What Is Personalized What Is Personalized Medicine For Patients Medicine For Patients Medicine For Patients Medicine For Patients With Lymphoma?With Lymphoma?

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports:

Receipt of honoraria or consultation fees: See attached list.

Participation in a company sponsored speaker’s bureau:

Stock shareholder:

Other support (please specify): Member, Board of Directors – Tesaro bio, Inc.

Conflict of Interest Disclosure FormNAME :James O. Armitage, M.DAFFILIATION: University of Nebraska Medical Center

DISCLOSURE� I have no potential conflict of interest to report I have the following potential conflict(s) of interest to report

Other support (please specify): Member, Board of Directors – Tesaro bio, Inc.

Scientific advisory board

James O. Armitage, M.D.Consultant:GlaxoSmith KlineSeattle GeneticsGenetechRocheSpectrumZiopharmBoard of Director’s for Tesaro bio , Inc.

What Most People Mean By What Most People Mean By “Personalized Medicine”“Personalized Medicine”

•• Targeted therapyTargeted therapy•• Molecular therapyMolecular therapy•• Molecular therapyMolecular therapy•• Customized therapyCustomized therapy•• Individualized therapyIndividualized therapy

Personalizing Management Personalizing Management Based On The Based On The Based On The Based On The Characteristics Of The Characteristics Of The DiseaseDisease

A First Attempt at Applying A First Attempt at Applying Biology to Lymphoma Biology to Lymphoma Classification Classification ((Gall & MalloryGall & Mallory ))

•• LymphosarcomaLymphosarcoma•• LymphosarcomaLymphosarcoma

•• Reticulum cell sarcomaReticulum cell sarcoma

•• Giant follicular lymphomaGiant follicular lymphoma

Classifying NHLClassifying NHL

•• Rappaport (pattern, size & shape)Rappaport (pattern, size & shape)•• Lukes/Collins (biology)Lukes/Collins (biology)•• Lennert (biology)Lennert (biology)•• Working Formulation (politics)Working Formulation (politics)

ProposalProposal

Lymphoma Classification Lymphoma Classification --A Moving TargetA Moving Target

TestingTesting

RefusalRefusal

New ObservationsNew Observations

AcceptanceAcceptanceand Applicationand Application

There Are Three Things Certain There Are Three Things Certain in Lifein Life

1.1. You will die You will die

10

1.1. You will die You will die

2.2. You will pay taxesYou will pay taxes

3.3. The lymphoma classification The lymphoma classification

will changewill change

The WHO (Previously REAL) The WHO (Previously REAL) Classification Is Based On Classification Is Based On Clinical/Pathological Syndromes Clinical/Pathological Syndromes Clinical/Pathological Syndromes Clinical/Pathological Syndromes (Including Immunology And (Including Immunology And Genetics) Rather Than Just Genetics) Rather Than Just MorphologyMorphology

WHO Classification of Lymphoid WHO Classification of Lymphoid MalignanciesMalignancies

Cellular Origin of Disease

Precursor CellB-Cell T-Cell

Peripheral CellB-Cell T-CellB-Cell T-Cell

•Lymphoblastic leukemia/lymphoma

B-Cell T-Cell•Hodgkin•SLL/CLL•Follicular

•Mycosis fungoides•ATL•Sezary Syndrome

•Mantle cell •Angioimmunoblastic•Marginal Zone •Peripheral (unspecified)•Diffuse large B-cell •Anaplastic Large cell•Burkitt

Where Was Mantle Cell Lymphoma Where Was Mantle Cell Lymphoma In The Working Formulation?In The Working Formulation?

TypeType PercentPercent

Diffuse Small CleavedDiffuse Small Cleaved 40%40%Diffuse Small CleavedDiffuse Small Cleaved 40%40%Follicular Small Cleaved Follicular Small Cleaved 29%29%Small Lymphocytic Small Lymphocytic 12%12%Diffuse Large CellDiffuse Large Cell 10%10%LymphoblasticLymphoblastic 8%8%

We Still Don’t Cure Enough We Still Don’t Cure Enough Patients. How Can We Do Patients. How Can We Do Patients. How Can We Do Patients. How Can We Do Better?Better?

Dissecting a Cancer into Molecularly and Clinically Distinct Subgroups by Gene Expression Profiling

Diffuse Large B Cell Lymphoma

Lymphoma Biopsies

Gen

es

Dissecting a Cancer into Molecularly and Clinically Distinct Subgroups by Gene Expression Profiling

Diffuse Large B Cell Lymphoma

5-year Survival

Overall Survival (years)

Pro

babi

lity PMBL 64%

GCB 59% DLBCL

ABC 30%DLBCL

5-year Survival

Subtypes of Diffuse Large BSubtypes of Diffuse Large B--Cell Lymphoma Cell Lymphoma In The 2008 WHO ClassificationIn The 2008 WHO Classification

MorphologicalCentroblasticImmunoblasticAnaplastic

GeneticGCBNon GCB

(includes ABC)

OtherEBV positive in elderlyWith chronic inflammationIn lymphomatoid Anaplastic

Plasmablastic

ImmunologicalALK positiveCD5 positive

(includes ABC)

By Primary SiteCNSCutaneous leg type Mediastinal Intravascular Effusion

In lymphomatoid granulomatous

In HHV-8 associated Castlemans

18

Other Variants Of Diffuse Other Variants Of Diffuse Large BLarge B--Cell LymphomaCell Lymphoma

•• TesticularTesticular

•• Leukemic Leukemic DLBCLDLBCL•• Leukemic Leukemic DLBCLDLBCL

•• Interface DBCL/BurkittInterface DBCL/Burkitt

•• Interface mediastinal DLBCL/NSHDInterface mediastinal DLBCL/NSHD

•• Genetic subtypesGenetic subtypes——double hit, MYC+double hit, MYC+19

It Is Possible That Some It Is Possible That Some “Subtypes” Might Benefit “Subtypes” Might Benefit “Subtypes” Might Benefit “Subtypes” Might Benefit From Specific TreatmentsFrom Specific Treatments

CORAL StudyCORAL Study

RA R-DHAP R-DHAP CR/PR

BEAM ASCT

RANDOMIZ

Observation

Rituximab 375 mg2/8 wks/12 mo

J Clin Oncol 28:4184, 2010

ANDOMIZE

R-DHAP

R-ICE

Clinical Evaluation

R-DHAP

R-ICE

PBPC Evaluation

CR/PR

PD/SD

OFF

ZE

CORAL Trial ResultsCORAL Trial Results3-yr Progression-Free SurvivalGCB Non-GCB p

R-DHAP 52% 32% .01R-DHAP 52% 32% .01R-ICE 31% 27% .81

J Clin Oncol 29:4079, 2011

Gene Expression Defines Molecularly Gene Expression Defines Molecularly and Clinically Distinct Subgroups in and Clinically Distinct Subgroups in DLBCLDLBCL

Cytogenetic Change, % GCB DLBCL ABC DLBCL PMBL

C-rel amplification 16 0 25

Bcl-2 translocation 45 0 18

Gain of 3q 0 24 5

Gain/amplification of 9p24 0 6 43

Constitutive NF-κB Activation No Yes Yes

Outcome of Relapsed Diffuse Large BOutcome of Relapsed Diffuse Large B--Cell Lymphoma Cell Lymphoma

Controls R-EPOCH + Bortezomib

Blood 113:6069, 2009

Morphology Genetic Double Hit

Only MYC+ Double Expressers of BCL-2 and MYC protein by IHC

Ki-67 > 90%

DLBCL 0-12%2, 3 3-8% 2, 3 29-44% 4, 5 7-8% 6, 7

High grade B-cell lymphoma with

High Grade BHigh Grade B--cell Lymphomascell Lymphomas

lymphoma with features intermediate between DLBCL and Burkittlymphoma

29% 8 36% 8 N/A 61% 8

Burkitt Lymphoma

<1% 1 ~100% 1 <20% 1 ~100% 1

MYC Positive DLBCLMYC Positive DLBCL

•• Found in <10% of patientsFound in <10% of patients

•• High KiHigh Ki--67 (often >90%)67 (often >90%)•• High KiHigh Ki--67 (often >90%)67 (often >90%)

•• 5 year survival 32% with CHOP5 year survival 32% with CHOP--R*, R*,

although not all reports agreealthough not all reports agree

*Leukemia 2008;22:2226*Leukemia 2008;22:2226

EPOCHEPOCH--R In MYC Positive And R In MYC Positive And MYC Negative DLBCLMYC Negative DLBCL

CharacteristicCharacteristic MYC MYC ΘΘ MYC MYC ΘΘ

FrequencyFrequency 10%10% 90%90%

High IPIHigh IPI 50%50% 36%36%

EFS (4 yr)EFS (4 yr) 83%83% 76%76%

Lugano 2011, Abstract, DunleavyLugano 2011, Abstract, Dunleavy

Will Whole Genome Will Whole Genome Sequencing Make Future Sequencing Make Future Sequencing Make Future Sequencing Make Future Regimens Be Selected Regimens Be Selected Patient By Patient?Patient By Patient?

The New York TimesThe New York TimesThe New York TimesThe New York TimesThe New York TimesThe New York TimesThe New York TimesThe New York TimesSUNDAY, JULY 8, 2012SUNDAY, JULY 8, 2012

A New Approach on LeukemiaA New Approach on LeukemiaIn Gene Sequencing Treatment, Glimpses of the FutureIn Gene Sequencing Treatment, Glimpses of the Future

By GINA KOLATABy GINA KOLATA

GENETIC GAMBLEGENETIC GAMBLEFirst of three articlesFirst of three articles

Personalizing Management Personalizing Management Based On The Based On The Based On The Based On The Characteristics Of The Characteristics Of The PatientPatient

It Is Increasingly Clear That It Is Increasingly Clear That The Patient’s Response To The The Patient’s Response To The Tumor (i.e. Reflected In Tumor (i.e. Reflected In TThe he Tumor (i.e. Reflected In Tumor (i.e. Reflected In TThe he Tumor Microenvironment) Is Tumor Microenvironment) Is Important In PrognosisImportant In Prognosis

Infiltrating Immune Cells Identified Infiltrating Immune Cells Identified By Immunohistochemistry In By Immunohistochemistry In Follicular Lymphoma Impact Follicular Lymphoma Impact PrognosisPrognosis

•• Increased numbers of PDIncreased numbers of PD--1 positive 1 positive •• Increased numbers of PDIncreased numbers of PD--1 positive 1 positive lymphocytes improved prognosis lymphocytes improved prognosis (5(5--Yr OS 95% vs 50%) (Spain, UK)Yr OS 95% vs 50%) (Spain, UK)

•• Increased numbers of CD68 positive Increased numbers of CD68 positive macrophages worsened prognosis macrophages worsened prognosis (median OS 100 vs 71 months) (UK)(median OS 100 vs 71 months) (UK)

Survival In Patients With Follicular NHL Survival In Patients With Follicular NHL Is Predicted By Gene Expression Of Is Predicted By Gene Expression Of Host Immune Cells (Dave, et al)Host Immune Cells (Dave, et al)

GeneGene--ExpressionExpression Relative RiskRelative RiskSignatureSignature Of DeathOf Death _______ _______

ImmuneImmune--Response 1Response 1 0.15 (0.050.15 (0.05--0.46)0.46)(T(T--cell genes)cell genes)

ImmuneImmune--Response 2Response 2 9.35 (3.029.35 (3.02--29.90)29.90)(macrophage/dendritic(macrophage/dendritic

cell genes)cell genes)

High Numbers Of Macrophages High Numbers Of Macrophages Have An Adverse Prognostic Have An Adverse Prognostic Impact That Can Be Circumvented Impact That Can Be Circumvented With Rituximab (GELAWith Rituximab (GELA--GOELAMS)GOELAMS)

•• 194 patients randomized to receive 194 patients randomized to receive •• 194 patients randomized to receive 194 patients randomized to receive the CHVPthe CHVP--I regimen I regimen ±± rituximabrituximab

•• ≥10 macrophages/npf reduced EFS ≥10 macrophages/npf reduced EFS without rituximab (p=.012) but use of without rituximab (p=.012) but use of rituximab eliminated the adverse rituximab eliminated the adverse effect (p=.16)effect (p=.16)

An Antibody Blocking PDAn Antibody Blocking PD--1 Receptor in 1 Receptor in Relapsed Follicular LymphomaRelapsed Follicular Lymphoma

Treatment Regimen

Patients Response Rate

Rituximab Historical ~40%Rituximab Historical ~40%

Pidilizumab + Rituximab

29 66% (52% CR, 14% PR)

ASH 2012 M.D. Anderson

Pharmacogenomics In Pharmacogenomics In Determining Response To Determining Response To Determining Response To Determining Response To Lymphoma TherapyLymphoma Therapy

Influence of MethotrexateInfluence of Methotrexate AUCAUC on on Primary CNS Lymphoma OutcomesPrimary CNS Lymphoma Outcomes

AUC low AUCmid AUChigh p

Response rate 17% 28% 55% <0.001Response rate 17% 28% 55% <0.001

3-yr EFS 21.1% 20.8% 32.1% 0.04

3-yr OS 30.7% 30.5% 46% 0.06

Br J Cancer 102:673, 2010

Autologous Transplantation for Lymphoma Autologous Transplantation for Lymphoma with Highwith High--Dose Busulfan, Cyclophosphamide, Dose Busulfan, Cyclophosphamide, and Etoposideand Etoposide

Oral Busulfan

Targeted IV Busulfan p

Non-RelapseMortality

28% 3% 0.01

5-year Survival 28% 58% 0.01

Biol Blood Marrow Transplant 12:770, 2006

Interpatient PK Variability with Dosing Interpatient PK Variability with Dosing Based on BSABased on BSA

Doxorubicin 3-6 x

Busulfan 4 x

Teniposide 3-6 x

Carboplatin 2-3 xCarboplatin 2-3 x

Ifosfamide 10 x

Vincristine 11 x

5FU 5 x

Trimetrexate 5-11 x

Paclitaxil 5 x

J Clin Oncol 14:2590, 1996

Rituximab Clearance In Elderly (i.e. >60 years) Rituximab Clearance In Elderly (i.e. >60 years) Patients (DSHNHL)Patients (DSHNHL)

•• Males had a significantly more rapid rituximab clearance Males had a significantly more rapid rituximab clearance

(p=.003)(p=.003)

•• Females had a superior 3Females had a superior 3--year PFS: 68% v 61% (p=.06)year PFS: 68% v 61% (p=.06)

•• Males receiving rituximab over a longer period of time (8 Males receiving rituximab over a longer period of time (8

months rather than 3 months) had a superior 3 year PFS months rather than 3 months) had a superior 3 year PFS

(71% v 53%, p=.05) and OS (80% v 60%, p=.04)(71% v 53%, p=.05) and OS (80% v 60%, p=.04)

ASCO 2012, Abstracts 8024, 8025

NHL13 NHL13

A A multicentermulticenter, randomized phase III study of Rituximab as , randomized phase III study of Rituximab as maintenance treatment versus observation alone in p atients maintenance treatment versus observation alone in p atients with aggressive Bwith aggressive B--cell lymphoma cell lymphoma (DLBCL & FL G3B)(DLBCL & FL G3B)(DLBCL & FL G3B)(DLBCL & FL G3B)

ClinicalTrials.gov:ClinicalTrials.gov: NCT00400478NCT00400478

ulrich.jaeger@meduniwien.ac.atulrich.jaeger@meduniwien.ac.at

for the NHL13 Investigatorsfor the NHL13 Investigators

Cumulative relapse rate by treatment arm (ITT Population, all patients)

30%

40%

50%All patients A (treatment)

N=338B (observation)

N=345

Relapses 100 (14.7%) 36 (10.7%) 64 (18.7%)

Histologic/Cytologicconfirmation

62 19 43

Observation

0%

10%

20%

Time [months]

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81

A: RITUXIMAB B: OBSERVATION

Rituximab maintenance

ASH 2013, Abstract 851

Personalized Management Based On Personalized Management Based On Rapidity Of Response To TherapyRapidity Of Response To Therapy

Early reports suggested a better Early reports suggested a better Early reports suggested a better Early reports suggested a better

outcome in acute leukemia and outcome in acute leukemia and

aggressive lymphomaaggressive lymphoma

Interim PET Scans for Aggressive NHL

(Paris, n=90)

100

8070

90

60

100

8070

90

60

Pet (Pet (--))Pet (Pet (--))

Pet (Pet (++))

IPI 1IPI 1--22 IPI 3IPI 3--55

Free

Sur

viva

l

Free

Sur

viva

l

Blood 106:1376, 2005

6050403020100

0 0.5 1 1.5 2 2.5 3

6050403020100

0 0.5 1 1.5 2 2.5 3

Years Years

P = .004P = .004

Pet (Pet (++))Pet (Pet (++))

P = .01P = .01Eve

nt-F

ree

Surv

ival

Eve

nt-F

ree

Surv

ival

Response-Adapted Therapy

Lymphoma Treatment

Early PET Scan

Abnormal/Positive

Stop therapyAbbreviate therapyLess aggressive therapy

Additional therapyMore aggressive therapy

Normal/Negative Abnormal/Positive

It Is Likely That Tumor Biology, Patient

Immune Response,

Pharmacogenomics, And Tumor Pharmacogenomics, And Tumor

Response Rate Will All Help Guide

Future Management Decisions

The The Art of Art of Medicine Medicine –– Old Fashioned Old Fashioned Personalized MedicinePersonalized Medicine

•• Physicians helped patients before Physicians helped patients before

“modern” medicine“modern” medicine“modern” medicine“modern” medicine

•• A correct diagnosis and therapy A correct diagnosis and therapy are the are the

minimumminimum for good carefor good care

•• The art of medicine separates really The art of medicine separates really

excellent excellent physiciansphysicians

“Medicine Is An Art That Uses“Medicine Is An Art That UsesScience To Let Us Better Minister Science To Let Us Better Minister To Our Patients”To Our Patients”

William HarveyWilliam HarveyWilliam HarveyWilliam Harvey

“Medicine Is A Calling…Where “Medicine Is A Calling…Where Your Heart Will Be ExercisedYour Heart Will Be ExercisedEqually With Your Head”Equally With Your Head”

William OslerWilliam Osler

ConclusionConclusion

•• With increasingly “personalized” regimens, we’re With increasingly “personalized” regimens, we’re

getting better at maximizing the chance patients will getting better at maximizing the chance patients will

respond to therapyrespond to therapy——and we will soon be even betterand we will soon be even betterrespond to therapyrespond to therapy——and we will soon be even betterand we will soon be even better

•• We must not lose the concept of personalized caring We must not lose the concept of personalized caring

for the patientfor the patient——sometimes it’s the most important sometimes it’s the most important

thing we dothing we do