NK-cell Lymphoma Research Articles

Reactivation of Epstein-Barr Virus Hepatitis in T/Natural Killer (NK) Cells Mimicking Liver T/NK-Cell Lymphoma

Diagnosis of Epstein-Barr virus (EBV)-associated hepatitis, chronic active EBV infection, and EBV-associated lymphoproliferative diseases, is always challenging due to the overlapping symptoms and lack of diagnostic criteria. We report such a case of a 40-year-old man with unremarkable past medical history. He presented with fever of unknown origin for 1 month with jaundice for 2 days. Physical exams were unremarkable with body temperature at 98.6 °F. His liver function tests were elevated with alanine transaminase (ALT) 559 U/L, aspartate transaminase (AST) 892 U/L, alkaline phosphatase 319 U/L and total bilirubin 4.4 mg/dL. Computed tomography of his chest, abdomen and pelvis did not show lymphadenopathy or hepatosplenomegaly. A liver biopsy showed moderately acute hepatitis with hemophagocytosis, positive Epstein-Barr virus encoding RNA (EBER) in situ hybridization in CD3 and CD4-positive T cells and CD56-positive natural killer (NK) cells. CD20 was negative. The pathology diagnosis was consistent with reactivation of EBV hepatitis but NK-cell lymphoma needs to be excluded. Steatohepatitis with mild activity was present. His blood EBV DNA was 846,000 copies/mL and continued to increase to 2,000,000 copies/mL. Flow cytometric analysis of his bone marrow revealed an increased NK-cell activity but no T/NK-cell lymphoma was identified. Initial treatment with rituxan, etoposide and/or ruxolitinib/acyclovir failed or only had limited effect. However, subsequent valganciclovir greatly improved his conditions. In his 3 months follow-up, the patient was doing well with almost normal liver function tests except mildly elevated ALT (95 U/L) that was due to mild steatohepatitis. EBV DNA PCR was 2,009 copies/mL. To the best of our knowledge, this is the first documented case with reactivation of EBV hepatitis mimicking NK-cell lymphoma in the English literature. With appropriate anti-EBV viral treatments, the patient eventually became asymptomatic and was able to return to his routine life.

Güneydoğu Anadolu Bölgesindeki Non-Hodgkin Lenfoma Sınıflaması: 550 Hastanın İncelenmesi

Background: The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world. In this study we aimed to evaluate the gender, age, subtypes, biopsy sites, nodal and extranodal residential area, and stage of disease in the patients with NHL admitted to our hospital between January 2005 and December 2014.Materials and Methods: The records of NHL patients admitted to our hospital between January 2005 and December 2014 were retrospectively reviewed Results: Among 550 patients, 335 patients (60.9%) were male, 215 patients (39.1%) were female. The average age of over all the patients was 56 years (15-95). The average age of women was 57 (15-88), the average age of men was 54 years (15-95). The histological subtypes of NHL patients were as follows: 447 patients (81.3%) B-cell lymphoma, 84 patients (15.2%) T / NK cell lymphoma, 19 patients (3.5%) unclassified subtype. NHL patients divided into subtypes according to 2001 and 2008 WHO (World Health Organization) Classification and histopathologic subtypes were as follow: Diffuse Large B Cell Lymphoma (DLBCL) 295 patients (53,63%), small lymphocytic lymphoma (SLL) 37 patients (6.7%), Extranodal marginal zone lymphoma (MALT type) 37 patients (6,75%), peripheral T-cell Lymphoma 27 patients (4.9%), mantle cell lymphoma 26 patients (4.72%), Nodal Marginal Zone B-Cell Lymphoma 7 patients (1,3%), follicular lymphoma in 12 patients (2.1%), Burkitt's lymphoma 7 patients (1.3%), Splenic marginal zone B-cell lymphoma 4 patients (0,7). The most common subtype of NHL was DLBCL 295 patients (53,63%). Follicular lymphomas are less common in our center. Extranodal involvement rate was 38,5% of patients. According to the distribution of the sites of extranodal NHLs, the vast majority of patients 43% had GI tract involvement. The most commonly affected GI sites were stomach (27,8%). In this study 22.9% of the patients were in Stage 1, 26.7% in Stage 2, 19.5% in Stage 3, 30.9% in Stage 4 according to Ann- Arbor classification. In conclusion, the characteristics of NHLs in our region show some differences from other sites of the world. Conclusions: The characteristics of NHL patients vary according to geographical differences. Present study has revealed the importance of geriatric assessment. NHL was observed frequently in men. Environmental risk factors have to research, epidemiologically. The most common subtype of NHL was DLBL. Follicular lymphomas are less common in our center. Improvement of national cancer registration system and multicenter large-scale studies reviewing the treatment protocols are needed to ensure the early diagnosis and therapy of NHL.

Lymphomas arising in immune-privileged sites: insights into biology, diagnosis, and pathogenesis.

Session 2 of the 2018 European Association of Hematopathology/Society for Hematopathology Workshop focused on lymphomas arising in immune-privileged sites: both lymphomas arising in the traditionally described "immune sanctuary" sites of the central nervous system (CNS) and testes, as well as those arising at sites of local immune privilege. Primary CNS large B cell lymphoma and primary testicular large B cell lymphoma were discussed, and the biology of these unique tumors was highlighted by several cases showing the classic mutation profile including MYD88 L265P and CD79B. The tendency of these tumors to involve both the CNS and testis was also reinforced by several cases. Four cases of low-grade B cell lymphomas (LGBCL) of the CNS were discussed. Two were classic Bing-Neel syndrome associated with LPL, and two were LGBCL with plasmacytic differentiation and amyloid deposition without systemic disease. Rare examples of systemic T and NK cell lymphomas involving the CNS were also discussed. Several cases of breast implant-associated anaplastic large cell lymphoma (BI-ALCL) were submitted showing the typical clinicopathologic features. These cases were discussed along with a case with analogous features arising in a patient with a gastric band implant, as well as large B cell lymphomas arising alongside foreign materials. Finally, large B cell lymphomas arising in effusions or localized sites of chronic inflammation (fibrin-associated diffuse large B cell lymphoma [DLBCL] and DLBCL associated with chronic inflammation) were described. The pathogenesis of all of these lymphomas is believed to be related to decreased immune surveillance, either innate to the physiology of the organ or acquired at a local site.

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis.

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) "primary EBV-positive nodal T or NK cell lymphoma". Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms - which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.

Linfoma de células t periférico, no especificado. Estudio clínico-patológico en una cohorte de pacientes peruanos

Objetivos. La última clasifcación de la OMS de neoplasias hematopoyéticasy linfoides considera 29 linfomas de células T y NK maduras. Una de estas,corresponde al linfoma de células T periférico, sin otra especifcación (LCTPNOS). El objetivo de esta investigación fue evaluar las características clínicopatológicas de esta enfermedad y su asociación con infección por VEB en relación con la sobrevida global (SG). Métodos. Se estudiaron 65 casoscon diagnóstico de LCTP-NOS en el Instituto Nacional de EnfermedadesNeoplásicas, durante un periodo de 6 años. Se evaluaron las característicasclínico-patológicas y se comparó la SG y otros parámetros clínicos entre loscasos con infección y sin infección por VEB. Resultados. Hubo un 45 % decasos positivos para VEB. El promedio de edad fue de 50 años y hubo un 29 %de mujeres. La proporción de pacientes con y sin síntomas B fue similar. Losestadios fueron usualmente avanzados, con lactato deshidrogenasa elevada.El índice pronóstico internacional fue intermedio-alto o alto en la mayorparte de los casos. La SG en todos los casos a 5 años fue en promedio de un29,4 %. En general la respuesta al tratamiento con quimioterapia fue pobre.Aunque los casos VEB positivos tuvieron peor SG que los VEB negativos, ladiferencia no fue estadísticamente signifcativa. Hubo diferencia signifcativapara los síntomas B, siendo más frecuentes en los casos VEB positivos.También se encontró diferencia estadísticamente signifcativa en la SG a lostres años entre los LCTP-NOS VEB positivos con fenotipo citotóxico vs, los queno tuvieron fenotipo citotóxico. Conclusiones. El LCTP-NOS es una neoplasiade mal pronóstico, con baja SG y pobre respuesta al tratamiento conquimioterapia. Para una mejor valoración de la infección del VEB como factorpronóstico, se deben considerar la cantidad y tipo de linfocitos infectados.

Preliminary Results from a Multicenter, Single-Arm, Phase 2 Study of CS1001, an Anti-Programmed Death-Ligand 1 (PD-L1) Human Monoclonal Antibody (mAb), in Patients (pts) with Relapsed or Refractory Extranodal Natural Killer/T Cell Lymphoma (rr-ENKTL)

Background ENKTL is a subtype of mature T cell and NK cell lymphoma, with a higher incidence in Asia than in Europe and North America. Pts with rr-ENKTL have a poor prognosis after failing an L-asparaginase-based regimen, and lack effective treatment. Epstein-Barr virus (EBV) infection is one of the mechanisms and characteristics of ENKTL, which induces immune tolerance of tumor by upgrading PD-L1 expression in tumor cells. Blocking the PD-1 pathway could, therefore, be an effective treatment for ENKTL. A Phase 2 trial is being conducted to evaluate CS1001, a first full-length, fully human immunoglobulin G4 (IgG4) mAb directed against PD-L1, in pts with rr-ENKTL. Method This is a multicenter, single-arm, Phase 2 clinical trial to evaluate CS1001 monotherapy in rr-ENKTL. Pts aged 18-75 years with rr-ENKTL after failing prior asparaginase-based chemotherapy or chemoradiotherapy were eligible if they had ECOG performance status (PS) ≤ 1, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. All the pts will receive CS1001 1200 mg intravenously every 3 weeks for up to 2 years, until disease progression, intolerance, etc. The primary endpoint was objective response rate (ORR) assessed by an independent radiological review committee (IRRC) per Lugano 2014 criteria. Key secondary endpoints included ORR by investigators, complete and partial response rate, time to response, duration of response (DoR) and progression-free survival, overall survival and safety. Adverse events (AEs) were summarized according to NCI CTCAE v4.03. Result As of June 17, 2019, 29 pts (male: 16, 55.2%; median age: 44 years, range 30-74) were enrolled. Twenty (20, 69.0%) pts entering the study had an ECOG PS of 1. Twenty-two (22, 75.9%) pts had Stage IV of disease at screening. Eight (8, 27.6%) pts received 2 lines of prior systemic therapy and 6 (20.7%) pts received ≥3 lines of prior systemic therapy. The median duration of follow-up was 5.55 (range, 0.69-12.19) months. Among the 22 efficacy-evaluable pts, the investigator-assessed ORR was 40.9%. A total of 7 (31.8%) pts achieved complete response (CR), and 2 (9.1%) pts had partial response (PR); 1 additional pt achieved PR after pseudo-progression. The DoR ranged from 0.03+ to 8.61+ months; median DoR was not achieved. All CR pts were still in remission. The IRRC assessments were not available at the time of data cut-off. The median duration of treatment was 11.7 (range, 2.9 to 53.0) weeks. Fifteen (15, 51.7%) pts remained on treatment and 14 (48.3%) had discontinued from study treatment (12 due to progressive disease, 2 due to AEs). The majority of pts (25, 86.2%) had treatment-emergent AEs (TEAEs), of whom 21 (72.4%) pts reported treatment-related AEs (TRAEs). The most frequently reported (≥10%) TRAEs were pyrexia (6, 20.7%), blood thyroid stimulating hormone increased (4, 13.8%), white blood cell count decreased (4, 13.8%), and rash (3, 10.3%). Three (3, 10.3%) pts reported Grade (G) ≥3 TRAEs. Two (2) G5 AEs (death and haemophagocytic lymphohistiocytosis) were reported in 2 pts; none was assessed as related to CS1001 by the investigators. Serious AEs were observed in 5 (17.2%) pts, and 1 of them (sinus node dysfunction) was assessed as related to CS1001 by the investigator. Immune-related AEs (irAEs) were reported in 5 pts, including a G3 rash and the remaining irAEs were G1. TEAEs that led to permanent treatment discontinuation occurred in 2 (6.9%) pts, which included haemophagocytic lymphohistiocytosis (G5) and facial nerve disorder (G2). No death or permanent discontinuation due to AEs were assessed as related to the study drug. After data cut-off date, 3 additional pts reached response assessment time point, of which 2 pts achieved CR, resulting in ORR of 44% (11/25) and a CR rate of 36% (9/25). The updated data will be reported at the ASH conference. Conclusion In this study, CS1001 was shown to be active with a high CR rate and durable response, and was generally well-tolerated in pts with rr-ENKTL. The preliminary safety and efficacy profile of CS1001 support further exploration and development of CS1001 in rr-ENKTL pts. Disclosures No relevant conflicts of interest to declare.

PMU148 CUTANEOUS LYMPHOMAS IN GERMANY: LANDSCAPING ANALYSIS OF GERMAN STATUTORY HEALTH INSURANCE (SHI) CLAIMS DATA

Cutaneous T-cell lymphomas are a rare group of non-Hodgkin lymphomas with heterogeneous characteristics. The most common subtype is mycosis fungoides (MF), which manifests primarily on the skin. However, a large body of evidence is missing on patients with mature T/NK-cell lymphoma in the context of care research, particularly on patients with MF and Sézary syndrome (SS). This study therefore serves to provide reliable and representative epidemiological data on CTCL in Germany. The study was based on a retrospective analysis of a six-year (2012-2017) anonymized age- and sex-adjusted database from the German statutory health insurance (SHI) claims data system, providing a representative sample of ∼4,8 million insurants, which accounts for approx. 5.5% of the total German population. Patients received at least one full or semi-residential inpatient diagnosis or two confirmed outpatient diagnoses in different quarters of the year (C84* ICD-10 GM). Based on a cross-sectional study design, epidemiological data were obtained from continuously insured patients diagnosed with mature T/NK cell lymphoma and subtypes (all stages of disease were included). 1,336 prevalent patients diagnosed with cutaneous T-cell and NK-cell lymphoma (C84* ICD-10-GM) were identified out of 3,065,485 continuously insured persons in the database (2012-2017), revealing a prevalence rate of 0.0436%. The number of patients with mature T/NK-cell lymphoma has increased by 14% from 2012 to 2017. The annual mortality of the study population was 7%. Two-thirds of the patients (65%) were male and the average age was 66 years (SD± 15.09). Subgroup analysis revealed that MF (C84.0 ICD-10 GM) showed the largest patient group, whereas SS (C84.1 ICD-10-GM) demonstrated the smallest subcohort. The study provides real-world evidence on the administrative prevalence of cutaneous lymphoma in Germany. Key findings regarding age and gender distribution as well as prevalence of MF and SS patients were aligning with other international studies.

Gastrointestinal T- and NK-cell lymphomas and indolent lymphoproliferative disorders

Primary gastrointestinal (GI) T- and NK-cell lymphomas constitute a heterogeneous group of uncommon and aggressive neoplasms, which have unique clinical and pathologic features. The intestines are the most frequent sites of disease, but almost any GI organ may be involved. Enteropathy associated T-cell lymphoma (formerly EATL type 1) and monomorphic epitheliotropic intestinal T-cell lymphoma (formerly EATL type 2) represent the two most common entities. However, other types of peripheral T-cell lymphomas can also occur in the GI tract or involve it secondarily. Moreover, indolent T- and NK-cell lymphoproliferative disorders (LPDs) of the GI tract have also recently been recognized. In this review, we describe the salient clinical, histopathologic, immunophenotypic, and molecular characteristics of primary GI T/NK-cell lymphomas and indolent LPDs, which form the basis for classification of the different entities, and an algorithmic approach to the diagnosis of these rare diseases.

Abstract 2319: Accumulation and anti-tumor effect of chimeric antigen receptor (CAR) NK cells in metastasis uveal melanoma

Abstract Introduction: Metastatic uveal melanoma (MUM) is resistant to currently available treatments and overall prognosis is poor. MUM is an “immune cold” tumor and immune checkpoint blockades have only a marginal effect on this tumor. To bring immune cells to the tumor site and change the tumor microenvironment, we developed Chimeric Antigen Receptor (CAR)-NK cells targeting high molecular weight melanoma associated antigen (HMW-MAA/CPSG4). Methods: NK92 cell line derived from NK cell lymphoma was obtained from the American Type Culture Collection (ATCC). NK92 cells were transfected with retroviral pBMN-I vector co-expressing Green Fluorescent Protein (GFP) and anti-HMW-MAA-CD28-CD3z CAR construct. The efficacy of CAR construct transfection was confirmed by expression of His-Tag and F(ab)2 by using BD FACS Celesta flow cytometry. MUM cell line, TJU-UM001, was established from a hepatic metastasis of a uveal melanoma patient in our institution. TJU-UM001 cells have approximately 37,000 HMW-MAA molecules on their surface and are sensitive to NK92 cell killing. Tdtomato-transfected TJU-UM001 cells (106 cells) were intra-hepatically implanted into NOD-scid IL2Rgammanull (NSG) mice. Once establishment of hepatic tumor was confirmed by IVIS 200 imaging system (PerkinElmer) at Red Fluorescent Protein (RFP) excitation 535nm, 3 x 106 CAR-NK92 cells or NK92 cells without CAR constructs were injected into the spleen. Accumulations of GFP+ NK92 cells in the TJU-UM001 tumors in the liver were analyzed under fluorescence microscopy. In a separate experiment, 107 TJU-UM001 cells were subcutaneously implanted into NSG mice. The size of subcutaneous tumor was measured by Caliper. Once tumor became palpable (7-10 mm), 3 x 106 CAR- or non-CAR NK92 cells were directly injected to the MUM tumors. Forty thousand units of human IL-2 were intra-peritoneally injected into mouse once daily for 4 consecutive days after NK92 cell injections. Results: There were expressions of both His-tag and F(ab)2 on CAR-GFP NK92 cells. GFP and CD54 (ICAM-1) were expressed on 95% and 90% of CAR-GFP NK92 cells, respectively. There was no cross-expression of GFP or human CD54 on mouse cells. Therefore, GFP and CD54 were confirmed to be reliable markers for tracking CAR-GFP NK92 cells in mice. Both CAR- and non-CAR NK92 cells exhibited suppression of TJU-UM001 cell proliferation in in vitro assay. Direct injections of both CAR- and non-CAR NK92 cells showed anti-tumor growth effects on subcutaneously implanted TJU-UM001 tumors. More importantly, via splenic injection, CAR-NK92 cells accumulated selectively in the MUM tumors in the liver, while non-CAR NK92 cells were randomly distributed to normal liver tissue and the MUM tumors. These results support the rationale for hepatic arterial infusion of CAR-NK cells as treatment for uveal melanoma patients with hepatic metastasis. Citation Format: Bao Quoc Lam, Takahito Sugase, Mizue Terai, Meggie Danielson, Nadezhda Anikeyeva, Melissa A. Wilson, Yuri Sykulev, Takami Sato. Accumulation and anti-tumor effect of chimeric antigen receptor (CAR) NK cells in metastasis uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2319.

PB1794 EXTRANODAL NK/T CELL LYMPHOMA NASAL TYPE, A TERCIARY CENTER EXPERIENCE IN CENTRAL MEXICO

Background:Extranodal NK/T‐cell lymphoma (ENKTL) nasal type, is relatively rare, although the incidence has risen over the past century, the frequency varies in different geographic regions and racial populations, representing only 10–15% of all non‐Hodgkin lymphomas. It is usually clinically aggressive, originating from post‐thymic T‐lymphocytes and NK‐cellsAims:Our interest in ENKTCL nasal type is due to the prevalence of this entity in Mexico, which is comparable to that of countries with the most cases reported. This study aims to report our experience with ENKTCL nasal type, their main clinical and analytical characteristics and the impact they may have on response in a third level reference hospital in central MexicoMethods:A retrospective observational study was conducted, we collected all cases of patients with histopathological diagnosis of extranodal NK/T cell lymphoma nasal type from January 2013 to January 2019 in an attempt to examine clinical and analytical features, 56 patients were included. Data on clinical history, physical examination, performance status, baseline hematological and biochemical parameters, histology, imaging and bone marrow studies were collected from the computer database. The study included biopsy/excision material of patients registered within the hospital. Treatment records and responses were collectedResults:Information was obtained from 56 patients (30 men, 26 women) with a mean age of 39.6 years (16‐78 years); 58.9% of patients had B symptoms, in 57% some infection was identified, 7% had some hemorrhagic event, none of the patients had thrombotic manifestations, 3.6% were identified with infiltration to bone marrow, in 7.1% patients CNS infiltration was identified through cytological analisis, 69.6% presented with early clinical stages, all this at the time of diagnosis. Regimens that included L‐Asparginase were administered to 28 patients (50%), 5 did not receive treatment due to early mortality related to the disease and the rest received CHOP‐like regimens, 67.7% received radiochemotherapy as first line treatment. Median overall survival was 6 years. In the univariate analysis of prognostic factors, it was identified that hemoglobin less than 10 gr/dL (p < 0.01) and albumin less than 3.4 gr/dL (p < 0.02) had an impact on survival. No difference was observed in overall survival (OS) based on the received chemotherapy regimen, we did however observed OS was better in those who received concomitant radiotherapy with the first‐line regimen (p < 0.05).Summary/Conclusion:Extranodal nasal T‐cell / NK cell lymphoma is a relatively common neoplasm in Mexico, it is aggressive and with a high mortality. Our study did identify differences in overall survival in terms of some readily available tests, and since Mexico is a region with a higher prevalence in this type of lymphoma, more and better epidemiological and translational studies would be beneficial in our understanding of this entitiy in order to identify prognostic factors and potential therapeutic targetsimage

Emerging Trends in Chimeric Antigen Receptor T-Cell Immunotherapy in Young Adults and Pediatric Patients from the Vizient Clinical Database

Introduction Chimeric Antigen Receptor T-cell (CAR-T) Immunotherapy was approved by the FDA in 2017 for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL), as well as adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. CAR-T immunotherapy uses a patient's own T cells and modifies them in a laboratory to recognize and kill the patient's cancer. Since the CAR-T modified cells multiply and persist in the patient's bloodstream, they have the potential to protect the patient against recurrence. Beginning October 1, 2017, two new, unique ICD-10 procedure codes were assigned to CAR-T immunotherapy (XW033C3 for peripheral venous route and XW043C3 for central venous route), allowing for tracking of the procedure in administrative datasets. Objectives To describe trends in young adult patient populations, outcomes, and hospitals using the CAR-T procedure codes in administrative data. Methods A retrospective cohort of 40 patients under 25 years undergoing CAR-T procedures was identified from the Vizient Clinical Data Base / Resource Manager from 20 hospitals between October 2017 and August 2018. Results For the 40 patients, 30 of the 40 had a diagnosis of ALL. Eight of the remaining 10 patients had diagnoses of large B-cell lymphoma, one patient had blastic NK-cell lymphoma, and one patient had acute myoblastic lymphoma. The median length of stay was 17 days, the median ICU stay was 0 days, the median total cost of hospitalization for CAR-T encounter was $280,276 and median direct cost was $152,633. During the initial hospitalization, 23 (57.5%) of patients had an adverse event due to the immunotherapy. 20 patients (50.0%) had fever, 9 (22.5%) had sepsis and 7 (17.5%) had acute kidney failure and 3 patients (7.5%) had an in-hospital death. Within 30 days, 6 patients (15.0%) had an unplanned readmission to the index hospital, 2 (0.5%) with sepsis and 2 (0.5%) with an adverse event due to the immunotherapy. Conclusion Due to the recent implementation of the unique ICD-10 codes, more time and follow-up for these young adult patients is needed to determine outcomes for pediatric cancer patients receiving CAR-T immunotherapy, especially to track significant adverse events, including potentially cytokine release syndrome, neurologic complications and kidney/liver failure.

Mature T- and NK-cell lymphomas

Mature T- and NK-cell neoplasms are a heterogeneous hematological malignancy. The current treatment of mature T- and NK-cell lymphoma depends on combination chemotherapy with or without auto/allogeneic hematopoietic stem cell transplantation. Recent comprehensive, integrated genetic analyses have revealed distinct genetic and molecular subgroups, which are related to different therapeutic responses. Thus, the genetic landscape of mature T- and NK-cell neoplasms is essential for the development of novel treatment modalities and offers opportunities for individualized therapy. This review aims to discuss the recent progress regarding genetic and molecular analyses of mature T- and NK-cell neoplasms toward stratified therapy.

Epidemiology and Pathology of T- and NK-Cell Lymphomas.

This review will describe and update readers on the recent changes in the 2017 WHO classification regarding peripheral T-cell lymphomas. Signficant advances in molecular studies have resulted in revisions to the classification as well as introduction to provisional entities such as breast implant-associated ALCL and nodal PTCL with T-follicular helper phenotype. Major advances in molecular and gene expression profiling has expanded our knowledge of these rare and aggressive diseases.

Treatment progress of peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL), also known as mature T-cell lymphoma, is a group of malignant proliferative diseases derived from mature T cells. Because natural killer (NK) cells are similar in immunophenotype and function to T cells, NK-cell lymphoma and mature T-cell lymphoma are often classified as one class. The 60th American Society of Hematology (ASH) Annual Meeting has covered various fields about PTCL, especially in terms of treatment. Brentuximab vedotin combined with CHP regimen, histone deacetylase inhibitor combined with HMA regimen, and classic CHOP regimen together with lenalidomide or alemtuzumab provide new options for the treatment of PTCL patients; novel drugs represented by JAK inhibitors, daratumumab, and TP53 inhibitors have also initially demonstrated clinical utility, but large-scale clinical trials are still needed for validation. Key words: Lymphoma, T-cell, peripheral; Treatment

Prognostic Value of Interim and End-of-Treatment PET-CT in Patients with Mature T-Cell and NK-Cell Lymphomas: A 10-Year Single Institution Study

Background: Positron emission tomography combined with computed tomography (PET-CT) has been widely used for initial staging and monitoring of treatment response in patients with malignant lymphomas. The predictive value of interim PET-CT (iPET) and end-of-treatment PET-CT (ePET) is well-established for patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. However, there are limited data on their prognostic values in patients with mature T-cell and NK-cell lymphomas. In this study, we aimed to assess the value of iPET and ePET in the prediction of progression-free survival (PFS) and overall survival (OS) in patients with mature T-cell and NK-cell lymphomas.Methods: Data of 99 patients with mature T/NK-cell lymphomas who underwent iPET (after 2-4 cycles of chemotherapy; performed just before the next cycle) or ePET at the Kameda Medical Center were retrospectively analyzed. PET-CT scans were scored as positive or negative based on the Deauville score using a 5-point scale. While a Deauville score of 1-3 was considered to indicate complete metabolic response (CMR) (negative), a score of 4-5 was considered as persistent or progressive disease (positive). Standardized uptake value (SUV) was normalized relative to the injected dose and lean body mass and was measured for all lesions. The highest SUV for each scan was recorded as maximum SUV (SUVmax). To quantitatively interpret iPET scans, we determined the rate of reduction in SUVmax between baseline and iPET (ΔSUVmax). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test.Results: In total, 99 patients, including patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (n = 36), angioimmunoblastic T-cell lymphoma (AITL) (n = 28), anaplastic large cell lymphoma (ALCL) (n = 6), adult T-cell leukemia/lymphoma (ATLL) (n = 14), enteropathy-associated T-cell lymphoma (EATL) (n = 2), cutaneous T-cell lymphoma (CTCL) (n = 3), and NK/T-cell lymphoma (NKTCL) (n = 10), participated in this study. Of all patients, 55 (56%) were men, and the median age was 48 (range: 22-78) years. The majority of patients, except those with ATLL and NKTCL, were treated with CHOP or CHOP-like chemotherapy. After a median follow-up of 26 months, the 5-year PFS and OS rates for all patients were 24% and 41%, respectively. While 98 patients (99%) underwent iPET, 60 of them (61%) underwent ePET. Baseline PET-CT scan was positive in all cases, and the median SUVmax was 12.8 (range: 2.6-37.4). Using the ROC curve, ΔSUVmax values between baseline and iPET of >79% and >73% were predictive of better PFS and OS, respectively (PFS: sensitivity 77%, specificity 69%, area under the curve [AUC] 0.82, 95% confidence interval [CI] = 0.68-0.88 and OS: sensitivity 78%, specificity 63%, AUC 0.78, 95% CI = 0.62-0.83).While iPET results were negative in 49 of 98 (50%) cases, ePET results were negative in 35 of 60 (59%) cases. The proportion of patients with PTCL-NOS, AITL, ALCL, ATLL, EATL, CTCL, and NKTCL who achieved CMR with iPET or ePET were 53% (19/36), 82% (23/28), 67% (4/6), 36% (5/14), 50% (1/2), 67% (2/3), and 80% (8/10), respectively. The 5-year PFS and OS were significantly longer in patients with negative results on both iPET (PFS: 41% vs. 7%, p < 0.0001; OS: 67% vs. 15%, p < 0.0001) and ePET (PFS: 39% vs. 0%, p < 0.0001; OS: 72% vs. 11%, p < 0.0001).Conclusion: These results indicate that iPET and ePET are good predictors of PFS and OS in patients with mature T-cell and NK-cell lymphomas. Furthermore, our findings highlight the significance of iPET findings in the early identification of potential candidates for an intensive therapeutic strategy, with the aim of improving clinical outcomes. Risk-adapted treatment strategies based on iPET and ePET findings should be investigated in larger and prospective clinical trials. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Outcomes of Allogeneic Stem Cell Transplant in Peripheral T-Cell Lymphoma

Abstract Introduction: Peripheral T-cell Lymphoma represents a heterogeneous group of lymphoid malignancies characterized by poor prognosis with 5-year overall survival (OS) about 25% with conventional chemotherapy. Autologous stem cell transplant (Auto-SCT), as consolidation, is often considered in first complete remission (CR), providing between 30 to 40% long term disease-free survival. However, patients receiving Auto-SCT in second CR or with refractory disease have poor outcomes with progression-free survival ranging from 15-20% to 0%, respectively. In such cases, allogeneic stem cell transplant (Allo-SCT) may provide long term disease control. We intended to study outcomes of Allo-SCT in peripheral T-cell lymphoma patients. Methods: We have retrospectively evaluated long-term outcomes of adult peripheral T-cell lymphoma patients at Karmanos Cancer Institute. The objectives were to determine GVHD rate, overall survival (OS), relapse rate, progression-free survival (PFS) and non-relapse mortality (NRM) following Allo-SCT. Results: Between January 2005 and December 2017, 39 patients underwent Allo-SCT. The different diagnoses included peripheral T-cell lymphoma, not-otherwise-specified (n=16), angioimmunoblastic T-cell lymphoma (n=8), anaplastic T-cell lymphoma (n=8), hepatosplenic T-cell lymphoma (n=2), cutaneous T-cell (n=3) and NK cell lymphoma (n=2). The median age at transplant was 50 years (range, 21-67). The median number of prior therapies was 2 (range, 1-5) and 12 patients (31%) had failed prior Auto-SCT. Sixteen patients (41%) were in CR and 2 (5%) were in partial remission at the time of Allo-SCT, whereas 12 (31%) patients had relapsed disease and 9 (23%) had refractory disease. Twenty-one patients (54%) received matched related and 18 patients (46%) had unrelated Allo-SCT. Myeloablative conditioning regimen was used in 22 patients (56%), whereas reduced intensity regimen was used in 17 (44%) patients. Grade III-IV acute GVHD occurred in 25.6% (95% CI, 13.2-40.1%) and chronic GVHD occurred in 41% (95% CI, 25.1-56.3%). After a median follow-up of 3.08 years (95% CI, 2.49-7.28) among surviving patients, the estimated probabilities of 3-year OS and PFS were 35.9% (95% CI, 22.4-57.6%) and 32.5% (95% CI, 19.9-53%), respectively. The 3-year relapse rate was 23.9% (95% CI, 11.5-38.7%), whereas NRM was 35.9% (95% CI, 21.1-50.9%). No difference in OS and PFS was noticed in patients receiving Allo-SCT in first CR compared with patients receiving Allo-SCT beyond first CR (p=0.81; p=0.94). Similarly, no difference in OS and PFS was noted in patients with Allo-SCT followed by failed prior Auto-SCT compared with patients with upfront Allo-SCT (p=0.31; p=0.47). Seventeen of 39 patients were alive and 22 were deceased (n=7 disease relapse; n=15 NRM). Out of 39 patients, 13 (33%) alive patients are free of relapse and GVHD as of data analysis. Conclusion: Our study suggests that Allo-SCT is a viable treatment option for peripheral T-cell lymphoma and appears to provide cure in these highly selected patients. The survival advantage was noted in patients beyond first remission; therefore, it should be considered in all transplant eligible patients. In addition, certain proportion of patients who failed prior Auto-SCT benefited from Allo-SCT, which points towards potential role of graft-versus-lymphoma effect. Disclosures Deol: Novartis: Consultancy; Kite Pharmaceuticals: Consultancy.

Hemophagocytic Lymphohistiocytosis in Early Infancy- Pitfall of Differentiation between Hereditary and Infectious Reasons

Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell activity and high level of soluble interleukin-2 receptor.Here we present a 6-month-old girl with parents from Southern Italy. She suffered from hepatosplenomegaly and a recurrent high fever for 3 months' duration. On admission, she showed neurological symptoms including irritability and neck stiffness. Blood analysis revealed bicytopenia, namely anemia and thrombocytopenia. The first bone marrow aspirate was indicative for neither malignancies nor HLH. At this time, additional investigations indicated macrophage activation syndrome with elevated ferritin value (11.741ng/ml), soluble interleukin-2 receptor (CD25) levels (16.018U/ml), hypertriglyceridemia (582mg/dl) supportive of the diagnosis of HLH. Because of the worsening of her clinical condition, a second bone marrow aspirate and biopsy was performed 5 days later when the child became pancytopenic. The second bone marrow aspirate still did not show morphological signs of HLH, but microorganisms were detected in at least one macrophage, which were consecutively diagnosed as Leishmania amastigotes within macrophages by positive Leishmanial polymerase chain reaction from bone marrow specimen. Consistent with the diagnosis of visceral Leishmaniasis Amphotericin B (liposomal) therapy was initiated which resulted in dramatic resolution of fever, splenomegaly, ferritin levels, and recovery of blood counts within 96 hours.Familial hemophagocytic lymphohistiocytosis (FHL) manifests as acute illness with prolonged fever, cytopenias and hepatosplenomegaly. Onset typically occurs within the first months of life. Other findings include liver dysfunction and bone marrow hemophagocytosis. The median survival of children with typical FHL, without treatment, is less than two months. Acquired HLH is typically associated with T-/NK-cell lymphomas and autoimmune diseases but also with infections including EBV, malaria and Leishmaniasis. Even in non-endemic areas, our case of vertically transmitted Leishmaniasis highlights the importance of recognizing infectious etiologies of HLH compared with hereditary forms of HLH in early infancy to initiate appropriate therapy to prevent life-threatening complications. DisclosuresRusso:Novo Nordisk: Other: conference fee, travel and accomodation support ; Octapharma: Other: conference fee, travel and accomodation support. Lammle:Baxter: Other: congress travel and accomodation support ; Ablynx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: congress travel and accomodation support ; Siemens: Honoraria, Other: congress travel and accomodation support ; Bayer: Honoraria, Other: congress travel and accomodation support; Alexion: Other: congress travel and accomodation support .

Diffuse Large B Cell Lymphoma in an Adolescent: A Challenging Case with Intracerebral and Retinal Involvement

Diffuse large B-cell lymphoma (DLBCL) is a rare lymphoma type in pediatric patients with usually good prognosis. We present the difficult diagnostic procedure and the complicated course in an adolescent patient with DLBCL.Case report: The 16-year-old female patient presented with a history of fever episodes during the past 3 weeks, hepatosplenomegaly, leukopenia, anemia, hypertriglyceridemia, massive hyperferritinemia and elevation of lactate dehydrogenase. Leukemia was excluded by bone marrow puncture. Initially, no significant lymph node enlargement was detected by imaging of the mediastinum and the abdomen but a pathological signal of the bone marrow could be observed in magnetic resonance imaging (MRI). Hemophagocytic lymphohistiocytosis (HLH) was diagnosed and the patient was treated with prednisone 0.5 mg/kg per day. The overall condition and the laboratory values improved but deteriorated on cessation of the steroid treatment. The result of the bone marrow biopsy then revealed an infiltration of a malignant B-cell lymphoma. Diagnosis of a DLBCL, Non-GCB-type with a BCL6-break was subsequently made in a biopsy of a lymphnode which had shown increased uptake in PET scan. Treatment according to the current NHL-BFM registry including administration of Rituximab was started. The course of disease was complicated by HLH symptoms with persistent fever and pancytopenia, renal failure, severe Methotrexate excretion failure requiring Carboxypeptidase treatment and Herpes virus encephalitis. After recovery progression of DLBCL was found and the treatment was switched to DA-EPOCH regimen and repeated systemic Rituximab administrations. Five months after diagnosis the girl suffered from visual impairment and convulsions. Ophthalmoscopy revealed retinal lesions and intracerebral lesions were detected by MRI but no abnormalities of cerebrospinal fluid (CSF) were found. Biopsy of a brain lesion confirmed cerebral involvement of DLBCL. Intensified treatment included high- dose steroids, cranio-spinal irradiation, high-dose Cytarabin and intrathecal Rituximab. Response of the cerebral lesions but no improvement of the visual impairment was found. Salvage treatment with Gemcitabin, Cisplatin and Rituximab was administered because of persistent nodal and extranodal lymphoma manifestations. The patient finally died due to refractory disease and severe bone marrow failure.Conclusion: This case of DLBCL in an adolescent girl is extraordinary in many ways. DLBCL, especially the non-GCB type, is a rare disorder in pediatric patients. Predominant bone-marrow involvement has been described in only few older patients with non-GCB-type DLBCL and mostly aggressive clinical course. HLH as a presenting feature is rather observed in T- or NK-cell lymphoma than in DLBCL. Finally, central nervous system (CNS) relapse occurs in only about 6% of adults with DLBCL regardless of CNS prophylaxis. Retinal and intraparenchymal CNS involvement without abnormalities in the CSF has been typically described for primary CNS lymphoma in adults. All these conditions have contributed to the adverse outcome in our patient. DisclosuresNo relevant conflicts of interest to declare.

Impact of Allogeneic Hematopoietic Cell Transplantation (allo-HCT) on the Outcomes of Angioimmunoblastic T-Cell Lymphoma (AITL): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Introduction: AITL is a distinct clinicopathologic entity among the mature T-cell and NK-cell lymphomas, accounting for approximately 1-2% of all non-Hodgkin lymphomas. Although autologous HCT (auto-HCT) provides high response rates, there is a high relapse risk associated with this procedure. Allo-HCT may result in a lower risk of relapse in part due to a graft-versus-lymphoma effect mediated by alloreactive donor cells. The role of allo-HCT in AITL with advanced disease (prior auto-HCT failure, or chemorefractory state) is not well described. Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.Methods: We evaluated 249 adult (≥18years) patients with AITL who received a first allo-HCT during 2000-2016. Patients receiving mismatched unrelated donor, cord blood or haploidentical donor transplantation were excluded due to small numbers. The primary end-point was overall survival (OS). Secondary endpoints included cumulative incidence of acute graft-versus-host disease (GVHD), chronic GVHD, non-relapse mortality (NRM), relapse/progression (R/P) and progression-free survival (PFS).Results: Baseline patient characteristics are summarized in Table. The median patient age was 56 years (range=21-77 years). The graft source was mainly peripheral blood. Median follow-up of survivors was 49 months (range=4-170 months).The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42)% and 12 (95% CI=8-17)%, respectively. The cumulative incidence of chronic GVHD at 2 years was 58% (95% CI=51-64)%. The 1-year NRM was 19% (95% CI=14-24)%, while the 4-year R/P, PFS, and OS were 21% (95% CI=16-27)%, 49% (95% CI=42-56)% and 56% (95% CI=49-63)%, respectively [Figure]. On multivariate analysis, chemoresistant status at allo-HCT was associated with a significantly higher risk for progression (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (RR=3.46 95% CI=1.75 - 6.87). Subgroup analysis looking at the effect of prior auto-HCT (no prior auto-HCT vs prior auto-HCT), the 4-year PFS (50% vs 47%, p=0.60) and OS (57% vs 54%, p=0.70) were not significantly different. Similarly, on comparing the disease status at allo-HCT (CR1 vs CR>1 vs PR vs refractory), there was no significant difference in the 4-year PFS (58% vs 45% vs 47% vs 38%, p=0.41) or OS (70% vs 54% vs 50% vs 52%, p=0.27). The 1-year NRM was 24%, while the 4-year R/P, PFS, and OS in patients with refractory AITL were 32%, 38%, and 52%, respectively. The most common cause of death was organ failure.Conclusion: In this largest series of mostly advanced AITL patients, allo-HCT was shown to provide durable disease control (4-year PFS=47%) with a clear plateau in relapse at 1-year post-transplantation. Allo-HCT provided durable disease control even in patients with a failed prior auto-HCT and those subjects with refractory disease at the time of allografting. DisclosuresKharfan-Dabaja:Alexion Pharmaceuticals: Speakers Bureau; Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria. Sureda:Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria; Roche: Honoraria; BMS: Consultancy, Honoraria. Hamadani:Merck: Research Funding; Celgene Corporation: Consultancy; ADC Therapeutics: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Ostuka: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Takeda: Research Funding; Cellerant: Consultancy.

Lethal Midline Granuloma in a 15-Year-Old Girl: A Diagnostic Dilemma

Objective: To report a case of lethal midline granuloma and discuss the diagnostic and treatment dilemma, and management.&#x0D; Methods&#x0D; Design: Case Report&#x0D; Setting: Tertiary Government Hospital&#x0D; Patient: One&#x0D; Results: A 15-year-old girl under treatment for pulmonary tuberculosis presented to the Emergency Room for epistaxis and a nasopalatine lesion. She was managed as a case of nasopalatine osteomyelitis for one month and discharged on antibiotics. She returned due to bleeding after being lost to follow up for 3 more months. Hemostasis, debridement and biopsy yielded atypical cells, possibly lymphoma. Immunohistochemistry confirmed the diagnosis of NK-cell lymphoma. Unfortunately, she expired prior to initiation of chemotherapy.&#x0D; Conclusion: Clinicians must have a high index of suspicion for lethal midline granuloma in chronic, non-healing midline lesions. Multiple biopsies confirm the diagnosis, and earlier initiation of treatment may improve prognosis.&#x0D; &#x0D; Keywords: Granuloma, lethal midline; Lymphoma, extranodal NK-T-cell