what is personalized medicine for patients with lymphoma? · “personalized medicine” ••...
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What Is Personalized What Is Personalized Medicine For Patients Medicine For Patients Medicine For Patients Medicine For Patients With Lymphoma?With Lymphoma?
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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.
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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
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Personalizing Management Personalizing Management Based On The Based On The Based On The Based On The Characteristics Of The Characteristics Of The DiseaseDisease
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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
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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)
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ProposalProposal
Lymphoma Classification Lymphoma Classification --A Moving TargetA Moving Target
TestingTesting
RefusalRefusal
New ObservationsNew Observations
AcceptanceAcceptanceand Applicationand Application
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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
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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
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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
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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%
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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?
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Dissecting a Cancer into Molecularly and Clinically Distinct Subgroups by Gene Expression Profiling
Diffuse Large B Cell Lymphoma
Lymphoma Biopsies
Gen
es
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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
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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
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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
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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
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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
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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
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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
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Outcome of Relapsed Diffuse Large BOutcome of Relapsed Diffuse Large B--Cell Lymphoma Cell Lymphoma
Controls R-EPOCH + Bortezomib
Blood 113:6069, 2009
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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
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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
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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
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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?
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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
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Personalizing Management Personalizing Management Based On The Based On The Based On The Based On The Characteristics Of The Characteristics Of The PatientPatient
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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
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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)
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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)
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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)
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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
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Pharmacogenomics In Pharmacogenomics In Determining Response To Determining Response To Determining Response To Determining Response To Lymphoma TherapyLymphoma Therapy
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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
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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
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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
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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
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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
[email protected]@meduniwien.ac.at
for the NHL13 Investigatorsfor the NHL13 Investigators
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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
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ASH 2013, Abstract 851
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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
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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
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Response-Adapted Therapy
Lymphoma Treatment
Early PET Scan
Abnormal/Positive
Stop therapyAbbreviate therapyLess aggressive therapy
Additional therapyMore aggressive therapy
Normal/Negative Abnormal/Positive
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It Is Likely That Tumor Biology, Patient
Immune Response,
Pharmacogenomics, And Tumor Pharmacogenomics, And Tumor
Response Rate Will All Help Guide
Future Management Decisions
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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
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“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
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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