Peripheral TPeripheral T--cell lymphomascell lymphomas

Alma MaterAlma MaterStudiorumStudiorum

1088 1088 d.Cd.C..

EpidemiologyEpidemiology

PTCL endemic areasPTCL endemic areas

HTLV1HTLV1--related ATLLrelated ATLLEBVEBV--related NK/T cell lymphoma, nasal typerelated NK/T cell lymphoma, nasal typeEATCL (HLA EATCL (HLA haplotypeshaplotypes favouring favouring gliadingliadin allergy & GSE)allergy & GSE)

DerivationDerivation

Innate ImmuneInnate ImmuneSystemSystem

DerivationDerivation

Adaptive Immune SystemAdaptive Immune System

Cytological featuresCytological features

Lack of immunophenotypic markers of clonality, Lack of immunophenotypic markers of clonality, although the presence of although the presence of an an aberrantaberrant immunoimmuno--phenotypephenotype assists in the diagnosis.assists in the diagnosis.

12 TMAs from 193 PCTLs12 TMAs from 193 PCTLs

ββF1F1

CD4CD4 CD8CD8

CD4CD4 CD8CD8

CD4+/CD8+CD4+/CD8+CD4CD4--/CD8/CD8--CD4+/CD8CD4+/CD8--CD4CD4--/CD8+/CD8+

0%0%

25%25%

50%50%

75%75%

100%100%

PTCL NOSPTCL NOS

38%38%

8%8%

47%47%

7%7%

CD4 and CD8 expressionCD4 and CD8 expression

In vivo administration of antiIn vivo administration of anti--CD4 antibodies!CD4 antibodies!

Haematologica 2007; 92: 581Haematologica 2007; 92: 581--2.2.

GEP= gene expression analysisGEP= gene expression analysisIHC= immunohistochemistryIHC= immunohistochemistry

GCGCMZMZ

AACC

DD

PTCL PTCL –– CD52 negativeCD52 negative

PTCL PTCL –– CD52 positiveCD52 positive

0%0%10%10%20%20%30%30%40%40%50%50%60%60%70%70%80%80%90%90%

100%100%

GEPGEP IHCIHC

NegativeNegativePositivePositive

Potential therapeutic implicationsPotential therapeutic implications

•• Alemtuzumab has no efficacy in a Alemtuzumab has no efficacy in a proportion of PTCL patients.proportion of PTCL patients.

•• Alemtuzumab can cause severe Alemtuzumab can cause severe immune suppression.immune suppression.

•• Should CD52 antigen availability be Should CD52 antigen availability be assessed before therapy start?assessed before therapy start?

CD3CD3 CD79CD79 CD30CD30

BlakolmerBlakolmer K et al. Immunoreactivity of BK et al. Immunoreactivity of B--cell markers (CD79a, L26) in rare cases of extranodal cytotoxic cell markers (CD79a, L26) in rare cases of extranodal cytotoxic peripheral Tperipheral T-- (NK/T(NK/T--) cell lymphomas. Mod Pathol 2000; 13:766) cell lymphomas. Mod Pathol 2000; 13:766--72.72.Went P et al. Marker expression in PTCL: a proposed clinicoWent P et al. Marker expression in PTCL: a proposed clinico--pathologic score. JCO 2006; 24:2472pathologic score. JCO 2006; 24:2472--9.9.

CoCo--expression of Bexpression of B--cell markerscell markers

TCR gamma: monoclonal patternsTCR gamma: monoclonal patterns

Molecular genetic studiesMolecular genetic studies (PCR studies for rearrangement of the T(PCR studies for rearrangement of the T--cell cell receptor genes) are often required in order to evaluate the clonreceptor genes) are often required in order to evaluate the clonality ality

of Tof T--cell proliferations. cell proliferations.

M8 3 2 M8 3 2 γγ++ γγ++ HH22O M8 4 O M8 4

138:31138:31--43, 2007.43, 2007.

ALKALK--cc

Specific genetic abnormalitiesSpecific genetic abnormalities have not been identified have not been identified for most Tfor most T--cell and NKcell and NK--cell neoplasms.cell neoplasms.The few exceptions are The few exceptions are t(2;5) and variantst(2;5) and variants in ALKin ALK++

ALCL and ALCL and iso7qiso7q in HSTCL.in HSTCL.

Leukemia (2006) 20, 313–318Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-

cell lymphomaB Streubel, U Vinatzer, M Willheim, M Raderer and A Chott

Novel C

GH

Novel C

GH

observ

ations

observ

ations

PTCLs and gene expression profilingPTCLs and gene expression profilingTracey L et al. Blood 2003 (CTCL)Tracey L et al. Blood 2003 (CTCL)

MartinezMartinez--Delgado B et al. Clin Cancer Res 2004 (NOS); Delgado B et al. Clin Cancer Res 2004 (NOS);

MartinezMartinez--Delgado B et al. Leukemia 2005 (NOS); Delgado B et al. Leukemia 2005 (NOS);

Piccaluga PP et al. The Lancet Oncology 2005 (NOS);Piccaluga PP et al. The Lancet Oncology 2005 (NOS);

BallesterBallester B et al. Oncogene 2006 (NOS, AITL, ALCL); B et al. Oncogene 2006 (NOS, AITL, ALCL);

De Laval L et al. Blood 2007 (AITL); De Laval L et al. Blood 2007 (AITL);

Piccaluga PP et al. JCI 2007 (NOS); Piccaluga PP et al. JCI 2007 (NOS);

Piccaluga PP et al. Haematologica 2007 (NOS);Piccaluga PP et al. Haematologica 2007 (NOS);

Piccaluga PP et al. Cancer Res 2007 (AITL);Piccaluga PP et al. Cancer Res 2007 (AITL);

LamantLamant L et al. Blood 2007 (ALCL);L et al. Blood 2007 (ALCL);

CuadrosCuadros M et al. JCO 2007 (NOS);M et al. JCO 2007 (NOS);

Miyazaki K et al. Blood 2008 (Miyazaki K et al. Blood 2008 (γδγδTCLTCL););

PisePise--MasisonMasison CA et al. Blood 2009 (ATLL);CA et al. Blood 2009 (ATLL);

GazzolaGazzola A et al. Haematologica 2009 (NOS);A et al. Haematologica 2009 (NOS);

Hartmann S et al. Br J Hartmann S et al. Br J HaematolHaematol 2009 (NOS);2009 (NOS);

HumagHumag Y et al. Blood 2009 (Extranodal NK/T lymphoma, nasal type);Y et al. Blood 2009 (Extranodal NK/T lymphoma, nasal type);

IqbalIqbal J et al. Blood 2009 (AITL and NOS);J et al. Blood 2009 (AITL and NOS);

PivaPiva R et al. JCO 2010 (ALCL, AITL, NOS).R et al. JCO 2010 (ALCL, AITL, NOS).

PTCL: overall survivalPTCL: overall survival

0

20

40

60

80

100

120

0 8 16 24 32 40 48 56 64 72

Control Dauno 5mM Imatinib 1 mM

TimeTime

Prop

ortio

nPr

opor

tion

PIT valuePIT value00

CENSORCENSOR FAILFAIL TOTALTOTAL MEDIANMEDIAN3131 3131 6262 5.115.11

11 4141 8080 121121 2.112.1122 2626 6666 9292 1.461.46

3/43/4 88 3535 4343 0.70.7

Test: p<0.001Test: p<0.001

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818

Overall SurvivalOverall Survival

PTCLPTCL--NOS Cases by PIT (N= 304)NOS Cases by PIT (N= 304)

Proliferation and prognosis in Proliferation and prognosis in PTCL/NOSPTCL/NOS

0

.2

.4

.6

.8

1

Cum

. Sur

viva

l

0 20 40 60 80 100 120 140 160 180Time

p<0.0001

Score 1

Score 2

Score 3

0

.2

.4

.6

.8

1

Cum

. Sur

viva

l

0 20 40 60 80 100 120 140 160 180Time

p<0.0001

Score 1

Score 2

Score 3

ClinicoClinico--pathological score: pathological score: Age, PS, LDH, KiAge, PS, LDH, Ki--67 67

Univariate, p=0.027; Multivariate, p=0.6Univariate, p=0.027; Multivariate, p=0.6

Went et al, JCO, 2006Went et al, JCO, 2006CuadrosCuadros, JCO, 2007, JCO, 2007

VariableVariable IPIIPI PITPIT IPTCLPIPTCLP mPITmPIT

PTCL subsetPTCL subset AllAll PTCLPTCL--UU PTCLPTCL--UU PTCLPTCL--UU

Age > 60 Age > 60 XX XX XX XX

ECOG ECOG ≥≥ 11 XX XX XX XX

LDH (LDH (abnabn. values). values) XX XX XX

Stage IIIStage III--IVIV XX

ENS > 2ENS > 2 XX

BM+BM+ XX

PltsPlts < 150K< 150K XX

KIKI--67 67 ≥≥ 80%80% XX

Prognostic models in peripheral TPrognostic models in peripheral T--cell lymphomacell lymphoma

Modified from: Gutierrez-Garcia: Ann. Oncol: epub July 14, 2010

Angioimmunoblastic T cell lymphomaAngioimmunoblastic T cell lymphoma

Elderly patients (median age >60 y)Elderly patients (median age >60 y)

Clinical featuresClinical features

•• Generalized lymphadenopathyGeneralized lymphadenopathy•• HepatosplenomegalyHepatosplenomegaly•• Skin rashSkin rash•• BM commonly involvedBM commonly involved•• Usually advanced clinical stageUsually advanced clinical stage•• Systemic symptomsSystemic symptoms•• Polyclonal hypergammaglobulinemiaPolyclonal hypergammaglobulinemia•• Clinical course aggressiveClinical course aggressive•• Median survival: < 3 yrsMedian survival: < 3 yrs

Low cellular densityLow cellular density

DiagnosisDiagnosis CENSORCENSOR FAILFAIL TOTALTOTAL MEDIANMEDIAN

Angioimmunoblastic TAngioimmunoblastic T--cell lymphomacell lymphoma 8787 154154 241241 2.262.26

Peripheral TPeripheral T--cell lymphomacell lymphoma--NOSNOS 112112 218218 330330 2.012.01

Test: p=0.89Test: p=0.89

Overall SurvivalOverall SurvivalPeripheral TPeripheral T--cell Lymphomacell Lymphoma--NOS, andNOS, and

Disease subDisease sub--group: Angioimmunoblastic Tgroup: Angioimmunoblastic T--cell lymphoma cell lymphoma

Prop

orti

onPr

opor

tion

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

TimeTime

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919

International Peripheral TInternational Peripheral T--cellcellLymphoma ProjectLymphoma Project

Prominent, branching high endothelial venulesProminent, branching high endothelial venules

ClearClear cellscells

CD21CD21

Follicular dendritic cell hyperplasiaFollicular dendritic cell hyperplasia

CD3CD3 CD20CD20

EBEREBERCD4CD4 CD8CD8

Blood 2007; 109:4952-63.

Cancer Res 2007; 67:10703-10.

TTHFHFAITLAITL

BclBcl--66CD10CD10PDPD--11ICOSICOSSAPSAPCXCL13CXCL13CCR5CCR5

CXCL13CXCL13

FollicularFollicular TT--cellscells

EarlyEarly AITLAITLAdvancedAdvanced AITLAITL

ClassicClassic AITLAITL

PDPD--1 monoclonal antibody1 monoclonal antibody

Br J Br J HaematolHaematol 2008; 143: 1392008; 143: 139--141.141.

The inducible T-cell co-stimulator (ICOS) molecule is expressed on subsets of T-cells and is a new marker of lymphomas of T follicular helper cell

derivation

T. Marafioti, J.C. Paterson, E. Ballabio, A. Chott, Y. Natkunam, M. Rodriguez-Justo, A. Plonquet, S.M. Rodriguez-Pinilla, W. Klapper, M.-L. Hansmann, S.A. Pileri, P.G. Isaacson, H.

Stein, M.A. Piris, D.Y. Mason, and P. Gaulard. Haematologica, 95:432Haematologica, 95:432--9,9, 2010.2010.

2007 Nov 15;67(22):10703-10.

VEGFVEGF

AADsAADs

VEGF & VEGFR2/KDRVEGF & VEGFR2/KDR

45 cases tested by IHC45 cases tested by IHC

Rationale for the usage Rationale for the usage of thalidomide and of thalidomide and

bevacizumabbevacizumab

VEGFVEGF

KDRKDR

GottardiGottardi M et al. Complete remission induced by thalidomide in a case ofM et al. Complete remission induced by thalidomide in a case ofangioimmunoblastic Tangioimmunoblastic T--cell lymphoma refractory to autologous stem cell cell lymphoma refractory to autologous stem cell transplantation. transplantation. LeukLeuk Lymphoma 2008; 49:1836Lymphoma 2008; 49:1836--8.8.

AguiarAguiar BujandaBujanda D. Complete response of relapsed angioimmunoblastic TD. Complete response of relapsed angioimmunoblastic T--cell cell lymphoma following therapy with lymphoma following therapy with bevacizumabbevacizumab. Ann . Ann OncolOncol 2008; 19:3962008; 19:396--7. 7.

RamasamyRamasamy K et al. Successful treatment of refractory TK et al. Successful treatment of refractory T--cell lymphoma with cell lymphoma with thalidomide and thalidomide and dexamethasonedexamethasone. Haematologica 2006; 91(8 Suppl):ECR44.. Haematologica 2006; 91(8 Suppl):ECR44.

DoganDogan A et al. Pathology and clinical features of angioimmunoblastic A et al. Pathology and clinical features of angioimmunoblastic TT--cell cell lymphoma after successful treatment with thalidomide. Leukemia 2lymphoma after successful treatment with thalidomide. Leukemia 2005; 005; 19:87319:873--5.5.

BrunsBruns I et al. Complete remission in a patient with relapsed I et al. Complete remission in a patient with relapsed angioimmunoblastic Tangioimmunoblastic T--cell lymphoma following treatment with cell lymphoma following treatment with bevacizumabbevacizumab. . Leukemia 2005; 19:1993Leukemia 2005; 19:1993--5. 5.

Strupp C et al. Angioimmunoblastic lymphadenopathy (AILD) may respond to thalidomide treatment: two case reports. Leuk Lymphoma. 2002 Jan;43(1):133-7.