Conflict of Interest Disclosure Form NAME :James O. Armitage, M.D AFFILIATION: University of Nebraska Medical Center

Transcription

1 What Is Personalized Medicine For Patients With Lymphoma?

2 Conflict of Interest Disclosure Form NAME :James O. Armitage, M.D AFFILIATION: 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 Type of affiliation / financial interest Receipt of grants/research supports: Receipt of honoraria or consultation fees: Participation in a company sponsored speaker s bureau: Stock shareholder: Other support (please specify): Scientific advisory board Name of commercial company See attached list. Member, Board of Directors Tesaro bio, Inc. James O. Armitage, M.D. Consultant: GlaxoSmith Kline Seattle Genetics Genetech Roche Spectrum Ziopharm Board of Director s for Tesaro bio, Inc.

3 What Most People Mean By Personalized Medicine Targeted therapy Molecular therapy Customized therapy Individualized therapy

4 Personalizing Management Based On The Characteristics Of The Disease

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7 A First Attempt at Applying Biology to Lymphoma Classification (Gall & Mallory) Lymphosarcoma Reticulum cell sarcoma Giant follicular lymphoma

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

9 Lymphoma Classification - A Moving Target Proposal New Observations Testing Acceptance and Application Refusal

10 There Are Three Things Certain in Life 1. You will die 2. You will pay taxes 3. The lymphoma classification will change 10

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

12 WHO Classification of Lymphoid Malignancies Cellular Origin of Disease Precursor Cell B-Cell T-Cell Lymphoblastic leukemia/lymphoma Hodgkin SLL/CLL Follicular B-Cell Mantle cell Marginal Zone Diffuse large B-cell Burkitt Peripheral Cell T-Cell Mycosis fungoides ATL Sezary Syndrome Angioimmunoblastic Peripheral (unspecified) Anaplastic Large cell

13 Where Was Mantle Cell Lymphoma In The Working Formulation? Type Percent Diffuse Small Cleaved 40% Follicular Small Cleaved 29% Small Lymphocytic 12% Diffuse Large Cell 10% Lymphoblastic 8%

14 We Still Don t Cure Enough Patients. How Can We Do Better?

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16 Dissecting a Cancer into Molecularly and Clinically Distinct Subgroups by Gene Expression Profiling Diffuse Large B Cell Lymphoma Genes Lymphoma Biopsies

17 Dissecting a Cancer into Molecularly and Clinically Distinct Subgroups by Gene Expression Profiling Diffuse Large B Cell Lymphoma 5-year Survival Probability PMBL 64% GCB 59% DLBCL Overall Survival (years) ABC 30% DLBCL

18 Subtypes of Diffuse Large B-Cell Lymphoma In The 2008 WHO Classification Morphological Centroblastic Immunoblastic Anaplastic Plasmablastic Immunological ALK positive CD5 positive Genetic GCB Non GCB (includes ABC) By Primary Site CNS Cutaneous leg type Mediastinal Intravascular Effusion Other EBV positive in elderly With chronic inflammation In lymphomatoid granulomatous In HHV-8 associated Castlemans 18

19 Other Variants Of Diffuse Large B-Cell Lymphoma Testicular Leukemic DLBCL Interface DBCL/Burkitt Interface mediastinal DLBCL/NSHD Genetic subtypes double hit, MYC+ 19

20 It Is Possible That Some Subtypes Might Benefit From Specific Treatments

21 CORAL Study BEAM ASCT R A N R-DHAP R-DHAP CR/PR D O Clinical M Evaluation PBPC Evaluation I Z R-ICE R-ICE PD/SD E R A N D O M I Z E Observation Rituximab 375 mg 2 /8 wks/12 mo J Clin Oncol 28:4184, 2010 OFF

22 CORAL Trial Results 3-yr Progression-Free Survival GCB Non-GCB p R-DHAP 52% 32%.01 R-ICE 31% 27%.81 J Clin Oncol 29:4079, 2011

23 Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL Cytogenetic Change, % GCB DLBCL ABC DLBCL PMBL C-rel amplification Bcl-2 translocation Gain of 3q Gain/amplification of 9p Constitutive NF-κB Activation No Yes Yes

24 Outcome of Relapsed Diffuse Large B- Cell Lymphoma Controls R-EPOCH + Bortezomib Blood 113:6069, 2009

25 High Grade B-cell Lymphomas 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, % 4, 5 7-8% 6, 7 High grade B-cell lymphoma with features intermediate between DLBCL and Burkitt lymphoma 29% 8 36% 8 N/A 61% 8 Burkitt Lymphoma <1% 1 ~100% 1 <20% 1 ~100% 1

26 MYC Positive DLBCL Found in <10% of patients High Ki-67 (often >90%) 5 year survival 32% with CHOP-R*, although not all reports agree *Leukemia 2008;22:2226

27 EPOCH-R In MYC Positive And MYC Negative DLBCL Characteristic MYC Θ MYC Θ Frequency 10% 90% High IPI 50% 36% EFS (4 yr) 83% 76% Lugano 2011, Abstract, Dunleavy

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

29 The New York Times SUNDAY, JULY 8, 2012 A New Approach on Leukemia In Gene Sequencing Treatment, Glimpses of the Future By GINA KOLATA GENETIC GAMBLE First of three articles

30 Personalizing Management Based On The Characteristics Of The Patient

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

32 Infiltrating Immune Cells Identified By Immunohistochemistry In Follicular Lymphoma Impact Prognosis Increased numbers of PD-1 positive lymphocytes improved prognosis (5-Yr OS 95% vs 50%) (Spain, UK) Increased numbers of CD68 positive macrophages worsened prognosis (median OS 100 vs 71 months) (UK)

33 Survival In Patients With Follicular NHL Is Predicted By Gene Expression Of Host Immune Cells (Dave, et al) Gene-Expression Signature Relative Risk Of Death Immune-Response ( ) 0.46) (T-cell genes) Immune-Response ( ) 29.90) (macrophage/dendritic cell genes)

34 High Numbers Of Macrophages Have An Adverse Prognostic Impact That Can Be Circumvented With Rituximab (GELA-GOELAMS) GOELAMS) 194 patients randomized to receive the CHVP-I regimen ± rituximab 10 macrophages/npf reduced EFS without rituximab (p=.012) but use of rituximab eliminated the adverse effect (p=.16)

35 An Antibody Blocking PD-1 Receptor in Relapsed Follicular Lymphoma Treatment Regimen Patients Rituximab Historical ~40% Response Rate Pidilizumab + Rituximab 29 66% (52% CR, 14% PR) ASH 2012 M.D. Anderson

36 Pharmacogenomics In Determining Response To Lymphoma Therapy

37 Influence of Methotrexate AUC on Primary CNS Lymphoma Outcomes AUC low AUC mid AUC high p Response rate 17% 28% 55% < yr EFS 21.1% 20.8% 32.1% yr OS 30.7% 30.5% 46% 0.06 Br J Cancer 102:673, 2010

38 Autologous Transplantation for Lymphoma with High-Dose Busulfan, Cyclophosphamide, and Etoposide Non-Relapse Mortality Oral Busulfan Targeted IV Busulfan 28% 3% year Survival 28% 58% 0.01 p Biol Blood Marrow Transplant 12:770, 2006

39 Interpatient PK Variability with Dosing Based on BSA Doxorubicin Busulfan Teniposide Carboplatin Ifosfamide Vincristine 5FU Trimetrexate Paclitaxil 3-6 x 4 x 3-6 x 2-3 x 10 x 11 x 5 x 5-11 x 5 x J Clin Oncol 14:2590, 1996

40 Rituximab Clearance In Elderly (i.e. >60 years) Patients (DSHNHL) Males had a significantly more rapid rituximab clearance (p=.003) Females had a superior 3-year PFS: 68% v 61% (p=.06) Males receiving rituximab over a longer period of time (8 months rather than 3 months) had a superior 3 year PFS (71% v 53%, p=.05) and OS (80% v 60%, p=.04) ASCO 2012, Abstracts 8024, 8025

41 NHL13 A multicenter, randomized phase III study of Rituximab as maintenance treatment versus observation alone in patients with aggressive B-cell lymphoma (DLBCL & FL G3B) ClinicalTrials.gov: NCT ulrich.jaeger@meduniwien.ac.at for the NHL13 Investigators

42 Cumulative relapse rate by treatment arm (ITT Population, all patients) 50% All patients A (treatment) N=338 B (observation) N=345 40% 30% Relapses 100 (14.7%) 36 (10.7%) 64 (18.7%) Histologic/Cytologic confirmation Observation 20% 10% Rituximab maintenance 0% Time [months] A: RITUXIMAB B: OBSERVATION

43 ASH 2013, Abstract 851

44 Personalized Management Based On Rapidity Of Response To Therapy Early reports suggested a better outcome in acute leukemia and aggressive lymphoma

45 Interim PET Scans for Aggressive NHL (Paris, n=90) IPI 1-2 IPI 3-5 Event-Free Survival P =.01 Pet (-) Pet (+) Event-Free Survival P =.004 Pet (-) Pet (+) Years Years Blood 106:1376, 2005

46 Response-Adapted Therapy Lymphoma Treatment Normal/Negative Early PET Scan Abnormal/Positive Stop therapy Abbreviate therapy Less aggressive therapy Additional therapy More aggressive therapy

47 It Is Likely That Tumor Biology, Patient Immune Response, Pharmacogenomics, And Tumor Response Rate Will All Help Guide Future Management Decisions

48 The Art of Medicine Old Fashioned Personalized Medicine Physicians helped patients before modern medicine A correct diagnosis and therapy are the minimum for good care The art of medicine separates really excellent physicians

49 Medicine Is An Art That Uses Science To Let Us Better Minister To Our Patients William Harvey Medicine Is A Calling Where Your Heart Will Be Exercised Equally With Your Head William Osler

50 Conclusion With increasingly personalized regimens, we re getting better at maximizing the chance patients will respond to therapy and and we will soon be even better We must not lose the concept of personalized caring for the patient sometimes it s the most important thing we do