T-cell Lymphoproliferative Disease Research Articles

Severe lympho-depletion, abrogated thymopoiesis and systemic EBV positive T-cell lymphoma of childhood, a case

Epstein-Barr virus (EBV) associated T-cell and NK-cell lymphoproliferative diseases are lethal and extremely rare in Caucasians. We expand on the clinical, immunological and histogenetic characteristics associated with this second European case (19 years old, previously healthy, Caucasian boy) of systemic EBV positive T-cell lymphoma of childhood. We report, as novel findings, severe lympho-depletion and abrogation of thymopoiesis secondary to severe EBV activation and excessive immune activation. Similar to the first European case, we also detected a somatic missense variant in the proto-oncogene FYN. In the first European patient however, the FYN variant allele frequency (VAF) was 10% and the patient only experienced moderate leukopenia, whereas in our case, the VAF was 48% and the patient experienced severe leukopenia and lymphopenia. This could suggest a pathogenic role of these FYN variants in driving excessive T cell activation. If confirmed, FYN might become target in future treatments of this fatal disorder.

Automated Gating and Interpretation of Clinical Flow Cytometry Data: A Computational Approach using Artificial Intelligence and Deep Learning

Abstract Flow cytometry (FCM) allows pathologists to accurately immunophenotype hematopoietic cells by detecting the expression of surface proteins with fluorochrome-conjugated antibodies. Accordingly, FCM plays a pivotal role in the diagnostic workup of many hematologic malignancies. However, post-analytic processing and the interpretation of FCM data are primarily manual processes that impact the consistency and limit the throughput of the method. The post-analytic processing workflow is colloquially referred to as ‘gating’ and involves the identification and characterization of immune cell populations by hand through successions of biaxial plots. The gated FCM data is then used by the pathologist to make a clinical interpretation and to then determine potential diagnoses from the patterns and cell frequencies seen in bivariate plots of the data. Since gating and interpretation are manually performed, post-analytic analyses of FCM data are not only laborious from a workflow perspective but remain subjective and prone to variability based on the experience and skill of both the medical laboratory scientist and pathologist. The objective of this study was to develop a computational pipeline that leverages machine learning-based (ML) solutions to automate gating and clinical interpretation of FCM data to increase the throughput and improve the repeatability of FCM analysis. Raw FCS files from clinical samples being evaluated for the presence of T-cell lymphoproliferative disease were exported from the on-instrument database. Automated gating was performed using open-source, supervised-ML packages for flow cytometry data (flowCore and flowDensity; R). These packages implement all processing steps that would typically be done manually (e.g. applying compensation, quality control (QC), and gating). Plots of interest were then generated from the gated data and classified as normal or abnormal using the clinical interpretations that were applied during the normal clinical workflow. These binary labels were used to train an ML-based classifier (VGG-19; Python). To evaluate pipeline performance, we collected FCS files from 1,188 samples that were analyzed by our flow cytometry lab. The automated gating pipeline was used to gate for CD4+CD3+ cells and to create bivariate plots for CD7/CD26 expression. 1150 (96.8%) passed QC and were all gated correctly by visual inspection. Of the 38 (3.2%) samples that failed QC, 13 (1.1%) were lymphopenic and were gated correctly by visual inspection, and the remaining 25 (2.1%) were gated manually. Using the CD7/CD26 plots, the classifier demonstrated promising predictive performance and achieved a precision of 0.85 and recall of 0.83 (weighted average across classes). Our findings represent a novel effort to automate both the gating and interpretation of FCM data using artificial intelligence. These results suggest that ML-based tools have potential utility in aiding the processing and interpretation of FCM data and can augment the efficiency and consistency of workflows in the clinical flow cytometry laboratory.

Ulcerating mass on the upper eyelid as manifestation of a primary CD30+T-cell lymphoproliferative disease

Ulcerating mass on the upper eyelid as manifestation of a primary CD30+T-cell lymphoproliferative disease

SYSTEMIC EPSTEIN-BARR VIRUS-RELATED T-CELL LYMPHOPROLIFERATIVE DISORDER: A RARE CAUSE OF DYSPNEA AND PULMONARY INFILTRATES IN AN IMMUNOCOMPETENT ADULT

SYSTEMIC EPSTEIN-BARR VIRUS-RELATED T-CELL LYMPHOPROLIFERATIVE DISORDER: A RARE CAUSE OF DYSPNEA AND PULMONARY INFILTRATES IN AN IMMUNOCOMPETENT ADULT

Cytomegalovirus DNAemia and disease: current-era epidemiology, clinical characteristics and outcomes in cancer patients other than allogeneic haemopoietic transplantation.

High-intensity chemotherapy and advances in novel immunotherapies have seen the emergence of cytomegalovirus (CMV) infections in cancer patients other than allogeneic haemopoietic cell transplantation (HCT). Aim To evaluate the epidemiology, clinical characteristics and outcomes of CMV infection in this population. A retrospective review of cancer patients other than allogeneic HCT who had CMV DNAemia and/or disease from July 2013 till May 2020 at a quaternary cancer centre was performed. Of 11 485 cancer patients who underwent treatment during this period, 953 patients had CMV DNA testing performed and 238 of them had CMV DNAemia. After excluding patients with allogeneic HCT, 62 patients with CMV DNAemia were identified, of whom 10 had concurrent CMV disease. The most frequent underlying malignancies were B-cell lymphoproliferative disease (LPD) (31%; 19/62), T-cell LPD (21%; 13/62), chronic lymphocytic leukaemia (11%; 7/62) and multiple myeloma (10%; 6/62). Most patients had lymphopenia (77%; 48/62), multiple cancer therapies (63%; 39/62 received ≥2 previous therapies), co-infection (56%; 35/62 had ≥1 co-infection) and corticosteroid therapy (48%; 30/62) within 1 month before CMV diagnosis. CMV DNAemia and disease were observed in patients receiving novel immunotherapies, including bispecific antibody therapy, chimeric-antigen receptor T-cell therapy and immune checkpoint inhibitors. Patients with haematological malignancy, particularly B-cell LPD, T-cell LPD, chronic lymphocytic leukaemia and multiple myeloma, were frequently identified to have CMV DNAemia and disease. Lymphopenia, multiple cancer therapies, co-infection and recent receipt of systemic corticosteroids were also commonly observed. Future studies are necessary to determine optimal identification and management of CMV in these patients.

Bone Marrow Histology in Hemophagocytic Lymphohistiocytosis.

Bone marrow (BM) samples are obtained through aspiration and trephine biopsy. Hemophagocytic lymphohistiocytosis (HLH) has been largely studied in BM aspirate smears. To investigate the histologic features of HLH in trephine biopsy. Patients with hemophagocytosis in BM aspirate smears were assigned to HLH (n = 127) and non-HLH (n = 203) groups. We quantified hematoxylin-eosin and CD68 immunohistochemical staining of their trephine biopsies. No significant correlation was noted in the hemophagocytosis count between aspirate smears and trephine biopsies. Compared with the non-HLH group, the HLH group had a higher hemophagocytosis count (13 versus 9 per tissue section, P = .046), lower percentage of the adipocytic area (36.7% versus 50.3%, P < .001), and higher percentage of the foamy area (19.1% versus 14.5%, P < .001). The HLH group had more histiocyte infiltrates (total histiocyte density, 9.2% versus 7.3%; P < .001) and more fat-infiltrating histiocytes (histiocyte density of the fat-associated part [HD-FA], 7.6% versus 6.2%; P < .001). We identified the following poor prognostic factors in the HLH group: age 50 years or older (median overall survival [mOS], 95 versus 499 days; P = .04), Epstein-Barr virus-positive T-cell lymphoproliferative diseases (EBV+TLPDs) (mOS, 51 versus 425 days; P < .001), hemophagocytosis count of 6 or higher per tissue section (mOS, 66 versus 435 days; P = .02), and HD-FA of 9% or greater (mOS, 61 versus 359 days; P = .02). Multivariate analysis revealed that age 50 years or older (hazard ratio [HR], 2.38; P < .001), EBV+TLPDs (HR, 2.07; P < .001), and hemophagocytosis count of 6 or higher per tissue section (HR, 2.07; P = .002) were independent prognostic factors for HLH. The HLH group had higher hemophagocytic activity, higher cellularity, a more foamy appearance, more histiocyte infiltrates, and more fat-infiltrating histiocytes. High hemophagocytic activity and marked histiocyte infiltrates in the BM fat were associated with poorer prognosis.

Treatment Advances in EBV Related Lymphoproliferative Diseases.

Epstein Barr virus (EBV) can affect 90% of the human population. It can invade B lymphocytes, T lymphocytes and natural killer cells of the host and remain in the host for life. The long latency and reactivation of EBV can cause malignant transformation, leading to various lymphoproliferative diseases (LPDs), including EBV-related B-cell lymphoproliferative diseases (EBV-B-LPDs) (for example, Burkitt lymphoma (BL), classic Hodgkin’s lymphoma (cHL), and posttransplantation and HIV-related lymphoproliferative diseases) and EBV-related T-cell lymphoproliferative diseases (EBV-T/NK-LPDs) (for example, extranodal nasal type natural killer/T-cell lymphoma (ENKTCL), aggressive NK cell leukaemia (ANKL), and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). EBV-LPDs are heterogeneous with different clinical features and prognoses. The treatment of EBV-LPDs is usually similar to that of EBV-negative lymphoma with the same histology and can include chemotherapy, radiotherapy, and hematopoietic stem cell transplant (HSCT). However, problems such as serious toxicity and drug resistance worsen the survival prognosis of patients. EBV expresses a variety of viral and lytic proteins that regulate cell cycle and death processes and promote the survival of tumour cells. Based on these characteristics, a series of treatment strategies for EBV in related malignant tumours have been developed, such as monoclonal antibodies, immune checkpoint inhibitors, cytotoxic T lymphocytes (CTLs) and epigenetic therapy. These new individualized therapies can produce highly specific killing effects on tumour cells, and nontumour cells can be protected from toxicity. This paper will focus on the latest progress in the treatment of EBV-LPDs based on pathological mechanisms.

EBV associated T- and NK-cell lymphoproliferative diseases: A comprehensive overview of clinical manifestations and novel therapeutic insights.

EBV is a ubiquitous virus that infects nearly all people around the world. Most infected people are asymptomatic and do not show serious sequelae, while others may develop Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations characterised by EBV-infected T or NK cells. These disorders are more common in Asian and Latin American people, suggesting genetic predisposition as a contributing factor. The revised WHO classification classifies the lymphoproliferative diseases as: extranodal NK/T-cell lymphoma nasal type (ENKTL), aggressive NK-cell leukemia (ANKL), primary EBV-positive nodal T or NK cell lymphoma (NNKTL), systemic EBV-positive T-cell lymphoproliferative disease of childhood (STCLC), systemic chronic active EBV infection (sys CAEBV), hydroa-vacciniforme (HV) andsevere mosquito bite allergy (SMBA). Recent advances in the molecular pathogenesis of these diseases have led to the development of new therapeutic strategies. Due to the infrequency of the diseases and broad clinicopathological overlap, the diagnosis and classification are challenging for both clinicians and pathologists. In this article, we aim to review the recent pathological findings which can be helpful for designing new drugs, clinical presentations and differential diagnoses, and suggested therapeutic interventions to provide a better understanding of these rare disorders.

Molecular genetic features of cutaneous T-cell lymphomas development on example of mycosis fungoides and Sezary syndrome

Cutaneous T-cell lymphomas are a heterogeneous group of T-cell lymphoproliferative diseases affecting the skin. Mycosis fungoides and Sezary syndrome are the most studied variants of them. The literature review includes the latest published data on the pathological processes development in mycosis fungoides and Sezary syndrome and the diagnosis of these diseases. The genomic instability features in cutaneous T-cell lymphomas are described, the existing hypotheses of the origin of these diseases are considered based on the results of T-cell receptor repertoire studying.

Modern possibilities of therapy for primary cutaneous T-cell lymphomas: the first results of the use of brentuximab vedotin in the Russian Federation

Background. Primary cutaneous T-cell lymphomas are rare heterogeneous group of lymphoproliferative diseases characterized by primarily involving skin and subcutaneous adipose tissue. Half of these cases are mycosis fungoides (MF), for about 25% are cutaneous CD30+ lymphoproliferative diseases (CD30+ LPD): primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis (LyP). During the initiating treatment of patients with MF and Szary syndrome (SS), carried out on the territory of the Russian Federation, for about 30% of patients are resistant to various therapeutic effects, especially in the later stages. The problem of the treatment of CD30+ LPD is extracutaneous dissemination in case of pcALCL, steadily relapsing course of LyP without symptom-free intervals. These characteristics of the therapy of cutaneous lymphomas demand for the need to search for new treatment options. Brentuximab vedotin, according to the results of the international randomized ALCANZA trial, has shown high efficiency in the treatment of cutaneous T-cell lymphoproliferative diseases. Aim. To evaluate the efficacy of brentuximab vedotin application in patients with cutaneous T-cell lymphomas in adverse risk group received at least one line of systemic therapy. Materials and methods. The study included 21 patients: 16 men and 5 women. The diagnosis of MF was verified in 8 patients, SS in 5 patients, cutaneous CD30+ LPD in 6 patients (5 patients pcALCL, 1 patient LyP) and a primary cutaneous peripheral T-cell lymphoma, unspecified in 2 patients. The diagnosis of cutaneous T-cell lymphoma was verified on the basis of the anamnesis of the disease, on the character of cutaneous lesions, on histological, immunohistochemical and in some cases on molecular genetic testing of the biopted sample of the skin (the assessment of T-cell receptor gene rearrangement). Results. The late stages of the disease were diagnosed in 12 of 13 patients with MF/SS. Extracutaneous lesions were diagnosed in 57% of cases. The median of prior lines therapy was 3 (18 variants of treatment). The overall response to the treatment was achieved in 91% of cases (in 19 of 21 patients): the complete remission was obtained in 53% of cases, very good partial remission in 31% of cases and partial remission in 16% of cases. The progression of the disease was determined in 2 patients (after the first and fourth cycles). Some patients with partial remission as a result of therapy using brentuximab vedotin had the additional therapy (radiation therapy, interferon , the cycles of systemic therapy) and these acts gave an option of achieving deeper antitumor response. The early relapse was diagnosed in 2 of 19 patients who had responded to the treatment. The treatment tolerability was acceptable, and the toxicity did not exceed the already known one described in earlier studies. Thus, the stable overall antitumor response had been persisting in 89% of patients (the median of the observation was 10 months). Conclusion. The use of targeted therapy with brentuximab vedotin gave an option of achieving high treatment results in group of patients with advanced stages of the disease and inefficiency of several lines of therapy.

Concordance Study of CD30 Expression Detected By Multiple Immunohistochemistry Assays and Ventana CD30 Assay in Chinese Lymphoma Patients

Background: CD30 is emerging as an important biomarker guiding the clinical diagnosis, treatment, and evaluating the efficacy and prognosis of lymphoma. However, there is no standard procedure for specification and interpretation of the pathological detection of CD30 in China. This study intends to evaluate the staining and interpretation concordance of CD30 expression detected by the VENTANA CD30 assay and other multiple immunohistochemistry (IHC) assay in Chinese malignant lymphoma patients.Design: This is a multi-center, observational study enrolling 1,000 adult patients with a diagnosis of histologically confirmed malignant lymphoma in China. Patients, aged 18 years or older at diagnosis and who provided available formalin-fixed paraffin-embedded (FFPE) samples stored within 2 years, with diagnosis of classical Hodgkin's lymphoma, anaplastic large-cell lymphoma, large cell transformation of mycosis fungoides, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, extranodal NK/T-cell lymphoma, peripheral T cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, and pcCD30+ T-cell lymphoproliferative disease were eligible to participate. Exclusion criteria included sample insufficiency for CD30 testing, incomplete sample information, lack of written informed consent.Methods: Each eligible patient provides an available r FFPE sample. Tissue slides obtained from each eligible FFPE sample will be stained by the VENTANA CD30 assay and at least one of the following IHC assays [umAB256 (zhongshanjinqiao) + Ventana BenchMark; Ber-H2 (Maixin) + Ventana BenchMark；Ber-H2 (Maixin) + DAKO; Ber-H2 (DAKO) + DAKO; Ber-H2 (DAKO) + Ventana BenchMark;umAB256 (Zhongshanjinqiao) + Leica; JCM182 (Leica) + Ventana BenchMark;JCM182 (Leica) + Leica; Ber-H2 (DAKO) + Leica]. CD30 expression of all immunostained slides will be independently interpreted as a percentage of CD30 positive cells by trained pathologists. The primary endpoint will be the staining concordance of percentages of positive cells for CD30 expression detected by each of the nine IHC assays and VENTANA CD30 assay (interpreted by expert panel) Secondary endpoints will be the interpretation concordance of pathologists at sites and the expert panel by assessing CD30 expression detected by various IHC assays. Both primary and secondary endpoint will be evaluated by intraclass correlation coefficient ICC, Bland-Altman, and Pearson correlation method.Discussion: This planned study will explore more equivalent testing methods to detect the expression of CD30 in Chinese patients with lymphoma. DisclosuresShi: Takeda Pharmaceuticals: Current Employment. Li: Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Receiving lecture fees.

Chronic active Epstein\u2013Barr virus-associated secondary hemophagocytic lymphohistiocytosis in pregnancy: a case report

BackgroundSecondary hemophagocytic lymphohistiocytosis (sHLH) is a rare and fatal disease characterized by uncontrolled immune cell activation that can lead to a cytokine storm. Unfortunately, this condition can occur even during pregnancy, threatening both maternal and fetal lives.Case presentationA 23-year-old nulliparous woman at 26 weeks of gestation presented with continuous fever, coughing, and sore throat. Upon arrival at our hospital, her temperature was >38°C and laboratory findings indicated cytopenia (neutrophil count, 779/μL; hemoglobin level, 10.2 g/dL; platelet count, 29,000/μL), elevated ferritin level (1,308 ng/mL), and elevated soluble interleukin-2 receptor level (11,200 U/mL). Computed tomography showed marked splenomegaly. Bone marrow examination revealed hemophagocytosis, and blood examination showed a plasma Epstein–Barr virus (EBV) DNA level of 8.9 × 105 copies/μg. The monoclonal proliferation of EBV-infected T cells was confirmed by Southern blotting, and the patient was diagnosed with chronic active EBV-associated sHLH and T-cell lymphoproliferative disease. Immediately after admission, the patient’s condition suddenly deteriorated. She developed shock and disseminated intravascular coagulation, requiring endotracheal intubation along with methylprednisolone pulse and etoposide therapy. Although the patient recovered, she delivered a stillborn baby. After delivery, she was treated with reduced-dose dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) and steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapies. Five months after diagnosis, she received human leukocyte antigen-haploidentical allogeneic bone marrow transplantation from her sister. She remains in remission for 5 months from the time of transplantation to the present.ConclusionssHLH, which may cause maternal and fetal death, should be carefully considered in critically ill pregnant women, particularly those presenting with continuous fever and cytopenia.

Tre-P-22 - The primary cutaneous CD30- positive lymphoproliferative diseases; the own observations of the center, prospects of therapy

Primary cutaneous T-cell lymphomas are the heterogeneous group of T-cell lymphoproliferative diseases (LPD), which are developed mainly in the skin and characterized by diagnostic features, clinical course and therapeutic approach. Primary cutaneous anaplastic lymphoma (с-ALCL) and lymphomatoid papulosis (LyP) are diagnosed In a quarter of cases of all T-cell skin lymphomas. The tumor cells in primary cutaneous CD30-positive skin lymphomas express CD30 in more than 75% of cases. The majority of patients with cutaneous CD30+ LPD have an indolent course with a favorable prognosis, the resistant course of disease develops in about 30% of cases and fatal cases from lymphoma are registered in 8% of cases. Most commonly, the treatment of these forms of LPD includes the surgical removal, radiation therapy or small doses of methotrexate, the systemic chemotherapy is used to generalize the process. Recently, monoclonal antibodies have been included in clinical practice for the treatment of skin lymphomas, one of which is brentuximab vedotin, the use of which has shown a rather high efficiency in the treatment of CD30 + skin lymphomas: more than 2/3 of the patients responded to the treatment, despite the many lines of therapy (median of prior effect is 3.1 for c-ALCL). The general group of patients with cutaneous T-cell lymphomas and who received the consultative-diagnostic or inpatient treatment at the National Research Centre of Hematology includes 328 patients. Among them the CD30-positive cutaneous LPD were verified in 33 patients (10%): 16 patients with LyP, 17 patients with c-ALCL. The eruptions were regressed on its own without specific therapy in 75% of patients with LyP and 4 patients received the treatment. As well as one patient with the relapsing course of disease, with a long period of self-regression of the papules, with the lack of the treatment effect (phototherapy and low-dose methotrexate) received brentuximab vedotin (BV). The complete clinical response was achieved after the first cycle of monotherapy with BV and persists for more than a year. Patients with c-ALCL more frequently needed the specific therapy (76% of patients), only 4 patients were observed with the self-regression of the papules within 6-9 weeks. Most patients received the interferon alfa therapy with the complete clinical response; the rest patients - local radiation therapy, the small doses of methotrexate. The systemic chemotherapy was done to the 5 patients. Considering the common process, however 2 of them died from infectious complications during the chemotherapy, 2 patients had early recurrence and only 1 patient is in the long-lasting complete remission after the high-dose of chemotherapy. In summary, the primary cutaneous CD30 + lymphoproliferative diseases cover a spectrum of benign condition with the so-called "malignant" phenotype. LyP and c-ALCL have a favorable prognosis, 5-year survival rate is exceeding 95%, photo- and immunotherapy are successfully used in the treatment, while the use of systemic chemotherapy should be avoided (shortening of the remissions duration, progression of the infectious complications). The use of targeted therapy (brentuximab vedotin) increases the therapeutic ability in the situations where the routine treatment options are ineffective.

NKp46 Is a Useful Diagnostic Biomarker in Gastrointestinal T-Cell Lymphoproliferative Diseases and Constitutes a Therapeutic Target. a Celac Network Study

Introduction:Primary gastrointestinal (GI) T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which diagnoses and therapeutic options remain to be standardized. Beside aggressive lymphoma, such as enteropathy-associated T-cell lymphoma (EATL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), the indolent T-cell lymphoproliferative disease (indolent T-LPD) has been recently described. A differential diagnosis to consider is type II refractory coeliac disease (RCDII) that may complicate CD. Intraepithelial lymphocytes (IEL) from RCDII are dependent for survival on IL-15, which reprograms T-lymphocytes towards a cytotoxic NK phenotype. We previously showed that NKp46 is a new biomarker for both diagnosis and prognosis in GI T-LPD (ICML-2017 Lugano, unpublished).Patients and Methods:The expression of NK receptors was assessed on CD/RCD by flow-cytometry. The number of NKp46 positive IEL per 100 epithelial cells (NKp46+ IEL/100 EC) was studied by immunohistochemistry (IHC) on 195 biopsies from 84 CD/RCD, 44 GI T-cell lymphoma, and on a blinded confirmatory cohort of 48 CD/RCD.8B6A-PBD is an anti-NKp46 monoclonal antibody conjugated (ADC) to a potent cytotoxic drug, pyrrolobenzodiazepine (PBD). For in vivo assessment, tumor-bearing NOD-SCID mice were randomly assigned to PBS, isotype-matched irrelevant Ig-PBD controls, or 8B6A-PBD treatment groups. For ex vivo cytotoxicity assays, isolated cells from fresh small bowel biopsies of RCDII patients were incubated with 8B6A-PBD, Ig-PBD, anti-NKp46 deglycosylated or PBD alone.Results:NKp46 was the only NK receptor that differs between RCDII and CD or RCDI. By doing ROC analysis, a number of NKp46+ IEL/100 EC above 25 clearly discriminated RCDII from CD and RCDI, with excellent positive and negative predictive values of 100 and 95% respectively. Among CD and RCD patients, the survival was shorter if this count is above 25 (OS-5years 72.8% vs. 96.4%, P=0.0004). NKp46 was expressed in EATL (n=20/25) and MEITL (n=4/4) but was never expressed in indolent T-LPD (n=0/15). Positive NKp46 GI T-cell lymphoma had a shorter survival compared to negative NKp46 cases (OS-5years 5.4% vs. 50.5%, P=0.0011).In vivo the anti-NKp46-PBD promoted tumor regression (Fig. B) and prolonged survival (Fig. A) of NOD-SCID mice injected by human NKp46-transfected Raji tumors embedded in matrigel. Ex vivo and as a proof of concept, the anti-NKp46-PBD was highly potent (Fig. D) and selective (Fig. C) against NKp46 positive primary sorted IEL (n=5).Conclusion:NKp46 provides a new biomarker for both diagnosis and prognosis in GI T-LPD. We propose a diagnostic algorithm for GI T-LPD based on the NKp46 expression, which is adapted to immediate, individual patient management. Overall, our results demonstrate for the first time that anti-NKp46 ADC may serve as an effective therapy for RCDII, EATL and MEITL and provide strong preclinical rationale for evaluation of 8B6A-PBD in clinical studies. [Display omitted] DisclosuresCheminant:Innate Pharma: Research Funding. Bruneau:Innate Pharma: Research Funding. Malamut:Cellimmune: Research Funding. Pouyet:MI-mAbs: Employment. Lhospice:Innate Pharma: Employment. Molina:Merck Serono: Honoraria; Takeda: Other: travel support to the ASH meeting; Novartis: Honoraria. Cellier:Cellimmune: Research Funding. Cerf-Bensussan:Cellimmune: Research Funding. Hermine:Novartis: Research Funding; Celgene: Research Funding; AB Science: Equity Ownership, Honoraria, Patents & Royalties, Research Funding; Hybrigenics: Research Funding; INatherys: Equity Ownership, Research Funding.

Indolent T-Cell Lymphoproliferative Disorders of the Gastrointestinal Tract (iTLPD-GI): A Review.

Simple SummaryThis review aims to better define the clinical, pathological, and molecular features of the novel lymphoproliferative disease termed “indolent T-cell lymphoproliferative disorder of the gastro-intestinal tract (iTLPD-GI)”, to discuss potential pitfalls in differentiating this entity from other neoplastic and non-neoplastic disorders arising at the same site, and to point out a biomarker-based approach to the diagnosis.iTLPD-GI is a low-grade clonal T-cell lymphoproliferative disease arising in GI organs. It is an uncommon disease, and only recently has it been enlisted as a distinct provisional entity in the current WHO Classification. Data from the literature disclose high heterogeneity in terms of pathological and molecular features; on the other hand, establishing an accurate diagnosis of iTLPD-GI is of pivotal importance, since treatment options are different from that of other, more frequent lymphomas that arise in the gastrointestinal tract. In this review, we aimed to better define this novel entity, and to identify useful diagnostic biomarkers; moreover, we provide a biomarker-based approach to the diagnosis and describe the most common issues in differentiating iTLPD-GI from other neoplastic and non-neoplastic disorders.

Accumulating Knowledge of EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases of Childhood

Accumulating Knowledge of EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases of Childhood

Systemic T-Cell Lymphoproliferative Disease Associated with Epstein-Barr Virus: A Literature Review and a Case Report

Epstein-Barr virus (EBV) is ubiquitous, being identified in 90-95 % of adults. Its reactivation in immunodeficiency conditions often leads to clonal transformation of B-lymphocytes and development of B-cell lymphoproliferative diseases (LPD) and B-cell lymphomas. At the same time, in the countries of North-East and East Asia, as well as Latin America, non-immunocompromised patients sometimes demonstrate the development of EBV-associated T-cell lymphoproliferative diseases. The present paper reports a rare case of EBV-associated systemic T-LPD with lymphadenopathy, splenomegaly as well as acute autoimmune hemolytic anemia in a man of Caucasian race. Complex analysis of anamnestic, pathomorphological, and laboratory data allowed to distinguish this disease from T-cell lymphoma and choose the appropriate patient management strategy.

Comparison of Systemic EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases (LPD) of Childhood Based on Classification Evolution: New Classification, Old Problems.

Comparison of Systemic EBV-positive T-Cell and NK-Cell Lymphoproliferative Diseases (LPD) of Childhood Based on Classification Evolution: New Classification, Old Problems.

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy.

Indolent T-cell lymphoproliferative disease of the gastrointestinal tract (indolent GI T-LPD) is a benign neoplasm of CD4+ or CD8+ T cells that form primary tumors in the GI tract. Indolent GI T-LPD has recently been provisionally recognized as a distinct entity by the 2016 revision of the WHO classification of lymphoid neoplasms. Appropriate diagnosis of these cases is challenging as they may be misdiagnosed as T cell lymphoma that has an aggressive clinical course. Consequently, aggressive therapeutic approaches were usually chosen to treat these cases with no obvious benefit for most of the patients and potential side effects. Moreover, inflammatory diseases of the GI tract with similar symptoms may lead to misdiagnosis that leads to delays in administration of proper therapeutics against these cases. Therefore, it is of utmost importance to identify prognostic genetic biomarkers at the time of diagnosis for optimal medical care of these patients. TCR clonality analyses may not be useful for distinguishing these benign neoplasms from aggressive gastrointestinal T cell lymphomas; however, molecular genetic tests may prove useful as recurrent STAT3-JAK2 fusions, which may have diagnostic, prognostic or therapeutic value, have recently been identified. However, there is still lack of comprehensive information on the genetic and epigenetic factors associated with pathogenesis of indolent GI T-LPD. In this mini-review, we focus on the so far reported literature on indolent GI T-LPD cases, and discuss future directions for better differential diagnosis, risk stratification, and therapeutic target discovery with a special focus on the genetic and epigenetic alterations.

The application of CytoDiff for the differential diagnosis of reactive and tumor lymphocytosis.

CytoDiff reagent was developed to optimize the performance of a WBC differential evaluation. It determines the main population of white blood cells by the expression of linear markers. One of the additional possibilities of using CytoDiff is the differential diagnosis of reactive and tumor lymphocytosis. We studied peripheral blood samples of 76 patients of the All-Russian Central Research Center A.M. Nikiforova EMERCOM of Russia with absolute lymphocytosis of more than 3,0x109/l. The control group included 26 practically healthy people. All performed a clinical blood test on a 5Diff hematology analyzer with smear microscopy, and determination of leukocyte populations by phenotype using CytoDiff. Reference intervals were determined for subpopulations of lymphocytes using CytoDiff. An algorithm has been developed for evaluating the results obtained when determining leukocyte populations by phenotype using CytoDiff for differential diagnosis of reactive and tumor lymphoproliferation. To detect B-cell lymphoproliferative diseases, the use of a cut-off value of 13% or more of the number of leukocytes is optimal. At low values of the relative number of B-lymphocytes, it is important to take into account the results of microscopy of blood smears. If atypical mononuclear cells are absent in smears, then additional clinical and laboratory studies are necessary to establish the cause of lymphocytosis, including phenotyping of peripheral blood lymphocytes to exclude T-cell lymphoproliferative diseases. The expediency of using the CytoDiff reagent for the differential diagnosis of the reactive and tumor nature of lymphocytosis is shown. Already at the stage of primary screening studies, the use of CytoDiff makes it possible to efficiently collect blood samples from patients with possible lymphoproliferative diseases, which significantly reduces the time required for a diagnostic search.