Diffuse Large B-cell Lymphomas Targeting Molecular Pathways Wyndham - PowerPoint PPT Presentation

Diffuse Large B-cell Lymphomas Targeting Molecular Pathways Wyndham H. Wilson, M.D., Ph.D.

Evolution of DLBCL therapeutics. Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

DLBCL outcomes following R-CHOP by Cell of Origin Method Hans IHC Lymph2cx nanostring Frozen GEP Gold standard Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

Germinal Center B-cell DLBCL

Key Transcription Factors GCB DLBCL ABC DLBCL

Proto-Oncogene BCL-6 is a Transcriptional Repressor BCL-6 translocations associated with increased mRNA and protein levels Iqbal et al. Leukemia (2007) 21, 2332 – 2343

Proto-Oncogene BCL-6 is a Transcriptional Repressor Mutations MEF2B (transcriptional activator) Activates BCL-6 (11% DLBCL) Ying et al. Nature Immunology 14, 1084 – 1092 (2013)

Targeting BCL-6 Compound 79-6

BCL-6 Small Molecular Inhibitor (79-6) Cherietti et al Cancer Cell, Volume 17, Issue 4, 13 April 2010, Pages 315-316

Targeting mTOR and AKT Nelfinovir Everolimus

Everolimus in R/R Aggressive Lymphoma Witzig et al. Leukemia (2011) 25, 341 – 347

BCL-2 and MYC Translocations in GCB DLBCL 56% 22%

BCL-2 and MYC Amplifications Translocations 0% 4.9%

Concurrent Myc and Bcl-2 Protein Expression Adverse Training with R-CHOP treated DLBCL Validation Combined Johnson N A et al. JCO 2012;30:3452-3459

BCL-2-Rearrangement versus Expression

MYC-Rearrangement versus Expression

Targeting BCL-2 Venetoclax (ABT-199)

Targeting MYC

Activated B-cell ABC DLBCL Targeting B-cell Receptor Signaling

Constitutive Expression of NF-kB Target Genes Are Highly Expressed in NFKB in ABC DLBCL Activated B Cell-like Diffuse Large B Cell Lymphoma NF-kB target gene Lymphoma biopsy samples

Blockade of the NF-kB Pathway in ABC DLBCL by the Proteasome Inhibitor Bortezomib Activation of the NF-kB Signaling Pathway Bortezomib

Clinical Trial Paradigm B. Molecular Classification A. Clinical Treatment Paradigm GCB ABC Relapsed/Refractory Biopsy Gene Expression DLBCL Profiling (N= 49) If Clinically Indicated Proceed to Part B GCB DLBCL ABC DLBCL Part A (N = 10) (N = 5) Bortezomib ( N = 23) Immuno- Treat until disease progression or histochemistry maximum allowable cycles Mum-1 Bcl-6 CD10 ABC DLBCL GCB DLBCL (N = 12) (N = 12) Part B Bortezomib + DA-EPOCH Total GEP and/or IHC Included in (N = 44) Analysis of Clinical Outcome Treat until disease progression or maximum allowable cycles ABC DLBCL GCB DLBCL (N = 15) (N = 12)

ABC Outcome is Superior to GCB DLBCL Following Bortezomib and DA-EPOCH Median Survival 10.8 mos Median Survival 3.4 mos

BCR and MYD88 Signalling Pathways Ibrutinib Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

Response Rate in the Mutational Subsets ABC DLBCL NCI data 100 Percent Response (CR + PR) 80% 80 71% 60 40 34% 20 5/7 10/29 4/5 0/5 0/4 0/4 0 Mutant WT Mutant WT CD79B: Mutant MYD88: Mutant Mutant CARD11:

Targeting BCR and MYD88 Signaling in DLBCL Action of Lenalidomide Cancer Cell Volume 21, Issue 6 2012 723 - 737

R2CHOP in Untreated DLBCL compared to R-CHOP R-CHOP R2-CHOP R-CHOP R2-CHOP Grzegorz S. Nowakowski et al. JCO 2015;33:251-257

T Targeting Primary Mediastinal B-cell Lymphoma Nivolumab Pembrolizumab

Immunochemotherapy + X • Targeting GCB DLBCL • Lenalidomide (?) + R-CHOP • Everolimus + R-CHOP • Venetoclax + R-CHOP • Targeting ABC DLBCL • Bortezomib + R-CHOP • Ibrutinib + R-CHOP • Lenalidomide + R-CHOP • Ibrutinib + Lenalidomide + DA-EPOCH-R

Immunochemotherapy + X • Targeting PMBL/Mediastinal Gray Zone • Brentuximab vedotin + R-CHOP • Nivolumab + DA-EPOCH-R or R-CHOP