Periphere T-Zell Lymphome Wien, 13.10.2008 Gerald Wulf 23. Januar 2007

Biologie systemischer T-NHL: Heterogenität und Epidemiologie 14% 11% 18% 23% 6% 12% 7% 1% 2% 5% PTCL-U AILT NK/T ALK+ ALCL ALK - ALCL ATLL ETTL Cut ALCL HSTCL SCPTCL Other/Unclass Armitage et al. JCO 2008

Expressionsprofil von PTCL: Assoziation mit maturen T-Zelltypen AILT Geissinger et al. J Path 2006

Genexpressionsprofil von PTCL Piccalagua et al. JCI 2007 Martinez-Delgado Hemtol Oncol 2006

Genexpressionprofil von PTCL: Identifikation von Zielstrukturen Piccalagua et al. JCI 2007

Prognose des anaplastisch großzelligen Lymphoms Gisselbrecht et al. Blood 1998

Anaplastisch großzelliges Lymphom: Bedeutung von ALK-Positivität FFS OS Savage et al. Blood 2008

Prognose des kutanen anaplastisch großzelligen T-Zell Lymphoms Bekkenk et al. Blood 2002 Savage et al. Blood 2008

kutanes ALCL versus lymphomatoide Papulose Bekkenk et al. Blood 2002 Savage et al. Blood Reviews2007

IPI PIT Prognose systemischer T-NHL: klinische Faktoren Age, PS, LDH, ES, stage PIT Age, PS, LDH, BM Other studies have found no distinction between patients with 2 or more factors Gallamini et al. Blood. 2004

PTCL: approaches to improved treatment efficacy 6 x CHOP14 addition of humoral immunotherapy : consolidation/maintenance alemtuzumab 6-8 x CHO/E/P14 addition of humoral immunotherapy: alemtuzumab addition of cellular immunotherapy: allogeneic SC transplantation DHAP FBC12 dose escalation: HD therapy / autologous tx novel agents: antibodies small compounds Mega CHOEP Dexa BEAM TBI Cy

Standard chemotherapy in PTCL: anthracycline-based ? PTCL NOS AILT Armitage et al. JCO 2008

Periphere T-Zell Lymphome (PTCL): CX + Alemtuzumab Weidmann (Germany) Gallamini (Italy) Porcu (USA) Janik HOVON (NL) Furman Trümper Target group PTCL excl: alk+ALCL excl. alk+ALCL Incl. alk+ ALCL, ATLL, PTLD, CTCL, LGL CD52-positive, ATLL PTCL, excl: all ALCL, hepatospl. EATLwithout measurable disease Probably incl. 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 CONSOLID. Dose esc. Yes No 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. No pts 33 20 8 10 17 2 37 13

8x CHOP-21 + Alemtuzumab OS PFS Gallamini et al. Blood 2007

DSHNHL Trial 2003-1 peripheral T-NHL 6 x CHOEP-14 + Peg-F 6 x CHOP-14 DSHNHL 2003-1: phase II alemtuzumab consolidation in PTCL DSHNHL Trial 2003-1 peripheral T-NHL 18 – 60 years: 6 x CHOEP-14 + Peg-F 60 – 70 years: 6 x CHOP-14 + Peg-F CR / PR no infection Alemtuzumab- consolidation 133 mg in / 4 wks 36 Gy Bulk/E RTx

DSHNHL Trial 2003-1 DSHNHL 2003-1: treatment outcome (ITT) Therapy arm EFS OS 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 30.07.07

CHOP + Alemtuzumab phase III: DSHNHL 2006-1B / ACT-2 documentation BII RE forms : progress : F RE F death : D S BI PT C C C C C C C H O P T-cell lymphoma 61-80 years eligible for chemotherapy all stages, except stage I IPI 0 w/o bulk R A A A A A A C H O P days 1 15 29 43 57 71

EBV-associated secondary NHL post CHOP w alemtuzumab case primary secondary interval post outcome histology histology alemtuzumab m, 41y PTCL NOS EBV + (endoth.) 10 months refractory to CT, CD2+,3+,5+ death recurr. EBV – f, 32y PLTCL EBV+, CD20+ - cerebral mass 9 months RX cerv. DLBCL 12 months RX, rituximab cut. ind B-NHL 21 months PLTCL 21 months alive m, 59y AILT EBV+, CD20+ 23 months early death B-lymphoprol. AILT n = 20, HOVON 69 trial, 8x CHOP-21 w 8x 90 mg alemtuzumab Kluin-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) 360 133 cumulative 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 0 sec. NHL

Hochdosistherapie und autologe SZT bei PTCL Author (year) n Regimen Response OS Histology Gisselbrecht (2002) 43 33 BEAM + ASCT ACVBP No data 32% (5-year ) 39% (5-year) ALCL : 29 (ALK unknown) PTCL: 55 (12 LBL) Corradini (2006) 62 Mito/Mel or BEAM 74% CR/PR 34% (12-year ) ALCL: 19 PTCL-U: 28 Mercadal 41 HighCHOP/ESHAP 60% CR/PR 39% (4-year ) No ALK+ ALCL D´Amore 129 BEAM na 67% (3-year ) Rodriguez (2007) 26 MegaCHOP+/-IFE 73% CR/PR 73% (3-year ) Reimer (ASH 2005) 65 Cy/TBI 69% CR/PR 50% (3-year )

HD Therapie bei PTCL phase II: Probleme primär refraktär sekundär refraktär stabile Remission 100% 65-75% 35…% Dx 3yEFS HDT

HD Therapie bei PTCL phase II: MegaCHOEP II / III n=36 1.5 year rate 95%CI total 31 % (16%;46%) 3 year rate 24 % (9%;38%) DSHNHL 08.03.07

HD Therapie bei PTCL phase II: autologe versus allogene SZT

Allogene SZT bei rezidiviertem aggressiven NHL: konv. Konditionierung Sung-Won et al. Blood 2006

PTCL im Rezidiv: allogene SCT nach Dosis-reduzierter Konditionierung Corradini et al. JCO 2004

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 [%] novel substances agent target indication ORR author [%] Gemcitabine nucleosid PTCL 60 Sallah 2001 AraG 506U78 analoga PTCL 14 Czucsman 2004 a Denileukin Il-2R PTCL 50 Dang 2004 a Difitox Depsipeptide HDAc PTCL 26 Piekarz 2005a SAHA SGN30 CD30 ALCL 33 Forero-Torres 2004a Zanolimumab (CD4), Daclizumab (Il-2R), Bevacizumab Sorafenib (TKI), Thalidomide (IMID), Bortezomib (proteasome)

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)

Ihnen für Ihre Aufmerksamkeit Vielen Dank DSHNHL Kompetenznetz maligne Lymphome Ihnen für Ihre Aufmerksamkeit