update on t-cell non-hodgkin lymphoma in china huaqing wang, m.d. cancer hospital and institute of...
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Update on T-cell Non-Hodgkin Lymphoma in
China
Huaqing Wang, M.D.
Cancer Hospital and Institute of
Tianjin Medical University
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International Variationhttp://www-dep.iarc.fr/
MalesMales FemalesFemales
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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
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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
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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
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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
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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% 。
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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
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…. the Remaining Cases of NHL
• Environmental factors (e.g., pesticides, solvents, PCBs)
• Lifestyle factors– Obesity– Diet– Alcohol– UV light
• Genetic factors
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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
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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
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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
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0.3
0.4
0.5
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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
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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
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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
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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
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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
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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
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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
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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+
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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
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0.5
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0.9
1.0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
SurvivalFFSOAS
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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
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0.5
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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
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Phase II study of Bevacizumab and CHOP (A-CHOP) for patients with PTCL or NK Cell Neoplasms
ECOG 2404
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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