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Harnessing Epigenetics in the Treatment of LymphomaJennifer Amengual, MD
Harnessing Epigenetics in the Treatment of Lymphoma
Jennifer Amengual, MDAssistant Professor of Medicine and
Experimental TherapeuticsColumbia University Medical Center
April 12, 2019
Disclosure Information
• I have the following relevant financial relationships to disclose:– Speaker: Epizyme
• I will discuss the following off label use and/or investigational use in my presentation:– Romidepsin + Lenalidomide– Romidepsin + Pralatrexate– Romidespin + Duvelisib– SAHA + Niacinamide– Romi + GDP– SAHA + CHOP– Azacitidine– Azacitidine + Romidepsin– Tazemetostat– DS-3201b
Outline
• Background on Epigenetics
• Learning Objectives
1. Epigenetic Therapies Approved for Lymphoma
2. Epigenetic Therapies in Development for T-cell Lymphoma
3. Epigenetic Therapies in Development for B-cell Lymphoma
• HDAC Inhibitors
• DNMT Inhibitors
• EZH2 Inhibitors
• Summary
• Future Directions
EpigeneticsA mechanism for regulating gene activity independent of DNA sequence
Dysfunction of Epigenetic Modifiers is Common in Lymphoma
Schmitz NEJM 2018
GC-DLCBL and FL
are enriched for BCL2 translocation,
EZH2 mutation, inactivation CREBBP, EP300,
ARID1A, BCL7A and KMT2D.
T-cell of Follicular T-Helper Origin
AITL is enriched for TET2, DNMT3a, and
IDH2 mutations
Lymphomas Derived from the Germinal Center
Palomero Nat Genet 2014Rodriguez-Cortes Curr Op Hem 2016
EZH2, KMT2D – Histone Methyltransferase
CREBBP, EP300 – Histone Acetyltransfersase
ARID1A, BCL7A – SWI/SNF
DNMT3A- DNA Methyltransferase
TET2 – Methylcytosine dioxygenase (DNA methylation)
IDH1/2 – Isocitrate Dehydrogenase (DNA methylation)
Epigenetic Drugs in Development
Sermer Nature Reviews 2019
Drug Class Approval Potential Applications
5-Azacitidine DNMT Inhibitor MDSCMMoL
GC-DLBCLAITL and TFH
Decitabine DNMT Inhibitor MDS GC-DLBCLAITL and TFH
Vorinostat HDAC Inhibitor CTCL
Romidepsin HDAC Inhibitor PTCL, CTCL GC-DLBCL
Belinostat HDAC Inhibitor PTCL GC-DLCBLSarcoma
Panobinostat HDAC Inhibitor Multiple Myeloma
GC-DLBCLAITL and TFH
Tazemetostat EZH2 Inhibitor FL, GC-DLBCLATLLSarcoma
Birabresib BET Inhibitor ALLDLBCL
GSK3326595 PRMT5 Inhibitor NHL
Enasidenib IDH2 Inhibitor AML GC-DLBCLAITL and TFH
Ivosidenib IDH1 Inhibitor AML GC-DLBCLAITL and TFH
Outline
• Background on Epigenetics
• Learning Objectives
1. Epigenetic Therapies Approved for Lymphoma
2. Epigenetic Therapies in Development for T-cell Lymphoma
3. Epigenetic Therapies in Development for B-cell Lymphoma
• HDAC Inhibitors
• DNMT Inhibitors
• EZH2 Inhibitors
• Summary
• Future Directions
Outline• Background on Epigenetics
• Learning Objectives
1. Epigenetic Therapies Approved for Lymphoma
2. Epigenetic Therapies in Development for T-cell Lymphoma
3. Epigenetic Therapies in Development for B-cell Lymphoma
• HDAC Inhibitors
– Vorinostat, Romidepsin, Belinostat Approved for Rel/Ref T-cell lymphoma
• DNMT Inhibitors
• EZH2 Inhibitors
• Summary
• Future Directions
Closed Chromatin
Transcriptional
Activation
HDACs
HDACIs
HATs
HDAC Inhibitors
Transcriptional
Repression
Open Chromatin
BCL6, p53, HSP90, NFkB, STAT3DNA Damage, Metabolomics
Common Side Effect Profile:Gastrointestinal disturbances, cytopenias
RomidepsinBelinostat
• Romidepsin• 14 mg/m2 i.v. infusion days 1, 6, 15/28 days
• NCI Phase 2 Study:
– ORR 38% (17 of 45 pts)
– 18% CR rate
– DOR = 8.9 m
• Pivotal Trial:
– ORR 25% (33 of 130 pts)
– 15% CR rate
– DOR 17 months, PFS 4 m
Piekarz Blood 2011, Coiffier JCO 2012
HDAC Inhibitors Approved for PTCL
• Belinostat• 1000 mg/m2 i.v. daily x 5 days/21
days
• BELIEF Study:
– ORR 26% (31/120 pts)
– 11% CR rate
– DOR = 13.6 m
– PFS 1.6 m
– OS 7.9 m
O’Connor JCO 2015
Can We Enhance HDAC Inhibitor Effects in PTCL?
CTCL (n=10)
PTCL (n=11)
Time (in weeks)
Pro
bab
ility
of
Surv
ival
Median EFS: 16 weeks
Mehta-Shah ICML 2015
EFS
• Romi+Lenalidomide• Lenalidomide- IMID
• PTCL ORR 60% (6/10 pts)
– All PRs
• CTCL 56% (5/9 pts)
• 18% CR rate
• DOR = 8.9 m
• Grade 3 Tox: • Neutropenia 48%, thrombocytopenia
38%, anemia 33%, electrolyte abn 43%
• Romi+Pralatrexate• Pralatrexate –anti-fol
• PTCL ORR 71% (10/14 pts)
• 29% CR rate
• PFS = 4.4 m
• Grade ≥ 3 Tox: • Febrile Neutropenia 14%,
thrombocytopenia 28%, anemia 29%, mucositis 14%
Amengual Blood 2018
• Romi+Duvelisib• Duvelisib – PI3K inh
• PTCL ORR 50% (8/16 pts)
• CR 19%
– CTCL 32% (6/19 pts)
• PFS = 8.3 m
• Grade 3 Tox: • Neutropenia 18%, AST/ALT increase
40%, Rash 17%, pneumonia 17%
Horowitz Blood 2018
HDAC Inhibitors Produce Limited Clinical Response in
B-cell Lymphoma
Drug Disease Patients (n) ORR n (%)
CR (disease)
DOR (months) Reference
Vorinostat, phase I
DLBCL, MCL, SLL, HD, other
35 5/35 (14%)
1(DLBCL) 2-12 O’Connor et al, JCO, 2006
Vorinostat,phase II
FL, MZL, MCL 37 10/35 (29%)
6 (NA) 18 Kirschbaum et al, ASH, 2008
Vorinostat,phase II
HD 25 1/25 (4%)
0 NA Kirschbaum et al, ASH, 2007
MGCD0103,phase II
HD 33 9/27 (33%)
2 (HD) NA Bociek et al, ASCO, 2008
MGCD0103,phase II
DLBCL, FL 50 4/17 (23%)
1 (DLBCL) 5.6-11.2 Crump et al, ASCO, 2008
Panobinostatphase I/II
HD, NHL, other 128 7/12 (58%) in HD
2 (AML) NA Ottmann et al, ASH, 2008
Belinostat, phase I
DLBCL, FL, CLL, other
16 0 (5 patients
with SD)
0 NA Gimsing et al, Eur J Haematol,
2008
Vorinostat, Phase II
DLBCL 18 1/18 (5%)(1 pt with
proloned SD)
1 >468 days Crump et al, Annal of Onc
2008
Can We Enhance HDAC Inhibitor Effects in DLCBL?
• SAHA-RCHOP• 72 patients Phase I/II
• Newly diagnosed ≥Stage II bulky
• ORR 81%, CR 52%
• GC-DLCBL 2 yr PFS 81% v 67%,
• GC-DLBCL OS 90 v 87%
• Unexpected and significant febrile neutropenia 38%, sepsis 19% →not recommended for broad use
Persky Am J Hematol 2018
• Romi-GDP Phase I• Relapsed/Refractory
• 10 pt with DLBCL, 10 w PTCL
• DLTs: thrombocytopenia, thromboembolic event, hypotension, AKI, anorexia
• ORR 40%, all PRs
• 1 yr OS 30%
• PFS lower than expected, toxicity greater than expected
Reiman Leuk & Lymph 2018Amengual Blood 2013
• SAHA-Niacinamide• Niacinamide is a Class III HDAC
inhibitor/Sirtuin Inhibitor
• 21 patients all subtypes
• Relapsed/Refractory
• ORR 25%
• 10% CR (DLCBL, HL)
• DLT: AST/ALT 12%, Infection 12%
• Well tolerated oral drugs
• Weak effect
AcetylationAbrogates
Bcl6
AcetylationActivates
p53
Outline
• Background on Epigenetics
• Learning Objectives
1. Epigenetic Therapies Approved for Lymphoma
2. Epigenetic Therapies in Development for T-cell Lymphoma
3. Epigenetic Therapies in Development for B-cell Lymphoma
• HDAC Inhibitors
• DNMT Inhibitors
• EZH2 Inhibitors
• Summary
• Future Directions
DNMT Inhibitors
Promoter Region Exon
Me Me Me
TFs
Inactive
3’5’
Promoter Region Exon 3’5’
Active
TFs
DNMTInhibitors
Side Effects:Cytopenias, Gastrointestinal Disturbances,
Asthenia and Fatigue
AzacitidineDecitabine
TET and IDH Mutations Lead to DNA Methylation
Sermer Nature Reviews 2019
5-Azacitidine is Effective in TCL
• 5-Azacytidine• 19 Relapsed/Refractory PTCL
• DLTs: thrombopenia, thromboembolic event, hypotension, AKI, anorexia
• ORR 53% (10/19)
• AITL 75% (9/12) vs PTCL 15% (1/7)
• AITL 42% CR (5/12)
• AITL responders, only 2 POD Day 86, 499
• TET2 mutated in 8/10 AITL, 1/4 PTCL
Delarue ASH 2016 Falchi ASH 2018
• Oral 5-Azacitidine + Romidepsin• Phase I/II Study Rel/Ref Lymphoma
• 36 pts enrolled, 16 with TCL
• Grade 3-4 Tox: neutropenia 39%, lymphopenia 39%, thrombocytopenia 28%
• ORR TCL 79% (11/14)
• CR TCL 43% (6/14)
• All 6 patients with AITL responded
5-Azacitidine Primes the Effects of Chemo in DLCBL
• 5-Azacytidine + SAHA• Phase Ib 18 pts w Rel/Ref DLCBL
• ORR 6.7% (1/15)
• Grade 3-4 Tox: theomboembolism (1), diarrhea (1), ALP increase (1), thrombocytopenia (8), anemia (3), neutropenia (2)
• Chemosensitization: 5/7 patients treated with chemotherapy following the study had responses and an OS of 79-825 Days
Pera Clinical Epigenetics 2016 Clozel Cancer Discovery 2013
• 5-Azacytidine + RCHOP• Phase I increased doses of AZA
• Prephase treatment with AZA x 5 days → RCHOP
• 12 pts w newly diagnosed DLCBL
• ORR 100% (12/12)
• CR 92% (11/12)
• Tox: Reactivation of HCV, prolonged neutropenia, 4 patients neutropenic fever
Outline
• Background on Epigenetics
• Learning Objectives
1. Epigenetic Therapies Approved for Lymphoma
2. Epigenetic Therapies in Development for T-cell Lymphoma
3. Epigenetic Therapies in Development for B-cell Lymphoma
• HDAC Inhibitors
• DNMT Inhibitors
• EZH2 Inhibitors
• Summary
• Future Directions
Role of EZH2 in the Germinal Center (GC) Reaction
1. Margueron Nature 2011, Molecular Cell 2008 3. Di Croce Nature structural & molecular biology 2013 4. Bodor
Blood 2013 5. Morin Nature Genetics 2010 6. Beguelin Cancer Cell 2013 7. Velichutina Blood 2010
• EZH2:
Histone Methyltransferase
– Activating Mutations
– 30% of GC-DLBCL
– 27% of FL
– Upregulated in ATLL
– Cancers harboring mutations in
the SWI/SNF Complex
demonstrate unchecked
activation of EZH2
H3K27me3
H2AK119ub
H3K4me3
Acetylation
xxHDAC
1/2 CBX
RING1B
PCGF 1
KDM2B
PRC1
BCORSUZ12
EEDEZH2
SET
RbAP46/48PCL
JARID2
PRC2
MLL Complex UTX
EP300
Condensed Chromatin
PRC= Polycomb Repressor Complex
EZH2 Inhibition is Effective in EZH2 Mutated FL and DLCBL
Morschhauser ICML 2017
• Tazemetostat Phase II• 218 patients enrolled
• Grade 3-4 Tox: thrombocytopenia 9%, anemia 8%, neutropenia 7%
Follicular Lymphoma
EZH1/2 Inhibition TCL
• DS-3201b EZH1/2 Dual Inhibitor
• 15 patients NHL first in man study
– FL 5, DLBCL 3, MZL 2, ATLL 2, AITL 2, PTCL NOS 1
• Toxicities: • thrombocytopenias 73%, anemia 47%, lymphopenia
40%, neutropnia 40%; dysgeusia 47%, diarrhea 27%
• ORR 53%
• CR 1/15
• PR 7/15
• TCL ORR 80%
• CR 1/5 (AITL)
• PR 3/5
Maruyama ASH 2017
• Adult T-cell Leukemia Lymphoma• Overall Survival = 24 wks after frontline therapy
• Acute subtype 69%, OS=19 weeks• Lymphomatous 20%, OS=37 weeks• Chronic 7%, OS=89 weeks• Smoldering 4%, OS not reached
• DS-3201 led to a 50% ORR in ATLL
Phillips Cancer 2010
EOB < 0
EOB 0-20
EOB ≥ 20
Dual Epigenetic Targeting with EZH2 and HDAC Inhibition
Lue, Amengual ASH 2016
Summary
• Lymphomas originating from the germinal center (FL, DLBCL, AITL) may be the most sensitive to epigenetic therapies
• HDAC inhibitors are approved for relapsed refractory PTCL/CTCL
– Vorinostat, Romidepsin, Belinostat
– HDAC inhibitors have been combined with chemo and other novel agents to improve response rates for PTCL and select subtypes of DLBCL
• DNMT inhibitors have strong efficacy in AITL and may sensitize lymphomas to chemotherapy
• EZH2 inhibitors have enhanced efficacy in EZH2 mutated lymphomas such as FL with plans for FDA filing in 2019
Future Directions
• Additional epigenetic targets have been identified.
– BET inhibitors
– IDH 1/2 inhibitors
– PRMT5 inhibitors
• Keep an eye out for Phase II studies designed to confirm or refute findings of Phase I
– PDX-Romi
– AZA-Romi
– Romi-Len
– Duvalisib-Romi
– DS-3201
• Epigenetic therapies are being tested for their ability to enhance Checkpoint Blockade
– Look for studies with epigenetic priming prior to PD-1 and PDL-1 inhibitors
Thank you
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