T-cellslymfom - ljusning vid horisonten? Fortbildningsdagarna SFH Uppsala 2016 Fredrik Ellin med dr, överläkare Medicinkliniken, Länssjukhuset Kalmar

DISCLOSURES Fortbildningsdagarna 5-7 okt 2016 Uppsala Konsultuppdrag/advisory board/betalda föreläsningar Advisory board CTI Life Sinces Forskningsstöd ej aktuellt Fortbildningsdagarna 5-7 okt 2016 Uppsala

† Vad är T-cellslymfom? T-cellslymfom B-cellslymfom Disease entities T-cell lymphoma T lymphoblastic leukemia/lymphoma Anaplastic large cell lymphoma, ALK+ Anaplastic large cell lymphoma, ALK-* Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma NOS Enteropathy-associated T-cell lymphoma Hepatosplenic T-cell lymphoma NK/T-cell lymphoma, nasal type Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides Sézary syndrome Primary cutaneous CD30 positive T-cell lymphoproliferative disorders Primary cutaneous gamma-delta T-cell lymphomas Hydroa vacciniforme-like lymphoma T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Chronic lymphoproliferative disorders of NK cells Aggressive NK cell leukemia Systemic EBV-positive T-cell lymphoproliferative disease of childhood Adult T-cell leukemia/lymphoma T-cellslymfom † B-cellslymfom

T-cellslymfom WHO 2008 Anaplastiskt storcelligt lymfom, ALK+ Angioimmunoblastiskt T-cellslymfom Perifert T-cellslymfom UNS Subcutant panniculitliknande T-cellslymfom Primärt kutant anaplastiskt storcelligt lymfom Lymfomatoid papulomatos Mycosis fungoides Primärt kutant T-cellslymfom Enteropatiassocierat T-cellslymfom Hepatospleniskt T-cellslymfom NK/T-cellslymfom, nasal typ T-cells prolymfocytleukemi Storcellig granulär leukemi Adult T-cellsleukemi/lymfom Perifera Omogna T-cells lymfoblastlymfom

PTCL i Sverige 2000 -2009

Behandling av PTCL; grundrekommendation Yngre Äldre Mycket gamla/sköra CHOEP-14 x6 CHOP-14/21 x6 mini-CHOP SVIP Bendamustin Velbe Gemzar Etoposid … ASCT

Undantag till CHOEP/CHOP-behandling: I NK/T-cellslymfom Stadium I/II (lokaliserad) Stadium III/IV Strålbehandling (+ evt kemoterapi) Metothrexate/asparaginase-baserad kemoterapi

Undantag till CHOEP/CHOP-behandling: II Hepatospleniskt γδ T-cellslymfom Mycket ovanligt lymfom CHOP ineffektivt Platinabaserad terapi möjligen mer effektiv Allogen SCT att föredra före Autolog SCT

Överlevnad utifrån subtyp International T-Cell Lymphoma Project JCO 2008;26:4124-4130

Behandling av PTCL; grundrekommendation Yngre Äldre Mycket gamla/sköra CHOEP-14 x6 CHOP-14/21 x6 mini-CHOP SVIP Bendamustin Velbe Gemzar Etoposid … ASCT

CHOP eller CHOEP ALK- PTCL NOS AITL ALK + Schmitz N et al. Blood 2010;116:3418-3425 ALK- PTCL NOS AITL ALK +

ALK+ ALCL Totalöverlevnad åldersgrupp 40-65 år Opublicerade data

Behandling av PTCL; grundrekommendation Yngre Äldre Mycket gamla/sköra CHOEP-14 x6 CHOP-14/21 x6 mini-CHOP SVIP Bendamustin Velbe Gemzar Etoposid … ASCT

NLG T-01 d'Amore F et al. JCO 2012;30:3093-3099

ALK- ALCL, AITL, PTCL NOS, EATL ASCT intention documented at beginning of treatment? YES NO auto SCT ITT non-auto SCT

1st line treatment of PTCL Patterns of treatment failure refractory chemosensititve, but eventually relapsing cured? ~30% 18% 12% ~40% Diagnosis 2 yr 7 yr 7-10 yrs End of induction, consolidation

Primärbehandling PTCL Publikation Behandling N Överlevnad Studietyp Simon et al CHOP vs VIP-r-ABVD 86 2y EFS 41% vs 45% Prospektiv randomiserad Escalon et al CHOP vs ”hyperintense” 95 3y OS 43% vs 49% Retrospektiv, non-ALCL Mahdevan et al PEGS (platinum, gemcitabin, steroid 33 2y PFS 12% 21% beh i 1:a relaps, prospektiv Savage et al CHOPx4+ECV (etoposide, cyklofosfamid, vinkristin) 34 ”ingen effekt” retrospektiv Kim et al CHOP-EG (etoposid/gemcitabin) 26 1y OS 70% Gallamini et al A(lemtuzumab)-CHOP 24 Advani et al CEOP/Pralatrexat 2y PFS 39% Reimer et al CHOP + ASCT 83 3y PFS 36% d’Amore et al CHOEP + ASCT 160 5y PFS 44%

Randomiserade studier primärbehandling CHOP vs A-CHOP N=116 3y EFS 23% vs 26% >60 år (ACT-2), ej ALCL + ASCT N= - ≤ 60 år (ACT-1), ej ALCL CHOP vs Ro-CHOP N=420 (pågående) ROCHOP CHOP vs BV-CHP N=450 (pågående) ECHELON-2

1st line treatment of PTCL Patterns of treatment failure refractory chemosensititve, but eventually relapsing cured? ~30% 18% 12% ~40% Diagnosis 2 yr 7 yr 7-10 yrs End of induction, consolidation

Relaps och överlevnad Vivien Mak et al. JCO 2013;31:1970-1976 Fredrik Ellin et al. Blood 2015;126:36-41

Relapsbehandling PTCL

BV & relaps CD30+ PTCL (non-ALCL) Steven M. Horwitz et al, Blood. 2014 May 15; 123(20): 3095–3100

BV till PTCL inom Franska NPP Subtyp CD30-uttryck

BV+CHP (fas I)

4:e reviderade WHO-klassifikationen 2016 ALCL ALK+ ALCL ALK+ ALCL ALK - ALCL ALK- Breast implant-associated ALCL Angioimmunoblastiskt TCL Angioimmunoblastiskt TCL Nodal PTCL with TFH phenotype Perifert T-cellslymfom UNS Follicular T-cell lymphoma Perifert T-cellslymfom UNS

4:e reviderade WHO-klassifikationen 2016 Enteropati-associerat TCL Enteropati-associerat T-cellslymfom (celiaki-associerat) typ I typ II Monomorphic epitheliotropic intestinal TCL

Perifera TCL Javeed Iqbal et al. Blood 2014;123:2915-2923

PTCL NOS – 2 huvudgrupper TBX21 IFNγ , NF-κB GATA3 proliferation MYC, mTOR,PI3K Javeed Iqbal et al. Blood 2014;123:2915-2923

AITL Mamiko Sakata-Yanagimoto et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet. 2014 Feb; 46(2): 171-175 Teresa Palomero et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet. 2014 Feb; 46(2): 166–170.

Molekylärt landskap AITL Gener/signalväg Frekvens Distrubition TET2 DNMT3 Samvarierar IDH2 RHOA 60% AITL och TFH-PTCL TCR- aktivering 50% CD28 Ca 10% Endast AITL CARD11 Vanligare CTCL PIK3 Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived Lymphomas. Vallois et al, Blood First Edition Paper, prepublished online July 1, 2016; DOI 10.1182/blood-2016-02-698977

TCR-mutation vid AITL Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived Lymphomas. Vallois et al, Blood First Edition Paper, prepublished online July 1, 2016; DOI 10.1182/blood-2016-02-698977

ALCL JAK1/STAT3-aktivering i ca 35% av systemiska ALK- ALCL JAK1/STAT3-mutationer STAT3-aktiverande chimera kinaser JAK-inhibitorer? Crescenzo R, et al. Cancer Cell. 2015 Apr 13;27(4):516-32

ALCL och andra CD30+ PTCL Bortezomib? ca 1/3 PTCL uttrycker IRF4 t(6;14) IRF4/TRA mkt ovanlig IRF4 copy number gain och IRF4 SNP CD30-NFκB-IRF4 feedback loop Bortezomib? Rebecca L. Boddicker et al. Blood 2015 May 14;125(20):3118-27

VAV1-rearrangemang Azathioprin? (hämmar RAC1) I 11% av PTCL NOS och ALK- ALCL Medierar effekt via RAC1 Azathioprin? (hämmar RAC1) Rebecca L. Boddicker et al. Blood 2016;128:1234-1245

ERBB4+ ALK- ALCL; ny subgrupp Aberrant uttryck av ERBB4 (och COL29A1) 24% av ALK- ALCL (ej andra PTCL) Hodgkin-liknande morfologi Ingen uppenbar koppling till överlevnad Ingen immunfärgning för ERBB4 ännu Irene Scarfò et al. Blood 2016;127:221-232

Representative cases of genetic subtypes of ALCL Representative cases of genetic subtypes of ALCL. (A) ALK-negative ALCL with DUSP22 rearrangement. Representative cases of genetic subtypes of ALCL. (A) ALK-negative ALCL with DUSP22 rearrangement. The tumor cells are positive for CD30 and are negative for ALK, TIA-1, and p63. FISH using a breakapart probe to the DUSP22-IRF4 locus on 6p25.3 shows abnormal separation of the red and green signals on 1 allele (pair of arrows). (B) ALK-negative ALCL with TP63 rearrangement. The tumor cells are positive for CD30, TIA-1, and p63 and are negative for ALK. FISH using a dual-fusion probe to TBL1XR1 on 3q26 and TP63 on 3q28 demonstrates 2 pairs of abnormal fusion signals, indicating 2 copies of inv(3)(q26q28) (TBL1XR1/TP63 fusion; 2 pairs of arrows). (C) ALK-negative ALCL lacking DUSP22 and TP63 rearrangements (triple-negative ALCL). The tumor cells are positive for CD30 and TIA-1 and are negative for ALK and p63. (D) ALK-positive ALCL. The tumor cells are positive for CD30, ALK, and TIA-1 and are negative for p63. Photomicrographs were taken using an Olympus DP71 camera, Olympus BX51 microscope, and Olympus DP Manager image acquisition software at an original magnification of ×400 (insets, ×1000). Original magnification of FISH images, ×600. Edgardo R. Parrilla Castellar et al. Blood 2014;124:1473-1480 ©2014 by American Society of Hematology

DUSP22 och TP63 Edgardo R. Parrilla Castellar et al. Blood 2014;124:1473-1480

TACK! Svenska Lymfomgruppen Svensk förening för hematologi Alla som registrerar i Svenska Lymfomregistret Mats Jerkeman, docent, Onkologiska kliniken, SUS Lund Thomas Relander, docent, Onkologiska kliniken, SUS Lund Hans Hagberg, docent, Onkklogiska kliniken, Akademiska sjukhuset Francesco d’Amore, proffessor, Aarhus Universitet Mathew Maurer, docent, Dept of Epidemiology, Mayo Clinic