Seite 1 23. Januar 2007

Periphere T-Zell Lymphome

Wien, 13.10.2008

Gerald Wulf

14%

11% 18%

23%

6%12%7%

1%2%

2%5%

PTCL-U AILT NK/TALK+ ALCL ALK - ALCL ATLLETTL Cut ALCL HSTCLSCPTCL Other/Unclass

Biologie systemischer T-NHL: Heterogenität und Epidemiologie

Armitage et al. JCO 2008

Geissinger et al. J Path 2006

Expressionsprofil von PTCL: Assoziation mit maturen T-Zelltypen

AILT

Martinez-Delgado Hemtol Oncol 2006

Genexpressionsprofil von PTCL

Piccalagua et al. JCI 2007

Piccalagua et al. JCI 2007

Genexpressionprofil von PTCL: Identifikation von Zielstrukturen

Gisselbrecht et al. Blood 1998

Prognose des anaplastisch großzelligen Lymphoms

Anaplastisch großzelliges Lymphom: Bedeutung von ALK-Positivität

Savage et al. Blood 2008

FFS OS

Prognose des kutanen anaplastisch großzelligen T-Zell Lymphoms

Savage et al. Blood 2008

Bekkenk et al. Blood 2002

kutanes ALCL versus lymphomatoide Papulose

Savage et al. Blood Reviews2007

Bekkenk et al. Blood 2002

Gallamini et al. Blood. 2004

IPIAge, PS, LDH, ES, stage

PITAge, PS, LDH, BM

Prognose systemischer T-NHL: klinische Faktoren

addition of humoral immunotherapy :consolidation/maintenancealemtuzumab

dose escalation:HD therapy / autologous tx

MegaCHOEP

addition of humoral immunotherapy:alemtuzumab

addition of cellular immunotherapy: allogeneic SC transplantation

DHAP

FBC12

6 x CHOP146-8 x CHO/E/P14

TBICy

DexaBEAM

novel agents:antibodiessmall compounds

PTCL: approaches to improved treatment efficacy

Standard chemotherapy in PTCL: anthracycline-based ?

PTCL NOS AILT

Armitage et al. JCO 2008

Weidmann

(Germany)

Gallamini

(Italy)

Porcu

(USA)

Janik

(USA)HOVON

(NL)

Furman

(USA)

Trümper

(Germany)

Target group

PTCL

excl: alk+ALCL

PTCL

excl. alk+ALCL

PTCL

Incl. alk+ ALCL, ATLL, PTLD, CTCL,

LGL

PTCL

CD52-positive,

ATLL

PTCL,

excl: all ALCL,

hepatospl.

EATLwithout measurable

disease

PTCL

Probably incl. alk+ALCL

PTCL

excl. alk+ALCL

CT regimen

FCD CHOP 21 x8

CHOP-21 x8

EPOCH CHOP-14 x8

CHOP-21 x6

CHO(E)P-14 x6

Camp

timing

INDUCTION INDUCTION INDUCTION INDUCTION INDUCTION INDUCTION CONSOLID.

Dose esc.

Yes Yes Yes Yes Yes No Yes

Camp Total dose

292 mg 180-300 mg

77-293 mg 180-540 mg

673 mg 435-495 mg 180 mg

Cam route

i.v. s.c. s.c. i.v. s.c. s.c. i.v.

No pts 33 20 8 10 17 2 37

Periphere T-Zell Lymphome (PTCL): CX + Alemtuzumab

8x CHOP-21 + Alemtuzumab

OS PFS

Gallamini et al. Blood 2007

DSHNHL Trial 2003-1

CR / PRno infection

peripheral T-NHL

18 – 60 years:

6 x CHOEP-14+ Peg-F

Alemtuzumab-consolidation

133 mg in / 4 wks

36 Gy Bulk/E RTx

60 – 70 years:

6 x CHOP-14+ Peg-F

DSHNHL 2003-1: phase II alemtuzumab consolidation in PTCL

DSHNHL 30.07.07

Therapy arm

EFS OS

2 - years rate 95% CI 2 - years rate 95% CI

≤ 60 years(n=27)

38.1%[14.0%; 62.2%]

63.5%[40.8%; 86.2%]

> 60 years(n=14)

22.9% [ 0.0%; 48.0%] 55.0%[28.1%; 81.9%]

total(n=41)

32.0%[14.2%; 49.8%]

61.0%[43.6%; 78.4%]

with MabCampath (n=29)

43.9%[20.8%; 67.0%]

73.6%[54.6%; 92.6%]

DSHNHL Trial 2003-1

DSHNHL 2003-1: treatment outcome (ITT)

1days

15 29 43

R

71

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

57

S C

RE

BI PT C

BII

C C C C

RE F Dprogress : F death :

T-cell lymphoma

61-80 yearseligible for chemotherapyall stages, except stage I IPI 0 w/o bulk

documentation

forms :

CHOP + Alemtuzumab phase III: DSHNHL 2006-1B / ACT-2

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

A AA AAA

EBV-associated secondary NHL post CHOP w alemtuzumab

n = 20, HOVON 69 trial, 8x CHOP-21 w 8x 90 mg alemtuzumabKluin-Nelemans et al. Blood 2008: 02-138800

EBV associated secondary NHL post CHOP w alemtuzumab

HOVON 69 GITIL-trial ACT-2 DSHNHL 2003-1

CX 8x CHOP-21 8x CHOP-28 6x CHOP-14 6x CHO(E)P-14

alemtuzumab 720 240 (n=20) 360 133cumulative 120 (n=4)

time of cx 24 32 12 12 / 4[weeks]

observation 24+ 11 (5-42) 24+[months]

n 20 24 41 / 29

EBV-associated 3 0 0sec. NHL

Author (year)

n Regimen Response OS Histology

Gisselbrecht (2002)

4333

BEAM + ASCTACVBP

No data32% (5-year )39% (5-year)

ALCL : 29 (ALK unknown)PTCL: 55 (12 LBL)

Corradini (2006)

62Mito/Mel or BEAM

74%CR/PR

34% (12-year )ALCL: 19 PTCL-U: 28

Mercadal (2006)

41HighCHOP/ESHAP

60% CR/PR

39% (4-year ) No ALK+ ALCL

D´Amore (2006)

129 BEAM na 67% (3-year ) No ALK+ ALCL

Rodriguez (2007)

26MegaCHOP+/-IFE

73% CR/PR

73% (3-year ) No ALK+ ALCL

Reimer(ASH 2005)

65 Cy/TBI69% CR/PR

50% (3-year ) No ALK+ ALCL

Hochdosistherapie und autologe SZT bei PTCL

100% 65-75% 35…%

primärrefraktär

sekundärrefraktär

stabileRemission

Dx HDT 3yEFS

HD Therapie bei PTCL phase II: Probleme

Years

Ev

en

t fr

ee

su

rviv

al

(%)

0 1 2 3 4 5 6

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

DSHNHL 08.03.07

1.5 year rate 95%CI

total 31 % (16%;46%)

3 year rate

24 % (9%;38%)

n=36

HD Therapie bei PTCL phase II: MegaCHOEP II / III

1days 15 29 43

FBC

CHOP

CHOP

CHOP

CHOP

DHAP

BE AM

R

first-line treatment of mature (peripheral) T-cell lymphoma (PTCL), patients 60 years

inclusion criteria

• Peripheral T-cell lymphoma, unspec’d (PTCLu)• Angioimmunoblastic T-cell lymphoma (AIL)• Anaplastic large cell lymphoma, ALK negative• Extranodal NK/T-cell lymphoma, nasal type• Enteropathy type T-cell lymphoma• Hepatosplenic T-cell lymphoma• Subcutaneous panniculitis type T-cell lymphoma

• all stages and IPI except stage I with aaIPI 0

CR, PR, NC

R = At diagnosis, patients are randomized to allogeneic or autologous transplantation. Donor search (family or unrelated) will beinitiated only in patients randomized to allogeneic transplantation. Patients randomized to allogeneic tx but without a donor will receive autologous tx. Peripheral blood stem cells are harvested after DHAP in patients who are to receive autologous tx(randomized or crossed over from the allogeneic transplant arm because no donor is available).

ASCT = autologous stem cell transplantation, SCT = allogeneic stem cell transplantation

SCT

ASCT

CHOP

CHOP

CHOP

CHOP

DHAP

CR, PR, NC

64 |––-–– 4 - 6 weeks –-–––|

HD Therapie bei PTCL phase II: autologe versus allogene SZT

Allogene SZT bei rezidiviertem aggressiven NHL: konv. Konditionierung

Sung-Won et al. Blood 2006

n=111

PTCL im Rezidiv: allogene SCT nach Dosis-reduzierter Konditionierung

Corradini et al. JCO 2004

n=17

allogeneic SCT in relapsed PTCL: Göttingen experience

indication: relapsed peripheral T-cell lymphoma, chemosensitive

conditioning: fludarabin/busulfan (12 mg/kg bw)/cyclophosphamide

n: 20

OS: 11/20, median observation 4 months (range 1-47 months)

early death (TRM100): 3 / 20

late death (relapse): 3 / 20

late death (non-relapse): 3 / 20

agent target indication ORR author [%]

Gemcitabine nucleosid PTCL 60 Sallah 2001AraG 506U78 analoga PTCL 14 Czucsman 2004 a

Denileukin Il-2R PTCL 50 Dang 2004 aDifitox

Depsipeptide HDAc PTCL 26 Piekarz 2005aSAHA

SGN30 CD30 ALCL 33 Forero-Torres 2004a

Zanolimumab (CD4), Daclizumab (Il-2R), Bevacizumab

Sorafenib (TKI), Thalidomide (IMID), Bortezomib (proteasome)

novel substances

Zusammenfassung PTCL

heterogene Gruppe von histologisch, immunologisch und nach

Expressionsprofil klassifizierbaren Typen

ALK pos. ALCL: unter Anthracyclin-haltige Chemotherapie gute Prognose,

ansonsten Ergebnisse der konventionellen Therapie unbefriedigend

Primärtherapie

in Studien Evaluation von Alemtuzumab (DSHNHL 20061B, ACT-2)

HD-Therapie mit autologer bzw. allogener Stammzelltransplantation

(DSHNHL 2006-1A)

Sekundärtherapie

allogene SZT (DSHNHL 2003-R4); innovative, zielgerichtete Therapien (Studien)

Vielen Dank

DSHNHL

Kompetenznetz maligne Lymphome

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