLENIC GAMMA-DELTA T-CELL LYMPHOMA • PLASMA CELL MYELOMA / • SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA • EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA OF MALT TYPE • / SEZARY SYNDROME • NODAL MARGINAL ZONE B-CELL LYMPHOMA • ANAPLASTIC LARGE-CELL LYMPHOMA, T/NULL CELL, PRIMARY • FOLLICULAR LYMPHOMA (GRADES I, II, III) CUTANEOUS TYPE • • PERIPHERAL T-CELL LYMPHOMA, NOT OTHERWISE CHARACTERIZED • DIFFUSE LARGE B-CELL LYMPHOMA MEDIASTINAL LARGE B-CELL LYMPHOMA • ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA PRIMARY EFFUSION LYMPHOMA • ANAPLASTIC LARGE-CELL LYMPHOMA, T/NULL CELL, PRIMARY • BURKITT’S LYMPHOMA / BURKITT CELL LEUKEMIA SYSTEMIC TYPE “Indolent” Lymphomas: WHO Classification

MATURE (PERIPHERAL) B-CELL NEOPLASMS

• B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA / SMALL LYMPHOCYTIC LYMPHOMA • LYMPHOPLASMACYTIC LYMPHOMA • SPLENIC MARGINAL ZONE B-CELL LYMPHOMA (+/- VILLOUS LYMPHOCYTES) • HAIRY CELL LEUKEMIA • EXTRANODAL MARGINAL ZONE B-CELL LYMPHOMA OF MALT TYPE • NODAL MARGINAL ZONE B-CELL LYMPHOMA ( +/- MONOCYTOID B-CELLS) • FOLLICULAR LYMPHOMA (GRADES 1 and 2)

MATURE (PERIPHERAL) T-CELL NEOPLASMS

• T-CELL GRANULAR LYMPHOCYTIC LEUKEMIA • MYCOSIS FUNGOIDES / SEZARY SYNDROME • ANAPLASTIC LARGE-CELL LYMPHOMA, PRIMARY CUTANEOUS TYPE Relative Frequency of Types of Lymphomas

T/NK-cell lymphomas 12% large B-cell lymphoma Burkitt Other 46.5% 30% small B-cell lymphomas • follicular lymphoma, grade 1/2 [25%] • small lymphocytic lymphoma [7%] • mantle cell lymphoma [6%] • MALT marginal zone lymphoma [7.5%] 2.5% 9% • nodal marginal zone lymphoma [<2%] • lymphoplasmacytic lymphoma [<2%]

Adapted from Lichtman (Ed). Wiliams . 7th Ed. 2006 Characteristics of “Indolent” Lymphomas

• GENERALLY MALIGNANCIES OF SMALL, MATURE LYMPHOCYTES

• MOST COMMONLY B-CELL TUMORS

• HIGH PROPORTION OF NON-DIVIDING CELLS WITH LOW PROLIFERATION RATE

• LYMPHOID DISEASES WITH HETEROGENEOUS HISTOLOGIES

• FREQUENT INVOLVEMENT OF BLOOD AND BONE MARROW

• LONG MEDIAN SURVIVAL

• INITIAL SENSITIVITY TO AND RADIOTHERAPY

• ADVANCED STAGE AT DIAGNOSIS Staging of Lymphomas

• PHYSICAL EXAM WITH ATTENTION TO LN AREAS, LIVER,

• BLOOD COUNT WITH EVALUATION OF BLOOD SMEAR

• SERUM CHEMISTRIES

• CHEST X-RAY

• CT SCANS OF NECK, CHEST, ABDOMEN AND PELVIS

• ADDITIONAL RADIOLOGIC STUDIES AS INDICATED (e.g., PET SCAN)

• BONE MARROW BIOPSY

• DETERMINATION OF ANN ARBOR STAGE Staging of Lymphomas

Stage I Stage II Stage III Stage IV single lymph node 2 adjacent lymph > 2 lymph node widespread disease region / organ node regions regions in different + / - lymph node parts of the body involvement Prognosis of non-Hodgkin Lymphomas

- INDOLENT LYMPHOMAS - advanced stage, considered incurable, but long survival.

- AGGRESSIVE LYMPHOMAS - frequently curable.

- HIGHLY AGGRESSIVE LYMPHOMAS - frequently curable. Follicular Lymphoma: Biopsy

low magnification high magnification (40x): (400x): tumor cell distribution tumor cell size

reported pattern % follicular grading centroblasts / hpf follicular > 75% grade 1-2 0 – 15 follicular + diffuse 25 – 75% grade 3 > 15 focally follicular < 25% - grade 3A centrocytes present diffuse 0% - grade 3B sheets of centroblasts

Image from https://www.moffitt.usf.edu/pubs/ccj/v3n2/dept3.html Follicular Lymphoma Cell

SmIg

CD19 CD20 DR CD22

CD10 CD80

bcl-2 t(14;18) bcl-2 Follicular Lymphoma t(14;18)

www.pathologyoutlines.com/chromosomes.html Follicular Lymphoma

HISTOLOGY: SMALL CLEAVED AND LARGER NONCLEAVED LYMPHOCYTES ARRANGED IN NODULAR AGGREGATES; THE NUMBER OF LARGE CELLS PRESENT DETERMINES THE TUMOR GRADE (1, 2 or 3).

IMMUNOPHENOTYPE: CD5-, CD10+, CD19/20+, CD23-, SIg+.

CYTOGENETICS: t(14;18).

EPIDEMIOLOGY: 22% OF NHL; MEDIAN AGE 55.

CLINICAL: ADVANCED STAGE AT Dx (> 80%); PROGRESSION MORE RAPID IN MIXED AND LARGE CELL TYPES; TRANSFORMATION TO AGGRESSIVE LYMPHOMA IN 25% PATIENTS.

TREATMENT: NO SURVIVAL ADVANTAGE TO EARLY Rx FOR ADVANCED GRADE 1 (or 2) DISEASE. STANDARD FIRST THERAPIES FOR ADVANCED GRADE 1 (or 2) DISEASE INCLUDE or OBINUTUZUMAB (ANTIBODIES TO CD20), CVP + R/G, R- OR G-CHOP, OR R- OR G- BENDAMUSTINE; FOR GRADE 3 FOLLICULAR R-CHOP IS A STANDARD FIRST THERAPY. Lymphoplasmacytic Lymphoma (Waldenstrom’s)

https://www.moffitt.usf.edu/pubs/ccj/v3n2/dept3.html Lymphoplasmacytic Lymphoma (Waldenstrom’s)

sIg

CD19 CD20 CD22

t(9;14) Lymphoplasmacytic Lymphoma (Waldenstrom’s)

HISTOLOGY: SMALL BENIGN-APPEARING LYMPHOCYTES WITH PLASMACYTIC DIFFERENTIATION.

IMMUNOPHENOTYPE: CD5+ or -, CD10-, CD19/20+, CD23-, SIg+, CIg+.

CYTOGENETICS: t(9;14)(p13;q32).

EPIDEMIOLOGY: <5% OF NHL; MEDIAN AGE 55 - 65; POSSIBLE ROLE OF Hep C.

CLINICAL: USUALLY ADVANCED STAGE AT DX; PARAPROTEINEMIA (WALDENSTROM’S).

TREATMENT: NO ADVANTAGE TO EARLY Rx. TREAT FOR SYMPTOMS OR REAL / IMPENDING ORGAN DYSFUNCTION. STANDARD FIRST THERAPIES INCLUDE IBRUTINIB, RITUXAN, FLUDARABINE (ALONE OR IN COMBINATION), BENDAMUSTINE (ALONE OR IN COMBINATION WITH RITUXAN), CHLORAMBUCIL OR BORTEZOMIB (IN COMBINATION WITH R AND STEROIDS OR ) Extranodal Marginal Zone Lymphoma (MALT)

https://www.moffitt.usf.edu/pubs/ccj/v3n2/dept3.html Marginal Zone Lymphoma (MALT)

sIg

CD19 CD20 CD22 Extranodal Marginal Zone Lymphoma (MALT)

HISTOLOGY: ASSO. WITH EPITHELIAL TISSUE (MALT-LYMPHOMA) OR OTHER EXTRANODAL SITES. CELLULAR HETEROGENEITY INC. SMALL LYMPHOCYTES, PLASMA CELLS, MONOCYTOID B-CELLS. LYMPHOEPITHELIAL LESIONS SEEN IN MALT-LYMPHOMAS.

IMMUNOPHENOTYPE: CD5-, CD10-, CD19/20+, CD23+/-, SIg+, CIg+/-.

CYTOGENETICS: 3 IN 60% OF CASES.

EPIDEMIOLOGY: GASTRIC MALT LYMPHOMA IS ASSO. WITH H. PYLORI INFECTION. NONGASTRIC MALT LYMPHOMA IS ASSO. WITH . HEP C IS ASSO. WITH SMZL, NMZLS.

CLINICAL: GASTRIC MALT LYMPHOMA FREQUENTLY LOCALIZED AT DIAGNOSIS. NONGASTRIC MALT LYMPHOMA IS LESS COMMONLY EARLY STAGE AT DIAGNOSIS. MEDIAN AGE AT DIAGNOSIS IS 50 – 60s.

TREATMENT: ANTIBIOTICS FOR EARLY STAGE H. PYLORI ASSO. GASTRIC MALT LYMPHOMA. IN SOME CASES, SURGERY, RADIATION THERAPY AND / OR IMMUNOCHEMOTHERAPY ARE ALSO APPROPRIATE THERAPIES. TREATMENT OF HEP C MAY BE APPROPRIATE FOR SOME PATIENTS. Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

https://www.moffitt.usf.edu/pubs/ccj/v3n2/dept3.html Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

sIg

CD19 CD20 + CD38 CD52 + ZAP-70

CD23 CD5

+ Ig VH mutation Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

HISTOLOGY: SMALL ROUND BENIGN-APPEARING LYMPHOCYTE.

IMMUNOPHENOTYPE: CD5+, CD10-, CD19/20+, CD23+, SIg+/-.

CYTOGENETICS: OCC. TRISOMY 12; del13q; del11q; del17p.

EPIDEMIOLOGY: 5% OF NHL; MEDIAN AGE 60.

CLINICAL: ADVANCED STAGE AT DX (>60 - 80%); FREQ. BLOOD INVL. (CLL).

TREATMENT: NO ADVANTAGE TO EARLY Rx. TREAT FOR SYMPTOMS OR REAL / IMPENDING ORGAN DYSFUNCTION. STANDARD FIRST THERAPIES INCLUDE IBRUTINIB, FLUDARABINE COMBINATIONS USUALLY WITH RITUXIMAB AND CYTOXAN (FCR OR FR), BENDAMUSTINE +/- RITUXAN, CHLORAMBUCIL + OBINUTUZUMAB. Non-Hodgkin Lymphomas: Treatment Overview

• Watch and wait (for indolent lymphomas only) • Chemotherapy • Radiation therapy • Monoclonal antibody therapy • Combination therapies • Radioimmunotherapy (RIT) • Bone marrow and stem cell transplants • Investigational therapies Standard Therapeutic Approaches to non-Hodgkin Lymphomas

INDOLENT LYMPHOMAS: palliative approach in general • advanced stage: watch & wait or palliative therapies • early stage: regional radiation

AGGESSIVE LYMPHOMAS: curative therapy • advanced stage: combination chemotherapy (e.g., CHOP or R- CHOP) • early stage: combined modality therapy (radiation + R-CHOP)

HIGHLY AGGRESSIVE LYMPHOMAS: curative therapy with combination chemotherapy + R Older “Standard” Approaches to Treatment of iNHLs

LIMITED STAGE DISEASE - INVOLVED FIELD OR REGIONAL IRRADIATION ADVANCED-STAGE DISEASE - DEFERRED THERAPY (WATCH AND WAIT) - SINGLE ALKYLATING AGENT - COMBINATION CHEMOTHERAPY (CVP, CHOP, C-MOPP)

Current "Standard" Approaches to B-Cell iNHLs

LIMITED STAGE DISEASE - INVOLVED FIELD OR REGIONAL IRRADIATION ADVANCED-STAGE DISEASE - DEFERRED THERAPY (WATCH AND WAIT) - RITUXIMAB or OBINUTUZUMAB +/- CHEMOTHERAPY - IBRUTINIB FOR SLL/CLL Antibody Structure and Function

From Biological Therapy of Lymphoma 3(4): 2000 Baylor-Charles A. Sammons Cancer Center Rituximab (Rituxan) an antibody for CD20 Rituximab Mechanisms

TUMOR CELL

CDC C’ LYSIS Y ADCC NK LYSIS Y CELL RITUXIMAB

APOPTOSIS APOPTOSIS Rituximab Monotherapy for Relapsed Indolent Non-Hodgkin Lymphomas

AUTHOR # PTs CR PR

MALONEY 34 3 (4%) 14 (41%) MCLAUGHLIN 151 9 (6%) 67 (44%)

COLOMBAT 50 10 (20%) 23 (47%) HAINSWORTH 62 (1ST Rx) 4 (7%) 24 (40%) 60 (Rx x4) 22 (37%) 22 (37%) Rituxan + CHOP for Indolent NHL: PFS

100 90

80 free

- 70 60 50 40 30 Previously untreated patients (n=29)

20 Previously treated patients (n=9) % Progression % 10 0 0 10 20 30 40 50 60 70 80 90 100 110 Months

Median TTP 82.3 mo. Czuczman et al. J Clin Oncol. 2004;22:4711. Phase III study of CHOP-R vs CHOP in Untreated Advanced FL (N=428)

Time to Treatment Failure

Hiddemann W, et al. Blood 2005;106:3725-3732. R+CVP vs. CVP as first therapy for follicular lymphoma

Marcus et al. J Clin Oncol 2008;26:4579. CVP R vs. CVP as first therapy for follicular lymphoma

Hochster et al. Blood (ASH Abstracts) 2005;106: #349. Bendamustine

• Bifunctional alkylating nitrogen mustard group – induces DNA damage resulting in apoptosis and mitotic cell death • Lacks cross-resistance with other alkylating agents

Carboxylic acid Nitrogen mustard

Purine-like ring Bendamustine in Rituximab-Refractory NHL: Phase III Results

• ORR – Patients with ≥ 1 dose of bendamustine (n = 100): 75% – Patients with ≥ PR to last regimen (n = 51): 88% – Patients with no response to last regimen (n = 36): 64% • Response rates did not significantly differ by histology

Histology Pts, N ORR CR Cru PR SD PD Unk

Follicular 62 74 15 5 55 15 10 2 Small lymphocytic 21 71 5 0 67 19 5 5 Lymphoplasmacytic 1 100 0 0 100 0 0 0 Lymph node marginal zone 9 78 11 0 67 22 0 0 Extralymph node marginal zone 7 86 43 0 43 14 0 0 Total 100 75 14 3 58 16 7 2

. Median PFS: 9.3 mos . Median DOR: 9.2 mos Kahl, B, et al. Cancer. 2009 STILL study: Bendamustine + Rituximab (BR) vs R- CHOP in Untreated Advanced FL, MCL, & Indolent NHL

Response BR R-CHOP P n = 166 n = 149 CR, % 40 31 0.0323 PFS, months 55 35 0.0002 PFS (FL), months NR 47 0.02 TTNT, months NR 41 0.0002 Deaths, n 34 33 --

Adverse Events BR R-CHOP P Grade 3/4 , % 11 47 < 0 .0001 Grade 3/4 leukocytopenia, % 12 38 < 0.0001 G-CSF use, % 4 20 < 0.0001 Alopecia, % 15 62 < 0.0001 Infections, n 95 121 0.0403 Peripheral neuropathy, n 18 73 < 0.0001

Rummel et al. ASH 2009. Abstract 5., ASCO 2012 Abstract 3 BRIGHT study: R-CHOP/CVP vs. R- Bendamustine in Untreated Indolent NHL and MCL

Ian W. Flinn et al. Blood 2014;123:2944-2952 ©2014 by American Society of Hematology Obinutuzumab (GA101) Mechanisms of Action Increased Direct Cell Death Enhanced ADCC Type II versus Type I antibody Glycoengineering for increased affinity to FcyRIIIa

Effector cell

B cell

GA101 Complement Lower CDC Type II versus Type CD20 FcyRIIIa I antibody

ADCC = antibody-dependent cell-mediated cytotoxicity CDC = complement-dependent cytotoxicity GALLIUM: Obinutuzumab-chemo vs. Rituximab- chemo (CHOP, CVP or bendamustine)

Marcus R et al. N Engl J Med 2017;377:1331-1344. B Cell Lymphomas: New Treatment Paradigms

Mechanism of Action Therapeutic Agent

Immunomodulatory agents (IMiDs) • lenalidomide

B cell receptor (BCR) signal transduction inhibition • ibrutinib • Idelalisib • Copanlisib • Duvelisib • Umbralisib BCL2 inhibition • Venetoclax

Histone • EZH2 inhibitors (tazemetostat; CPI-1205) Monoclonal antibodies • Polatuzumab (CD79)

Immune checkpoint blockade • Nivolumab • Pidilizumab • Pembrolizumab • Atezolizumab Chimeric antigen receptor (CAR) modified T cells • CART-19 B cell malignancies: therapeutic targets

Ag CAR T cells sIg sIg therapeutic vaccination

CD19 CD20 monoclonal antibodies C C D D 7 7 9 9 immunoconjugates BiTE antibody A B SYK CD30 PI3Kδ BTK B cell receptor IMiDs E3 ubiquitin kinase inhibitors ligase cyclin dependent BCL 2 protein cdk-cyclin kinase inhibitors inhibitors BCL2 DNA chemotherapy

Cytotoxic T cells PD1 PDL1/2

PD1 antibodies Lenalidomide: Mechanism of Action Phase II Trial of Lenalidomide - Rituximab +/- Dexamethasone in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab

Chong, E. A., Schuster, S. et al ASH 2011 Lenalidomide - Rituximab in Rituximab Resistant NHL

• For each patient, PFS for failed previous rituximab-based therapy compared to PFS for lenalidomide and rituximab

Chong, E. A., Schuster, S. et al ASH 2011 RELEVANCE trial: Rituximab plus lenalidomide or chemotherapy in untreated advanced follicular lymphoma

F Morschhauser et al. N Engl J Med 2018;379:934-947. B Cell Receptor Kinase Inhibitors

Ibrutinib Idelalisib B Cell Receptor Signal Transduction and Inhibition

B cell receptor

PIP3 CD79B CD79A BLNK PLCg2 PDK P Btk

PI3K AKT P P P P P

Lyn Syk

P ibrutinib idelalisib

MAPK/NF-kB PI3K/Akt pathway pathway

B-cell activation and proliferation

9/20/2014 Ibrutinib (BTK Inhibitor): Phase 1 Results

* 1 CLL patient had nodal response with ** Based on IgM NE = not evaluable Advani, R, Fowler, N et al ICML 2011 Ibrutinib and rituximab in Waldenström's Macroglobulinemia

MA Dimopoulos et al. N Engl J Med 2018;378:2399-2410. Response to Ibrutinib in Waldenström's Macroglobulinemia, According to Mutation Status

Treon SP et al. N Engl J Med 2015;373:584-586. Ibrutinib in relapsed/refractory nodal marginal zone lymphoma

Ariela Noy et al. Blood 2017;129:2224-2232

©2017 by American Society of Hematology DAWN study: Ibrutinib in relapsed/refractory FL

Gopal AJ et al. Journal of Clinical 2018, 36, 2405-2412. Copyright © 2018 American Society of Clinical Oncology PI3 Kinase inhibitors in NHL

C. L. Batlevi A. Younes Annals of Oncology, 2017. 28(9): 2047–9 Copanlisib in iNHL

FL (n=104): ORR 59% (CR12%; PR 47%)

MZL (n=23): ORR 70% (CR 9%; PR 61%)

Dreyling M et al. Journal of Clinical Oncology 2017 35:35, 3898-3905 BCL2 Control of Cell Death

Bax Bcl-2 Bak

Mitochondria

Cell Death Mechanism of Action of Venetoclax

1 An Increase in BCL-2 2 Venetoclax Binds to and 3 Apoptosis is Initiated Expression Allows the Inhibits Overexpressed BCL-2 Cancer Cell to Survive Active Apoptosome Caspase Venetoclax

Pro-apoptotic Anti-apoptotic APAF-1 Proteins Proteins (BAX, BAK) (BCL-2) BH3-only Cytochrome c Procaspase

BAX BAK BCL-2 BCL-2

Mitochondria Mitochondria Mitochondria

. BH3-only family member proteins include BIM, BAD, PUMA, and NOXA

72 Venetoclax in Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL).

Roberts AW et al. N Engl J Med 2016;374:311-322. Single-agent Venetoclax in Rel/Ref NHL

Davids, MS et al. Journal of Clinical Oncology 2017, 35, 826-833. Mechanisms of Cytotoxic T Cells

AP Cell CD8 T Cell CD8 T Cell Y Y

Tumor Cell Apoptosis = Tumor Cell Antigen AP Cell = Antigen Presenting Cell Immune Checkpoint Pathways

AP Cell CD8 T Cell CD8 T Cell Y PD-1 Y B7 CTLA-4 PD-L1

Tumor Cell x Apoptosis

PD-1 = programmed cell death protein 1 PD-L1 = programmed death-ligand 1 CTLA-4 = cytotoxic T-lymphocyte-associated protein 4 Immune Checkpoint Pathways: Nivolumab in Lymphomas

Tumor Objective Complete Partial Stable Disease Response Response Response n (%) n (%) n (%) n (%) Classical (n=23) 20 (87) 6 (26) 14 (61) 3 (13)

B-Cell Non-Hodgkin Lymphoma (n=31) 8 (26) 3 (10) 5 (16) 16 (52)

Diffuse Large B-Cell (n=11) 4 (36) 2 (18) 2 (18) 3 (27) Follicular (n=10) 4 (40) 1 (10) 3 (30) 6 (60) Other B-Cell (n=10)* 0 0 0 7 (70) Mantle Cell Lymphoma (n=4) 0 0 0 3 (75) Primary Mediastinal B-Cell (n=2) 0 0 0 2 (100) T-Cell Non-Hodgkin Lymphoma (n=23)* 4 (17) 0 4 (17) 10 (43)

Cutaneous T-Cell- 2 (15) 0 2 (15) 9 (69) Mycosis Fungoides (n=13) Peripheral T-Cell (n=5) 2 (40) 0 2 (40) 0

*Additional subtypes included small lymphocytic lymphoma (n=2), MALT (n=1) and B-cell lymphoma not otherwise specified (n=1) †Additional subtypes included other cutaneous T-cell lymphoma (n=3) and other non-cutaneous T-cell lymphoma (n=2); 1 patient achieved a best response of stable disease in the latter group Checkpoint inhibitor in NHL – select trials

Pianko MJ, Liu Y, Bagchi S, Lesokhin AM. Stem Cell Investig. 2017 Apr 19;4:32. Phase II Study of Pidilizumab, a Humanized Anti-PD-1 Monoclonal Antibody, in Combination with Rituximab

Efficacy (n = 29) n (%) ORR 19 (66)

CR 15 (52)

PR 4 (14)

Measurable tumor regression 25 (86)

Median time to response, days 88

Median PFS, mo 21.1 In responders (n = 19) NR Pts with tumor regression (n = 25) NR

Westin et al. ASH 2012, Abstract 793. Action of Chimeric Antigen Receptor-Modified T Cells (CAR T Cells)

Y Apoptosis CAR T Cell Tumor Cell

Porter, D et al. NEJM 2011; 365: 725 Redirecting T cells: Mechanism of Action of CAR T cells

• Gene transfer technology is used to T cell stably express CARs on T cells, conferring novel antigen specificity1,2 CTL019 cell

• CART19 cells can thus be directed against any tumor cell that expresses

the CD19 surface antigen Native TCR • CART19 therapy takes advantage of

the cytotoxic potential of T cells Anti-CD19 CAR construct thereby killing tumor cells in an CD19 antigen-dependent manner1,3

• Persistent CART19 cells consist of both effector (cytotoxic) and central Dead tumor cell memory T cells3

1. Milone MC, et al. Mol Ther. 2009;17:1453-1464. 2. Hollyman D, et al. J Immunother. 2009;32:169-180. Tumor cell 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73. Chimeric Antigen Receptor-Modified T Cells against CD19 in FL Characteristics of the Patients at Baseline.

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Response Rates: Follicular Lymphoma

FL: ORR at 3 Months 77% FL: Best Response Rate 77% (N = 13) (N = 13) - CR: 6 - CR: 9 - PR: 4 - PR: 1 - PD: 3 - PD: 3

• 3 patients with PRs by CT/MR criteria at 3 months converted to CRs by 6 months • 1 patient with PR at 3 months who remained in PR at 6 and 9 months had PD at approximately 12 months

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Results: Follicular Lymphoma

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Results: Progression-free Survival in Follicular Lymphoma

PFS at median follow-up 64.1%, N = 13 Median follow up 14.3 months

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Results: Response Duration in Follicular Lymphoma

RD at median follow-up 83.3%, N = 10 Median follow up 16.8 months

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Results: Overall Survival in Follicular Lymphoma

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Adverse Events of Special Interest That May Have Been Related to CTL019 Therapy.

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Time to Next Treatment: CAR T Cells vs. Antecedent Therapy

Schuster SJ et al. N Engl J Med 2017;377:2545-2554. Chimeric Antigen Receptor-Modified T Cells against CD19 in CLL/SLL Durable Molecular Remissions in CLL Treated With CAR T Cells After Failure of Ibrutinib

Turtle CJ et al.; Journal of Clinical Oncology 2017, 35, 3010-3020. Factors correlating with response in CLL Treated With CAR T Cells After Failure of Ibrutinib

Turtle CJ et al.; Journal of Clinical Oncology 2017, 35, 3010-3020. Toxicities of CAR T cell therapy

Carl H. June et al. Science 2018;359:1361-1365 The Future

Patient-, target- and pathway-specific therapies

• Individualized treatment selection

• Improved prediction of response to therapy

• Improved prediction of development of resistance and modification of therapy Improved drug development Questions?