· lymphomas derived from the germinal center palomero nat genet 2014 rodriguez-cortes curr op hem...

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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

[email protected]

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






• HDAC Inhibitors

• DNMT Inhibitors

• EZH2 Inhibitors

• Summary


Outline• Background on Epigenetics





• HDAC Inhibitors

– Vorinostat, Romidepsin, Belinostat Approved for Rel/Ref T-cell lymphoma

• DNMT Inhibitors

• EZH2 Inhibitors

• Summary


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






• HDAC Inhibitors

• DNMT Inhibitors

• EZH2 Inhibitors

• Summary


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






• HDAC Inhibitors

• DNMT Inhibitors

• EZH2 Inhibitors

• Summary


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

· lymphomas derived from the germinal center palomero nat genet 2014 rodriguez-cortes curr op hem...

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