National Lymphoma Translational Research

Program: From Genomics to Therapeutics

5th most common in Singaporean Males 6th most common in Singaporean Females

Increasing trend observed in Singapore

Gastric

Gastric

Lymphoma

Lymphoma

0

2

4

6

8

10

12

14

16

1973-1977 1983-1987 1993-1997 2003-2007

Males

Females

Age-standardizedrate(per100,000peryear)

A National Concerted Effort Needed: Rising Incidence of NHL

Singapore Cancer Registry 2008-2012

Singapore Cancer Registry 2003-2007

Peripheral T Cell and NK/T cell Lymphoma (PTCL & NKTL): Geographical Distribution

Frequencies of PTCL and NKTL in Asia and the Far West

0%

5%

10%

15%

20%

25%

30%

Vancouve

r

Omah

a,U

SA

Lyon,F

rance

London,U

K

India

Japan

Mala

ysia

China

Singa

pore

Hongkong

Korea

Frequency

Novelty of the proposal built around the endemic problem

of T cell lymphomas in Asia

% o

f P

TCL

& N

KTL

of

all N

HL

Non-Hodgkin’s Lymphoma

T cell B cell

PTCL

NKTL

WHO Classification of Mature T-cell and NK-Cell Neoplasms

LEUKEMIC or DISSEMINATED CUTANEOUS

T-cell prolymphocytic leukemia Subcutaneous panniculitis-like T-cell

lymphoma

T-cell granular lymphocytic leukemia Mucocutaneous {gamma}{delta}T-

ell lymphoma

Aggressive NK-cell leukemia Mycosis fungoides

Adult T-cell lymphoma/leukemia Sézary syndrome

Hepatosplenic T-cell lymphoma Primary cutaneous anaplastic large

cell lymphoma

EXTRANODAL MAINLY NODAL

Extranodal NK/T-cell lymphoma,

nasal type Peripheral T-cell lymphoma,nos

Enteropathy-type T-cell lymphoma Angioimmunoblastic T-cell

lymphoma

Anaplastic large cell lymphoma

NK/T Cell Lymphoma

Tse E , and Kwong Y Blood 2013;121:4997-5005

0

1

2

3

4

5 EBV PCR

Clinical Trial

Undetected Undetected

SMILE Regimen

PTCL and NKTL: An Unmet Need Globally and Asia in particular

Inferior survival of PTCL & NKTL compared to aggressive B cell NHL

Aggressive B cell lymphoma

PTCL & NKTL

Lack of therapeutic targets

P<0.0001 Lacks molecular prognostic classifiers

P = 0.55

Poor survival across major subtypes of PTCL and NKTL

Approach 1: Integrated genomic

profiling

Approach 3: Towards rational

targeted molecular therapy

Approach 2: Functional studies driven by genomic

discoveries

• Mutational landscape - JAK3 activating mutation (Cancer Discovery 2012)

• Genetic predisposition - BCL6-LPP germline driver in B-cell lymphoma (Nature Genetics 2013)

• Host-pathogens

• Inhibition of JAK/STAT pathway

• Inhibition of NFKB, EZH2 (AJP, 2012; Blood 2013)

• Inhibition of DNA methylation (manuscript in preparation)

• Inhibition of MATK (Leukemia 2012, 2013)

• Translate findings from research grade material to clinically implementable assays

• Molecular biological and prognostic subgroups (Blood, accepted )

Unraveling Mature T Cell Lymphoma: Three-prong approach

Approach 1: Integrated Genomic Profiling

Availability of Tissues: A Competitive advantage

Khor CC, GIS Teh BT, NCCS Steve Rozen, Duke-NUS

Wing-King Sung, NUS Ong Choon Kiat, NCCS

Stat

Stat

Nucleus

Cell

Prolifera

tion

Jak

1

Jak

3

P

P

P

P

P P

A572V

A573V

c

IL

2

A572 A573

Janus Kinase 3–Activating

Mutations Identified in Natural

Killer/T-cell Lymphoma

Cancer Discovery 2012

Tan SY, SGH

Further pinpointed culprit for high risk of

follicular lymphoma

- American Journal of Human Genetics

Adeline Seow

Angioimmunoblastic T Cell Lymphoma: mutation spectrum

AIT

L12

AIT

L2

TR

43

13

TR

43

23

22

9A

07

PB

00

09

33

14

43

KC

07

PB

22

99

9A

TR

42

50

07

PB

82

24

A

AIT

L11

AIT

L9

04

PB

25

03

1A

AIT

L1

07

PB

43

37

A

42

6A

08

PB

25

43

4A

19

4A

17

A

AIT

L10

AIT

L3

AIT

L7

09

PB

26

73

A

16

8A

21

1A

09

PB

28

51

2

14

82

TA

20

2A

TR

42

41

49

6A

TR

42

03

11

6A

TR

42

32

TR

42

45

TR

42

54

28

2A

TR

42

66

TR

43

12

AIT

L 5

z2

85

9

Mutation frequency

(N)

TET2 2 2 2 2 2 2 2 2 2 2 2 2 2 3 2 70% (28)

RHOA 37.5% (15)

DNMT3A 17.5% (7)

ASXL3 5% (2)

IDH2 5% (2)

KDM5B 5% (2)

TP53 5% (2)

CDKN2A 2.5% (1)

EP400 2.5% (1)

KSR2 2.5% (1)

ROR2 2.5% (1)

RAD23A 2.5% (1)

SOX9 2.5% (1)

USP1 2.5% (1)

TET2 RHOA DNMT3A IDH2

TET2 x 0.152 0.081 1

RHOA x 1 0.135

DNMT3A x 0.323

IDH2 x

Pathways involved

Gene symbol

Mutation Gene Description

N %

TET2 28 70 Involved in DNA demethylation

RHOA† 15 37.5 Small GTPase; regulates cell motility

DNMT3A 7 17.5 DNA methyltransferase

ASXL3 2 5 Polycomb group protein; putative histone methyltransferase

IDH2 2 5 Involved in Krebs cycle; role in DNA methylation

KDM5B 2 5 Histone demethylase

TP53 2 5 Tumor suppressor; induces growth arrest or apoptosis

CDKN2A 1 2.5 Tumor suppressor; stablises p53; cyclin-dependent kinase inhibitor

EP400 1 2.5 Component of histone acetyltransferase complex

KSR2 1 2.5 Kinase suppressor of RAS2; negative regulator of MAP signaling

ROR2 1 2.5 Receptor tyrosine kinase; involved in the early formation of chondrocytes

RAD23A 1 2.5 Involved in nucleotide excision repair

SOX9 1 2.5 Involved in skeletal development

USP1 1 2.5 Deubiquitinating enzyme

Manuscript in revision

Maarja-Liisa Nairismägi

Chng WJ, NUHS Ng SB, NUHS Tan SY, SGH

Joanne, NCCS Maarja-Liisa, NCCS Huang DC, NCCS TEH BT, NCCS

Functional Studies based on genomic discoveries

Tan Jing, NCCS

Cancer Discovery 2012

Oncogenic activation of JAK3 in NKTL

Leukemia 2013

Constitutive JAK3 activation in >70% NKTL

Functional Studies based on genomic discoveries

Results validated

JAK-Related Disorders and JAK Inhibitors.

O'Shea JJ et al. N Engl J Med 2013;368:161-170

Translational Relevance

Epitheliotropic Intestinal T Cell Lymphoma

28

Figure 3

Leukemia 2012

Approach 3: Biological rationale and perspectives that can be translated in clinical practice both diagnostically

and therapeutically

23/ 2/ 14 2:02 PMPaper: Bortezomib (BTZ) and Panobinostat (PAN) Combination Is Ef fec… and Maintenance Treatment May Be Essential for Sustained Response

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3669 Bortezomib (BTZ) and Panobinostat (PAN) Combination Is Effectivein Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma (PTCL)or NK/T-Cell Lymphoma (NKL) and Maintenance Treatment May BeEssential for Sustained Response

Program: Oral and Poster AbstractsSession: 623. Lymphoma - Chemotherapy, excluding Pre-Clinical Models: Poster III

Monday, December 10, 2012, 6:00 PM-8:00 PM

Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Daryl Tan, MD1,2, William YK Hwang, MBBS, FRCP, FAMS3,4, Colin Phipps Diong5*, Wee Lee Goh, BSC6*, Lionel K.Y See,

BSc3*, Yiong Huak Chan, PHD7*, Soon Thye Lim, MRCP MBBS8*, Soo Chin Ng, MBBS MRCP9*, S Fadilah, MBBS10*, Soo-

Yong Tan, MBBS, FRCPath, DPhil11*, Won Seog Kim, MD12* and Yeow Tee Goh, MD3*

1Department of Hematology, Singapore General Hospital, SG, Singapore2Raffles Cancer Center, Singapore, Singapore3Department of Hematology, Singapore General Hospital, Singapore, Singapore4Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School Singapore, Singapore, Singapore5Department of Hematology, Singapore General Hospital6Department of Hematology, Singapore General Hospital, Sinapore, Singapore7Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore8Medical Oncology, National Cancer Centre of Singapore, Singapore, Singapore9Sime Darby Medical Centre, Kuala Lumpur, Malaysia10Hospital Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia11Department of Pathology, Singapore General Hospital12Samsung Medical Center, Souel, South Korea

Background

Relapsed/refractory PTCL and NKL after conventional chemotherapy carry a poor prognosis and there is currently noproven salvage treatment available. Numerous preclinical studies have demonstrated synergistic interactions betweenproteasome and histone deacetylase (HDAC) inhibitors. Inhibition of HDAC6 by PAN abrogates BTZ-induced protectiveaggreosome formation and accentuates BTZ induced endoplasmic reticulum stress, leading to further apoptosis. Primaryend point of this ongoing phase II multi-center open-label clinical study (NCT00901147) is the objective response rate(ORR) according to the Revised Response Criteria (2007) among eligible patients (pts) treated with this novel combinationof BTZ and PAN. Secondary end points include the evaluation of the progression-free survival (PFS) and the assessment ofthe safety and tolerability of the combination.

Methods:

Pts with histologically confirmed PTCL or NKL who failed or were refractory to 1 prior systemic therapy, and had

measurable disease and ECOG performance status 0–2 were eligible. Pts were accrued according to a 2-stage Gehan

design. Pts receive thrice weekly oral PAN (20 mg) and twice weekly BTZ (IV 1.3 mg/m2), both for 2 of 3 weeks for up to8 cycles. Preliminary response data were available for all 11 pts recruited for stage 1 of the study. A response rate of>25% will allow the study to proceed to stage 2.

Results:

Among pts enrolled, histologies included: angioimmunoblastic T-cell lymphoma (AITL) n=4, PTCL (unspecified) n=4, ALK+Anaplastic large cell lymphoma n=1 and NKL, nasal type n=2. The median age was 52 (35-72) years, and 70% were male.The ORR was 54.5% with 18% attaining a complete response. Four pts (36%) had a partial response, and stable diseasewas noted in 2 (18%). Pts received a median of 2 prior therapies (range 1-3); 27% received an autogous stem celltransplantation (SCT). Common treatment-related grade 3/4 adverse events included thrombocytopenia (36%),neutropenia (27%), diarrhoea (18%) and fatigue (9%). Peripheral neuropathy of any grade was observed in 35%. Amongpts who responded or had stable disease, the median PFS was 6 months and disease progression occurred at a median of2.5 months after stopping trial drugs. Two deaths have occurred: 1 due to progressive disease and 1 associated with anunrelated cardiac event. 3 pts successfully underwent subsequent allogeneic SCT.

Conclusions

The study regimen shows activity across T/NK-cell lymphomas and ORR greatly exceeds the predefined threshold of 25%allowing, together with early tolerability data, continuation of study enrolment in stage 2. The early progression of thedisease after stopping trial drugs albeit the high initial ORR suggests that the novel combination provides a tonicsuppression of tumor proliferation and ongoing treatment will be beneficial for pts without option for subsequentalternative treatment like SCT. An extended phase of maintenance treatment will be incorporated into stage 2 of the studyto allow pts to optimally benefit from the combination. Our interim findings may have implications on the design of futurestudies seeking proteasome and HDAC inhibition in PTCL or NKL. Ongoing correlative studies are designed to determine ifthe study regimen is more active in diseases with up-regulation of NF-kappa B activity or transcription factors/ co-regulators known to be modified by acetylation.

Disclosures: Tan: Novartis: Research Funding; Janssen: Equity Ownership, Honoraria, Research Funding. Goh: Novartis:Honoraria, Research Funding; Jansen: Honoraria, Research Funding.

See more of: 623. Lymphoma - Chemotherapy, excluding Pre-Clinical Models: Poster IIISee more of: Oral and Poster Abstracts

<< Previous Abstract | Next Abstract >>

*signifies non-member of ASH

Singapore Lymphoma Study Group The Lymphoma Leukemia Molecular Profiling Project

Published in Blood

Approach 3: Clinical Applications

Substantial number of cases of PTCL-nos were re-classified into recognized PTCL subgroups

Robust molecular classifiers and oncogenic pathways that reflect the pathobiology of tumor cells and their microenvironment were identified for

major PTCL-entities

N = 372

Gene expression signatures delineate prognostic subgroups of PTCL

Clinical Applications

NEJM, under review

Translational Relevance

• Defined robust molecular diagnostic and prognostic signatures for the more common subtypes of PTCL and segregated them into meaningful biological and prognostic subtypes

• Identified enriched oncogenic pathways associated with the different PTCL entities and the biologic insight gained provides possible novel therapeutic targets for intervention

Next Aim:

To translate this to daily clinical application using

readily available Formalin Fixed Paraffin Embedded

Tissue (FFPE)

Potential Strategies for PTCL

• AITL :

– NF-κB pathway via bortezomib or carfilzomib

– specific inhibitors against IDH2 mutation that are being developed.

– Reverse the immunosuppressive microenvironment (e.g lenalidomide)

• ALK(-) ALCL:

– drugs that target mitotic cells ( e.g. aurora kinase inhibitors ) in combination with drugs that target PI3- Kinase/AKT pathway.

• GATA3 subgroup PTCL-NOS:

– drugs that target mTOR (e.g. rapamycin, temsirolimus)

23/ 2/ 14 3:55 PMManagement of B- cell non- Hodgkin lymphoma in Asia: resource- stratif ied guidelines : The Lancet Oncology

Page 1 of 2http:/ / www.thelancet.com/ journals/ lanonc/ art icle/ PIIS1470- 2045(13)70450- 9/ fulltex t#art icle_upsell

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doi:10.1016/S1470-2045(13)70450-9 Cite or Link Using DOI

Copyright © 2013 Elsevier Ltd All rights reserved.

Management of B-cell non-Hodgkin lymphoma in Asia: resource-

stratified guidelines

Dr Daryl Tan MD a b , Soo Yong Tan MD c d e, Soon Thye Lim MD d f, Seok Jin Kim MD g, Prof Won-Seog Kim MD g, Prof Ranjana

Advani MD h, Prof Yok-Lam Kwong MD i

Summary

Treatment of B-cell non-Hodgkin lymphomas has undergone substantial developments in the past 10 years. The introduction of

rituximab has greatly improved survival outcomes in patients. Clinical practice guidelines based on current evidence have been

developed to provide recommendations for standard treatment approaches. However, guidelines do not take into account

resource limitations in resource-poor countries. The huge disparities in economy, health-care infrastructure, and access to novel

drugs between Asian countries can hinder the delivery of optimum care to patients with lymphoma in Asia. We outline guidelines

appropriate to different levels of health-care resources and expertise, aiming to provide advice on diagnosis and treatment, unify

interpretation of results, and allow the design of future studies in Asia. In this resource-adapted consensus, we summarise

recommendations for diagnosis, staging, risk stratification, and treatment of common B-cell non-Hodgkin lymphomas in Asia.

To read this article in full you will need to login or make a payment

a Raffles Cancer Center, Raffles Hospital, Singapore, Singapore

b Department of Haematology, Singapore General Hospital, Singapore, Singapore

c Department of Pathology, Singapore General Hospital, Singapore, Singapore

d Duke-National University of Singapore, Graduate Medical School, Singapore, Singapore

e Institute of Molecular and Cell Biology, Singapore, Singapore

f Department of Medical Oncology, National Cancer Center, Singapore, Singapore

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Blood 2012

Lancet Oncology 2013

Lancet Oncology 2009

Asian Lymphoma Study

Group

Our competitive advantage: Significant Scientific

Recognition

A focus and niche

problem

Established track

records

Inter- disciplinary

research

Patient samples, cell

lines, xenografts

Pharmaceutical Interest,

clinical impact

Build on existing

structure

Multi Institutional

Team

Extensive collaborations

Singapore Lymphoma Study Group

Transitional Awards

Metagenomic and Methylation Profiling of Gastrointestinal Lymphomas

Dr Joanne Ngeow, NCCS

Delineating oncogenic pathways of Natural Killer / T-cell Lymphoma and identification of molecular subsets of

prognostic and clinical importance Dr. Ng Siok Bian, NUHS

PPG TCR Industry funding

2010 2012 2014 2016 2018 2020

Discovery Pre-trial

validation Clinical Trials

Implementation: Routine care

• Characterization

of mutational

landscape

• Highly recurrent

mutations

• Definition of

molecular

subtypes

• Molecular

epidemiology

• Validation of

mutational data &

outcomes

correlation

• Functional

studies

• Establish

clinically useful

platforms

• Commercial

collaborations

• Integration of

genomics data into

clinical trials

• Personalized

medicine initiatives

• Commercial

collaborations

• Routine diagnostic

tests

• Treatment

decisions

• Implementation of

novel agents

targeting molecular

subtypes

National Lymphoma Translational Research Road Map

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