Subtype Of Peripheral T-cell Lymphoma Research Articles

A preclinical model of peripheral T‐cell lymphoma GATA3 reveals DNA damage response pathway vulnerability

Peripheral T‐cell lymphoma (PTCL) represents a rare group of heterogeneous diseases in urgent need of effective treatments. A scarcity of disease‐relevant preclinical models hinders research advances. Here, we isolated a novel mouse (m)PTCL by serially transplanting a lymphoma from a germinal center B‐cell hyperplasia model (Cγ1‐Cre Blimp1fl/fl) through immune‐competent mice. Lymphoma cells were identified as clonal TCRβ+ T‐helper cells expressing T‐follicular helper markers. We also observed coincident B‐cell activation and development of a de novo B‐cell lymphoma in the model, reminiscent of B‐cell activation/lymphomagenesis found in human PTCL. Molecular profiling linked the mPTCL to the high‐risk “GATA3” subtype of PTCL, showing GATA3 and Th2 gene expression, PI3K/mTOR pathway enrichment, hyperactivated MYC, and genome instability. Exome sequencing identified a human‐relevant oncogenic β‐catenin mutation possibly involved in T‐cell lymphomagenesis. Prolonged treatment responses were achieved in vivo by targeting ATR in the DNA damage response (DDR), a result corroborated in PTCL cell lines. This work provides mechanistic insight into the molecular and immunological drivers of T‐cell lymphomagenesis and proposes DDR inhibition as an effective and readily translatable therapy in PTCL.

Immune Checkpoint Inhibitors in Peripheral T-Cell Lymphoma.

Peripheral T-cell lymphomas (PTCLs) are highly heterogeneous and present significant treatment challenges. Immune checkpoint therapies, such as PD-1 and CTLA-4 inhibitors, have significantly changed the clinical management paradigm of tumors. The roles of immune checkpoints in PTCL and related agents have been actively explored over recent years. PD-1 and PD-L1 expression is detectable in both PTCL and immune cells within the tumor microenvironment and forms the basis for the exploration of antibodies targeting these proteins. Such antibodies are currently being investigated in clinical trials to guide individualized therapy. PD-1/PD-L1 inhibitors alone and in combination with chemotherapy, radiotherapy, or targeted therapy have shown broad clinical efficacy and improved the survival of cancer patients. Studies of other immune checkpoint proteins, such as CTLA-4, TIM-3, LAG-3, and TIGIT, are likely to provide potential novel targets for immunotherapy. Here, we review the role of and recent advances in immune checkpoint blockade in common subtypes of PTCL, focusing on the anti-tumor immune responses to PD-1/PD-L1 blockers.

Cost-effectiveness of brentuximab vedotin plus chemotherapy for previously untreated CD30-positive peripheral T-cell lymphoma in Canada

Aims To support reimbursement requests in Canada, we evaluated the cost-effectiveness of brentuximab vedotin (Adcetris) in combination with cyclophosphamide, doxorubicin, and prednisone (A + CHP) compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as frontline treatment for CD30-expressing peripheral T-cell lymphomas (PTCLs) using results from the ECHELON-2 clinical trial. The PTCL subtypes included were systemic anaplastic large cell lymphoma (sALCL), PTCL–not otherwise specified (PTCL-NOS), and angioimmunoblastic T-cell lymphoma (AITL). Materials and methods A partitioned survival model consisting of three health states (progression-free survival [PFS], post-progression survival [PPS], and death) was constructed from the perspective of the Canadian publicly funded healthcare system over a lifetime horizon. Efficacy, safety, and health-related quality-of-life (HRQoL) data were obtained from ECHELON-2. Medical resource use and costs were derived from Canadian literature and standard sources. Incremental cost-effectiveness ratios (ICERs) per life-years (LYs) and quality-adjusted life-years (QALYs) gained were calculated. Sensitivity analyses were performed to account for uncertainty in key parameters. All costs are reported in Canadian dollars. Results A + CHP, when compared with CHOP, was associated with an estimated mean gain of 2.90 LYs and 2.38 QALYs and a mean incremental cost of $76,491. The ICER for A + CHP compared with CHOP was estimated at $26,340 per LY gained and $32,177 per QALY gained. In sensitivity analyses, the ICERs remained below $60,000 per QALY gained. Time horizon, patient starting age, and discount rate affected the results, as the ICER was driven by long-term survival gains observed with A + CHP compared with CHOP. Limitations Real-world downstream treatments (such as stem cell transplantation) may differ from the treatment protocol followed in the ECHELON-2 trial. Conclusions A + CHP compared with CHOP provides a cost-effective treatment option with improved clinical outcomes that are clinically relevant and a comparable safety profile for adults with previously untreated CD30-expressing sALCL, PTCL-NOS, or AITL in Canada.

Circulating Tumor DNA-Based Genotyping and Monitoring for Predicting Disease Relapses of Patients with Peripheral T-Cell Lymphomas.

Plasma circulating tumor DNA (ctDNA) could reflect the genetic alterations present in tumor tissues. However, there is little information about the clinical relevance of cell-free DNA genotyping in peripheral T-cell lymphoma (PTCL). After targeted sequencing plasma cell-free DNA of patients with various subtypes of PTCL (n=94), we analyzed the mutation profiles of plasma ctDNA samples and their predictive value of dynamic ctDNA monitoring for treatment outcomes. Plasma ctDNA mutations were detected in 53 patients (56%, 53/94), and the detection rate of somatic mutations was highest in angioimmunoblastic T-cell lymphoma (24/31, 77%) and PTCL, not otherwise specified (18/29, 62.1%). Somatic mutations were detected in 51 of 66 genes that were sequenced, including the following top 10 ranked genes: RHOA, CREBBP, KMT2D, TP53, IDH2, ALK, MEF2B, SOCS1, CARD11, and KRAS. In the longitudinal assessment of ctDNA mutation, the difference in ctDNA mutation volume after treatment showed a significant correlation with disease relapse or progression. Thus, a ≥ 1.5-log decrease in genome equivalent (GE) between baseline and the end of treatment showed a significant association with better survival outcomes than a < 1.5-log decrease in GE. Our results suggest the clinical relevance of plasma ctDNA analysis in patients with PTCL. However, our findings should be validated by a subsequent study with a larger study population and using a broader gene panel.

Advances and Personalized Approaches in the Frontline Treatment of T-Cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogenous subset of non-Hodgkin lymphoma characterized by an aggressive clinical course. Historically, the treatment of PTCLs have been analogous to that of aggressive B-cell lymphomas; however, it has been well-established that overall responses and complete remission rates are far inferior using near-identical chemotherapy strategies. Recently, there has been a plethora of newer agents designed to target distinguishing cellular and molecular features of specific PTCL subtypes. These agents have been proven to yield superior anti-lymphoma responses and, in some cases, overall survival in the relapsed, refractory, and frontline treatment setting. In this review, we will summarize and highlight the most influential clinical trials leading to the Food and Drug Administration (FDA) approval of several novel therapeutic agents against PTCL, with an emphasis on emerging studies and strategies to expand their potential use in the frontline treatment setting.

POSC49 The Cost-Effectiveness of Brentuximab Vedotin in Frontline Systemic Anaplastic Large Cell Lymphoma in France

Systemic anaplastic large cell lymphoma (sALCL) is a rare type of non-Hodgkin lymphoma and one of the subtypes of peripheral T-cell lymphoma. The objective of this study was to estimate the cost-effectiveness of brentuximab vedotin (BV) in combination with cyclophosphamide, doxorubicin and prednisone (CHP) chemotherapy versus current chemotherapies in France.

Classificação do linfoma em gatos e sua relação com a detecção do DNA pró-viral do vírus da leucemia felina

ABSTRACT: In this retrospective and prospective study, histopathological and immunohistochemical analyses of 62 cases of lymphomas in cats were performed to classify the anatomic forms and subtypes, according to the WHO guidelines, and correlate it to FeLV proviral DNA detected using PCR. The most common anatomical form was gastrointestinal (40.3%, 25/62), followed by multicentric (29%, 18/62), mediastinal (17.7%, 11/62) and extranodal (12,9%, 8/62). Among the lymphoma subtypes, diffuse large B-cell lymphoma (DLBCL) (30.6%, 19/62) was the most commonly diagnosed followed by peripheral T-cell lymphoma (PTCL) (29%, 18/62) and enteropathy associated T-cell lymphoma type 2 (14.5%, 9/62). DNA extraction from paraffin-embedded neoplastic tissue was obtained in 28 cases and FeLV proviral DNA was detected by PCR, in 23 of these. Of the cases presenting with FeLV proviral DNA, nine (32%) were of the multicentric form, five (22%) of the mediastinal and extranodal forms and four (17%) of the gastrointestinal form. The most frequent subtypes with FeLV proviral DNA, independent of the anatomical form, were DLBCL (39.1%, 9/23) and PTCL (34.7%, 8/23). The presence of the FeLV proviral DNA in 23 cats of this study, probably had association with the multicentric form of lymphoma and higher occurrence in the DLBCL and PTCL subtypes.

Angioimmunoblastic T-cell lymphoma: treatment strategies and prognostic factors from a retrospective multicenter study in China

Angioimmunoblastic T-cell lymphoma (AITL) is a unique sub-type of peripheral T-cell lymphoma (PTCL). We aimed to evaluate treatment programs and prognostic factors of 121 newly diagnosed patients with AITL in China from January 2001 to December 2018. The median age was 58 years with male predominance. Bone marrow involvement appeared in only 8.3% of patients, which was different from the previously published literature. The 5-year progression-free survival (PFS) and 5-year overall survival (OS) were 29.7% and 44.0%, respectively. Univariate and multivariate analyses showed that involvement of >5 nodal areas, age and Beta-2 microglubulin were highly predictive of OS but only the involvement of fewer than five nodal areas was significant for PFS. We identified a novel prognostic model including the three factors that may be applied in clinical practice and offer an alternative to IPI and PIT.

Clinical Significance of Plasma Epstein-Barr Virus DNA in Peripheral T-Cell Lymphomas

Introduction: The clinical implications of plasma Epstein-Barr virus (EBV) DNA in patients with peripheral T-cell lymphoma (PTCL) remain unclear. Objective: This study aimed to explore the clinical correlations of pre- and post-treatment plasma EBV-DNA concentrations with treatment outcomes and prognosis in patients with PTCL. Methods: We retrospectively reviewed 128 patients diagnosed with PTCL with available data on pre-treatment plasma EBV-DNA, including 63 patients for whom post-treatment plasma EBV-DNA data were also available. Patients with extra-nodal NK/T-<X00_Del_TrennDivis></X00_Del_TrennDivis>cell lymphoma were excluded from this study. Results: Pre-treatment plasma EBV-DNA was elevated (e.g., ≥500 copies/mL) in 35.2% of PTCL patients, with significant differences in positive rates between different subtypes of PTCL (p < 0.001). High pre-treatment EBV-DNA concentrations were associated with advanced age (>60 years), elevated lactate dehydrogenase levels, high International Prognostic Index (IPI), and positive EBV-encoded RNAs-ISH in tumor specimens. In multivariate analyses, pre-treatment EBV-DNA ≥500 copies/mL was an independent prognostic factor after adjusting for IPI and pathological subtypes (hazard ratio = 2.14, p = 0.032). For patients with elevated pre-treatment EBV-DNA, normalization of EBV-DNA concentrations after first-line chemotherapy was significantly associated with better overall response rate (81.3% vs. 22.2%, p = 0.014), progression-free survival (12.0 months vs. 3.7 months, p = 0.011), and overall survival (37.9 months vs. 7.8 months, p = 0.012). For patients achieving remission to first-line therapy, rebound of EBV-DNA levels during follow-up was associated with disease relapse or progression. Conclusions: These results suggest that pre-treatment plasma EBV-DNA concentration is a strong prognostic factor for PTCL. For patients with elevated pre-treatment EBV-DNA, dynamic monitoring of EBV-DNA changes after initiation of therapy is useful for predicting treatment outcome and disease relapse.

Single-Cell Sequencing Technology Reveals the Heterogeneity of the Immune Microenvironment and Key Molecules of Drug Resistance in Angioimmunoblastic T-Cell Lymphoma

Objective:Angioimmunoblastic T-cell lymphoma (AITL) is a common subtype of peripheral T-cell lymphoma (PTCL). AITL is an aggressive malignancy with a poor prognosis, and its clinical manifestations vary greatly among individuals. The current chemotherapy regimens based on anthracycline show limited efficacy, and there is no best rescue treatment for patients with relapsed and refractory (RR) AITL. In addition, the lack of optimal AITL models in vitro greatly limits the basic research on the mechanism of disease occurrence and progression, and also hinders the development of new drugs and preclinical trials. Our study aims to deeply analyze the tumor heterogeneity and clonal evolution of AITL, discovering key molecules of drug resistance and potential theraputic targets.Methods:We detected fresh lymph node samples from newly diagnosed and relapsed/ refractory AITL patients using single-cell RNA sequencing, combined with imaging mass cytometry (IMC) and whole exome sequencing. IMC was performed to analyze the spatial position relationship and protein expression characteristics of different subgroups in the tumor microenvironment of AITL. In addition, AITL patient-derived organoid model was established to study the regulatory role of YY1 and its inhibitors in relapsed and refractory AITL.Results:ScRNA-seq revealed the significant differences in the tumor microenvironment of newly diagnosed and RR-AITL patients (Fig A,B). B cells and myeloid subgroups may play important roles in the development of AITL (Fig C). Transcription factor YY1, highly expressed in follicular helper T cell (Tfh) of RR-AITL patients, promoted the proliferation and drug resistance of AITL cells (Fig E,F). The proportion of CD8+ T cells in the RR-AITL sample was reduced, while the proportion of Treg was increased, as well as the depletion of T cells (Fig G,H). Furthermore, the stemness of B cells in RR-AITL was enhanced and exhibits significant malignant characteristics (Fig C,I-K). We also found decreased interaction in RR-AITL samples (Fig L,M). Moreover, for the first time, we established AITL patient-derived organoid models that can be stablely cultured in vitro (Fig N). On this basis, we could further clarify the important roles of transcription factor YY1 in the drug resistance of AITL, evaluate the cytotoxic effect of YY1 inhibitor NP-001 on AITL tumor cells.Conclusion:In conclusion, our study revealed the differences between newly diagnosed and relapsed /refractory AITL in terms of immune microenvironment, single-cell transcriptomes, and signal pathway activation. YY1 may serve as an novel target for drug resistance for RR-AITL patients. These findings may provide a theoretical foundation for improving the clinical treatment of AITL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (CHEP-BV) Followed By BV Consolidation in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin, Etoposide, and Prednisone (CHEP-BV) Followed By BV Consolidation in Patients with CD30-Expressing Peripheral T-Cell Lymphomas

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

The Echelon-2 Trial: 5-Year Exploratory Subgroup Analyses of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Vs CHOP in Frontline Treatment of Pts with CD30-Positive Peripheral T-Cell Lymphoma

The Echelon-2 Trial: 5-Year Exploratory Subgroup Analyses of a Randomized, Double-Blind, Phase 3 Study of Brentuximab Vedotin and CHP (A+CHP) Vs CHOP in Frontline Treatment of Pts with CD30-Positive Peripheral T-Cell Lymphoma

First-Line Treatment and Survival of Stage I(E) Peripheral T-Cell Lymphoma in the Netherlands; A Nationwide Population-Based Cohort Study

Introduction: Peripheral T-cell lymphomas (PTCL) comprise a heterogenous group of mature T-cell neoplasms with generally an unfavorable prognosis. Presentation of PTCL with stage I(E) disease, according to the Ann Arbor classification, is uncommon. Clinical trials in diffuse large B-cell lymphoma (DLBCL) support the use of an abbreviated treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone combined with radiotherapy (combined modality therapy (CMT)) in case of stage I(E) disease. CMT in stage I(E) PTCL has been adapted in daily practice, but clinical trials are lacking. A recent population-based study conducted in Scandinavia indicated that the outcome in patients with limited stage PTCL is as poor as in patients with extensive disease. However, the outcomes of different treatment modalities were not analyzed.Aim: The aim of this nationwide population-based cohort study is to describe first-line treatment and outcome of patients with stage I(E) PTCL in comparison to advanced stage PTCL.Methods: All newly diagnosed patients ≥ 18 years with stage I(E) PTCL who were diagnosed in 1989-2018 were identified in the Netherlands Cancer Registry (NCR). Survival follow-up was available through February 1, 2021. The PTCL subgroups analyzed included anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), enteropathy associated T-cell lymphoma (EATL) and peripheral T-cell lymphoma NOS (PTCL NOS). Patients were categorized according to treatment regimen, i.e. chemotherapy, chemotherapy followed by autologous stem cell transplantation (ASCT), radiotherapy, CMT, and no/other therapy. Calendar period analyses (1989-1999 and 2000-2018) were conducted to assess trends in primary therapy and overall survival (OS) over time. The calendar periods were defined according to the implementation of CMT in patients with limited stage DLBCL from approximately 2000 onward in the Netherlands. The primary endpoint was OS, defined as all-cause-death post-diagnosis.Results: From 1989 to 2018, 854 patients with a median age of 62 years were diagnosed with stage I(E) PTCL, accounting for 19% of all PTCL diagnoses. In stage I(E), the predominant PTCL subtype was PTCL NOS (40%, n=343). Furthermore, 26% (n=222) of patients were diagnosed with ALCL, 3% (n=28) with AITL, 11% (n=93) with EATL and 20% (n=168) with other histological subtypes. In contrast, for patients with advanced stage disease, 42% was diagnosed with PTCL NOS, 23% with ALCL, 24% with AITL, 6% with EATL and 5% with other histological subtypes .To evaluate treatment and survival outcome in patients with stage I(E) PTCL, patients with ALCL, AITL, PTCL NOS and EATL were included for further analyses (n=686). Patients with ALCL, AITL and PTCL NOS were most commonly treated with CMT (n=164; 28%) or chemotherapy only (n=154; 26%). Only 10 patients (1%) received chemotherapy followed by ASCT. The remaining patients were treated with either radiotherapy only (n=116; 20%) or received other/no therapy (n=149; 25%). More patients were treated with CMT in 2000-2018 as compared to 1989-1999 (36% versus 17%, p<0.01). Patients with EATL were most commonly treated with either chemotherapy only or other/no treatment (both n=45; 48%), while 3 patients (4%) received chemotherapy in combination with ASCT (n=2) or CMT (n=1). In EATL, no differences in treatment strategy were observed over time.Overall, 5-year OS for all stage I(E) PTCL was 52%. There was no significant difference in outcome between the two time periods (53% vs. 52%, p=0.92). EATL had a worse prognosis when compared to ALCL, AITL and PTCL NOS (5-year OS 15% vs. 58%, respectively; p<0.01). Five-year OS was significantly higher for patients with ALCL, AITL and PTCL NOS treated with CMT (71%) as compared to patients treated with either chemotherapy alone or with radiotherapy alone (52%, and 53%, respectively; p<0.01). Independent predictors for poor prognosis were higher age, male gender and EATL subtype whereas CMT was associated with a lower risk of mortality when evaluated for in multivariable analysis.Conclusions: For stage I(E) ALCL, AITL and PTCL NOS, 5-year OS is 58%. This compares favorably to the reported outcomes in advanced stage disease. EATL, even when presenting with limited stage disease, is associated with a very poor prognosis. CMT is associated with superior OS when compared to either chemotherapy or radiotherapy alone. DisclosuresVan Der Poel: Roche, Janssen, Abbvie: Honoraria. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.

A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas

AbstractSignaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

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.

Bio-O2-08 - Mutational landscape of nodal peripheral T-cell lymphoma subtypes

<h3>Introduction:</h3> Nodal peripheral T-cell lymphoma (PTCL) subclassification (Angioimmunoblastic TCL, PTCL-with T Follicular Helper phenotype and PTCL-NOS) and therapeutic targeting is still controversial. Overall survival (OS) is only around 30% after 5 years. <h3>Methods:</h3> We performed targeted next-generation sequencing of 61 selected genes in 76 PTCL patients. Among the 76cases, 44 were classified as AITL, 18 as PTCL-TFH and 14 as PTCL-NOS. <h3>Results:</h3> Our analysis revealed a wide variety of genetic variants that possibly drive the development of AITL, PTCL-TFH and/or PTCL-NOS. We identified an average of 4 variants per patient, mainly clustered in genes regulating chromatin conformation (TET2, DNMT3A) and T-cell differentiation (RHOA, MTOR, IDH2, VAV1 and NOTCH1). More frequently mutated genes were TET2 (76,31%) and DNMT3A (27,63%). Multiple mutations were found in TET2, VAV1, RHOA, NOTCH1, MTOR, JAK1, ZEB1, ATM, DNMT3A and ARID1B. Main difference among the three Nodal PTCL classes was the higher frequency of RHOAG17V mutations (p<0.0001), present approximately 2 times more frequently in AITL cases (34,09%) than in PTCL-TFH (16,66%), and they were not detected in PTCL-NOS. All three Nodal PTCL subtypes share finding suggesting Clonal Hematopoiesis (CH) in TET2 and DNMT3A genes. Cases with higher variant allele frequencies (VAF)s in TET2 and DNMT3A genes vs. other mutated genes were attributed to CH. In our study we found this phenomenon to take place in all Nodal PTCL subtypes (AITL: 31,8%; PTCL-TFH: 50%; PTCL-NOS: 35,71%). A correlation was not found between specific mutations, mutational index, mutations attributed to CH and clinical outcome. <h3>Conclusions:</h3> There is a common molecular basis for the three Nodal PTCL with very frequent mutations in genes regulating chromatin conformation associated with mutations in genes governing T-cell differentiation. RHOA G17V mutations were highly significant enriched in AITL. Findings suggesting Clonal Hematopoiesis were found in the three types of nodal PTCL.

Genome-Wide miRNA Expression Profiling of Molecular Subgroups of Peripheral T-cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126→ SIPR2 and miR-145 → ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.

Analysis Of Peripheral T-Cell Lymphoma (PTCL) Subtype By Race and Geography Using The Comprehensive Oncology Measures For Peripheral T-Cell Lymphoma Treatment (COMPLETE) Dataset

Background COMPLETE is a national registry of PTCL patients designed to describe patient characteristics, treatments and outcomes in a ‘real world’ setting. Previous work has suggested that there may be geographic and/or racial differences in the incidence of PTCL subtypes. Using the COMPLETE dataset, we explored the influence of race and geography in the United States on the incidence of PTCL subtypes and examined for interactions between these two variables. Methods We identified patients with locked baseline records and performed univariate analyses comparing disease subtype, stratified by race and geography. A multivariable, multinomial response regression model was used to predict the classification of PTCL subtype based upon race and geographic region. An interaction term for race and region was assessed via a likelihood ratio test and found to be not significant (p = 0.43), thus was removed from the model. Results A total of 247 patients had locked baseline records. Given the small numbers of Asian (7 patients, 3%) and other/race unknown patients (6, 3%), only Black (43, 17%) and White (191, 77%) patients were included in the analyses. Results of the univariate analyses can be found in [Table 1][1]. PTCL-not otherwise specified (NOS) accounted for the largest histologic subtype (35% of patients), consistent with SEER (31%) and other data sources. A trend was noted in distribution of subtype by race and significant differences were seen in histologic distribution by region, with a higher proportion of angioimmunoblastic T-cell lymphoma (AITL) patients diagnosed in the West and a smaller proportion in the South. A higher proportion of patients diagnosed with PTCL-NOS were in the South compared to other regions while a higher proportion of patients in the Northeast were diagnosed with other histologic subtypes. The multinomial regression model suggests there was a relatively high likelihood of being diagnosed with PTCL-NOS for both races in the Midwest, South and West and a relatively high likelihood of being diagnosed with other subtypes of PTCL for patients in the Northeast. White patients in the West have the highest likelihood of being diagnosed with AITL. View this table: Table 1 Results of Univariate Analyses of PTCL Subtype by Race and Region Conclusions These results suggest there is a modest, independent influence of both race and region in the United States on histologic subtype of PTCL. Whether geographic differences are due to patient selection bias or potentially due to environmental factors cannot be determined in this study. As the sample size grows, further analyses are warranted to examine if the effect of race and region is enhanced or diminished while controlling for factors not measured in the current model. Disclosures: Carson: Allos: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Foss: merck: Research Funding; spectrum: Research Funding; eisai: Membership on an entity’s Board of Directors or advisory committees; millenium: Honoraria, Membership on an entity’s Board of Directors or advisory committees; celgene: Honoraria, Research Funding; seattle genetics: Research Funding. Pinter-Brown: Allos: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Horwitz: Spectrum (Allos): Consultancy, Research Funding. Rosen: Allos: Consultancy, Honoraria. Gisselbrecht: Allos: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Hsi: Allos: Research Funding; Seattle Genetics: Speakers Bureau; Eli Lilly: Research Funding; Abbott: Research Funding; Cellerant Therapeutics: Research Funding; BD Biosciences: Research Funding; Millennium: Research Funding. [1]: #T1

Aggressive T-cell lymphomas: 2021 Updates on diagnosis, risk stratification and management.

Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations. Gene expression profiling (GEP) can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma (ALCL). In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients. There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are CD25, CCR4, inhibition of PI3kinase - m TOR and JAK/STAT pathways. The ALK inhibitors are promising for ALK expressing tumors. Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell (ENK/T) lymphomas and cutaneous T-cell lymphomas (CTCL). Bispecific antibody based treatments as well as CAR-T cell based therapies are in clinical trials.