EBV-positive T-cell lymphomas
WHO 2022: EBV-positive T-cell lymphomas
Extranodal NK/T-cell lymphoma (ENKTL)
EBV-positive nodal T- and NK-cell lymphoma
Extranodal NK/T-cell lymphoma (ENKTL)
WHO 5: ENKTL will have the qualifier “nasal-type” dropped from its name in WHO-HAEM5 in accordance with the recognized presentation of this disease at various extranodal sites. The introduction of L-asparaginase-based chemotherapy in combination with radiotherapy has led to markedly improved outcomes for this lymphoma. Immune checkpoint inhibitor therapy has recently shown great promise for relapsed or refractory disease, in keeping with the finding that immune evasion is a critical pathway for ENKTL cell survival.
Natural killer/T-cell lymphoma (NKTL) is a sub-type of Epstein–Barr virus (EBV)-related non-Hodgkin lymphomas common in Asia and Latin America but rare elsewhere. It develops from transformation of natural killer (NK)-cells or cytotoxic T-cells, rarely both. Hemophagocytic syndrome is a common complication.
Advanced and recurrent NKTLs are typically treated with radiation therapy and multi-drug chemotherapy regimens including L-asparaginase with 5-year survival only about 40%.Most data we cite for therapy of advanced NKTL are from retrospective or uncontrolled studies and report similar outcomes with synchronous and metachronous therapy and with diverse radiation therapy and chemotherapy regimens, formats, schedules etc. There are also a myriad of radiation therapy doses, fields, and schedules. The many formats for radiation therapy and diverse chemotherapy regimens suggest no convincing data any strategy is best.
Behandeling
Beperkt stadium: Antracyclines (dauno, doxo, mito)
Uitgebreid stadium: Regimens tested included mSMILE, PEMD (pegylated-L-asparginase, etoposide, methotrexate, and dexamethasone), AspaMetDex (L-asparaginase, methotrexate, and dexamethasone), PGEMOX (gemcitabine, pegaspargase, and oxaliplatin) and GDP (gemcitabine, dexamethasone, and cisplatin), DDGP (pegaspargase, gemcitabine, cisplatin, and dexamethasone)
Refractair/recidief: gemcitabine, na falen van PEG-asparginase; pembrolizumab (PDL1 niet beschreven in biopt ptn, maar frequent aanwezig), antiCD30 (50% neg), antiCD38 (50% neg)
SMILE
Methotrexaat 2000 mg/m2 intraveneus op dag 1
Ifosfamide 1500 mg/m2 intraveneus op dag 2 t/m 4
Etoposide 100 mg/m2 intraveneus op dag 2 t/m 4
L-Asparaginase 6000 IE/m2 intraveneus op dag 8, 10, 12, 14, 16, 18, 20
Dexamethason 40 mg oraal dag 2 t/m 4
Modified SMILE
Yang et al 2013. https://link.springer.com/article/10.1007/s12032-013-0720-7:
Methotrexaat 1500 mg/m2 intraveneus op dag 1
Ifosfamide 1200 mg/m2 intraveneus op dag 2 t/m 4
Etoposide 60mg/m2 intraveneus op dag 2 t/m 4
PEG-Asparaginase 2500 U/m2 intraveneus op dag 8
Dexamethason 40 mg oraal dag 2 t/m 4
NK/T cell lymfomen (ENKL) zijn zeldzame en agressieve lymfomen. De prognose van deze patienten is somber; bij vergevorderde stadia (ENKL stadium 3-4) is de overall survival ondanks intensieve therapie slechts 25% (1). ENKL lymfomen zijn gekenmerkt door multidrug resistentie. Het 'SMILE'-regime was aanvankelijk ontworpen om deze resistentie te passeren door verschillende middelen te combineren. Het klassieke regime omvat dexamethason, methotrexaat, ifosfamide, etoposide en L-asparaginase. Dit SMILE schema wordt elke 28 dagen gegeven, en in geval van gevorderde stadia ENKL gedurende 6 cycli herhaald.
In 2009 werd het bovenstaande schema geoptimaliseerd tot het zogenaamde modified (m)SMILE, waarin L-asparginase ( op dag 8, 10, 12, 14, 16, 18 en 20) wordt vervangen door PEG-asparginase (enkel dag 7) (2). Deze aanpassing zorgt van (i) een verkorting van de cyclus duur, (ii) een vermindering in het aantal benodigde kuren (van 6 naar 4) als ook (iii) een afname in toxiciteit zoals mucositis en stollingsproblemen (3).
Patienten met vergevorderde stadia ENKL krijgen bij het klassieke SMILE regime 6 kuren. Door de intensificatie van mSMILE (van 6x28dg=168dg naar 4x21dg=84dg) kan de behandelduur gehalveerd worden.
Ook is de response rate van mSMILE bij vergevorderde ENKL lymfomen beter; het klassieke SMILE regime bereikt na 6 cycli een overall respons van 25%, terwijl na 4 mSMILE kuren een complete respons bij 80% van de patienten wordt beschreven(2).Daarmee creeert het mSMILE regime ook ruimte om toe te werken naar een consolidatie behandeling; allogene stamceltransplantatie. Het belang van deze consolidatie wordt geschetst door de 5-jaars overleving van 55% indien patienten met vergevorderde ENKL deze stap in de behandeling bereiken(4).
(1) Kim et al. A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis. The Lancet Oncology. 2016;17(3):389–400.
(2) Ghione et al. Modified SMILE (mSMILE) and Intensity-Modulated Radiotherapy (IMRT) for extranodal NK-T lymphoma nasal type in a single center population. Leuk Lymphoma. 2020 Dec; 61(14): 3331–3341
(3) Yang et al. Retrospective study of modified SMILE chemotherapy for advanced-stage, relapsed, or refractory extranodal natural killer (NK)/T cell lymphoma, nasal type. Medical oncology. 2013
(4) Tse et al. Allogeneic haematopoietic SCT for natural killer/T-cell lymphoma: a multicentre analysis from the Asia Lymphoma Study Group. Bone Marrow Transplant. 2014;49(7):902–906.
Nodal EBV-positive T and NK-cell lymphoma
Nodal EBV+ T/NK cell lymphoma which occurs mostly in East Asians, is now recognized as a distinct entity in WHO-HAEM5; previously it was subsumed as a subtype under the entity of PTCL-NOS. Patients typically present with lymphadenopathy with or without extranodal involvement, advanced-stage disease and B symptoms; they have a dismal prognosis. Morphologically, this lymphoma often resembles diffuse large B-cell lymphoma, lacking the coagulative necrosis and angioinvasion characteristic of ENKTL. It more often shows a cytotoxic T-cell than NK-cell immunophenotype; EBV is positive, by definition. The genetic landscape differs from that of ENKTL, with the most commonly mutated gene being TET2.