PTCL-NOS Research Articles

Genetic drivers of oncogenic pathways in molecular subgroups of peripheral T-cell lymphoma

AbstractPeripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A/B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2R172 mutation. CN losses were enriched in genes regulating PI3K–AKT–mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.

Prognostic value of peripheral blood absolute lymphocyte count for patients with peripheral T-cell lymphoma, not otherwise specified

Objective To explore the prognostic value of peripheral blood absolute lymphocyte count (ALC) for patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Methods The clinical data of 69 patients with PTCL-NOS treated in Tianjin Union Medical Center from January 2008 to January 2016 were analyzed retrospectively. The relationship between different levels of ALC and clinical characteristics, therapeutic efficacy and prognosis was analyzed. Results Among 69 patients, 23 cases (33.3%) had low ALC (<1.0×109/L), and 46 cases (66.7%) had high ALC (≥1.0×109/L). Compared with the high ALC group, the low ALC group showed the higher International Prognostic Index (IPI) and PTCL-NOS Prognostic Index (PIT) scores, advanced clinical stage and higher lactate dehydrogenase level (all P < 0.05). The total efficacy rate in the low ALC group was lower than that in the high ALC group [56.5% (13/23) vs. 67.4% (31/46)], but the difference was not statistically significant (χ 2 = 0.784, P = 0.376). The 3-year survival rate in the low ALC group was significantly lower than that in the high ALC group, and the difference was statistically significant (40.5% vs. 68.6%, χ2 = 7.846, P = 0.010). Univariate analysis showed that the US Eastern Cooperative Oncology Group performance status score≥2, IPI score≥2, Ann Arbor stage Ⅲ-Ⅳ and ALC<1.0×109/L were the poor prognostic factors (all P < 0.05), while Cox multivariate analysis showed that the Ann Arbor stage Ⅲ-Ⅳ and ALC<1.0×109/L were the independent risk factors for prognosis of patients with PTCL-NOS (P = 0.008, P = 0.029). Conclusion The decrease of peripheral blood ALC in patients with PTCL-NOS at the initial diagnosis suggests a poor prognosis, and ALC can be used as a new indicator for prognosis evaluation of PTCL-NOS patients. Key words: Lymphoma, T-cell, peripheral; Absolute lymphocyte count; Clinical features; Prognosis

Integration of transcriptional and mutational data simplifies the stratification of peripheral T-cell lymphoma.

The histological diagnosis of peripheral T-cell lymphoma (PTCL) can represent a challenge, particularly in the case of closely related entities such as angioimmunoblastic T-lymphoma (AITL), PTCL-not otherwise specified (PTCL-NOS), and ALK-negative anaplastic large-cell lymphoma (ALCL). Although gene expression profiling and next generations sequencing have been proven to define specific features recurrently associated with distinct entities, genomic-based stratifications have not yet led to definitive diagnostic criteria and/or entered into the routine clinical practice. Herein, to improve the current molecular classification between AITL and PTCL-NOS, we analyzed the transcriptional profiles from 503 PTCLs stratified according to their molecular configuration and integrated them with genomic data of recurrently mutated genes (RHOA G17V , TET2, IDH2 R172 , and DNMT3A) in 53 cases (39 AITLs and 14 PTCL-NOSs) included in the series. Our analysis unraveled that the mutational status of RHOA G17V , TET2, and DNMT3A poorly correlated, individually, with peculiar transcriptional fingerprints. Conversely, in IDH2 R172 samples a strong transcriptional signature was identified that could act as a surrogate for mutational status. The integrated analysis of clinical, mutational, and molecular data led to a simplified 19-gene signature that retains high accuracy in differentiating the main nodal PTCL entities. The expression levels of those genes were confirmed in an independent cohort profiled by RNA-sequencing.

Effect of Immunotherapy and Stem Cell Transplant on Survival in T Cell Lymphoma. NCDB Analysis

Introduction T cell lymphomas contribute to less than 15 percent of Non-Hodgkin lymphoma in adults. Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), Anaplastic large cell lymphoma (ALCL), Angioimmunoblastic T cell lymphoma (AITL) contribute to approximately 75 percent of these T cell lymphomas. We did a population based study to evaluate the role of stem cell transplant and immunotherapy on survival outcome in stage four T cell lymphoma. Methods Data was analyzed from 4395 men and women (≥ 18 years of age) registered in the National Cancer Database (NCDB) who were diagnosed with stage four T cell lymphoma – PTCL, ALCL and AITL between 2004 and 2013 and had follow-ups to end of 2014. The primary predictor variable was treatment received, and overall survival was the outcome variable. Additional variables addressed and adjusted included gender, age, race, Charleston Comorbidity Index and histology. Results The mean age of patients was 58 years with standard deviation of 16. In multivariate analysis, after adjusting for secondary predictor variables, treatment modality was a statistically significant predictor of overall survival. Chemotherapy, SCT and immunotherapy decreased the mortality risk by 52, 70 and 22 %, respectively. Among the group with immunotherapy, pts with PTCL NOS and AITCL ALK negative derived the greatest benefit. Conclusion SCT and immunotherapy leads to improved survival in pts with T cell lymphoma. Among pts with T cell lymphoma, PTCL and ALCL ALK -, derive the greatest benefit from immunotherapy. Further clinical; research needs to be done to evaluate the role of immunotherapy in T cell lymphoma

Transcriptomic Abnormalities in Epstein Barr Virus Associated T/NK Lymphoproliferative Disorders.

Epstein Barr virus positive T/NK lymphoproliferative disorders (EBV-TNKLPD) comprise a spectrum of neoplasms ranging from cutaneous lymphoid proliferations to aggressive lymphomas. The spectrum includes extranodal NK/T-cell lymphoma (ENKTL), aggressive NK-cell leukemia, and a group of EBV-TNKLPDs affecting children which are poorly characterized in terms of their molecular biology. Gene and miRNA expression profiling has elucidated RNA abnormalities which impact on disease biology, classification, and treatment of EBV-TNKLPD. Pathways promoting proliferation, such as Janus associated kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) and nuclear factor kB, are upregulated in ENKTL while upregulation of survivin and deregulation of p53 inhibit apoptosis in both ENKTL and chronic active EBV infection (CAEBV). Importantly, immune evasion via the programmed cell death-1 and its ligand, PD-1/PD-L1 checkpoint pathway, has been demonstrated to play an important role in ENKTL. Other pathogenic mechanisms involve EBV genes, microRNA deregulation, and a variety of other oncogenic signaling pathways. The identification of EBV-positive Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) as a tumor with a distinct molecular signature and clinical characteristics highlights the important contribution of the knowledge derived from gene and miRNA expression profiling in disease classification. Novel therapeutic targets identified through the study of RNA abnormalities provide hope for patients with EBV-TNKLPD, which often has a poor prognosis. Immune checkpoint inhibition and JAK inhibition in particular have shown promise and are being evaluated in clinical trials. In this review, we provide an overview of the key transcriptomic aberrancies in EBV-TNKLPD and discuss their translational potential.

Peripheral T-Cell Lymphoma, not Otherwise Specified (PTCL-NOS).

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a World Health Organization (WHO)-defined diagnostic category within the highly heterogeneous group of mature post-thymic T-cell neoplasms. It is the most common subtype of mature post-thymic T-cell neoplasms globally, accounting for up to 35% of PTCL cases in Europe and North America. PTCL-NOS is a diagnosis of exclusion, comprising several disease entities that differ in biology, clinical presentation, and outcome. The diagnosis of PTCL-NOS is made based on the presence of typical histopathological features of lymphoma, an aberrant T-cell immunophenotype, often with a loss of CD5 and CD7, and a clonal T-cell receptor (TCR) gene rearrangement, in the appropriate clinical context. Unlike other types of T-cell lymphoma, recurrent mutations to assist with the diagnosis have not been identified. Patients often present with advanced stage. Prognosis is poor, with a 5-year overall survival (OS) of 20-30%. Anthracycline-based combination chemotherapy remains the most frequently used frontline strategy, with overall response rates (ORR) of 50-60%, and complete response rates (CRR) of 20-30%. Prospective studies with intent-to-treat analyses have shown that consolidation with high-dose chemotherapy and autologous stem cell transplant (ASCT) results in progression-free survivals (PFS) that compare favorably with historical cohorts and may improve OS in selected patient populations. However, randomized data are still lacking. Over the past decade, therapeutic agents approved in the relapsed and refractory setting have produced response rates of up to 33% and median PFS up to 18 months. Overall, outcomes remain poor and there is a dire need for more effective treatments. This review discusses the latest information on the diagnosis and treatment of PTCL-NOS.

Whole Genome Sequencing Reveals Recurrent Structural Driver Events in Peripheral T-Cell Lymphomas Not Otherwise Specified

Historically, the differential diagnosis between different nodal peripheral T-cell lymphoma (PTCL) subtypes based on morphological and phenotypic grounds has posed great challenges. In the last few years, our knowledge of the molecular bases of different PTCLs has significantly expanded. However, peripheral T-cell lymphomas not otherwise specified (PTCL-NOSs) are still regarded to as a heterogeneous category encompassing PTCL cases not fitting other, more homogeneous, subtypes. In fact, PTCL-NOS is one of the few lymphoma subtypes where no recurrent driver mutations have been reported so far.In order to better characterized the PTCL-NOS genomic landscape, we decided to investigate 11 PTCL-NOS patients by a whole genome sequencing (WGS) approach (median coverage 27X). Ten out of eleven samples were collected from FFPE blocks and 2 were removed from analysis: one due to low cancer cell fraction (CCF) and the other based on cluster generation issues during sequencing likely caused by a hyper-fragmented DNA. Among the remaining 9 cases, we extracted 59,617 somatic base substitutions (range 2,471-10,756, median 6,358 per patient) and 20,531 small insertion-deletions (indels) (range 84-6,397, median 1,580). We were able to characterize the spectrum of FFPE-induced artefacts, mostly composed of point mutations and indels within LINE-1 (L1) elements, predominantly of the L1PA family. This is a crucial quality control step that could be applied to similar future studies from archive samples. Four samples were heavily involved by FFPE-related artefacts and were excluded for this reason.Using a non-negative matrix factorization (NNMF) algorithm we investigated for the first time the PTCL-NOS mutational signature landscape. We did not find novel processes in this entity, but rather known processes operative in other lymphoid malignancies. Among those: signatures 1 and 5, deriving from the age-related process of spontaneous deamination of methylated cytosines; signatures 2 and 13 deriving from aberrant activity of the APOBEC family of DNA deaminases; signatures 17 and 8, pertaining to two yet poorly characterized processes. The contribution of different processes to the mutational spectrum of each case was profoundly heterogeneous.Combining our data set with 64 previously published whole exome sequencing cases (23 ALCL, 15 AITLs, 9 PTCL-NOSs and 16 EATL-II), we confirmed the lack of recurrent driver mutations among PTCL-NOS. Taking advantage of WGS data, we therefore focused on structural variants (SVs: inversions, translocations, internal tandem duplications and deletions) and copy number alterations (CNAs). We found 372 SVs, with a stunning median of 73 per sample (range 56-86). Even more interesting, at least one complex event was observed in all but one patients, including one whole genome duplication (WGD) and five chromothripsis events in three patients, suggesting a critical role of SVs in shaping the PTCL-NOS genome. We found that known onco-drivers were recurrently disrupted by such events: the most frequent target was CDKN2A, deleted in 4 out of 5 patients, 2 of which carried homozygous deletions. Interestingly, PTEN loss was observed in 2 out of 4 CDKN2A-deleted patients. Given the high prevalence of these deletions, we extended our observation to an independent validation set of ALCLs (n=56), AITL (n=22) and PTCL-NOS (n=59) investigated by FISH (n=36), next generation sequencing (n=25) or SNP6 array series (n=76). Overall, CDKN2A was deleted in 22/59 (37%) PTCL-NOSs cases, and in 17/22 (77%) both alleles were lost. PTEN was deleted in 12/59 (20%) PTCL-NOS cases, all of which also carried a CDKN2A loss. Strikingly, the co-occurrence of CDKN2A and PTEN was found only among PTCL-NOS, and in none of the other entities. With the limitations of the small sample size, the presence of CDKN2A bi-allelic deletions was associated with inferior survival (25% [95% CI: 9-66%] 5-y OS for deleted cases vs 52% [95% CI: 28-96%] for wt/hemizygous cases, p=0.042) among patients treated with an autologous bone marrow transplant front line program for advance stage and high-risk disease (n=19).Our observations point at SVs as a main driver of PTCL-NOS, often involving known cancer genes and their downstream pathways. Furthermore, our data highlighted recurrent gene deletions that may be relevant for differential diagnosis within this category of lymphomas. DisclosuresBolli:Celgene: Honoraria. Chiappella:Roche: Other: lecture fees; Amgen: Other: lecture fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Nanostring: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Teva: Other: lecture fees. Corradini:Celgene: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Roche: Honoraria, Other: Advisory Board & Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Amgen: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer.

The NCCN-IPI Score Is Prognostic of Survival in Patients with Peripheral T-Cell Lymphoma, Not Otherwise Specified

Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) accounts for 15-20% of NHL and is characterized by a poor survival. The IPI and PIT scores are prognostic factors in survival in B-cell and T-cell lymphomas, but not without limitations. The aim of this study is to evaluate the prognostic value of the NCCN-IPI score in patients with PTCL-NOS.Methods: We included patients with a pathological diagnosis of PTCL-NOS who were diagnosed and treated at our institution between 1997 and 2017. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists at our institution to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratios (HR) for overall survival (OS).Results: A total of 173 patients with diagnosis of PTCL-NOS were included in this analysis. The median age at diagnosis was 58 years (range 18-91 years) with a male predominance (58%). Clinically, 47% of patients were 60 or older, 52% presented with ECOG >1, 82% had elevated serum LDH, 74% had extranodal disease, and 34% had stage I/II and 66% had stage III/IV. IPI score distribution was low-risk in 55% of patients, low-intermediate in 36%, high-intermediate in 48% and high-risk in 33%. PIT score distribution was low-risk in 53%, low-intermediate in 67%, high-intermediate in 38% and high-risk in 14%. NCCN-IPI score distribution was low risk in 40%, low-intermediate in 56%, high- intermediate in 63% and high risk in 11%. 22% of patients received CHOEP, 23% received CHOP, and 55% received other regimens. The overall response rate was 59%; 47% had a complete response and 12% had a partial response. The 5-year overall survival (OS) rate was 32% with a median OS of 12 months. PTCL-NOS patients with low, low-intermediate, high-intermediate and high-risk NCCN-IPI had 5-year OS rates of 46%, 36%, 26% and 0%, respectively (p<0.001). When compared with patients with low-risk NCCN-IPI, patients with low-intermediate (HR 3.2, 95% CI,1.1-9.5; p=0.044) and high-intermediate /high risk NCCN-IPI (HR 6.0, 95% CI 2.1-17; p=0.001) had worse OS.Conclusions: We have validated the NCCN-IPI score as a prognostic tool in patients with PTCL-NOS. This work can serve to address future prospective designs that allow selection of groups of patients at greater risk and thus lead to more individualized therapy. DisclosuresCastillo:Janssen: Consultancy, Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Beigene: Consultancy, Research Funding.

B-Symptoms, Performance Status and Response to First Therapy As Survival Predictive Factors for Peripheral T-Cell Lymphoma at Progression/Relapse: A Single Institute Analysis

IntroductionPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of generally aggressive lymphomas that account for 5-15%of non-Hodgkin lymphomas. PTCL, not otherwise specified (PTCL-NOS), is the most common subtype that accounts for 25.9% of PTCL, followed by angioimmunoblastic T-cell lymphoma (AITL), NK/T-cell lymphoma (NKTCL), Adult T-cell Leukemia/Lymphoma (ATLL), ALK-positive anaplastic large cell lymphoma (ALK+ ALCL), and ALK-negative ALCL (ALK- ALCL) (Vose J. et al, 2008). The Prognostic Index for PTCL-NOS (PIT; Gallamini A. et al, 2004) is a prognostic model widely used for PTCL-NOS. There are, however, no established risk factors developed specifically for PTCL after progression/relapse. We report the survival outcomes of 6 common subtypes of PTCL after first line therapy as well as after first progression/relapse, and report newly identified prognostic factors for PTCL after progression/relapse.MethodsWe identified 144 patients with newly diagnosed PTCL-NOS, AITL, ALK+ ALCL, ALK- ALCL, NKTCL and ATLL between 2005-2017 in our institution. After excluding patients who did not receive treatment in our institution, we performed a retrospective analysis of the remaining 132 newly diagnosed patients (PTCL-NOS n=47, AITL n=21, ALK- ALCL n=6, ALK+ ALCL n=9, NKTCL n=36, ATLL n=21). Furthermore, we analyzed 57 cases of first progression/relapse. Overall survival (OS) and progression-free survival (PFS) were estimated for newly diagnosed lymphoma (OS1 and PFS1) and at first progression/relapse (OS2 and PFS2), using the Kaplan-Meier method. OS1 and OS2 were further compared by PIT groups. Additionally, possible prognostic factors for OS2 were compared by log rank test. Variables that remained significant in univariate analysis were incorporated in multivariate analysis using the Cox proportional hazard regression model to further investigate independent prognostic factors. For patients who underwent autologous or allogeneic stem cell transplant (SCT), response to therapy was evaluated before SCT.ResultsThe overall response rate (ORR) for first line therapy was 74.2% (95% CI: 65.9-81.5%), with a complete response (CR) rate of 58.3% (95% CI: 49.4-66.8%). Median follow up was 26.5 months and the median OS and PFS were 43 months (95% CI: 30-57 months) and 14 months (95% CI: 8-20 months), respectively. There were significant differences in OS1 by subtype; ALK+ ALCL did not achieve the median, and ATLL fared the worst, with median OS1 of 7 months (Figure 1). There was a correlation between PIT scores and OS1 in our cohort (P < .001). Seventy-nine patients (60%) experienced progression/relapse after first line therapy. After excluding patients who did not receive salvage treatment at our institution, we analyzed the remaining 57 cases with progression/relapse (PTCL-NOS n=33, AITL n=10, ALK- ALCL n=4, ALK+ ALCL n=1, NKTCL n=9). The ORR and CR rates at progression/relapse were 46% (95% CI: 32.4-59.3%) and 25% (95% CI: 14.1-37.8%), respectively. The median OS2 was 13 months (95% CI: 6-23 months) and PFS2 was 3 months (95% CI: 2-7 months). There were no cases with ATLL in progression/relapse as all patients with ATLL were either too frail to receive salvage therapy after first progression/relapse, or proceeded to SCT in first remission. Neither PIT at diagnosis nor at first progression/relapse was predictive of OS2. Moreover, there was no correlation between PIT and OS2 in an analysis limited to only patients with PTCL-NOS. Multivariate analysis revealed that presence of B-symptoms (HR: 4.83, 95% CI: 2.10-11.0, P < .001) and Performance Status (PS) greater than 1 (HR: 6.13, 95% CI: 1.84-20.4, P = .003) were significantly associated with poor OS2. Achieving complete or partial remission after first line therapy was associated with superior OS2 (HR 9.34, 95% CI 0.16-0.71, P = .003). Complete or partial remission after first line therapy was the only independent predictive factor for PFS2 (HR 0.31, 95% CI: 0.15-0.65, P = .002).ConclusionThe presence of B-symptoms and poor PS at progression/relapse were associated with poor OS2. Achieving complete or partial remission after first line therapy was associated with superior OS2. To our knowledge, B-symptoms and response to previous therapy have never been reported as independent prognostic factors. A study with a larger sample size and longer follow-up period is warranted to further assess the validity of these factors. DisclosuresNishimura:Chugai pharmaceutical inc, Roche: Other: commissioned work. Mishima:Chugai pharmaceutical inc, Roche: Other: commissioned work. Yokoyama:Chugai pharmaceutical inc, Roche: Other: commissioned work. Terui:Bristol myers Squib: Honoraria; Celgene: Honoraria; Janssen Pharmaceutical KK: Honoraria; Takeda pharmaceutical: Honoraria; Novartis pharma: Honoraria.

Comparison of Prognostic Stratification between IPI, PIT, and NCCN-IPI in the Treatment of Nodal Peripheral T-Cell Lymphomas

BackgroundNodal peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of neoplasms, which include PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large-cell lymphoma-anaplastic lymphoma kinase positive (ALCL, ALK-pos), and ALCL, ALK-neg. International prognostic index (IPI) is a widely used tool for risk stratification and has shown a strong association with survival in nodal PTCL. The prognostic index for PTCL-U (PIT) is a specific prognostication tool for PTCL and has also shown prognostic relevance in nodal PTCL.The National Comprehensive Cancer Network-IPI (NCCN-IPI) has recently been reported to show better discrimination in higher risk patients with diffuse large B-cell lymphoma, but has never been investigated in nodal PTCLs. Thus, the aim of this study was to validate and compare the usefulness of risk stratification using NCCN-IPI in comparison with the IPI and PIT in patients with newly diagnosed nodal PTCL, particularly in determining high-risk patients.MethodsThis retrospective analysis was conducted using patient-level data from one Korean multicenter retrospective cohort (cohort A; NCT03040206; Eur J Nucl Med Mol Imaging 2018 e-pub) and two prospective Samsung Medical Center Lymphoma I (cohort B) and II (cohort C) cohorts (NCT00822731 and NCT01877109; Blood Cancer J 2016;6:e395) that included nodal PTCL patients. Among those enrolled in the three cohorts, patients were eligible if they were newly diagnosed, were histologically confirmed with nodal PTCL and had received curative intent systemic chemotherapy. Patients were excluded if the histologic subtype was uncertain or primary extranodal mature T-cell or NK/T-cell neoplasms. The study also excluded ALCL, ALK-pos.ResultsA total of 531 patients were screened for eligibility (A [n=396], B and C [n=135]). Eighty-four patients were excluded from this analysis due to following reasons: relapsed nodal PTCL (n=14), no systemic lymphoma therapy (n=14), uncertain histology (n=8), primary extranodal mature T-cell or NK/T-cell neoplasms (n=9), and ALCL, ALK-pos (n=39). Thus, 447 patients were analyzed. Median age at diagnosis was 60 years (range, 19-86) and 285 (64%) were male. PTCL-NOS (n=237, 53%) was the most common histologic subtype included, and AITL (n=154, 35%) and ALCL, ALK-neg (n=56, 13%) followed. Three-fourths of the patients (n=337) were advanced stage and approximately one-fourth of the patients (n=127) had bone marrow involvement at diagnosis. The majority of the patients (n=422, 94%) were treated with anthracycline-based regimen as primary chemotherapy. 77 patients (17%) underwent up-front autologous stem cell transplantation.With a median follow-up of 55.7 months (IQR 32.7-83.5), 5-year progression-free survival rate was 35.9% (95% CI, 31.0-40.8) and overall survival (OS) rate was 46.0% (95% CI, 40.7-51.3). In the univariate analysis, all the risk stratifications, the IPI, PIT, and, NCCN-IPI, were significantly associated with OS (Fig 1A, B, C). However, the 5-yr OS rates of IPI, PIT, and NCCN-IPI differed substantially in the high-risk group,18.2% (95% CI, 9.6-26.8) vs 22.4% (95% CI, 14.0-30.8) vs 10.8% (95% CI, 2.4-19.2), as well as in the low-risk group, 77.1% (95% CI, 69.3-84.9) vs 75.9% (95% CI, 65.3-86.5) vs 85.8% (95% CI, 76.0-95.6; Table 1), respectively. The absolute difference in OS between the low-risk and high-risk groups was 75.0% with NCCN-IPI stratification compared with 58.9% and 53.5% with IPI and PIT stratifications. Notably, 13.4% of the patients were classified as high-risk group using the NCCN-IPI stratification, which was substantially different from stratifications using the IPI (19.2%) and PIT (24.2%). Finally, the NCCN-IPI and histologic subtypes were found to be independent prognostic variables for OS in multivariate analysis (for low-intermediate NCCN-IPI, hazard ratio [HR] 1.80, 95% CI 0.79-4.12; high-intermediate NCCN-IPI, HR 2.19, 95% CI 0.83-5.76; high NCCN-IPI HR 3.63, 95% CI 1.28-1032; P=0.038: for AITL, HR 1.12, 95% CI 0.69-2.01; PTCL-NOS, HR 1.96, 95% CI 1.18-3.27; P<0.001).ConclusionOur study shows that the NCCN-IPI is a more powerful tool than the IPI and PIT for predicting OS in patients with nodal PTCLs. Compared with the IPI and PIT, the NCCN-IPI also shows better discrimination between low-risk and high-risk nodal PTCL patients, and may be more useful to find truly high-risk patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Naturally Occurring Canine Model of Peripheral T-Cell Lymphoma Not Otherwise Specified

Introduction: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) encompasses a heterogeneous and poorly understood group of neoplasms with poor responses to therapy and grave clinical outcomes in both canine and human patients. Because PTCL-NOS is relatively uncommon in human patients, an appropriate model is needed to facilitate elucidation of the underlying pathobiology and identification of novel therapeutic targets. A canine model of PTCL has the added potential to provide a large animal veterinary population for pre-clinical therapeutic trials and subsequent translation into human patients. Marked breed-specific predilection for this disease suggests that genetic risk factors may also be explored using the dog model.PTCL is the second most common type of lymphoma diagnosed in dogs. Similar to human patients, dogs with PTCL are usually middle-aged to older animals and typically present with peripheral lymph node involvement but systemic disease is not uncommon. Canine PTCLs are most commonly CD4-positive, often lose expression of CD5, and exhibit a histomorphology similar to that described in humans. The Boxer breed is significantly over-represented in the population of dogs that develop PTCL.Objective: In this study, we aimed to characterize the gene expression profile of canine PTCL and evaluate the molecular similarity to PTCL-NOS in human patients.Methods: RNA-sequencing was performed on lymph node aspirates from six dogs (3 Boxers and 3 non-Boxers) diagnosed with CD4+ PTCL and sorted CD4+ T-cells from control dogs. Gene expression was compared between neoplastic and non-neoplastic T cells. Gene set enrichment analysis was used to compare the gene expression profile of canine PTCL to a gene list created from a similarly designed, publically available, microarray study of human PTCL-NOS. The gene list was comprised of the top upregulated and downregulated genes in 28 cases of human PTCL-NOS when compared to sorted human control CD4+ T-cells.Results: Canine PTCL was significantly enriched for the gene set representative of human PTCL-NOS. Furthermore, similar to humans, canine PTCL upregulated pathways were involved in proliferation, cell adhesion, extracellular matrix modification, and signal transduction. Canine cases overexpressed GATA3 and CCR4; two markers which characterize a distinct subset of human PTCL-NOS associated with worse clinical outcomes. Canine cases also exhibit significant enrichment for the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) induced gene signatures, consistent with the GATA3 subgroup. Overexpression of platelet derived growth factors (PDGFRs) was conserved across both human and canine cases and has been suggested as a potential therapeutic target. GATA3 and PDGFR-alpha expression in canine cases was corroborated by immunohistochemistry. Boxers and non-Boxers exhibited markedly similar patterns of gene expression, with the exception that lymphomas from all three Boxers significantly upregulated ROS1 compared to non-Boxers.Conclusions: From this work we conclude that canine CD4+ PTCL is molecularly similar to an aggressive subset of human PTCL-NOS and may serve as a useful model to further investigate the molecular drivers of this aggressive and poorly understood disease. DisclosuresNo relevant conflicts of interest to declare.

Central Nervous System Relapse in Patients with Peripheral T-Cell Lymphoma

Introduction: Central nervous system (CNS) relapse or progression in peripheral T-cell lymphoma (PTCL) is a rare event. Due to its rarity, little is known about the incidence, risk factors and the clinical course after CNS relapse in PTCL.Methods: A total of 301 patients with PTCL were included in this study. All patients were diagnosed between 2003.1 and 2016.6 in Asan Medical Center, Seoul, Korea. Patients with CNS involvement at diagnosis and cutaneous anaplastic large-cell lymphoma were excluded.Histologic subtypes included peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) (n=151, 50.2%), anaplastic large-cell lymphoma (ALCL) (n=75, 24.9%, including ALK positive/negative/unknown, n=39/33/3 each), angioimmunoblastic T-cell lymphoma (AITL) (n=54, 17.9%), enteropathy-associated T-cell lymphoma (EATL) (n=21, 7%).Disease progression or relapse with CNS involvement was confirmed by pathology or MRI of the affected organ. Risk factors at diagnosis for subsequent CNS progression were analyzed with cox regression method. P value <.05 was considered as statistically significant.Results: Out of 301 patients enrolled, 197 patients were male and 104 patients were female. Median age at diagnosis was 57 (range: 15-86). During 75.1 months of median follow-up, 10 patients developed CNS relapse or progression (3.3%).Among those 10 patients with CNS involvement, 4 patients had PTCL-NOS, 4 patients had ALCL (3 ALK positive, 1 ALK negative) and 2 patients had EATL. Leptomeningeal involvement of lymphoma was found in 6 out of 10 patients. Brain or spinal parenchymal involvement was found in 1 patient. Three patients had both leptomeningeal and parenchymal involvement.Median time from initial diagnosis to CNS involvement was 3.6 months (95% confidence interval (CI): 1.1-6.2). All patients with CNS relapse or progression died, and their median overall survival (OS) from CNS involvement was 1.4 months (0.2-2.6). Median OS from diagnosis was 5.1 months (2.9-7.3) in these patients. On the other hand, median OS of patients without CNS relapse was 10.3 months (7.8-12.9) (p=0.002).Univariate analysis showed 2 risk factors associated with occurrence of CNS relapse or progression as follows; subcutaneous tissue or muscle involvement (hazard ratio (HR) 8.9 [95% CI: 2.5-31.5], p=0.001) and Ki-67 labeling index≥80% (HR 11.9 [1.5-94.8], p=0.02). Due to the small number of CNS events, multivariate analysis was not available. No association was found with age, sex, international prognostic index, histologic type, serum lactate dehydrogenase level, stage of the disease and number of involved extranodal sites.Conclusions: Our study demonstrated that although CNS relapse or progression in PTCL was rare (3.3%), it showed dismal prognosis with median OS of 1.4 months. Since CNS involvement occurred in the early course of the disease, we suggest that evaluation for CNS disease should be considered in highly selected patients. DisclosuresNo relevant conflicts of interest to declare.

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

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

Treatment Patterns and Outcomes of Relapsed/Refractory Peripheral T-Cell Lymphoma (RR-PTCL) Patients Treated in the Community Oncology Setting

Introduction: The majority of PTCL cases are pathologically heterogeneous, aggressive and chemorefractory; nearly 70% of patients who undergo induction chemotherapy develop RR disease. Data on how RR-PTCL patients are managed outside of clinical trials and academic settings have not been adequately studied. Understanding how PTCL patients are treated in the real world allows better design of future clinical trials and refined development of novel therapies. This study aimed to describe contemporary treatment patterns, clinical characteristics, and overall survival (OS) among RR-PTCL patients treated in the US community oncology setting.Methods: We conducted a retrospective, observational cohort study of RR-PTCL patients treated between 1/1/2010-12/31/2016. Data were collected from patient medical records abstracted from 30 community oncologists across all geographic areas in the US (38% South, 22% West, 7% Midwest, 26% Northeast, and 7% unknown). Patient characteristics, treatment patterns, adverse events (AEs), physician-reported response to first- and second-line (1L, 2L) treatments, and date of death were collected. Descriptive statistics were calculated to summarize patient characteristics and study outcomes. Median (95% confidence interval [CI]) OS from RR disease was calculated by the Kaplan-Meier method.Results: We analyzed 200 RR PTCL patients (71% received CHOP, 20% received CHOEP, and 9% received another regimen as 1L systemic therapy). The majority (58%) were PTCL not otherwise specified (NOS), 61% were males, and median age was 62 years (range: 20-90) (Table). Overall response rate (ORR) to 1L treatment was 80% (CR, 54%; PR, 26%), and ORR to 2L treatment was 55% (CR, 31%, PR, 24%). Among all PTCL patients and among those with PTCL NOS, the OS (95% CI) from RR disease was 13.0 months (95% 7.0-not estimable) and 9.0 months (95% 6.0-not estimable), respectively (Figure). Median time to RR disease from 1L initiation was 12.9 months. Median durations of 1L and 2L treatments were 4.4 months and 3.7 months, respectively. Among those who continued to 2L therapy, 27% received brentuximab vedotin (2% in combination), 19% received ICE (carboplatin/cisplatin, ifosfamide, etoposide), 13% received romidepsin (2% in combination with pralatrexate), 10% received pralatrexate monotherapy, 7% received GEMOX (gemcitabine, oxaliplatin), and the rest (22%) received other 2L regimens or an unknown regimen (2%). After 1L initiation, only 14/200 (7%) received hematopoietic stem cell transplant (HSCT) and 28/151 (19%) after 2L. AEs resulting in a dose reduction, discontinuation, or hospitalization during 1L treatment and occurring among ≥10% included anemia (39%), thrombocytopenia (27%), neutropenia (23%), mouth sores (16%), diarrhea (15%), neuropathy (14%), febrile neutropenia (13%), and vomiting (10%).Conclusions: While response to 1L treatment in this cohort was high (80%), all developed RR disease (or died), for whom the prognosis remains poor. Very few patients underwent HSCT in any line of therapy. Our data demonstrate the unmet medical need for RR-PTCL patients and the need for novel therapies in the 1L setting. It also underscores the need to better understand factors leading to treatment selection and optimal treatment sequencing in the real world. [Display omitted] DisclosuresNabhan:Cardinal Health: Employment, Equity Ownership. Laney:Cardinal Health: Employment, Equity Ownership. Feliciano:Seattle Genetics: Employment, Equity Ownership. Lee:Cardinal Health: Employment. Klink:Cardinal Health: Employment, Equity Ownership.

Risk factors and timing of autologous stem cell transplantation for patients with peripheral T-cell lymphoma.

High-dose chemotherapy with autologous stem cell transplantation (HDC-ASCT) is an option for patients with peripheral T-cell lymphoma (PTCL); however, neither prospective nor retrospective studies support proceeding with ASCT upfront, and the timing of HDC-ASCT remains controversial. We retrospectively analyzed the risk factors for outcomes of 570 patients with PTCL, including PTCL not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL), who received ASCT for frontline consolidation (n = 98 and 75, respectively) or alternative therapies after either relapse (n = 112 and 75) or primary induction failure (PIF; n = 127 and 83) between 2000 and 2015. Significant risk factors for overall survival (OS) after upfront ASCT were a ≥ 2 prognostic index for T-cell lymphoma (P < 0.001) and partial response (PR) at ASCT (P = 0.041) in PTCL-NOS patients, and > 60years of age (P = 0.0028) and PR at ASCT (P = 0.0013) in AITL patients. Performance status of ≥ 2at ASCT (P < 0.001), receiving ≥ 3 regimens before ASCT (P = 0.018), and PR at ASCT (P = 0.018) in PTCL-NOS patients and > 60years of age at ASCT (P = 0.0077) in AITL patients were risk factors for OS after ASCT with a chemosensitive PIF status. Strategies that carefully select PTCL patients may allow identification of individuals suitable for ASCT.

Rapidly progressive renal failure due to tubulointerstitial infiltration of peripheral T-cell lymphoma, not otherwise specified accompanied by uveitis: a case report

BackgroundRapid decline in renal dysfunction due to primary renal lymphoma, or secondary renal lymphoma by infiltration from a primary origin, is extremely rare. There are notably few reports indicating infiltration of T-cell lymphoma into the kidney.Case presentationA 61-year-old woman with a sudden body rash and liver dysfunction was brought to our hospital presenting with a dull headache and blurred vision. Laboratory tests revealed rapidly progressive renal failure. Histological examination of the kidney and skin indicated infiltration of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Infiltration of PTCL-NOS to the liver and spleen, and presence of Uveitis masquerade syndrome were suspected. Imaging showed that the lesion was limited to extralymphatic organs. Renal function was improved with administration of steroids, including pulse steroid therapy, before administering cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy.ConclusionsThis is the first reported case of rapidly progressive renal failure caused by perivascular tubulointerstitial nephritis with the direct invasion of PTCL-NOS. In our case, a single steroid dose showed dramatic results with respect to renal symptoms.

Microenvironmental immune cell signatures dictate clinical outcomes for PTCL-NOS

AbstractPeripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

A radiographic review of the subacromial architecture: a South African study

Peripheral T-cell lymphoma (PTCL), not otherwise specified (PTCL-NOS) is among the most common disease subtypes of PTCL, one that exhibits heterogeneous clinicopathological features. Although multiple disease-stratification models, including the cell-of-origin or gene-expression profiling methods, have been proposed for this condition, their clinical significance remains unclear. To establish a clinically meaningful stratification model, we analyzed gene-expression signatures of tumors and tumor-infiltrating immune cells using the nCounter system, which enables accurate quantification of low abundance and/or highly fragmented transcripts. To do so, we assessed transcripts of 120 genes related to cancer or immune cells using tumor samples from 68 newly diagnosed PTCL-NOS patients and validated findings by immunofluorescence in tumor sections. We show that gene-expression signatures representing tumor-infiltrating immune cells, but not those of cancerous T cells, dictate patient clinical outcomes. Cases exhibiting both B-cell and dendritic cell (DC) signatures (BD subgroup) showed favorable clinical outcomes, whereas those exhibiting neither B-cell nor DC signatures (non-BD subgroup) showed extremely poor prognosis. Notably, half of the non-BD cases exhibited a macrophage signature, and macrophage infiltration was evident in those cases, as revealed by immunofluorescence. Importantly, tumor-infiltrating macrophages expressed the immune-checkpoint molecules programmed death ligand 1/2 and indoleamine 2, 3-dioxygenase 1 at high levels, suggesting that checkpoint inhibitors could serve as therapeutic options for patients in this subgroup. Our study identifies clinically distinct subgroups of PTCL-NOS and suggests a novel therapeutic strategy for 1 subgroup associated with a poor prognosis. Our data also suggest functional interactions between cancerous T cells and tumor-infiltrating immune cells potentially relevant to PTCL-NOS pathogenesis.

A lower ALC/AMC ratio is associated with poor prognosis of peripheral T-cell lymphoma-not otherwise specified

Peripheral T-cell lymphomas-not otherwise specified (PTCL-NOS) generally have poor patient outcomes, with a 5-year survival rate of ∼32%. The most common prognostic system for patients with PTCL-NOS, the PTCL-U score, is often inadequate because it does not take into consideration the role of host immunity or the microenvironment induced by the tumor. In this paper we aimed to determine the correlation between the Absolute Lymphocyte Count/Absolute Monocyte Count (ALC/AMC) ratio and the prognosis of PTCL-NOS. Retrospective data from 58 patients diagnosed with PTCL-NOS were analyzed. We found that PTCL-NOS patients with lower ALC/AMC ratios (ALC/AMC < 2) had shorter overall survival (OS) and progression-free survival (PFS) periods (OS: P < 0.001; PFS: P = 0.001) compared with other patients (ALC/AMC ≥ 2). When we combined ALC/AMC ratio and PTCL-U scores, patients could be clearly divided into 3 groups with significantly different prognoses. This study suggests that the ALC/AMC ratio may be a simple, effective, and independent prognostic factor for OS and PFS, and may be helpful to identify high-risk PTCL-NOS patients. Since the ALC/AMC ratio is related to host immunity and tumor microenvironment and reflects immune status and individual differences, combining ALC/AMC with PTCL-U may be a better prognostic guide for PTCL-NOS patients.

Molecular Insights Into Pathogenesis of Peripheral T Cell Lymphoma: a Review

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative neoplasms, with at least 29 distinct entities described in current WHO classification. Using present diagnostic approaches, more than a third of PTCL cases cannot be classified, hence designated as PTCL-not otherwise specified (PTCL-NOS). Herein, we summarize the current genomic findings and their role in the molecular pathogenesis in different PTCL entities. Gene expression profiling (GEP) studies have identified distinct molecular signatures for accurate diagnosis and elucidated oncogenic pathways enriched in major PTCL entities. Furthermore, genomic characterization has identified recurrent somatic mutations and potential therapeutic targets. Further efforts are underway to develop genetically faithful murine models. GEP studies have identified molecular subgroups of PTCL, characterized by distinct genetic and epigenetic alterations. Understanding the molecular mechanisms of T cell lymphomagenesis using in vivo model will help to reveal novel therapeutic targets.