Mature T/NK cell leukemie

The family of mature T-cell and NK-cell leukaemias encompasses neoplastic T- and NK-cell proliferations that primarily present as leukaemic disease, including T-prolymphocytic leukaemia (T-PLL), T-large granular lymphocytic leukaemia (T-LGLL), NK-large granular lymphocytic leukaemia (NK-LGLL), adult T-cell leukaemia/lymphoma (ATLL), Sezary syndrome (SS) and aggressive NK-cell leukaemia (ANKL).

Enhanced molecular understanding is considered sufficiently mature to permit incorporation of such features in the diagnostic criteria or prognostic markers of these diseases, where relevant.

T-prolymphocytic leukaemia (T-PLL) is a rare form of mature T-cell leukaemia with a heterogeneous clinical course. Recent efforts to standardize diagnosis, staging and treatment response have led to unified diagnostic criteria, which include T lymphocytosis (>5 x 109/L) with appropriate phenotype, T-cell monoclonality and the presence of genetic aberrations including structural variants with breakpoints affecting the TCL1A or MTCP1 locus or expression of TCL1.

T-large granular lymphocytic leukaemia (T-LGLL). There is emerging evidence of clinical and phenotypic significance of specific mutations in T-LGLL. STAT3 mutation, found preferentially in CD8+T-LGLL and gamma/delta T-LGLL, is associated with neutropenia and poorer overall survival. STAT5B mutation is overrepresented

in the rare CD4+ T-LGLLs (present in up to 30% of cases); it is associated with a poor prognosis in CD8+ T-LGLL, but has no prognostic impact in CD4+ T-LGLL and gamma/delta T-LGLL.

Adult T-cell leukaemia/lymphoma (ATLL). Genetic analyses of ATLL have revealed novel events that highlight the importance of immune evasion including CTLA4::CD28 and ICOS::CD28 fusions, REL C-terminal truncations, recurrent alterations in HLA-A and HLA-B and structural variations disrupting the 3′-untranslated region of CD274 (PD-L1). Furthermore, the frequency and pattern of somatic alterations appear to be correlated with clinical behavior. Specifically, aggressive subtypes show more genetic alterations, whereas STAT3 mutations are more common in indolent subtypes. Based on clinical and serological features, prognostic indices of ATLL have been better defined, and a prognostically meaningful genetic classification has recently been

proposed.

Sezary syndrome (SS), while closely related to mycosis fungoides but a distinct entity, is included in this section to highlight its primary site of clinical presentation and consideration in the differential diagnosis of mature T-cell leukaemias. Comprehensive analyses of genomic signatures highlight the contribution of cellular aging and UV exposure observed in SS.

NK-cell leukaemia (ANKL). Genome-wide sequencing studies have provided novel insights into pathogenetic events in ANKL. They implicate mutations in genes of the JAK/STAT and RAS/MAPK pathways, epigenetic modifiers (TET2, CREBBP, KMT2D), and immune checkpoint molecules CD274 (PD-L1)/PDCD1LG2 (PD-L2) in disease pathogenesis.

Intravascular NK/T-cell lymphoma was considered a form of ENKTL in WHOHAEM4R. This highly aggressive lymphoma is often, but not invariably, EBV positive, does not present with mass lesions and shows a predilection for skin and central nervous system. Since its nosological nature is still unclear, it is now described

under aggressive NK-cell leukaemia rather than extranodal NK/Tcell lymphomas, pending further studies to determine where it fits best.