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

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

Dec 06, 2023 470 likes •973 views

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

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Diffuse Large B-cell Lymphomas Targeting Molecular Pathways

Wyndham H. Wilson, M.D., Ph.D.

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Evolution of DLBCL therapeutics.

Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

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DLBCL outcomes following R-CHOP by Cell of Origin

Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

Hans IHC

Method

Lymph2cx nanostring Frozen GEP Gold standard

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Germinal Center B-cell DLBCL

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Key Transcription Factors

GCB DLBCL ABC DLBCL

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BCL-6 translocations associated with increased mRNA and protein levels

Proto-Oncogene BCL-6 is a Transcriptional Repressor

Iqbal et al. Leukemia (2007) 21, 2332–2343

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Mutations MEF2B (transcriptional activator) Activates BCL-6 (11% DLBCL)

Proto-Oncogene BCL-6 is a Transcriptional Repressor

Ying et al. Nature Immunology 14, 1084–1092 (2013)

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Compound 79-6

Targeting BCL-6

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BCL-6 Small Molecular Inhibitor (79-6)

Cherietti et al Cancer Cell, Volume 17, Issue 4, 13 April 2010, Pages 315-316

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Everolimus Nelfinovir

Targeting mTOR and AKT

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Everolimus in R/R Aggressive Lymphoma

Witzig et al. Leukemia (2011) 25, 341–347

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BCL-2 and MYC Translocations in GCB DLBCL

56% 22%

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Translocations 4.9% Amplifications BCL-2 and MYC 0%

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Johnson N A et al. JCO 2012;30:3452-3459

Concurrent Myc and Bcl-2 Protein Expression Adverse with R-CHOP treated DLBCL

Training Validation Combined

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BCL-2-Rearrangement versus Expression

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MYC-Rearrangement versus Expression

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Venetoclax (ABT-199)

Targeting BCL-2

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Targeting MYC

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

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Lymphoma biopsy samples

NF-kB target gene

NF-kB Target Genes Are Highly Expressed in Activated B Cell-like Diffuse Large B Cell Lymphoma

Constitutive Expression of NFKB in ABC DLBCL

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Activation of the NF-kB Signaling Pathway

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

Bortezomib

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Part A Bortezomib ( N = 23) Part B Bortezomib + DA-EPOCH (N = 44)

Treat until disease progression or maximum allowable cycles

Relapsed/Refractory DLBCL (N= 49)

Proceed to Part B If Clinically Indicated Treat until disease progression or maximum allowable cycles Biopsy

GCB DLBCL (N = 12) ABC DLBCL (N = 12) GCB DLBCL (N = 15) ABC DLBCL (N = 12)

Total GEP and/or IHC Included in Analysis of Clinical Outcome

Gene Expression Profiling Immuno- histochemistry

  • A. Clinical Treatment Paradigm
  • B. Molecular Classification

GCB DLBCL (N = 10) ABC DLBCL (N = 5)

Mum-1 Bcl-6 CD10

GCB ABC

Clinical Trial Paradigm

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Median Survival 10.8 mos Median Survival 3.4 mos

ABC Outcome is Superior to GCB DLBCL Following Bortezomib and DA-EPOCH

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BCR and MYD88 Signalling Pathways

Kieron Dunleavy et al. Clin Cancer Res 2014;20:5182-5193

Ibrutinib

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Response Rate in the Mutational Subsets ABC DLBCL

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

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Cancer Cell Volume 21, Issue 6 2012 723 - 737

Action of Lenalidomide Targeting BCR and MYD88 Signaling in DLBCL

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R2CHOP in Untreated DLBCL compared to R-CHOP

Grzegorz S. Nowakowski et al. JCO 2015;33:251-257

R-CHOP R-CHOP R2-CHOP R2-CHOP

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T Targeting Primary Mediastinal B-cell Lymphoma

Nivolumab Pembrolizumab

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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
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Immunochemotherapy + X

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