Current and upcoming treatment approaches to uncommon subtypes of PTCL (EATL/MEITL, SPTCL, HSTCL).

Rare subtypes of peripheral T-cell lymphoma (PTCL) including enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and hepatosplenic T-cell lymphoma (HSTCL) are underrepresented in most registry and clinical studies. Most of the literature is obtained from small case series, single-institution retrospective studies and subgroup analyses of the largest studies with few recent and ongoing exceptions. While the pathogenesis and biology of these entities have yet to be fully elucidated, global efforts by the scientific community have started to shed some light on the most frequently deregulated pathways. In this review, we highlight the most pertinent clinical and pathologic features of rare subtypes of PTCL including EATL/MEITL, SPTCL and HSTCL. We also summarize the results of recent developments identifying potential targets for novel therapeutic strategies based on molecular studies. Finally, we highlight the underrepresentation of these rare subtypes in most clinical trials, making evidence-based therapeutic decisions extremely challenging.

ß-Actin G342D as a Cause of NK Cell Deficiency Impairing Lytic Synapse Termination.

NK cell deficiency (NKD) occurs when an individual's major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of ß-actin-related diseases with over 60 ACTB (ß-actin) variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, and susceptibility to infections, molluscum contagiosum virus, and EBV-associated lymphoma had functional NKD for over a decade. A de novo ACTB variant encoding G342D ß-actin was identified and was consistent with the individual's developmental and platelet phenotype. This novel variant also was found to have direct impact in NK cells because its expression in the human NK cell line YTS (YTS-NKD) caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but they demonstrated defective serial killing because of prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D ß-actin results in a novel, to our knowledge, mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing, leading to overall reductions in NK cell cytotoxicity.

Preclinical Development of a Romidepsin Nanoparticle Demonstrates Superior Tolerability and Efficacy in Models of Human T-Cell Lymphoma and Large Granular Lymphocyte Leukemia.

Histone deacetylase (HDAC) inhibitors are a widely recognized and valued treatment option for patients with relapsed or refractory peripheral T cell lymphomas (PTCL). Romidepsin is a relatively selective Class I HDAC inhibitor originally approved for patients with relapsed or refractory (R/R) cutaneous T cell lymphoma (CTCL) and subsequently R/R PTCL. Unfortunately, the FDA approval of romidepsin for R/R PTCL was withdrawn due to a negative Phase 4 post-marketing requirement (PMR), diminishing further the treatment options for patients with PTCL. Herein we describe the development of a first-in-class polymer nanoparticle of romidepsin (Nanoromidepsin) using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic disposition, with improved tolerability and safety in murine models of T-cell lymphoma. Nanoromidepsin also exhibited superior anti-tumor efficacy in multiple models including in vitro T cell lymphoma (TCL) cell lines, ex vivo LGL leukemia primary patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival (OS) compared to romidepsin in murine xenograft models. These findings collectively justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

Lymphomatoid Papulosis With T-cell Receptor-Gamma Delta Expression: A Clinicopathologic Case-series of 26 Patients of an Underrecognized Immunophenotypic Variant of Lymphomatoid Papulosis.

Lymphomatoid papulosis (LyP) has several histopathologic presentations. LyP featuring gamma-delta (γδ) T-cell receptor expression may masquerade as and may be misdiagnosed as aggressive cutaneous T-cell lymphoma, particularly primary cutaneous γδ T-cell lymphoma (PCGDTL) or γδ mycosis fungoides. We performed a clinicopathologic analysis of the largest series of LyP featuring γδ T-cell expression. We identified 26 patients with a diagnosis of LyP with γδ T cells from our institutions, as well as through a comprehensive review of the literature, and characterized these cases. Most cases were treated with topical steroids or not treated at all. The majority of cases showed a CD4 - CD8 + phenotype and featured at least one cytotoxic marker. Histopathologic features included an intraepidermal or dermal infiltrate with large cells and frequent angiotropism. One case was initially misdiagnosed as PCGDTL, requiring further therapy. Our case series, the largest international cohort of γδ T cell predominant LyP cases, confirms marked clinicopathologic heterogeneity that may contribute to misdiagnosis, reasserting the need to identify classic clinical features, CD30 + T-cell components, and markers of cytotoxicity when dealing with this differential diagnosis. A limitation of this study includes somewhat limited follow-up, histologic, and immunophenotypic information for some cases.