Acute hyperleukocytic leukemias (AHL) are associated with a very high early mortality rate mostly due to respiratory failure or intracranial bleeding. The pathophysiological process leading to these complications is called leukostasis but the biological mechanisms underlying its development and progression remain unclear. Although traditionally related to “overcrowding” of leukemic blasts in the capillaries of the microcirculation, leukostasis is likely to result from direct endothelial cell damage. This damage is probably mediated by soluble cytokines released during the interaction between leukemic cells and vascular endothelium and by the subsequent migration of leukemic blasts in the perivascular space. Leukemic cell's ability to respond to chemotactic cytokines and their expression of specific adhesion molecules are probably more important in determining whether leukostasis will develop than the number of circulating blasts. This could explain why leukostasis does not develop in all patients with AHL. The identification of the adhesion molecules, cytokines and receptors mediating endothelial cell damage in AHL should become a priority if therapeutic improvements are desired. Leukapheresis is widely used but it is unclear whether it provides additional benefit to a simpler and less invasive intervention with allopurinol, hydroxyurea and intravenous fluids. Cranial irradiation is not generally recommended. Induction chemotherapy should be started without delay. It is hoped that specific pharmacological inhibitors of the interaction between leukemic cells and vascular endothelum will result in an improved outcome for this very high-risk population.

Key Points: The oral PI3K-δ,γ inhibitor duvelisib demonstrated clinical activity and a favorable safety profile in patients with CTCL and PTCL. Duvelisib induced cell-autonomous killing of TCL lines and reprogrammed PTCL-associated macrophages in vivo.

Sézary syndrome (SS) is an aggressive leukaemia of mature T cells with poor prognosis and limited options for targeted therapies. The comprehensive genetic alterations underlying the pathogenesis of SS are unknown. Here we integrate whole-genome sequencing (n=6), whole-exome sequencing (n=66) and array comparative genomic hybridization-based copy-number analysis (n=80) of primary SS samples. We identify previously unknown recurrent loss-of-function aberrations targeting members of the chromatin remodelling/histone modification and trithorax families, including ARID1A in which functional loss from nonsense and frameshift mutations and/or targeted deletions is observed in 40.3% of SS genomes. We also identify recurrent gain-of-function mutations targeting PLCG1 (9%) and JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11%). Functional studies reveal sensitivity of JAK1-mutated primary SS cells to JAK inhibitor treatment. These results highlight the complex genomic landscape of SS and a role for inhibition of JAK/STAT pathways for the treatment of SS.

Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)(-)CD34(-)CD117(+/-)CD94(+)CD16(-) "stage 4" subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80(-) (stage "4a") and NKp80(+) (stage "4b"). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin(-)CD34(-)CD117(+)CD94(-)CD16(-) "stage 3" cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.

Summary: Cutaneous T‐cell lymphomas (CTCL) are a heterogeneous group of malignancies derived from skin‐homing T cells. The most common forms of CTCL are Mycosis Fungoides (MF) and Sezary Syndrome (SS). Accurate diagnosis remains a challenge due to the heterogeneity of presentation and the lack of highly characteristic immunophenotypical and genetic markers. Over the past decade molecular studies have improved our understanding of the biology of CTCL. The identification of gene expression differences between normal and malignant T‐cells has led to promising new diagnostic and prognostic biomarkers that now need validation to be incorporated into clinical practice. These biomarkers may also provide insight into the mechanism of development of CTCL. Additionally, treatment options have expanded with the approval of new agents, such as histone deacetylase inhibitors. A better understanding of the cell biology, immunology and genetics underlying the development and progression of CTCL will allow the design of more rational treatment strategies for these malignancies. This review summarizes the clinical epidemiology, staging and natural history of MF and SS; discusses the immunopathogenesis of MF and the functional role of the malignant T‐cells; and reviews the latest advances in MF and SS treatment.

The clinical and laboratory data of 48 leukapheresis‐treated patients with hyperleucocytic leukaemia (HL) was reviewed to assess the correlation between the degree of leucoreduction and early mortality. Leukapheresis resulted in > 50% leucoreductions and postapheresis WBC counts <100 × 10⁹/l in most patients (64.5%). Patients presenting with neurological, respiratory or renal complications had higher early mortality rates than patients without such complications, despite similar initial WBC counts and comparable leucoreductions. Thus, in these patients, more efficient leucoreduction was not associated with improved early survival.