Update on T-cell Non-Hodgkin Lymphoma in

China

Huaqing Wang, M.D.

Cancer Hospital and Institute of

Tianjin Medical University

International Variationhttp://www-dep.iarc.fr/

MalesMales FemalesFemales

发病率 (Incidence)亚洲国家的发病率较西方国家高，在非霍奇金淋巴瘤中的比例

15-20%一项国际性回顾研究评估了北美、欧洲和亚洲 22个地区

1314 例 T 细胞淋巴瘤 *

* Arimitage.International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes. J Clin Onco2008; 26(25):4124-30

International PTCL StudyMajor NHL Types by Region

Percent NA EU Asia

PTCL, unspecified 33.7 22.1 22.1

Angioimmunoblastic 15.7 30.8 17.6

Anaplastic, ALK+ 16.0 9.1 3.6

Anaplastic, ALK- 7.7 11.6 2.5

NK/T-cell 5.0 5.4 22.1

ATLL 2.0 1.4 24.6

Trends in incidence of PTCL by subtype from 1992 to 2005, 13 SEER registries

PTCL incidence increased by 280%.

Abouyabis et al., Leuk & Lymphoma 2008;49:2099

T-cell Lymphoma Classification: WHO

Predominantly leukemic/disseminatedT-cell prolymphocytic leukemiaT-cell large granular lymphocyticNK/T-cell leukemia/lymphomaAdult T-cell leukemia/lymphoma

Predominantly nodalAngioimmunoblastic T-cell lymphomaAnaplastic large cell lymphomaPeripheral T-cell lymphoma(Unspecified)

Predominantly ExtranodalMycosis FungoidesSezary syndromePrimary cutaneous CD30+ disorders

Anaplastic large cell lymphoma

Lymphomatoid papulosisSubcutaneous panniculitis-like T-cellNK/T-cell lymphoma-nasalEnteropathy-type intestinal lymphomaHepatosplenic T-cell lymphoma

Precursor T/NK NeoplasmsPrecursor T lymphoblastic

leukemia/lymphomaBlastic NK lymphoma

Peripheral T/NK Neoplasms

天津地区 20 年恶性淋巴瘤的发病率

天津医科大学肿瘤医院回顾性了分析 1986~2005年天津地区 20年恶性淋巴瘤的发病情况：

外周 T 细胞占非霍奇金淋巴瘤的比例高达 34% ， 外周 T 细胞非特指型为 10.8% ， NK/T 细胞淋巴瘤为 14.9% ， 皮肤 T 细胞淋巴瘤为 2.0% ，

肠病型 T 细胞淋巴瘤为 0.5% 。

Known Risk Factors

• Immune modulation– Congenital immunodeficiencies– Immunosuppression– HIV– Autoimmune disorders

• Infectious organisms– Human T-cell lymphotrophic virus

• (HTLV-1) - ATLL

– Epstein-Barr virus (NK/T-cell, AITL?)– H Pylori

• Familial aggregation

…. the Remaining Cases of NHL

• Environmental factors (e.g., pesticides, solvents, PCBs)

• Lifestyle factors– Obesity– Diet– Alcohol– UV light

• Genetic factors

IILGOLGITILGISL/NHLCSGGIMURELLGR. TOSCANOGR. RO/BOHOSTIEO

Samsung Medical Center Seoul

Queen Mary Hospital

Programa Nacional de Cancer del Adulto Chile (PANDA)Santiago de Chile – Hospital del Salvador

(GATLA) Grupo Argentino de

Tratamiento de la Leucemia Aguda

Buenos Aires – FUNDALEULa Plata – Hospital San Martin

Nebraska UniversityCleveland Clinic

Memorial Sloan Kettering CC

Stanford UniversityNCI

MD AndersonYale-New Haven CC

Utah UniversityNashville-Vanderbilt UMC

CALGB Columbus-Ohio

St. Bartholomew’s Hospital, London

Guy's and St Thomas, LondonNewcastle University

Christie Hospital, ManchesterSouthampton University

Royal Wolverhampton Hospitals NHS Trust

SAKKCzech

Lymphoma Study Group

National Oncological

Institution (NOU)GELCAB

Tel Hashmer Sheba Medical CenterTel Aviv Sourasky Medical Center

Beilinson Medical CenterRambam Medical Center

Shaare Zedek Medical Center

Moscow-Cancer Research Center

of RAMN

Uruguayan Society of Hematology (SHU)

Montevideo-Hospital Maciel

GEMOH BrazilUniversity of CampinasSao Paulo-Santa Casa Medical School

International T-cell NHL Study: Sites (N = 1314)

• North America– Vancouver, Bethesda (NCI), Nebraska,

Massachusetts (MGH), California (USC), Arizona

• Europe– Barcelona, Norway, Wuerzburg, London, Lyon,

Leeds, Madrid, Bologna, Modena

• Asia– Bangkok, Hong Kong, Singapore, Tokyo, Nagoya,

Okayama, Fukuoka, Seoul

CENSOR FAIL TOTAL MEDIANFFS 72 261 333 0.91OAS 112 221 333 2.01

PTCL-NOS Cases

Pro

po

rtio

n

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Time

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Overall and Failure-free Survival

Pro

po

rtio

n

Time

IPI CENSOR FAIL TOTAL MEDIAN0/1 36 47 83 5.032 36 67 103 2.13 20 53 73 1.41

4/5 9 38 47 0.68

Test: p<0.001

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Overall Survival

PTCL-NOS Cases by IPI

Time

Pro

po

rtio

n

Anthracycline as part of initial tx CENSOR FAIL TOTAL MEDIANyes 98 173 271 2.1no 14 34 48 1.57

Test: p=0.14

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Overall Survival

PTCL-NOS Cases by Anthracycline Initial Tx

Time

Pro

po

rtio

n

Transplant reason CENSOR FAIL TOTAL MEDIANinital tx 8 15 23 1.46

0 24 24 0.71

Test: p<0.001

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11

subseq. to recur.

Failure-free Survival

PTCL-NOS Cases by Transplant Reason

CENSOR FAIL TOTAL MEDIAN 45 32 77 10.4 56 21 77 .

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

SurvivalFFSOAS

Time

Pro

po

rtio

nOverall and Failure-free Survival

Anaplastic large cell lymphoma, ALK+

Time

Pro

po

rtio

nOverall and Failure-free Survival

Anaplastic large cell lymphoma, ALK-

CENSOR FAIL TOTAL MEDIAN 30 39 69 1.33 36 33 69 4.49

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

SurvivalFFSOAS

Time

Pro

po

rtio

n

CENSOR FAIL TOTAL MEDIAN 4 30 34 0.29 5 29 34 0.36

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7

SurvivalFFSOAS

Overall and Failure-free Survival

NK/T-cell lymphoma, nasal type

Phase II study of Bevacizumab and CHOP (A-CHOP) for patients with PTCL or NK Cell Neoplasms

ECOG 2404

O.A. O’Connor, B. Pro, L. Pinter-Brown, L. Popplewell, N. Bartlett, A. Shustov, M.J. Lechowicz, K. Savage, B. Coiffier, E.

Jacobsen, P.L. Zinzani, A. Goy, J. Zain, S. Wilroy, M. Patterson, A. Boyd, M. Saunders, P. Cagnoni, S. Horwitz

PROPEL: A Multi-center Phase 2 Open-label Study of Pralatrexate with Vitamin B12 and Folic Acid

Supplementation in Patients with Relapsed or Refractory Peripheral T-cell Lymphoma (PTCL)

Blood 112: 261a, 2008

DesignPhase 2 single arm, open label, multi-center, non-randomized, international

Target Population Adult patients with relapsed or refractory PTCL

Number of Patients Minimum of 100 evaluable patients

TreatmentPralatrexate 30 mg/m2 IV x 6 weeks followed by 1 week rest (7 week cycle) in combination with vitamin supplementation

Primary Endpoint Response rate by IWC (CR + CRu + PR)

Secondary Endpoints

• Duration of response

• Progression-free survival

• Overall survival

PROPELStudy

IWC: International Workshop Criteria

Histopathology

Per Independent Central Review

(N=111) n Percent

Per Investigator

(N=111) n Percent

PTCL-unspecified 59 53% 51 46%

Anaplastic large cell lymphoma, primary systemic type 17 15% 17 15%

Angioimmunoblastic T-cell lymphoma 13 12% 18 16%

Transformed mycosis fungoides 12 11% 13 12%

Blastic NK lymphoma (with skin, lymph node, or visceral involvement)

4 4% 4 4%

T/NK-cell lymphoma-nasal 2 2% 1 <1%

Extranodal peripheral T/NK-cell lymphoma unspecified 1 <1% 2 2%

Adult T-cell leukemia/lymphoma (HTLV 1+) 1 <1% 2 2%

T/NK-cell leukemia/lymphoma 0 0% 1 <1%

Mycosis fungoides (not transformed)* 1 <1% 0 0%

Inconsistent with T-cell lymphoma* 1 <1% 0 0%

Aggressive T-cell lymphoma 0 0% 1 <1%

Aggressive large cell T-cell lymphoma 0 0% 1 <1%

*Two treated patients excluded from efficacy analysis

PROPELHistology

PROPELSummary of Response by Central Review: IWC

Pralatrexate(N=109)

n Percent 95% CI

Best Response

CR+CRu+PR 29 27% 19-36

CR 10 9%

CRu 1 <1%

PR 18 17%

SD 23 21%

PD 40 37%

UE 3 3%

ND: off-treatment in C1 14 13%

69% of responders did so after Cycle 1

C1: Cycle 1

Youn H. Kim, Sunil Reddy Stanford Cancer Center, Stanford, CASean Whittaker St. Thomas’ Hospital, London, UK

Mariefrance Demierre, Adam Lerner Boston Medical Center, Boston, MA

Ellen J. Kim, Alain H. Rook Hospital of the Univ. of Penn, Philadelphia, PA

Madeleine Duvic M D. Anderson Cancer Center, Houston, TX

Tadeusz Robak Medical University, Lódz, Poland

Jürgen C. Becker Univeritätsklinikum, Würzburg, Germany

Alexey Samtsov AKademika Lebedeva, Saint-Petersburg, Russia

William McCulloch Gloucester Pharmaceuticals, Cambridge, MA

Archibald G. Prentice Royal Free Hospital, London, UK

On Behalf of All Investigators

Clinically Significant Responses Achieved Clinically Significant Responses Achieved with Romidepsin in Treatment-Refractory with Romidepsin in Treatment-Refractory Cutaneous T-Cell Lymphoma: Final Results Cutaneous T-Cell Lymphoma: Final Results from a Phase 2B, International, Multicenter, from a Phase 2B, International, Multicenter, Registration StudyRegistration Study

ASH 12/2008, Abstract# 263

Romidepsin• Novel bicyclic peptide• Potent pan-histone

deacetylase (HDAC) inhibitor

Greatest activity against:

− Class I (HDACs 1, 2, 8)− Class II (HDACs 4, 5, 6)− Class IV (HDAC 11)

• In vitro efficacy− HUT-78 (TCL cell line)

IC50 = 1.4 x 10-

9M

Romidepsin

CHCH33 HNHN

HH

HH33CCHH

OO NHNHOO

SS HNHNSS

HNHN

OOCHCH33

OOHH

CHCH33

CHCH33OO

OO

HH

Molecular Weight 540.71

HDAC Inhibitors: Multifunctional Anticancer Agents

Acetylation of Histone and Non-Histone Proteins

Altered Gene ExpressionAnd Protein Function

Angiogenesis VEGF, VEGFR, MMPs, Activin A, Ang2, eNOS

Cellular TransformationC-myc, Ras, Raf, Bcl-6, p53

Cell Cycle Arrestp21, p27, Cyclin A & D

ApoptosisHsp90, Bcl-2, Bcl-XL, Bax,

Fas, Caspase-3 & 9

Cellular DifferentiationMDR-1, Na-I Symporter, CD25, CAR (Adenovirus Receptor),

RARα & β

Patient CharacteristicsAs-Treated Population (N=96)

Age (yrs), median (range) 57 (21 – 89)

Sex (n, %) Men 59 (61.5%)

Women 37 (38.5%)

Clinical Stage (n, %)

IB 15 (15.6%)

IIA 13 (13.5%)

IIB 21 (21.9%)

III 23 (24.0%)

IVA 24 (25.0%)

ECOG Status0 49 (51.0%)

1 47 (49.0%)

Prior Systemic CTCL Therapies, median (range)

3 (1-11)

Pruritus at Study Entry, n (%)

Moderate 23/52 (44.2%)Severe 29/52 (55.8%)

71% with advanced

stage (≥IIB)

Response by CTCL Clinical StageEvaluable Population (N=72)

Clinical Stage N=72 ORR CR/CCR PR

IB-IIA 24 7 (29%) 1 ( 4%) 6 (25%)

IIB 16 9 (56%) 2 (13%) 7 (44%)

III 18 8 (44%) 1 ( 6%) 7 (39%)

IVA 14 6 (43%) 2 (14%) 4 (29%)

Responses in advanced disease (stages IIB-IVA)• 48% ORR for ≥ IIB• 8 patients with Sézary syndrome, 4 (50%) had a PR

Conclusions

• Single agent romidepsin is active in CTCL with an overall response rate (ORR) of 42% in evaluable patients including 6 CRs

• In advanced stage disease (IIB-IVA) the ORR is 48%

– ORR in stage IIB 56%, SS 50%

• Pruritus relief in 63% of patients with mod-severe pruritus at baseline despite the exclusion of the use of steroids and antihistamines

• Most AEs associated with romidepsin were mild (grades 1-2) and manageable

• Romidepsin does not have a significant effect on the QT Interval

Agents In Development for T-Cell NHL

• HDAC inhibitors– Vorinostat– Romidepsin– LBH 589

• Folate antagonists– Pralatrexate

• Lenalidamide• Syk inhibitor – R788• Proteosome inhibitors

• Purine analogues• Gemcitabine• Platinum agents• Bevacizimab• Campath• Ontak• Endostar• Tranditional Chinese

herbs