Type Of Peripheral T-cell Lymphoma Research Articles

TP53 and KMT2D mutations associated with worse prognosis in peripheral T-cell lymphomas.

There are limited studies on mutation profiling for Peripheral T-cell lymphomas (PTCL) in the Chinese population. We retrospectively analyzed the clinical and genetic landscape of 66 newly diagnosed Chinese patients. Targeted next-generation sequencing (NGS) was performed for tissues from these patients. At least one mutation was detected in 60 (90.9%) patients, with a median number of 3 (0-7) mutations, and 32 (48.5%) cases detected with more than 4 mutations. The genes with higher mutation frequencies were TET2, RHOA, DNMT3A, IDH2, TP53, STAT3, and KMT2D respectively. When mutant genes are classified by functional group, the most prevalent mutations are related to epigenetics and signal transduction. IPI ≥2, PIT ≥2, and failure to achieve partial remission (PR) were factors for inferior progression-free survival (PFS) and overall survival (OS). Multivariate analysis showed TP53 was an adverse factor for PFS (HR, 3.523; 95% CI, 1.262-9.835; p = 0.016), and KMT2D was an adverse factor for OS (HR, 10.097; 95% CI, 1.000-101.953; p = 0.048). Mutation profiling could help differentiate distinct types of PTCL and serve as a useful tool for determining treatment options and prognoses.

The Role of Epigenetic Modifier Mutations in Peripheral T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a group of diseases with a low incidence, high degree of heterogeneity, and a dismal prognosis in most cases. Because of the low incidence of these diseases, there have been few therapeutic novelties developed over time. Nevertheless, this fact is changing presently as epigenetic modifiers have been shown to be recurrently mutated in some types of PTCLs, especially in the cases of PTCLs not otherwise specified (PTCL-NOS), T follicular helper (TFH), and angioimmunoblastic T-cell lymphoma (AITL). These have brought about more insight into PTCL biology, especially in the case of PTCLs arising from TFH lymphocytes. From a biological perspective, it has been observed that ten-eleven translocators (TET2) mutated T lymphocytes tend to polarize to TFH, while Tregs lose their inhibitory properties. IDH2 R172 was shown to have inhibitory effects on TET2, mimicking the effects of TET2 mutations, as well as having effects on histone methylation. DNA methyltransferase 3A (DNMT3A) loss-of-function, although it was shown to have opposite effects to TET2 from an inflammatory perspective, was also shown to increase the number of T lymphocyte progenitors. Aside from bringing about more knowledge of PTCL biology, these mutations were shown to increase the sensitivity of PTCLs to certain epigenetic therapies, like hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACis). Thus, to answer the question from the title of this review: We found the Achilles heel, but only for one of the Achilles.

A Prospective Study of Short-Term Chemotherapy Bridging Allogeneic-SCT in High Risk Peripheral T-Cell Lymphoma

Background: Results of conventional therapy in patients with peripheral T-cell lymphoma (PTCL) are dismal. Current guidelines recommend consolidation with autoSCT after 6 course of induction for most PTCL patients, but one third of new diagnosed patients progressed before autoSCT. Allogeneic hematopoietic stem cell transplantation (alloSCT) can cure relapsed/refractory patients, even those failured to HDT/ASCT. We hypothesized that AlloSCT as first-line consolidation post short course of induction could improve outcome in high-risk PTCL patients. Patients and Methods: A prospective study was conducted in high-risk PTCL patients (except ALK+ ALCL, and stage 1 with aaIPI 0) who were scheduled to undergo upfront allo-SCT after 3 x CHOEP(or -like) induction chemotherapy (registered in Clinical Trials, NCT03672084). Matched sibling donor(MSD) was the first choice, an unrelated donor or haploidentical family donor(Haplo-donor) search was performed in patients without MSD. From Jan.2018 to June 2022, 23 newly diagnosed patients enrolled, 8 PTCL-NOS, 1 ALK-negative ALCL, 6 AITL and 9 HSTL. After 1st line induction, 12 proceeded upfront alloSCT(10 in CR,1 in PR and 1 in SD), 9 of 11 with progressive disease received transplant after 2nd line chemotherapy (salvage alloSCT), the other 2 (diagnosed with PTCL-NOS) did not undergo transplantation because of PD. All patients received myeloablative conditioning and antithymocyte globulin was administered for Haplo-SCT (with 2.5mg/kg daily on days -5 to -2). All patients received cyclosporineA, MMF and short-term MTX as GVHD prophylaxis (Patients characters were in Table 1). Results: Untill July 30,2022，we had an interim results with the median follow up of 367(38-1237)d. For all transplanted patients, the median age was 38(4-63) years old, five had a MSD and the other 16 had a haplo-donor. Before alloSCT, 11 patients (52.4%) were in CR and 6 (28.6%) in PR, 1 (4.7%) in SD, and 3(14.3%) in PD. All but one patients had CR post alloSCT, 1 in PR received donor lymphocyte infusion(DLI) on D30 then had got CR on D60. One patient received a second alloSCT from another haplo-donor because of secondary graft failure. Acute GVHD of grade II-IV occurred in 9 of 21 patients (42.9%) (6 of grade III-IV). Thirteen of 20 (65%) evaluable patients developed chronic GVHD, which was extensive in 4 cases(20%). Four patients, all diagnosed with HSTL, experienced with post-SCT relapse on day 60,75, 180 and 455 respectively. Two had response to salvage chemotherapy with DLI, and stay in CR at last follow-up. Three patients died, 2 of lymphoma and 1 of pneumonia on day 280. The estimated 1- and 2-year event-free survival (EFS) in all transplanted cases were 78% and 67%, and those of overall survival(OS) were all 83%. The D100 and 1-y toxicity-related mortality(TRM) were 0% and 6.4%, respectively. There were no differences in PFS and OS between upfront and salvage alloSCT. The patients who diagnosed with HSTL had a significant poor PFS compared to other types of PTCL, with the 1y PFS of 56% vs 92% (p=.017), and had a comparable 1-y OS ,78% vs 92% (p=.337). This result may due to the higher relapsed rate of HSTL (44% vs 0%, p=0.003). So we involved a prophylaxis DLI in HSTL patients recently. Conclusions: Upfront AlloSCT in high-risk PTCLs was feasible with low TRM, and it could provide long-term disease control. And the strategy of haplo-donor SCT can bring more patients to AlloSCT. However, half of patients had progressed disease after 1st line induction, due to the strong anti-lymphoma effect of allograft, salvage alloSCT had been shown increased response rate in this group of refractory patients. The treatment strategy of short-term induction followed by alloSCT may improve the outcome for high-risk PTCL patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Rare monomorphic epithelial intestinal T-cell lymphoma of the stomach with a giant gastric perforation rescued by liver-covering sutures followed by a total gastrectomy and lateral hepatectomy: a case report

BackgroundMonomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), a type of peripheral T-cell lymphoma, rarely involves the stomach as the primary organ. Advanced MEITL, for which there is currently no established treatment, causes gastrointestinal perforations and is characterized by a poor response to chemotherapy.Case presentationA 69-year-old man had undergone chemotherapy for MEITL of the whole stomach. He subsequently developed acute abdominal pain, and computed tomography revealed a giant perforation in the anterior gastric wall adjacent to the lateral segment of the liver. The perforation was rescued through closure with liver-covering sutures. Thereafter, a total gastrectomy and a left hepatectomy were performed and he recovered enough to tolerate oral intake. However, despite ongoing chemotherapy, the patient died 83 days after the gastric perforation (10 months after being diagnosed with the lymphoma) owing to rapid progression of the MEITL.ConclusionIn the rare case of a giant gastric perforation after chemotherapy for gastric MEITL, rescue is possible through liver-covering sutures followed by a total gastrectomy and lateral hepatectomy.

Bio-P-16 - Peripheral T-cell lymphoma: molecular profiling distinguishes subclasses, recognizes the tumor architecture and identifies prognostic markers

<h3>Introduction:</h3> Peripheral T-cell lymphomas (PTCLs) are aggressive tumours with unfavourable prognosis, with around 30% OS after 5 years. Histological and molecular studies have revealed a striking degree of heterogeneity, with three major PTCL subtypes defined. Consistent diagnosis and prognostication are still difficult to achieve, because of the difficulty of reproducing results, and the dearth of clinically applicable prognostic biological markers. <h3>Methods:</h3> We have analyzed a series of 105 PTCL cases (66 angioimmunoblastic T-cell lymphoma, AITL; 21 PTCL-not otherwise specified, PTCL-NOS; and 18 PTCL-with T follicular helper phenotype, PTCL-TFH) patients using a customized NanoString platform that includes 208 genes associated with T-cell differentiation, oncogenes and tumor suppressor genes, deregulated pathways and stromal cell subpopulations. Specifically, the platform includes genes expressed by the multiple cell types present in PTCL specimens, together with normal T-cell populations. These are used to try and enable the deconvolution of the T-cell lymphoma microenvironment, and thereby develop an integrated perspective on the cell composition of PTCL tumor specimens. <h3>Results:</h3> A comparative analysis of the various histological types of PTCL (AITL, PTCL-NOS and PTCL-TFH) showed specific sets of genes to be associated with each of the diagnoses, including TFH markers, cytotoxic markers and genes whose expression was a surrogate for specific cellular subpopulations, including follicular dendritic cells, mast cells and genes belonging to specific cell-survival pathways (NF-κB). Unsupervised analysis of the expression of the genes here studied revealed clusters of co-regulated genes that identified the main cell components of the tumor. The analysis did not reveal any differences in survival probability associated with the histological sub-classification, but did identify specific genes and gene sets whose expression was associated with changes in survival probability for each of the PTCL subtypes, independently of the clinical variables included in the International Prognostic Index (IPI). These included a B-cell gene set in cases of AITL, the expression of proliferation markers in PTCL-NOS, and the expression of cytotoxic markers in cases with a diagnosis of PTCL-TFH. For each PTCL lymphoma type, a multivariate analysis identified genes that allow the series of cases to be stratified into different risk groups. This was validated for AITL in an independent series of 54 additional cases. <h3>Conclusions:</h3> In summary, our study supports the current division of PTCL into these three categories (AITL, PTCL-NOS and PTCL-TFH), identifies gene sets potentially useful for this classification and recognizes the expression of B-cell genes as an IPI-independent prognostic factor for AITL subtype.

P13-6 The effectiveness of mogamulizumab against refractory angioimmunoblastic T cell lymphoma

Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma that accounts for less than 10% of all lymphomas in adults. Although the 5-year overall survival (OS) rate of ALK+ anaplastic large cell lymphoma (ALCL) is around 70%, those of other types of PTCL (ALK- ALCL, angioimmunoblastic T cell lymphoma [AITL] and PTCL not otherwise specified [PTCL(NOS)]) is only 30 to 40% and that of adult T cell leukemia/lymphoma is less than 30% Therefore, a new targeted therapy for PTCL is mandatory. Since 2011, forodesine, romidepsin, pralatrexate, mogamulizumab and other new drugs have been introduced for the treatment of relapsed PTCL, but improved prognosis of PTCL has not been definitely demonstrated.

Measurement of PD-1 Expression on Lymphoma Cells By Flow Cytometry Is a Useful Tool in Diagnosing and Monitoring Minimal Residual Disease in Angioimmunoblastic T-Cell Lymphoma

Introduction: Angioimmunoblastic T-cell Lymphoma (AITL) is one of the most common types of peripheral T-cell lymphoma (PTCL), representing about 15-20% of cases of PTCL. Diagnosis of AITL is often challenging and a definitive diagnosis requires a use of ancillary testing including broad panels of immunohistochemistry and molecular studies. We evaluated the utility of evaluation of Programmed-Death-1 (PD-1) expression on lymphoma cells by flow cytometry as a diagnostic tool as well as monitoring minimal residual disease (MRD) of AITL.Methods: The study group was composed of 81 patients who were diagnosed with PTCL at Memorial Sloan Kettering Cancer Center between May 2015 and July 2017. This includes 36 patients with AITL, 6 with ALK-negative anaplastic large cell lymphoma (ALCL, ALK-), 2 with ALK-positive anaplastic large cell lymphoma (ALCL, ALK+), 9 with adult T-cell leukemia/lymphoma (ATLL), 11 with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 6 with nodal involvement by mycosis fungoides (MF), 5 with T-cell large granular lymphocytic leukemia (T-LGL), and 6 with T-cell prolymphocytic leukemia (T-PLL). The expression of PD-1 (CD279) on lymphoma cells was evaluated by 10-color flow cytometry using BV605-conjugated anti-CD279 antibody, and mean fluorescence intensity (MFI) was evaluated. Immunohistochemistry for PD-1, CD10, BCL6, and CXCR13 were also performed on tissue samples of AITL. Flow cytometry for variable regions of T-cell receptor beta chain (Vbeta) and genetic analysis for T-cell receptor gene rearrangement were performed on sorted abnormal T-cell population by flow cytometry in selected cases for the evaluation of clonality. Peripheral blood sample was used for the monitoring of MRD.Results: All AITL cases with tissue biopsy showed PD-1 immunoreactivity by immunohistochemistry (IHC), and PD-1 expression by flow cytometry showed excellent correlation with IHC. The abnormal CD4-positive PD-1 bright T-cell population detected by flow cytometry in AITL cases was confirmed to be clonal by restricted Vbeta fragment expression and molecular genetic analysis (Fig 1). On tissue samples, expression of other T-follicular helper cell markers was not observed by IHC in 7 cases (25%), and additional 3 cases (11%) presented with concomitant lymphoid neoplasm, which obscured morphologic and immunohistochemical evaluation for AITL. The latter 3 cases would be misdiagnosed by morphologic assessment alone. However, flow cytometry reliably detected AITL in all 10 challenging cases. Overall flow cytometry including PD-1 expression had 100% sensitivity in detection of AITL. The expression of PD-1 was significantly higher in AITL than that of other PTCL (CD279-BV605 MFI; Mean ± SEM; 6990.0 ± 934.9 vs. 547.3 ± 155.5; p<0.0001) (Fig 2A). PD-1 MFI differentiated AITL from other PTCL with high sensitivity and specificity (AUC 0.978; Fig 2B). The significant increase in PD-1 expression in AITL was a consistent finding with peripheral blood specimen. In 54 patients who had circulating lymphoma cells in peripheral blood, PD-1 expression was significantly higher in AITL than that of other PTCL (CD279-BV605 MFI; Mean ± SEM; 3079.0 ± 508.8 vs. 341.8 ± 54.17; p<0.0001: AUC 0.986) (Fig 2C, 2D). In 12 AITL patients who had tissue sample with concomitant bone marrow and peripheral blood specimens, flow cytometry detected lymphoma cells in bone marrow and peripheral blood in all patients. Among them, 9 patients were followed for monitoring of MRD. MRD in peripheral blood was not detected in 4 patients after therapy (Median 4.5 months; Range; 2-6 months); 2 patients received stem cell transplant, and 2 patients received chemotherapy only, and all 4 patients were free of disease at the time of last follow up (Median 18.5 months; Range 17-26 months). 5 patients kept having MRD after therapy (Median 13 months; Range: 3-21 months), and one of 5 patients presented with new lesion of AITL 12 months after the initial diagnosis.Conclusions: Flow cytometric immunophenotyping with anti-PD-1 antibody reliably detects neoplastic population in AITL cases, and PD-1 MFI differentiates AITL from other PTCL with high sensitivity and specificity. Bright PD-1 expression alone is a reliable indicator of TFH immunophenotype by flow cytometry. Measurement of PD-1 expression by flow cytometry is a useful tool both in diagnosing and monitoring MRD of AITL. [Display omitted] DisclosuresMoskowitz:ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria; Incyte: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy; BMS: Consultancy; Mundipharma: Consultancy; Aileron Therapeutics: Research Funding. Dogan:Celgene: Consultancy; Roche Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Peer Review Institute: Consultancy.

Comprehensive genomic analysis identifying heterogeneity in peripheral T‐cell lymphoma

Peripheral T‐cell lymphoma (PTCL) is a heterogeneous entity generally with a poor prognosis. Recent genomic analyses have characterized genomic alterations and described gene expression profiling and epigenetic mechanisms in PTCL, leading to reveal molecular pathophysiology in detail. One of several important findings is that heterogeneities exist in both the disease and in individuals. Among PTCL subtypes, adult T‐cell leukemia/lymphoma (ATLL) and peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) are common in Japan. ATLL is an incurable T‐cell malignancy induced by human T‐cell lymphotropic virus type 1 (HTLV‐1). The global genomics of ATLL can be summarized as alterations involving T‐cell receptor (TCR) signaling and immune escape mechanisms. This highlights the fact that ATLL is a viral‐mediated T‐cell malignancy. Interestingly, several previous studies have found that the genomics of ATLL differ according to geographical region and age at diagnosis, suggesting disease heterogeneity, though they share HTLV‐1 infection as initial disease hit. Clonal expansion of the cells acquired by somatic mutations in ATLL‐related genes is identified in a part of HTLV‐1 carriers who developed ATLL later. The risk for ATLL may be updated based on findings in detail. PTCL‐NOS is a heterogeneous disease type of T‐cell lymphoma that does not correspond to any other type of PTCL. Several studies have stratified PTCL‐NOS according to transcriptional, genomic, microenvironmental, and clinical aspects. These kinds of analysis from multiple aspects are useful to understand the heterogeneous group. These efforts will help guide suitable translational research to target PTCL.

Retrospective Review of Prognostic and Predictors Markers in Newly Diagnosed Angioimmunoblastic T Cell Lymphoma at UT MD Anderson Cancer Center

Retrospective Review of Prognostic and Predictors Markers in Newly Diagnosed Angioimmunoblastic T Cell Lymphoma at UT MD Anderson Cancer Center

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous group of mature T-cell neoplasms that comprise 10–15% of non-Hodgkin lymphoma cases in the United States. All subtypes of PTCL, except for ALK+ anaplastic T-cell lymphoma, are associated with poor prognosis, with median overall survival (OS) rates of 1–3 years. The diagnosis of PTCL is mainly based on clinical presentation, morphologic features, and immunophenotypes. Recent advances in genome sequencing and gene expression profiling have given new insights into the pathogenesis and molecular biology of PTCL. An enhanced understanding of its genomic landscape holds the promise of refining the diagnosis, prognosis, and management of PTCL. In this review, we examine recently discovered genetic abnormalities identified by molecular profiling in 3 of the most common types of PTCL: RHOAG17V and epigenetic regulator mutations in angioimmunoblastic T-cell lymphoma, ALK expression and JAK/STAT3 pathway mutations in anaplastic T-cell lymphoma, and T-follicular helper phenotype and GATA3/TBX21 expression in PTCL-not otherwise specified. We also discuss the implications of these abnormalities for clinical practice, new/potential targeted therapies, and the role of personalized medicine in the management of PTCL.

Identification of archaea community of the Papallacta geothermal source, located in Napo province –Ecuador, through new generation sequencing

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

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.

PS1306 JAB1/CSN5 STABILIZES PD‐L1 PROTEIN AND CORRELATES WITH STAT3 ACTIVATION IN T‐CELL LYMPHOMAS

Background:Peripheral T‐cell lymphomas (PTCL) represent 8–10% of all non‐Hodgkin lymphomas and are generally associated with poor clinical outcome with the exception of ALK+ anaplastic large cell lymphomas (ALCL) The genetic basis and transcriptional regulation of PD‐L1 has been recently investigated by our group in various PTCL types including ALK+ and ALK‐ ALCL (ASH 2018 poster). However, PD‐L1 can be regulated at the post‐translational level as well. The Jab1 (c‐Jun activation domain‐binding protein‐1), initially discovered as a c‐Jun co‐activator, represents the fifth component of an evolutionary highly conserved 8‐subunit protein complex, named COP9 signalosome (CSN). The Jab1/CSN5 gene operates as an oncogene in cancer through multiple mechanisms and recent evidence suggests that it is also involved in immune checkpoint regulation through PD‐L1 stabilization and decreased degradation. Moreover, the recent discovery of a novel Jab1/CSN5 inhibitor (CSN5i3) designed for clinical use may allow for novel investigational therapies combining targeted therapy and immunotherapy approaches.Aims:This study aimed to investigate the expression patterns of Jab1/CSN5 in PTCL tumors as well as its biologic effects on PD‐L1 protein stabilization.Methods:The PTCL study group included a cohort of 80 patients diagnosed and treated at Karolinska University Hospital (Sweden) and MD Anderson Cancer Center (USA). All tissue samples were formalin‐fixed, paraffin‐embedded (FFPE) diagnostic biopsies obtained prior to therapy. Jab1/CSN5, PDL1 and T705‐pSTAT3 expression were assessed by immunohistochemistry performed on tissue microarrays or full tissue sections using specific antibodies. For all proteins, the percentage of positive neoplastic cells was evaluated with counting of at least 500 lymphoma cells in representative microscopic fields. The in vitro study model included five T‐cell lymphoma cell lines. A T‐cell lymphoma (Karpas 299) and leukemia (Jurkat) cell lines were used in an ex vivo animal model (xenografts in SCID mice), following Jab1/CSN5 gene silencing using shRNA constructs. In addition, the cell lines were treated with the novel Jab1/CSN5 inhibitor, CSN5i3, or with the selective STAT3 inhibitor XIII and the levels of the relevant proteins were assessed by Western blot analysis.Results:The percentage of Jab1/CSN5+ lymphoma cells was significantly higher in ALK+ ALCL and ALK‐ ALCL as compared to angioimmunoblastic T‐cell lymphoma (AITL), PTCL‐NOS, and other histologic types of PTCL (p &lt; 0.001, Kruskal‐Wallis). As continuous variables, the percentage of Jab1/CSN5+ tumor cells significantly correlated with that of PDL1 (Spearman R = 0.33, p = 0.03) and T705‐pSTAT3 (Spearman R = 0.42, p = 0.01) in the entire cohort of PTCL. Knocking down Jab1/CSN5 using shRNA in Karpas 299 xenograft tumors resulted in longer survival of SCID mice as compared to control mice, which was associated with significantly decreased PD‐L1 protein levels in tumor cells. Treatment of T‐cell lymphoma cell lines with the STAT3 inhibitor XIII resulted in downregulation of Jab1/CSN5. Similarly, treatment of T‐cell lymphoma and leukemia cells with the novel inhibitor of Jab1/CSN5 activity, CSN5i3, decreased the protein level of PD‐L1 in vitro at a concentration‐dependent manner.Summary/Conclusion:Jab1/CSN5 regulates PD‐L1 through stabilization of the protein and can be efficiently targeted by CSN5i3 in preclinical models of T‐cell lymphomas and leukemias. Jab1/CSN5 expression significantly correlates with PD‐L1 protein levels and STAT3 activation in PTCL and its clinical significance is currently under investigation.

Transcriptional analysis distinguishes breast implant-associated anaplastic large cell lymphoma from other peripheral T-cell lymphomas

Breast implant-associated anaplastic large cell lymphoma is a new provisional entity in the revised World Health Organization classification of lymphoid malignancies, the pathogenesis and cell of origin of which are still unknown. We performed gene expression profiling of microdissected breast implant-associated anaplastic large cell lymphoma samples and compared their transcriptional profiles with those previously obtained from normal T-cells and other peripheral T-cell lymphomas and validated expression of selected markers by immunohistochemistry. Our results indicate that most breast implant-associated anaplastic large cell lymphomas exhibit an activated CD4+ memory T-cell phenotype, which is associated with CD25 and FoxP3 expression. Gene ontology analyses revealed upregulation of genes involved in cell motility programs (e.g., CCR6, MET, HGF, CXCL14) in breast implant-associated anaplastic large cell lymphomas compared to normal CD4+ T-cells and upregulation of genes involved in myeloid cell differentiation (e.g., PPARg, JAK2, SPI-1, GAB2) and viral gene transcription (e.g., RPS10, RPL17, RPS29, RPL18A) compared to other types of peripheral T-cell lymphomas. Gene set enrichment analyses also revealed shared features between the molecular profiles of breast implant-associated anaplastic large cell lymphomas and other types of anaplastic large cell lymphomas, including downregulation of T-cell receptor signaling and STAT3 activation. Our findings provide novel insights into the biology of this rare disease and further evidence that breast implant-associated anaplastic large cell lymphoma represents a distinct peripheral T-cell lymphoma entity.

Molecular and Genomic Landscape of Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphoma (PTCL) is an uncommon group of lymphoma covering a diverse spectrum of entities. Little was known regarding the molecular and genomic landscapes of these diseases until recently but the knowledge is still quite spotty with many rarer types of PTCL remain largely unexplored. In this chapter, the recent findings from gene expression profiling (GEP) studies, including profiling data on microRNA, where available, will be presented with emphasis on the implication on molecular diagnosis, prognostication, and the identification of new entities (PTCL-GATA3 and PTCL-TBX21) in the PTCL-NOS group. Recent studies using next-generation sequencing have unraveled the mutational landscape in a number of PTCL entities leading to a marked improvement in the understanding of their pathogenesis and biology. While many mutations are shared among PTCL entities, the frequency varies and certain mutations are quite unique to a specific entity. For example, TET2 is often mutated but this is particularly frequent (70-80%) in angioimmunoblastic T-cell lymphoma (AITL) and IDH2 R172 mutations appear to be unique for AITL. In general, chromatin modifiers and molecular components in the CD28/T-cell receptor signaling pathways are frequently mutated. The major findings will be summarized in this chapter correlating with GEP data and clinical features where appropriate. The mutational landscape of cutaneous T-cell lymphoma, specifically on mycosis fungoides and Sezary syndrome, will also be discussed.

TET2 Mutation Associated with Organ Infiltrations in ATLL

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma that is caused by HTLV-1. The prognosis of acute and lymphomatous variants of ATLL is poor, ranging from 2 weeks to >1 year. Compared to other types of malignant lymphomas, the organ infiltration is frequently observed in ATLL (Yamada et al. Leuk Lymphoma 1997). We previously reported the landscape of genetic mutations in ATLL, and showed that various mutations occurred in the TCR-NFκB pathway in more than 90% of ATLL cases (Kataoka et al. Nat Genet 2015). These somatic mutations are thought to develop ATLL in combination with viral genes such as HTLV-1 bZIP factor (HBZ). Among them, mutations in TET2, an epigenetic regulator, was observed in about 10% of ATLL cases. Higher frequencies inTET2 mutation was reported in other types of peripheral T-cell lymphoma (PTCL); it was observed in about 80% of angioimmunoblastic T-cell lymphoma (AITL) and in about 50% of PTCL, not otherwise specified. In PTCL, it has been reported that additional mutations in lymphoid progenitors derived from TET2 mutated hematopoietic stem cells cause increased cell proliferation and anti-apoptosis, leading to the disease progression. In ATLL, the role of TET2 mutation in disease progression is still unknown. In this study, we investigated the role of TET2 mutation in ATLL using mouse model and acute and lymphomatous variant ATLL cohort.Materials and methods: As an animal model of HTLV-1 infection or ATLL, transgenic mice expressing HBZ under the control of the mouse CD4 promoter (HBZ-Tg) were generated with C57BL/6 background. Heterozygous TET2 knock-down mice (TET2KD) were generated with C57BL/6 background by gene trapping (Tang et al. Transgenic Res 2008; Shide et al. Leukemia 2012). HBZ-Tg/TET2KD compound mice (double mutant) were generated by crossing them. HBZ-Tg, TET2KD, and double mutant mice were investigated by cell counts, organ weight, FACS analysis, pathological analysis, and survival analysis. The relationship between the TET2 mutation status and the clinical feature was investigated using our acute and lymphomatous variant ATLL cohort (n=115).Result: At 12 months, compared to wild type mouse (WT), sporadic splenomegaly and lymphadenopathy were observed in HBZ-Tg. No significant increase was observed in peripheral blood (PB) leukocyte and mononuclear cell (MNC) of BM and spleen, but an increase was observed in the estimated whole body MNC (Femur x 100/6 + spleen) (WT vs. HBZ-Tg; estimated whole body MNC (x106 cells/body), 416±162 vs. 621±147, p=0.01). In FACS analysis, the frequency of CD4+ T-cell was increased in PB, spleen, and BM (WT vs. HBZ-Tg; PB-CD4+ T-cell%, 4.9±0.9 vs. 28.2±22.8, p<0.05; spleen CD4+ T-cell%, 10.3±3.1 vs. 18.2±3.3, P<0.01; BM-CD4+ T-cell%, 1.2±0.6 vs. 2.5±1.1, p<0.05), and the estimated whole body CD4+ T-cell count was also increased (WT vs. HBZ-Tg; CD4+ T-cells (x106 cells/body) 13.6±7.6 vs. 41.9±24.4, p<0.01). In the survival analysis, compared to WT, the shortened overall survival (OS) was observed in HBZ-Tg (median survival time (MST, month), unreached vs. 11.1, p<0.01). In pathological analysis, HBZ-Tg showed increased leukocyte infiltration to various organs such as lung and liver, and the infiltrated cells were mainly composed of T-cells. In the lung, in addition to the cell infiltration, alveolar edema was observed, which was presumed to be the main cause of death.Next, to elucidate the role of TET2 mutation in ATLL, the double mutant was analyzed. At six months, compared to HBZ-Tg, no increase was observed in the number of PB leukocyte, spleen-MNC, and BM-MNC, and also in the frequency and the number of CD4+ T-cells in PB, spleen and BM. However, in pathological and survival analysis, the double mutant showed severe cell infiltration in lung and liver and demonstrated inferior OS (median OS (month), 11.1 vs. 6.0, p<0.05). Further, the double mutant showed increased frequency of CD103 (integrin alpha E), an adhesion molecule, expressing cells (CD4+CD103+% in spleen; 6.7±1.0 vs. 10.9±1.9, p<0.05). In the acute and lymphomatous variant ATLL cohort analysis, genetic and clinical investigation revealed that organ infiltration detectable by imaging studies was frequently observed in TET2 mutated patients (WT-Pt (n=100) vs. TET2 mutated-Pt (n=15); extra nodular lesion, 78/100 vs. 14/15).Conclusion: In both mice model and human cohort, TET2 mutation exacerbated organ infiltration of ATLL cells. DisclosuresNo relevant conflicts of interest to declare.

Genetic Basis, Expression Patterns and Clinical Significance of PD-L1 in Peripheral T-Cell Lymphomas (PTCL)

Introduction: The PD-1 / PD-L1 interaction is a crucial immune checkpoint in cancer, which has been targeted by monoclonal antibodies currently used in clinical trials. The genetic basis and transcriptional regulation of PD-L1 has been previously investigated in ALK+ and ALK- anaplastic large cell lymphomas (ALCL) by our group (Atsaves et al, Leukemia 2017, (7):1633-1637), however, the regulatory mechanisms of PD-1/PD-L1 immune checkpoint in other T-cell lymphomas are not yet known. PD-L1 expression in neoplastic cells has been associated with worse clinical outcome in other hematologic malignancies including Hodgkin lymphoma, diffuse large B-cell lymphoma (DLBCL) and plasma cell myeloma, however, the clinical significance of PD-L1 expression in neoplastic cells and in the immune cells of the tumor microenvironment in PTCLs has not been studied to date. In this study, we investigated PD-L1 gene copy number alterations using a genome-wide approach and diagnostic biopsies. We also assessed for the expression patterns of PD-L1 in the neoplastic cells and histiocytes in PTCL tumors as well as for their possible associations with clinical outcome.Methods: The PTCL study group included 64 patients (median age 62 years; 61% males, various histologic types), diagnosed and treated at Karolinska University Hospital (Sweden). All tissue samples were obtained prior to therapy. PD-L1 expression was assessed by immunohistochemistry performed on tissue microarrays or full tissue sections using a PD-L1 monoclonal antibody (SP263, Ventana). At least 500 lymphoma cells were counted to calculate the percentage of PDL1-positive tumor cells. PD-L1 expression in histiocytes was scored as “high” or “low” (arbitrary) based on the number of positive infiltrating histiocytes. Overall survival (OS) defined as time from diagnosis to death or last follow-up was chosen as the endpoint for outcome. Survival analyses were performed using the Kaplan-Meier method (log-rank test) and Cox hazards models. In addition, a pilot series of 24 PTCLs were analysed by Oncoscan (Affymetrics) for PD-L1 gene copy number alterations and the results were confirmed by digital q-RT PCR at the mRNA level. Genomic DNA and total RNA were extracted from diagnostic formalin-fixed, paraffin-embedded (FFPE) biopsies using standard protocols. Associations between PD-L1 expression and PTCL type were statistically analysed with Fisher's exact, chi-square, Mann-Whitney and Kruskal-Wallis tests. Survival analysis was performed using the Kaplan-Meier method (log rank test) and Cox proportional hazards model.Results: Whole genome analysis using Oncoscan (Affymetrics) showed low-level chromosomal gains in 2 (8.3%) PTCLs, which were confirmed by digital q-RT PCR that demonstrated slightly increased PD-L1 mRNA levels (PD-L1/reference gene <2). No correlation of the gene copy number findings with PD-L1 protein expression assessed by immunohistochemistry was seen. Expression of PD-L1 was observed in 92% ALK+ ALCL, 57% ALK- ALCL, 38% PTCL, NOS and 18% angioimmunoblastic T-cell lymphomas (AILT) and less frequently in other PTCL types (p=0.0019). After a median follow up of 66 months, PD-L1 expression by the lymphoma cells was associated with superior OS in the entire study group and in the subgroup of PTCL other than ALK+ ALCL (p<0.0001, logrank). By contrast, high PD-L1 expression in histiocytes was associated with inferior OS (p<0.0001, logrank). The PTCL patients with PD-L1-positive tumor cells and PD-L1-low expression in histiocytes showed a 5-year OS 71% as compared to 24% for the PTCLs with PD-L1-negative tumor cells and PD-L1-high expression in histiocytes (p=0.0002, logrank) and this difference remained highly significant in the subgroup of PTCL other than ALK+ ALCL (p=0.0005, logrank). Both the PD-L1 negativity in lymphoma cells (p=0.0007) and PD-L1-high expression in histiocytes (p=0.04) were independent adverse prognostic factors in the multivariable analysis (Cox model).Conclusions: Copy number alterations of the PD-L1 gene (9p24.1 locus) are uncommon in PTCL subtypes and therefore, PD-L1 gene expression is likely regulated at the transcriptional of post-translational levels in T-cell lymphomas. PD-L1 negativity in the lymphoma cells and high PD-L1 expression in histiocytes are strong adverse prognostic factors in PTCL, however, larger series are needed to confirm these associations in each histologic type of PTCL. DisclosuresÖsterborg:Pharmacyclics: Research Funding; Janssen: Research Funding; Gilead: Consultancy, Research Funding; Abbvie: Research Funding; Beigene: Research Funding.

Frequency, distribution, and immunomorphologic characteristics of peripheral T-cell lymphoma, not otherwise specified in a tertiary care center in Southern India.

In world literature, Peripheral T-cell lymphomas (PTCLs) constituted about 12% of non-Hodgkin's lymphomas (NHL) of which PTCL not otherwise specified (NOS) was the most common subtype. This study was undertaken to ascertain the frequency and to assess the morphologic and immunophenotypic characteristics of PTCL, NOS over a period of 5 years in a tertiary care referral center in Southern India. Slides and blocks of all PTCL, NOS were retrieved, and a detailed morphologic and immunophenotypic study using a wide panel of antibodies was done. During this study, NHL constitutes 77.61% of all lymphomas. PTCL formed about 12.55% (251 cases) of all NHL. PTCL NOS was the most common subtype (30.68%). The most common site of involvement was lymph nodes (75%) followed by extranodal sites such as soft tissue (8.33%), gastrointestinal tract including oral cavity (6.67%), nasal cavity (5%), central nervous system (1.67%), lung (1.67%), and spleen (1.67%). PTCL, NOS showed a broad morphologic spectrum and had varied morphologic patterns with some mimicking reactive hyperplasia and some mimicking known type of T-cell lymphomas, B-cell lymphomas, and Hodgkin's lymphoma. PTCL, NOS constituted about 30.68% of all PTCLs in our institution during a 5-year period and was the second most common type of PTCL. Immunophenotyping using a wide panel of T-cell antibodies is necessary to distinguish PTCL, NOS from other lymphomas which they mimic, as they are known to carry a worse prognosis.

Two cases of angioimmunoblastic T-cell lymphoma with concomitant positive serology for acute Epstein-Barr virus infection.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare type of peripheral T-cell lymphoma. Epstein-Barr virus (EBV) is known to be associated with pathogenesis and histological progression of AITL and the onset of the disease often mimics an infectious process. Here we describe two cases of patients with serology for acute EBV infection at the onset of AITL.

Development of a modified prognostic index for patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation.

Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia-lymphoma in order to construct a new, large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor levels (> 5,000 U/mL), high adjusted calcium levels (≥ 12 mg/dL), and high C-reactive protein levels (≥ 2.5 mg/dL) were independent adverse prognostic factors used in the training set. We used these five variables to divide patients into three risk groups. In the validation set, median overall survival for the low-, intermediate-, and high-risk groups was 626 days, 322 days, and 197 days, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a promising new risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy.