Pivotal Genetic Pathways Influencing Treatment in Lymphoma. Philip J. Bierman, M.D. April 24, 2015
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1 Pivotal Genetic Pathways Influencing Treatment in Lymphoma Philip J. Bierman, M.D. April 24, 2015
2 Personalized Treatment in Lymphoma
3 What is Personalized Therapy? Customized therapy Individualized therapy Precision therapy Targeted therapy Genomic therapy
4 Possible Outcomes of Lymphoma Therapy J Clin Oncol 23:7342, 2005
5 Personalized Lymphoma Therapy is Not New Histology Stage Age Performance status Site(s) of disease Height and weight (BSA) Renal function Hepatic function
6 How we Currently Personalize Lymphoma Therapy Choice of chemotherapy regimen Number of chemotherapy cycles Dose of chemotherapy agents Use of surgery Use of radiation therapy Use of CNS prophylaxis Transplant in first remission Supportive care (growth factors, antibiotics, etc)
7 Other Potential Personalized Therapy Approaches Gene expression profile Other molecular and genetic abnormalities Single nucleotide polymorphisms Idiotype vaccines CAR T cell immunotherapy Pharmacokinetics Response adapted therapy
8 High Throughput Methods of Tumor Investigation Field Target Method Information Epigenetics Chromatin Genomics Transcriptomics Proteomics DNA RNA Proteins Methylation profiling Chromatin immunoprecipitation Automated sequencing SNP array with sequencing Array comparative genomic hybridization Gene expression profiling RNA sequencing sirna Mass spectroscopy Methylation patterns of nucleotides Transcription factor associations with DNA DNA sequences involved with histone methylation or acetylation DNA sequence Copy neutral loss of heterozygosity Association with risk or outcome of malignancy Gains or losses of DNA mrna levels Changes in RNA sequences Critical mrnas for cell functioning Quantity and quality of expressed proteins Cancer Genetics 206:257, 2013
9 Gene Expression Patterns of Diffuse Large B Cell Lymphoma Nature 403:503, 2000
10 Gene Expression Profile: Mediastinal Large B Cell Lymphoma vs. Diffuse Large B Cell Lymphoma Blood 102:3871, 2003
11 Characteristics of Mediastinal Large B Cell Lymphoma Patients Identified by Gene Expression Profile Younger than DLBCL patients Better 5 yr survival than DLBCL patients More likely to have lung, pleural, and pericardial involvement than DLBCL patients Gene expression profile characteristics of Hodgkin lymphoma cell lines multiple B cell signaling components cytokine pathway components, TNF family members, and extracellular matrix elements J Exp Med 198:851, 2003 Blood 102:3871, 2003
12 Oncogenic Pathways in Subtypes of Diffuse Large B cell Lymphoma N Engl J Med 362:1417, 2010
13 Overall Survival of Diffuse Large B cell Lymphoma According to Gene Expression Profile p = 0.01 Nature 403:503, 2000
14 Overall Survival of Diffuse Large B cell Lymphoma According to Gene Expression Profile P = P = 0.05 Nature 403:503, 2000
15 Hans Algorithm for Immunohistochemistry Classification of Diffuse Large B Cell Lymphoma CD10 GCB + + BCL-6 + MUM1 Non-GCB GCB Non-GCB Blood 103:275, 2004
16 Overall Survival of Diffuse Large B cell Lymphoma in the Rituximab Era p = 0.01 J Clin Oncol 26:4587, 2008
17 CORAL Study R A N D O M I Z E R-DHAP R-ICE Clinical Evaluation R-DHAP R-ICE PBPC BEAM ASCT CR/PR Evaluation PD/SD 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
18 CORAL Trial Results J Clin Oncol 28:4184, 2010
19 CORAL Trial Results R-DHAP R-ICE J Clin Oncol 29:4079, 2011
20 ABC Type of Diffuse Large B Cell Lymphoma Dependence on constitutive activation of the B cell receptor (BCR) and/or NF ĸB signaling pathways Frequent somatic mutation within CD79A/B, CARD11, MYD88 and TNFAIP3 pathways
21 BCR Signaling Pathway Cancer Genetics 206:257, 2013
22 Targeted Agents for Relapsed and Refractory Diffuse Large B cell Lymphoma Target Response Rate Fostamatinib SYK 22% Ibrutinib BTK 38% Idelalisib PI3k 0% Enzastaurin PkC 22% Temsirolimus mtor 28% Everolimus mtor 30% Lenalidomide 28%
23 Bortezomib Clin Exp Med 7:83, 2007
24 Effects of Bortezomib in Non Hodgkin Lymphoma The Oncologist 17:694, 2012
25 Outcome of Relapsed Diffuse Large B Cell Lymphoma Controls R-EPOCH + Bortezomib Blood 113:6069, 2009
26 Phase II Trial of R CHOP + Bortezomib for Diffuse Large B cell Lymphoma J Clin Oncol 29:690, 2011
27 REMoDL-B Trial (NCT ) Patients with DLBCL in need of full course R CHOP (stage II AX IV) Consent Biopsy sent to HMDS for molecular profiling R CHOP #1 Randomisation Stratified for molecular phenotype and IPI 5x R CHOP + bortezomib 1.6mg/m 2 days 1+8 sc 5x R CHOP Follow up
28 PYRAMID Trial (NCT ) Randomized phase II Non GCB diffuse large B cell lymphoma All stages R CHOP vs. Bortezomib + R CHOP
29 LYM2034 Trial (NCT ) Randomized phase II Non GCB diffuse large B cell lymphoma Stage II IV R CHOP vs. Bortezomib + R CHOP
30 Phase II Trial of Ibrutinib for Relapsed and Refractory Diffuse Large B Cell Lymphoma ABC Subtype GCB Subtype p Complete Response 8% 0% Partial Response 32% 5% Overall Response 40% 5%.0126 ASH 2013, abstract 686
31 Ibrutinib Response in ABC Genotype Response Rate CD79B Mutation 3/5 (60%) CT79B Wild type 7/19 (37%) CD79B + MYD88 Mutation 4/4 (100%) MYD88 Mutation only 0/4 (0%) ASH 2013, abstract 686
32 Phase Ib Trial of Ibrutinib + R CHOP for Non Hodgkin Lymphoma Recommended dose 560 mg/day ORR 100% for diffuse large B cell lymphoma Complete response rate: 71% for GCB type diffuse large B cell lymphoma Complete response rate: 100% for non GCB type diffuse large B cell lymphoma Lancet Oncol 15:1019, 2014
33 PHOENIX Phase III Trial (NCT )
34 Signaling Pathways in ABC DLBCL Cancer Cell 21:723, 2013
35 Phase II Trials of Lenalidomide for Relapsed and Refractory Diffuse Large B Cell Lymphoma Non GCB Subtype GCB Subtype Complete Response 29% 4% Partial Response 24% 4% Overall Response 53% 8% Median PFS 6.2 mo. 1.7 mo. Cancer 117:5058, 2011
36 Lenalidomide plus R CHOP in Elderly Patients with Diffuse Large B cell Lymphoma Lancet Oncol 15:730, 2014
37 Phase II Trial of Lenalidomide + R CHOP (R2 CHOP) for Diffuse Large B Cell Lymphoma J Clin Oncol 33:251, 2015
38 E1412 Trial (NCT ) DLBCL Stage II Bulky Stage III IV
39 Other Algorithms for Predicting Cell of Origin for Diffuse Large B Cell Lymphoma Choi MUM1, GCET1, CD10, BCL6, FoxP1 Muris BCL2, CD10, MUM1 Nyman MUM1, FoxP1 Natkunam LMO2 Tally CD10, GCET1, MUM1, FoxP1 J Clin Oncol 29:200, 2011
40 Cell of Origin: Concordance Between Immunohistochemistry and Gene Expression Profile Algorithm Concordance Choi 87% Choi modified 87% Hans 86% Hans modified 87% Muris 77% Nyman 81% Natkunam 74% Tally 93% J Clin Oncol 29:200, 2011
41 Poor Concordance of Immunohistochemistry Classifiers of Cell of Origin Clin Cancer Res 19:6686, 2013
42 Outcome of Diffuse Large B cell Lymphoma According to Immunohistochemistry Determination of Cell of Origin Algorithm CRRate 5 yr PFS Colomo GCB non GCB Hans GCB non GCB Muris GCB non GCB Choi GCB non GCB Tally GCB non GCB Blood 117:4836, % 78% 77% 76% 72% 78% 71% 78% 82% 71% 48% 55% 54% 52% 48% 56% 48% 52% 63% 54%
43 Determination of Diffuse Large B cell Lymphoma Cell of Origin Using Formalin Fixed Paraffin Embedded Tissue Blood 123:1214, 2014
44 Potential Biomarkers for DLBCL Therapy Gene Mutation Function Agent CREBBP/EP300 Histone acetyltransferase HDAC inhibitors EZH2 H3K27 methyltransferase EZH2 inhibitors CXCR4 Chemokine receptor CXCR4 inhibitors or antibodies CD79A/CD79B BCR component BTK,SYK,PKC inhibitors CARD11 Couples BCR to NF κb MALT1 inhibitors MYD88 Couples TLRs to NF κb IRAK1/4 inhibitors Nat Rev Clin Oncol 11:585, 2014
45 Distribution of 1314 Peripheral T Cell Lymphomas by Consensus Diagnosis J Clin Oncol 26:4124, 2008
46 Gene Expression Profiling of PTCL Blood 123:2915, 2014
47 Reclassification of PTCL NOS Cases Molecular Classification AITL 14% ALK ALCL 11% ATLL 3% γδ PTCL 9% Blood 123:2915, 2014
48 Representative Genes in Major PTCL Groups Blood 123:2915, 2014
49 Mutations in Molecularly-Defined Peripheral T-cell Lymphomas Blood 123:2915, 2014 Chao et.al ( under review)
50 IDH Mutations in T cell Lymphomas IDH1R132 IDH2R172 IDH2R140 PTCL NOS 0/43 0/43 0/43 ALCL 0/50 0/50 0/50 EATL 0/8 0/8 0/8 CTCL 0/17 0/17 0/17 HSTCL 0/10 0/10 0/10 NK/TCL 0/10 0/10 0/10 AITL 0/79 15/79 1/79 Blood 119:1901, 2012
51 Function of IDH Mutations Functions of IDH Mutations Neurosurg Focus 37:E13,
52 Cancers with IDH Mutations Gliomas AML, MDS, myeloproliferative neoplasms Colon cancer Prostate cancer Chondrosarcoma Cholangiosarcoma Thyroid carcinoma Angioimmunoblastic T cell lymphoma
53 Ongoing Clinical Trials AG 221 AML IDH 2 mutant hematologic malignancies glioma, AITL, cholangiocarcinoma, chondrosarcoma other solid tumors AG 120 AML, MDS glioma, cholangiosarcoma, chondrosarcoma other solid tumors
54 BRAF Exon 15 Mutation Analysis in Peripheral B cell Neoplasms Cases Mutated % Mutated Hairy cell leukemia Splenic marginal zone lymphoma Splenic lymphoma/leukemia, U Chronic lymphocytic leukemia Follicular lymphoma Diffuse large B cell lymphoma Mantle cell lymphoma Burkitt Lymphoma N Engl J Med 364:2305, 2011
55 Vemurafenib for Hairy Cell Leukemia (ASH 2014) Abstract Patients Complete Response Overall Response % 100% % 96% % 91%
56 Integrative Analysis of Hodgkin Lymphoma and Primary Mediastinal Large B cell Lymphoma Blood 116:3268, 2010
57 Potential Targets of 9p24.1 Amplification Blood 116:3268, 2010
58 The PD 1 Pathway in Classical Hodgkin Lymphoma Reed Sternberg cells are surrounded by ineffective immune cells PD 1 inhibits T cells in classical Hodgkin lymphoma PD 1 ligand is present on the surface of Reed Sternberg cells in >85% of classical Hodgkin lymphoma cases
59 Immunoblogists.wordpress Checkpoint Inhibitor PD 1
60 PD 1 Blockade with Nivolumab in Relapsed and Refractory Hodgkin Lymphoma N Engl J Med 372:311, 2015
61 PD 1 Blockade for Lymphoid Malignancies (ASH 2014) Abstract Agent Disease Complete Response Overall Response 290 Pembrolizumab Hodgkin Lymphoma 21% 66% 289 Nivolumab Hodgkin Lymphoma 17% 87% 291 Nivolumab B Cell Lymphoma 6% 26%
62 Stromal Gene Signatures in Diffuse Large B cell Lymphoma N Engl J Med 359:2313, 2008
63 Diffuse Large B Cell Lymphoma Gene Expression Profile Stromal 1 signature Extracellular matrix deposition Monocyte infiltration Good prognosis Stromal 2 signature Tumor blood vessel density/angiogenesis Genes highly expressed in endothelial cells Poor prognosis N Engl J Med 359:2313, 2008
64 How Single Nucleotide Polymorphisms Influence Cancer Susceptibility Chemotherapy metabolism or toxicity Response to treatment
65 Rituximab: Antibody Dependent Cellular Cytotoxicity Clinical Lymphoma 2:145, 2001
66 Fc RIIIA Polymorphism Associations Rituximab response in follicular lymphoma Progression free survival after R CHOP in follicular lymphoma Rituximab response in Waldenstrom s macroglobulinemia Survival following R CHOP for diffuse large B cell lymphoma Rituximab induced neutropenia after autologous transplantation for lymphoma
67 Influence of Polymorphisms in Cancer Therapy Drug Genotype Effect Tamoxifen CYP2D6*4 toxicity Response 6 MP TPMT*2 TPMT*3A TMPT*3C toxicity Irinotecan UGT1A1*28 toxicity CA Cancer J Clin 59:42-55, 2009 Nat Clin Pract Oncol 6:153-62, 2009
68 Analysis of SNPs in Diffuse Large B Cell Lymphoma Patients Treated with R CHOP SNP Function Outcome NCF4 rs AG/GG ABCG2 rs AC/AA GSTA1 rs TT NAD(P)H oxidase subunit ATP binding cassette transporter Glutathione S transferase isoform hematologic toxicity infection toxicity cardiac toxicity infec on toxicity infec on toxicity Leukemia 23:1118, 2009
69 Analysis of SNPs in Diffuse Large B Cell Lymphoma Patients Treated with R CHOP SNP Function Outcome GSTA1 rs CT/TT CYBA rs4673 TT ABCC2 rs AT/AA Detoxification of alkylating agents Encodes NAD(P)H oxidase subunit Encodes multi drug resistance protein EFS EFS EFS Leukemia 23:1118, 2009
70 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
71 Sources of Interpatient Variability in Drug Response Age Lifestyle Environment Gender Compliance Drug drug interactions Renal function Liver function Comorbidity Somatic genetic variability Host/germline genetic variability Oncologist 16:811, 2011
72 Influence of Methotrexate AUC in the IELSG20 Trial for Primary CNS Lymphoma 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
73 Summary Personalized therapy for lymphoma is not new Lymphomas exhibit a variety of genomic alterations that account to some degree for variations in treatment results We are beginning to use the results of these alterations to customize therapy for patients with an increased (or decreased) likelihood of responding to a particular regimen Techniques for identifying these alterations need to be standardized and more readily available Good patient care requires use of these approaches but still requires knowledge of lymphoma idiosyncrasies We cannot ignore the influence of host related genetic alterations and clinical prognostic factors Results from ongoing trials are awaited
74 JAMA 307:2497, 2012
75 The Doctor" by Luke Fildes 1891
76
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