Natural Killer Cell Lymphoma Research Articles

Current Progress in Investigating Mature T- and NK-Cell Lymphoma Gene Aberrations by Next-Generation Sequencing (NGS).

Despite efforts to abrogate the severe threat to life posed by the profound malignancy of mature natural killer/T-cell lymphoma (NKTCL), therapeutic advances still require further investigation of its inherent regulatory biochemical processes. Next-generation sequencing (NGS) is an increasingly developing gene detection technique, which has been widely used in lymphoma genetic research in recent years. Targeted therapy based on the above studies has also generated a series of advances, making genetic mutation a new research hotspot in lymphoma. Advances in NKTCL-related gene mutations are reviewed in this paper.

Paraneoplastic orbital myositis in a patient with natural killer/T-cell lymphoma

Paraneoplastic orbital myositis can occur in patients with natural killer/T-cell lymphoma (NKTL). A discrepancy between ocular motility examinations and imaging findings may suggest paraneoplastic orbital myositis in patients with malignancy. Extraocular muscle biopsy should be performed for definite diagnosis and appropriate treatment, especially in patients with atypical clinical manifestations.

Clinical impact of lymphatic spread in patients with limited-stage upper aerodigestive tract NK/T cell lymphoma.

BackgroundWe investigated whether distancemax, that is, the degree of distance between the upper aerodigestive tract (UAT) mass and the farthest pathologic lymph node, was significantly associated with survival in patients with limited-stage UAT natural killer/T cell lymphoma (NKTCL).MethodsA total of 157 patients who received chemotherapy (CTx) with/without radiotherapy (RTx) were enrolled.ResultsIn the survival analysis, an elevated lactate dehydrogenase level [progression-free survival (PFS) hazard ratio (HR), 2.948; 95% confidence interval (CI), 1.606‒5.404; P<0.001; overall survival (OS) HR, 2.619; 95% CI, 1.594‒4.822; P=0.003], short distancemax (PFS HR, 0.170; 95% CI, 0.071‒0.410; P<0.001; OS HR, 0.142; 95% CI, 0.050‒0.402; P< 0.001), and CTx combined with RTx (HR, 0.168; 95%CI, 0.079‒0.380; P<0.001; OS HR, 0.193; 95% CI, 0.087‒0.429; P<0.001) had an independent predictive value for PFS and OS.ConclusionThe evaluation of the degree of lymphatic spread and local control by CTx combined with RTx is essential in patients with limited-stage UAT NKTCL.

Chidamide ,Oral Subtype-Selective Histone Deacetylase Inhibitor (HDACI) Monotherapy Was Effective on the Patients with Relapsed or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma

Background:Chidamide is an orally bioavailable benzamide class of histone deacetylase inhibitor (HDACi), that selectively inhibits activity of HDAC1, 2, 3 and 10. It was approved by the Chinese FDA for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). However, the efficacy and safety of Chidamide remain to be determined in relapsed or refractory extranodal natural killer T-cell lymphoma (ENKTCL), and the optimal dosing schedule was unclear. The purpose of the current study were to evaluate the clinical response and toxicity for R/R-ENKTCL at two dosing schedule of Chidamide monotherapy.Methods:This is an open-label, prospective phase II trial in China. Inclusion criteria included histologically confirmed ENKTCL, disease progression or non-response after asparaginase-based chemotherapy. Chidamide 30mg BIW or 10mg daily was taken at least 6 weeks until disease progression or the occurrence of unacceptable toxicity. Utility of PET-CT in the therapeutic evaluation was employed. Serum EBV-DNA was monitored weekly. At the time of this abstract submission, the trial is still ongoing.Results: A total of 15 relapsed or refractory ENKTCL patients failed to asparaginase-based chemotherapy or autologous hematopoietic stem cell transplantation (ASCT) were enrolled in this study (10mg QD group, n=9 and 30mg BIW group, n=6, respectively). Median previous chemotherapy regimens was 3(2-5), 2 patient relapsed following ASCT. 12 patients were evaluable for response and 3 patients still under treatment less than 6 weeks. ORR was 50.0% (6/12) with CR rate 33.3 %(4/12) . Three patients got CR in 30mg group, one patient got CR in 10mg group (table1,figure 1). The median time to response was 5.9 (1.1 to 8.1) weeks. Median follow-up time was 3.7 months (0.8-11.5) so far. All four CR patients were still in disease-free more than 6.9 months (6.9-10.5). Serum EBV-DNA load during the course of treatment was declined or stable in all responders only two cases with elevated EBV-DNA level observed due to disease progression (figure 2). Most adverse events (AEs) were grade 1 or 2, and AEs ≥grade 3 hematologic toxicity were similar in both groups included neutropenia (50.0% vs. 44.4%) and thrombocytopenia (33.3% vs. 33.3%). 30mg group experienced a higher incidence of nausea and vomiting(100% vs. 44.4%). Meanwhile, we also treated six refractory B cell lymphoma patients, including three diffused large B cell lymphoma (DLBCL), two mantle cell lymphoma (MCL) and one follicular lymphoma. One DLBCL patient and one MCL patient obtained PR respectively.Conclusions: Our study suggested that Chidamide was effective as single agent in the treatment of relapsed or refractory malignant lymphoma.. The therapeutic outcome for previous heavily-treated ENKTCL was encouraged without clinical EBV reactivation. It is too early to draw conclusions of response difference between two dosing schedule. Further clinical trial warranted.(ClinicalTrials.gov, NCT 2878278 )Disclosures: No relevant conflicts of interest to declare. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein–Barr Virus Relation

Extranodal NK/T-Cell Lymphoma, nasal type (ENKTL-NT) has some salient aspects. The lymphoma is commonly seen in Eastern Asia, has progressive necrotic lesions in the nasal cavity, makes midfacial destructive lesions, and shows poor prognosis. The lymphoma cell is originated from either NK- or γδ T-cells, which express CD56. Since the authors first demonstrated the existence of Epstein–Barr virus (EBV) DNA and EBV oncogenic proteins in lymphoma cells, ENKTL-NT has been recognized as an EBV-associated malignancy. Because the angiocentric and polymorphous lymphoma cells are mixed with inflammatory cells on a necrotic background, the diagnosis of ENKTL-NT requires CD56 immunostaining and EBER in situ hybridization. In addition, serum the EBV DNA level is useful for the diagnosis and monitoring of ENKTL-NT. Although ENKTL-NT is refractory lymphoma, the prognosis is improved by the development of therapies such as concomitant chemoradiotherapy. The basic research reveals that a wide variety of intracellular/cell surface molecules, cytokines, chemokines, and micro RNAs are involved in lymphomagenesis, and some of them are related to EBV. Understanding lymphoma behavior introduces new therapeutic strategies, such as the usage of immune checkpoint inhibitors, peptide vaccines, and molecular targeting therapy. This review addresses recent advances in basic and clinical aspects of ENKTL-NT, especially its relation to EBV features.

Daratumumab Efficiently Targets NK/T Cell Lymphoma with High CD38 Expression

CD38 expression can be detected on a majority of NK/T cell lymphoma (NKTCL). Based on the clinical data of 94 patients with ENKTL, high CD38 surface expression was an adverse prognostic factor for progression free survival, and these patients had significantly inferior outcomes (Wang, 2015). This corroborates with our own studies showing that relapsed and refractory NKTCL patients almost always exhibit high CD38 expression, thereby proposing that it may be worthwhile to target CD38 as a novel therapeutic option.Daratumumab is a human anti-CD38 monoclonal antibody which has shown significant anti-cancer activity in multiple myeloma. In this study, we investigated the potential cytotoxic effects and mechanisms of actions of Daratumumab in a panel of 10 NKTCL cell lines. Firstly, we identified that cell lines can be stratified into CD38Hi, CD38Mid and CD38Lo as quantified by mRNA expression and CD38 protein surface expression which was qualitatively analysed by FACS and IHC. Daratumumab is able to induce antibody dependent cellular cytotoxicity (ADCC) in a CD38-dependent manner and in a dose-dependent fashion. We also observe a greater induction of antibody dependent cellular phagocytosis (ADCP) activation in correlation with CD38 expression. Furthermore, complement-dependent cytotoxicity (CDC) was significantly triggered by Daratumumab in CD38Hi and CD38Mid cells. However, we found evidence of an additional level of regulation provided by the expression of complement inhibitory proteins(CIPs) CD46, CD55 and CD59 on NKTCL cell lines which can limit and inhibit the induction of CDC regardless of CD38 surface expression levels.All-trans retinoic acid (ATRA) is a vitamin A derivative that binds to retinoic acid receptor alpha leading to the upregulation of CD38 expression. Treatment with ATRA increases CD38 mRNA and surface protein expression in all CD38Hi-Lo NKTCL cell lines. Interestingly CD38Lo cell lines showed the greatest fold increase of CD38 mRNA and surface protein expression. Notably, addition of ATRA to SNK-10, a CD38LoCD55Hi cell line, prior to Daratumumab treatment was able to improve the induction of ADCC but not CDC. This suggests a critical role for CIPS in mediating the induction of CDC in NKTCL.Subsequent investigation for the efficacy of Daratumumab in vivo is currently being performed.We also discovered a synergistic cytotoxic effect in NKTCL CD38Hi cell lines mediated by L-Asparaginase (a component of the current chemotherapeutic regimen in NKTCL) treatment in combination with Daratumumab. Altogether,these results propose a rationale therapeutic option for single or combined Daratumumab treatment in the clinic especially for relapsed and refractory patients. DisclosuresJin:Janssen China R&D: Employment. Yu:Janssen China R&D: Employment. Chen:Janssen China R&D: Employment. Yang:Janssen China R&D: Employment. Chng:Janssen China R&D: Research Funding.

The Role of FDG PET for Evaluation of Bone Marrow Status and Prognosis in T Cell Lymphomas

Objective: We investigated clinical value of FDG PET for evaluation of bone marrow (BM) tumor involvement status in peripheral T cell lymphoma (PTCL) or extranodal NK/T cell lymphoma (NKTCL).Methods: Patients with PTCL or NKTCL, who underwent initial staging with FDG PET and BM biopsy were analyzed. PET BM uptake was analyzed visually and quantitatively (bone marrow-to-liver ratio; MLR). Receiver-operating-characteristic (ROC) analysis was performed to evaluate the usefulness of FDG PET for predicting BM tumor involvement. Prognostic implication of FDG PET finding was also assessed.Results: A total of 109 (63 PTCL and 46 NKTCL) patients were analyzed. BM biopsy revealed tumor involvement in 64.2% of cases. In the ROC curve analysis for determining visually positive BM involvement by MLR, the area under curve (AUC) was 0.948 with sensitivity 90.2% and specificity 91.2%. The AUC using visual analysis was 0.76 (sensitivity 82.1% and specificity 38.6%). Predicting power of FDG PET for BM involvement was not different across lymphoma subtypes. Multivariate survival analysis revealed that BM FDG PET finding was an independent prognostic factor for survival in PTCL and NKTCL. Moreover, MLR was a significant prognostic factor for both PFS and OS (P = 0.001 and 0.005) in BM involvement-negative patients by BM biopsy.Conclusion: Although FDG PET findings fairly correlates with BM biopsy findings, FDG PET could not replace BM biopsy in PTCL and NKTCL. Rather, BM finding on FDG PET is an independent prognostic factor in these tumors, suggesting further biologic relevance of FDG PET findings. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chidamide, a HDAC Inhibitor, Combined with Cladribine, High Dose Gemcitabine and Busulfan with Autologous Stem Cell Transplantation in Patients with Relapsed/Refractory and Poor-Risk Lymphoma

IntroductionHigh dose chemotherapy (HDC), such as carmustine/etoposide/cytarabine/melphalan (BEAM), followed by autologous stem cell transplantation (ASCT) was a standard of care for patients with relapsed/refractory and poor-risk lymphomas for over decades. However, with the introduction of new drugs, such as rituximab, patients relapsed from or refractory to first line therapy benefit less from HDC with ASCT. To improve the survival of these patients with ASCT, better HDC combination is urgently needed. Our previous research indicated the combination of cladribine/gemcitabine/busulfan (CGB) had strong synergistic effect against lymphoma cell lines. Adding Histone deacetylases inhibitor (HDACi), vorinostat or chidamide (chi), to CGB further enhanced cytotoxicity, which warrant the clinical use of ChiCGB combination as conditioning chemotherapy. We started a phase II clinical trial to evaluate the efficacy and safety of ChiCGB followed by ASCT in patients with relapsed/refractory and poor-risk lymphomasPatients and methodsEligibility included ages 18 to 65 and one of the following lymphomas: High-risk and relapsed/refractory (R/R) diffuse large B cell lymphomas (DLBCL), T and natural killer/T (NK/T) cell lymphoma, and hodgkin lymphoma (HL). Additional eligibility criteria included adequate renal, hepatic, pulmonary, cardiac function, performance status 0 to 1, no active hepatitis B or C.Patients received oral chidamide 30mg on days -7, -4, 0, +3. Cladribine was administered intravenously at the dose of 10 mg from days -6 to -2. Gemcitabine was administered intravenously 4 hours after the finish of cladribine at the dose of 2500 mg/m2 on days -6 and -2. Busulfan was administered intravenously at dose of 3.2 mg/kg on days -6 to -2. Dexamethasone 10 mg i.v. was given from day -6 to -2. Infusion of peripheral blood stem cells was on day 0.CR, OS and progression free survival(PFS) were calculated using standard methods. Statistical analysis was done using Fishers exact test or Chi-square test / Kruskal-Wallis test. Kaplan-Meier method was used for time-to-event analysis including overall survival and progression free survival. The Wilcoxon test was used to evaluate the difference in time-to-event endpoints between patient groups.ResultsForty-three patients were enrolled between Apr. 2015 and Apr. 2017. Median age was 34 years (range, 22-62). The diagnoses were DLBCL (N=19), T&NK-NHL (N=20), HL (N=4). Eight patients had double/triple protein expression of C-myc, Bcl-2 or Bcl-6 protein identified by immunohistochemistry; 2 had IVLBCL; 1 had transformed DLBCL; 13 had stage IV extranodal natural killer/T cell lymphoma (ENKTCL); and 2 had lymphoblastic T cell lymphoma. Twenty-tow patients were in first CR, 21 had R/R disease, and 5 had PET positive tumor before HDC.Stem cells source was peripheral blood. Median infused CD34+cells count was 2.1×106/Kg (range, 1.0 to 11.6×106/Kg). Neutrophils and platelets were engrafted on a median day +11 (range, days +8 to +14) and day +12 (range, days +9 to +22), respectively.The median follow-up is 10.3 months (range, 3-26.5 months). The progression free survival (PFS) and overall survival (OS) of the whole cohort are 78.2% and 89.5%, respectively (Figure-1A). The PFS and OS in DLBCL group are 81.7% and 100% respectively (Figure-1B). Of 19 patients with DLBCL, only 2 with IVLBCL relapsed at 5.7 and 11.1 months post transplantation respectively. The EFS and OS in T&NK/T group are 73.7% and 78.8%, respectively (Figure-1C). Twelve of 16 patients with ENKTCL, 1 of 2 patients with lymphoblastic T cell lymphoma and 1 of 2 patients with T-NHL remain alive in CR at last follow-up. The EFS and OS in HL group are 75% and 100%, respectively. For the whole cohort, patients who had active disease before HDC demonstrated poorer EFS (80.9% vs. 53.3%; P=0.039) (Figure-1D).The most common adverse event was infection. Thirty-nine (90.7%) patients developed grade 3 neutropenic fever. Other notable toxicities included grade 2 (55.8%) and 3 (9.3%) mucositis, grade 2 (13.9%) and 3 (4.7%) dermatitis, grade 2 (9.3%) diarrhea and self-limited transaminase elevation. All these toxicities were manageable and there was no therapy-related mortality.ConclusionOur study showed ChiCGB combination can be safely administered as HDC before ASCT for patients with R/R or high-risk lymphomas. This combination showed promising early outcomes and warrant further clinical investigations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Chemotherapy of GEP Regimen(Gemcitabine,etoposide and Pegaspargase) for the Patients with Newly Diagnosed Extranodal Natural Killer/T Cell Lymphoma: a Phase II Clinical Trial

Introduction: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive form of non-Hodgkin's lymphoma,which is relatively more common in Asia and Latin America.Radiation therapy(RT) is widely administered for patients with localized nasal disease. However, local and systemic failures are observed frequently in patients who receive RT alone.Therefore, chemotherapy is needed in combination with RT to reduce the risk of recurrence. The patients with newly diagnosed stage III/IV ENKTL were rare and their prognosis was poorer.Chemotherapy was the major therapeutic tool for them.However,the optimal chemotherapy regimen for this disease has not been fully defined. Therefore, the purpose of this study is to prospectively evaluate efficacy and safety of GEP Regimen (Gemcitabine, Etopie and Pegaspargase ) in patients with newly diagnosed ENKTL(ClinicalTrials.gov number, NCT02705508).Methods: Enrolment began in March 2016 for a Phase II single-center clinical trial.Treatment GEP dosages were as follows: days 1 and 8,30min intravenous infusion of 1000mg/m2 gemcitabine;day1-3,4h intravenous infusion of 100mg/m2 etoposide;day1,deep intramuscular injection of 2500unit/m2 PEG-ASP at three different sites.The regimen was repeated every 3 weeks.Stage IE/IIE patients underwent four cycles induction chemotherapy, followed by involved-field radiotherapy after got complete remission,partial regression or stable disease.Three-dimensional conformal radiotherapy was done by linear accelerator at 2.0 grays (Gy) per daily fraction with 5-6 weeks. The involved-field radiation (IFRT) dose was 50-56Gy.Stage IIIE/IVE patients were given for six cycles unless there was disease progression or unacceptable side effects, or withdrawal of patient consent.Results: Until August 2, 2017, we have completed the enrolment of 20 patients with newly-diagnosed untreated ENKTL.The main clinical characteristics of the 20 patients are presented in Table 1.The median age was 50 years andranged from 20 to 70 years. The majority of patients initially presented withlocalized disease (stagesI and II; n = 17, 85%).All patients(n=20)have begun treatment and are evaluable for response. Of the 20 patients, complete remission (CR) rates is 100% to chemotherapy alone.Fifteen patients with localized disease(stage IE/IIE) achieved a CR after two cycles of GEP regimen. CR was achieved after 2 courses of chemotherapy in two stage IIIE/IVE patients and after 4 courses in one patient.Toxicities are recorded as the number of patients experiencing a certain adverse event.The most common grade 1-2 non-haematological (non-heme) adverse effects (AEs) are fatigue (n=12), nausea (n=10),oral mucositis (n=4).Fourteen(n=15) patients were confirmed to have decreased fibrinogen. Most of these were grade 1/2 and no bleeding or other adverse events were observed.Grade 3 non-heme AEs included fatigue (n=3), oral nausea (n=2), mucositis (n=1).There was no grade 4 non-heme toxicities during chemotherapy.Grade 1-2 hematological (heme) AEs included neutropenia (n=9), anemia (n=12) and thrombocytopenia(n=3). Common grade 3-4 haematological AEs was neutropenia (n=11), anemia (n=4) and thrombocytopenia(n=10).No patients interrupted treatment for severe adverse events and no treatment-related deaths occurred.Conclusions: Preliminary data indicate that the GEP regimen chemotherapy in newly diagnosedENKTL patients was efficacious and well-tolerated, while the long-term outcome is required to be followed up. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Identification of PTX3 and S100A9 As Serum Diagnostic and Therapeutic Response Biomarkers of NK/T Cell Lymphoma Patients

NK/T cell lymphoma (NKTCL) patients are frequently misdiagnosed as chronic nasosinusitis, which delays therapy and leads to poor prognosis. Our study aims to explore serum biomarkers to differentiate NKTCL patients from healthy individuals. Pretreatment and posttreatment serum samples from 16 newly-diagnosed NKTCL patients were collected. Serum samples from 16 matched healthy individuals were also collected. Comparative proteomic approach were utilized to identify the differentially expressed proteins. Enzyme-linked immunosorbent assay (ELISA) was performed to validate the candidate biomarkers. Receiver operating characteristic curve (ROC) analysis was employed to examine their sensitivity and specificity. Compared with healthy controls,109 upregulated and 82 downregulated proteins were identified in pretreatment serums of NKTCL patients. Among the differentially expressed proteins, PTX3 and S100A9 were selected as candidate biomarkers for further validation. ELISA assay showed that NKTCL patients present higher serum levels of PTX3 (p<0.0001) and S100A9 (p<0.0001) than normal controls. Moreover, the diagnostic sensitivity and specificity of PTX3 alone (cutoff point: 0.592ug/L), S100A9 alone (cutoff point: 51.16ng/ml), PTX3 in combination S100A9 were 78.87% and 84.44%, 73.24% and 80.0%, 74.65% and 93.33%, respectively. Furthermore, we found that posttreatment serum levels of PTX3 and S100A9 declined remarkably in treatment-sensitive NKTCL patients (p<0.001), while no significant changes were observed in treatment-resistant patients (p>0.05). In conclusion, serum PTX3 in combination with S100A9 could serve as potential biomarkers for NKTCL diagnosis and treatment response evaluation. Further confirmation of PTX3 and S100A9 in a larger cohort of patients will promote their clinical use. DisclosuresNo relevant conflicts of interest to declare.

Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma

Autologous EBV-Specific T Cells (CMD-003): Early Results from a Multicenter, Multinational Phase 2 Trial for Treatment of EBV-Associated NK/T-Cell Lymphoma

Genetic Background of Chronic Active Epstein-Barr Virus Disease

IntroductionEpstein-Barr virus (EBV) is associated with various benign and malignant diseases. Chronic active EBV disease (CAEBV) is a rare EBV-associated disease characterized by persistent EBV infection in natural killer (NK) and/or T cells, which is mainly prevalent in East Asia. While patients with CAEBV initially present with persistent or recurrent symptoms similar to ones present in infectious mononucleosis (IM), they often develop peripheral NK/T-cell lymphoma or multiple organ failure in the long run, and prognosis is dismal.Numerous aspects of the molecular pathogenesis of CAEBV are unresolved; it is unclear whether this disease is a clonal disorder. Although several case reports indicate the presence of primary immunodeficiency (PID) in patients with persistent EBV disease, the prevalence of PID or other inherited diseases in patients with CAEBV remains unclear. To reveal the genetic background of CAEBV, we performed whole-exome and targeted sequencing.Patients and MethodsWe studied 83 patients with CAEBV. The diagnosis of CAEBV was based on the fulfillment of the following criteria: (1) persistent or recurrent symptoms similar to those present in IM, (2) increased quantities of EBV viral load in either affected tissues or peripheral blood, and (3) exclusion of other possible diagnoses. The Institutional Review Board of Nagoya University Graduate School of Medicine approved this study.We performed whole-exome sequencing (WES) of T-, B-, and NK-cell subsets. Subsequently, we performed targeted gene sequencing of 605 genes associated with PID, inherited blood diseases, and hematological malignancies.ResultsRegarding germline mutations, we identified two patients who carried nonsense mutations in EVC2, which led to the diagnosis of Weyers acrofacial dysostosis (WAD). We also identified a patient who carried POLH mutations, which led to the diagnosis of the variant type of xeroderma pigmentosum, and a patient who carried an APC mutation, which led to the diagnosis of familial adenomatous polyposis. Mutations leading to the diagnosis of PID were not identified in any patient.WES led to the identification of at least one somatic mutation in 58% of patients. We identified DDX3X (n= 14; 16%), KMT2D (n= 4; 4.8%), BCOR / BCORL1 (n= 3; 3.6%), KDM6A (n= 3; 3.6%), and TET2 (n= 2; 2.4%) as undergoing recurrent mutations.We analyzed multiple EBV-infected cell subsets within a patient. One patient (UPN125) developed CAEBV in which both T and NK cells were positive for EBV DNA. The patient's CD4+ and CD56+ cells carried 21 and 27 mutations, respectively, of which 8 were shared including a DDX3X p.Arg534Cys driver mutation. Similar to UPN125, CD3+ and CD56+ cells of UPN404 carried a shared DDX3X p.Thr198Pro mutation and private mutations. CD19+ cells of UPN404 also carried the identical DDX3X mutation.In the survival analysis, patients carrying DDX3X mutations at diagnosis demonstrated a significantly worse OS compared with others (5-year OS: 40.6% vs. 78.6%; P= 0.007). Patients carrying KMT2D mutations also demonstrated poor prognosis (5-year OS: 50.0% vs. 73.9%; P= 0.02).DiscussionIn the present study, we found that CAEBV was a malignant disease carrying somatic driver mutations, the spectrum of which showed similarity with that of extranodal NK/T-cell lymphoma (ENKTL) and Burkitt lymphoma. DDX3X mutations and other shared mutations, which were present in multiple cell subsets in a patient, strongly suggest the presence of common ancestry, possibly lymphoid progenitor cells, which acquired driver mutations.We identified the presence of somatic DDX3X mutations as a marker of poor prognosis. A prospective study can be designed using genetic testing for DDX3X mutations and subsequent interventions, possibly chemotherapies used for ENKTL and early hematopoietic stem cell transplantation, to improve patient outcome.Furthermore, we identified several germline mutations. WAD caused by EVC / EVC2 mutations is characterized by the malformation of mesoderm and ectoderm caused by decreased hedgehog signaling mediated via EVC/EVC2 . Together with POLH and APC mutations, EVC / EVC2 mutations may be a genetic predisposition to CAEBV.In conclusion, we revealed the genetic background of CAEBV, which will lead to further clarification of its molecular pathogenesis and the development of therapeutic strategy. Clinical trials utilizing genetic diagnosis and stratified therapy are warranted. DisclosuresNo relevant conflicts of interest to declare.

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis

Pralatrexate (10-Propargyl-10-Deazaaminopterin (PRX)), a Novel Antifolate, Effects Durable Complete Remissions (CR) in Patients with a Diversity of Drug Resistant T-Cell Lymphomas with Minimal Toxicity.

PRX belongs to a new class of anti-folates designed to have improved affinity for the reduced folate carrier. A phase 2 study at 135 mg/m2 given on an every other week (w) basis treated 16 patients, including Hodgkin's Disease (HD) (n=5), aggressive B-cell lymphoma (BCL) (n=8), mantle cell lymphoma (n=2) and peripheral T-cell lymphoma (PTCL). A higher than anticipated incidence of stomatitis (6 of 16 patients with Grade 3 or 4 stomatitis) was associated with marked increase in stomatitis occurred in patients with Hcy and MMA less than 10 mM and 200 nM respectively. Patients with elevated Hcy and MMA who developed stomatitis with PRX did not develop advanced grade stomatitis after normalization of their Hcy and MMA with vitamins. The patient with chemotherapy refractory T-cell lymphoma attained a PET negative CR after one dose, while the other patients had stable/progressive disease. The study was amended to a weekly phase I study based on laboratory data. The dose escalation study was: 30 mg/m2 w x 3 every 4 w; 30 mg/m2 w x 6 every 7 w, then increasing by 15 mg/m2 on the 7 week schedule. To date, eleven patients have been accrued to the amended study, including 7 patients with T-cell lymphoma (PTCL, angioimmunoblastic lymphoma (n=2), acute T-cell acute lymphoblastic lymphoma; HTLV-1 associated adult T-cell leukemia/lymphoma (ATLL), panniculitic T-cell lymphoma, and a NK-T cell lymphoma). In total, 8 patients with T-cell lymphoma have been treated with PRX, with 5 of the 8 evaluable for response. 4 of 5 evaluable patients with T-cell lymphoma achieved a CR within the first cycle, despite being chemotherapy refractory. The one patient with NK-T cell lymphoma had a mixed response. 3 of 4 patients remain in CR at 4 to 9 mo. and remain on treatment. Patients with BCL and HD attained stable disease. Normalization of Hcy and MMA pre-treatment with vitamins abrogated the stomatitis. Little hematological toxicity (grade 2 thrombocytopenia in 2 patients) has been observed. PRX has achieved a remarkably high CR rate among patients with drug resistant T-cell lymphoma in this phase I study. The ongoing trial will identify the MTD on the weekly schedule, the DLT, and to define the scope of PRX activity in T-cell lymphomas.

Primary Cutaneous Lymphomas in Thailand: A 10-Year Retrospective Study.

Background Primary cutaneous lymphomas (PCLs) refer to cutaneous lymphomas that primarily develop in the skin with no evidence of extracutaneous disease at the time of diagnosis. The epidemiological and clinical data of PCLs in Thailand are lacking. Objectives To evaluate the frequency, demographic data, and clinical characteristics of different subtypes of PCLs in a tertiary care university hospital. Methods In total, 137 patients with PCLs diagnosed in our hospital in 2008–2017 were retrospectively reviewed. Results Of the 137 patients, 57 (41.6%) were male and 80 (58.4%) were female (M : F = 1 : 1.4). The median age at diagnosis was 40 years. Most patients (134, 97.8%) had cutaneous T-cell lymphomas (CTCLs). Three patients (2.2%) had cutaneous B-cell lymphomas (CBCLs). The most common subtype was mycosis fungoides (MF) (67.9%), followed by subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (21.2%), primary cutaneous anaplastic large cell lymphoma (pcALCL) (3.6%), lymphomatoid papulosis (LyP) (1.5%), primary cutaneous gamma/delta T-cell lymphoma (pcGDTCL) (1.5%), Sézary syndrome (SS) (0.7%), extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) (0.7%), primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS) (0.7%), primary cutaneous diffuse large B-cell lymphoma, leg type (pcDLBCL-LT) (1.5%), and primary cutaneous follicle center lymphoma (pcFCL) (0.7%). Most patients with MF presented with early-stage disease (84.0%), with hypopigmented MF the most common variant (42.6%). Conclusions Compared to earlier Caucasian and Asian studies, the present study revealed a higher proportion of CTCL patients with a younger age at onset and a female predominance. MF was the most common CTCL subtype, followed by SPTCL. More than 80% of MF patients were diagnosed at an early stage.

Hsa-miR-372-5p regulates the NIMA related kinase 7 and IL-1β release in NK/T-cell lymphoma

Epstein-Barr virus (EBV) infection is prevalent and associated with distinct diseases including infectious mononucleosis (IM), chronic active EBV infection (CAEBV) and NK/T-cell lymphoma (NKTL). However, the specific roles of EBV in these diseases remain unclear. Here, the whole miRNA expression datasets derived from 7 IM, 6 CAEBV, and 3 NKTL biopsies were obtained. Homo sapiens microRNA-372-5p (Hsa-miR-372-5p) was upregulated in both CAEBV and NKTL patients. Overexpression of hsa-miR-372-5p altered the expression of over 100 proteins. In addition, hsa-miR-372-5p may target NIMA related kinase 7 to regulate NLRP3 inflammasome activation in host cell. Taken together, we reported different miRNA expression profiles in distinct EBV associated diseases, which provided novel insights to understand how host miRNAs contribute to the mechanism of EBV associated diseases. Hsa-miR-372-5p, as well as other differential expressed miRNA, might serve as potential targets in the therapy of various EBV associated diseases.

Overview of the current treatment strategy in extranodal NK/T-cell lymphoma: from diagnosis to recurrence

: Extranodal natural killer/T cell lymphoma (ENKTL) is an extraordinary subtype of non-Hodgkin’s lymphoma (NHL), mainly involves the nasal cavity and the upper airway, and is influenced by the Epstein-Barr virus (EBV). Compared to other subtypes of T-cell lymphoma, ENKTL cannot be effectively treated with commonly used anthracycline-based systemic chemotherapy. Thus, the recent treatment of ENKTL has undergone significant changes based as informed by various clinical trials and prospective studies. Concurrent, sequential, and sandwich chemoradiotherapy, which is based on the alteration of the order of radiation and chemotherapy, has emerged as vital treatment approach for localized ENTKL. After the emergence of anthracycline-based systemic chemotherapy, nonanthracycline-based chemotherapy combined with L-asparaginase, including SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide), Asp-MTX-Dex (L-asparaginase, methotrexate and dexamethasone), and DDGP (dexamethasone, cisplatin, gemcitabine, and peg-asparaginase) has attracted attention in advanced and relapsed/refractory (R/R) ENKTL treatment. Moreover, autologous-stem cell transplantation (auto-SCT) or allogenic stem cell transplantation (allo-SCT) has been recommended as a treatment option when patients with advanced or relapsed ENKTL achieve remission by a salvage treatment strategy. Even if ENKTL recurs, the effectiveness of immune checkpoint inhibitors (ICIs) related to programmed death-ligand 1 (PD-L1) has been proven, which is representative of the broadening of treatment options compared to many years ago. However, despite the marked improvement of therapeutic strategies in ENKTL, some patients still have dismal outcomes. Based on the understanding of the molecular and immunologic biology of ENKTL, the treatment strategy and treatment prognostic prediction model of ENKTL has been continuously evolving, treatment experience has been gradually enriched, and related data has accumulated. In this review, we discuss the current and emerging treatments for early or advanced relapsed or refractory ENKTL.

Allogeneic Hematopoietic Stem Cell Transplantation in Extranodal Natural Killer/T-cell Lymphoma

Objective:Extranodal NK/T-cell lymphoma (ENKL) is aggressive and resistant to chemotherapy and radiotherapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for high-risk lymphomas owing to its associated graft-versus-lymphoma (GVL) effect. However, its application to ENKL is limited. We aim to summarize the characteristics of allo-HSCT for ENKL and, more importantly, evaluate whether allo-HSCT could offer any benefits for ENKL.Materials and Methods:A systematic review and data analysis were performed to evaluate the performance of allo-HSCT in the treatment of ENKL using studies obtained from PubMed, Medline, and Embase from January 2000 to December 2019 in the English language.Results:A total of 136 cases from 17 eligible publications were included in this study. It was found that after allo-HSCT, with an average follow-up time of 34 months (range: 1-121 months), 37.5% (52) of 136 patients had acute graft-versus-host disease (GVHD) and 31.6% (43) had chronic GVHD. Furthermore, 35.3% (48) of the patients were reported to have relapsed, but 2 of those relapsed only locally and achieved complete remission (CR) again with additional irradiation, chemotherapy, and donor lymphocyte infusions for one and rapid tapering and discontinuation of cyclosporine for the other, earning more than one year of extra survival. Finally, of the 136 patients, 51.5% (70) died because of primary disease progression (42.9%), infection (20.0%), GVHD (11.4%), organ failure (7.1%), hemorrhage (4.3%), and other causes (not specified/unknown) (14.3%).Conclusion:Allo-HSCT may be a treatment option for advanced or relapsed/refractory ENKL, but its role still requires more rigorous future studies.

Clinical analysis of patients with primary and secondary extranodal natural killer/T-cell lymphoma of central nervous system.

Extranodal natural killer (NK)/T-cell lymphoma (NKTL) is a rare non-Hodgkin lymphoma that rarely arise exclusively in or metastasizes to the central nervous system (CNS). Globally, CNS involvement of NKTL heralds a serious prognosis and there is no standard treatment. 19 of 414 patients (4.59%) with ENKL followed were diagnosed with CNS involvement between 2006 and 2020. Two patients had primary CNS (PCNS) NKTL, and 17 patients had secondary CNS (SCNS) invasion. A total of 9 patients survived and 10 patients died. The median overall survival time was 55 months, and the median survival time after CNS invasion was 17 months. The 5-year cumulative survival probability was 45.7%. In conclusion, CNS risk evaluation and prophylaxis treatment can be carried out for patients with NK/T-cell lymphoma prognostic index risk group III/IV. In terms of treatment, systemic therapy based on methotrexate combined with radiotherapy and intrathecal chemotherapy can be selected.

Clinical Characteristics and Prognostic Analysis of Extranodal NK/T-Cell Lymphoma Patients Treated with Pegaspargase Based Chemotherapy

To investigate the clinical characteristics of patients with extranodal NK/T-cell lymphoma (ENKL), and to analyze the factors that affecting the survival and prognostic of patients treated with pegaspargase based chemotherapy. The clinical data of 61 ENKL patients treated in Peking Union Medical College Hospital from January 2015 to June 2019 were enrolled and retrospectively analyzed. The clinical characteristics, survival rate and influencing factors of prognostic in patients were investigated. The male and female ratio in the whole group was 2.8∶1. The median age was 46 years old (range, 17-67 years old). 30 patients were in stage I/II, while 31 patients were in stage III/IV. The ratio of nasal and non-nasal type was 4.1∶1. The common sites of extranodal involvement were skin and subcutaneous tissue (26.2%), liver (14.8%), lung (13.1%) and gastrointestinal tract (13.1%). 9.8% of patients showed central nervous system involvement and 11.5% showed bone marrow involvement. The median follow-up time was 22 months (range, 1-53 months). The 2-year PFS and OS rates of patients in the whole group were 51.6% and 53.2%, respectively. The 2-year OS rate of patients at stage I/II was 87.5%, while that of patients at stage III/IV was only 21.2%, the difference showed statistically significant (P<0.0001). Patients with non-nasal type disease showed a higher proportion in adverse factors of prognosis, of whom the median OS was only 3 months. Multivariate analysis showed that age>60 years old and Ann Arbor stage III-IV were the independent adverse factors that affecting the prognosis of PFS and OS (HR=3.681, 95% CI 1.322-10.250; HR=4.611, 95% CI 1.118-19.009). The survival of ENKL patients has been significantly improved by pegaspargase based chemotherapy. Patients with stage I/II disease have achieved a relatively good 2-year OS rate of 87.5%, but the prognosis of stage III/IV and non-nasal type patients are still poor. Age>60 years old and Ann Arbor stage III/IV are independent adverse prognostic factors for ENKL patients.