Peripheral T-cell Lymphoma, Not Otherwise Specified Patients Research Articles

LACK OF SMARCB1 EXPRESSION CHARACTERIZES A SUBSET OF PERIPHERAL T‐CELL LYMPHOMAS ENRICHED IN CHILDREN AND YOUNG ADULTS

Introduction: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Because patients respond poorly to current treatment regimens, identification of new therapeutic strategies is required. In a mouse tumor model, conditional deletion of Smarcb1 encoding a member of the SWI/SNF chromatin remodeling complex causes the majority of mice to develop mature T-cell lymphomas. The human counterpart, SMARCB1, is a bona fide tumor suppressor gene associated with the development of for example, rhabdoid tumors and schwannomas, but has also been shown to be involved in lymphocyte development. Methods: SMARCB1 (INI1) gene and protein expression was assessed in 315 patients with diverse mature T cell lymphomas by array-based mRNA profiling, immunohistochemistry and/or Western Blot. The DNA methylome was analyzed in SMARCB1-negative pediatric PTCL-NOS patients (n = 5) and murine T cell lymphomas of the Cd4-cre::Smarcb1fl/fl model (n = 5) using the Infinium MethylationEPIC and Mouse Methylation BeadChip, respectively. Murine Smarcb1-deficient T-cell lymphomas were further studied using droplet-based single cell RNA sequencing (Chromium, 10X Genomics). Results: SMARCB1 expression was heterogeneous between and within the 315 different human mature T-cell lymphoma entities. Loss of SMARCB1 expression in PTCL-NOS patients correlated with young age (Wald test, p value = 0.011). Molecular characterization and DNA methylation analysis revealed that loss of SMARCB1 expression in human PTCL largely occurs via somatic mutation and/or epigenetic silencing, whereas in contrast to rhabdoid tumors, germline SMARCB1 mutations were not observed. Comparison of the DNA methylome of human and murine PTCL-NOSSmarcb1- showed similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Increase of myeloid cell populations was confirmed in murine tumors by scRNA-seq analyses, which further revealed an immunosuppressive and pro-inflammatory tumor microenvironment (TME). Treatment of tumor-bearing mice with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversion of the exhaustion phenotype. Conclusions: Here we describe SMARCB1-negative PTCL-NOS as a potential new molecular subtype of PTCL-NOS significantly enriched in young patients. A strong concordance between naturally occurring SMARCB1-deficient PTCL in humans and in the targeted mouse model were found regarding epigenetic features. Our results provide a rationale for further investigation of potential HDACi combination therapies in SMARCB1-negative PTCL-NOS. Keywords: aggressive T-cell non-Hodgkin lymphoma, genomics, epigenomics, and other-omics No conflicts of interests pertinent to the abstract.

Peripheral T-cell lymphoma-not otherwise specified, angioimmunoblastic T-cell lymphoma and anaplastic large cell lymphoma: Are the outcomes any different in Hispanics?

e18773 Background: Peripheral T cell lymphoma – not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) are unusual non-Hodgkin lymphomas with miscellaneous clinical characteristics which share the same treatment regimen (Blood PMID28115372 Cancer Treat ResPMID30596215 Blood PMID28115369). Gene expression profiling has facilitated their diagnosis; but much remains to be learned about risk factors, biological and clinical implications (Oncologist PMID16880242). This is the first national population-based analysis evaluating ethnic differences for Hispanics (HI) diagnosed with PTCL-NOS, AITL and ALCLin the US. Methods: Data were analyzed on PTCL-NOS, AITL and ALCL patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2018. Demographic, clinical and survival patterns were analyzed. Kaplan-Meier and Cox regression analyses were used when appropriate. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. Results: 12,749 patients were diagnosed with PTCL-NOS, AITL and ALCL (1,666 cases were HI = 798 PTCL-NOS, 316 AITL and 552 ALCL). Male predominated for HI and Non-HI (NH) in the 3 malignancies. HI were diagnosed at a younger median age than NH, PTCL-NOS 60 years(y) vs 65y, AITL 65y vs 69y, and ALCL 45y vs 55y, respectively [p <0.001]. White race predominated for both. When diagnosed with PTCL-NOS or AITL, HI were more likely diagnosed from 2015-2018 but those with ALCL were identified from 2000-2004. For the 3 malignancies limited information regarding B symptoms was available. Most of the cases of HI and NH were diagnosed at advanced stages in all subtypes. Overall, for both the tendency was towards not receiving radiation. HI vs NH diagnosed with PTLC-NOS had median survival of 1.2 vs 1.3y; AITL was 2.2 vs 1.7y and ALCL 6.0 vs 9.3y. Survival probability for 2, 5 and 10y were comparable among HI and NH for all malignancies and no difference in OS was noted. On multivariate analysis, patients who were older than 80y and between 60-80 y, had worse OS compared to those <60y. For all subtypes, those who were diagnosed at stage III/IV had worse OS than those at early stage I/II. Conclusions: Similar OS for HI and NH diagnosed with PTCL-NOS, AITL and ALCL. Nonetheless, diagnosis at younger age and early stage play a significant role to better survival. Although HI were more subjected to early age at diagnosis and less likely to be at a stage I/II, no impact in survival was evidenced, which suggests that unique responses may counteract within this race. It is captivating that no gradual increase in diagnosis was noted despite the continuous development of genetic testing and improved diagnostic tools, which highlights that socioeconomical variables may have been influencing its access.

Autologous or allogeneic hematopoietic cell transplantation for relapsed or refractory PTCL-NOS or AITL.

Fit patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) in relapsed or refractory (R/R) disease status often receive salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHCT) or allogeneic HCT (alloHCT). However, there is no consensus on the type of HCT that should be applied for such patients. Herein, we retrospectively evaluated the survival outcome of 760 adult R/R PTCL-NOS or AITL patients who underwent the first HCT. Among them, 318 relapsed after first remission (REL) and 442 were refractory to the primary therapy (PIF). The 4-year overall survival (OS) of autoHCT and alloHCT was 50 and 50% for REL patients, and 52 and 49% for PIF patients, respectively. In the multivariable analysis, alloHCT tended to be associated with better progression-free survival (PFS) in REL (hazard ratio [HR] 0.74; 95% confidence interval [CI]: 0.53-1.03), and significantly better PFS in PIF (HR 0.64; 95% CI: 0.46-0.88) compared with autoHCT. The subgroup analysis with propensity-score matching showed that alloHCT was associated with better OS for REL-sensitive and PIF-nonremission disease. This study suggested that the advantage of alloHCT for R/R PTCL-NOS or AITL is different, depending on the disease status at HCT.

Clinico-Epidemiological Features of Elderly Patients with Peripheral T-Cell Lymphoma Not Otherwise Specified: A Study from the Grupo De Estudio Latinoamericano De Linfoproliferativos (GELL)

Introduction: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is the most common PTCL subtype, accounting for approximately 25% of all PTCL cases. The median age at diagnosis is 60 years and is more prevalent among males. Currently, most epidemiological data on T- and NK-cell lymphomas come from developed countries. Thus, very few data are available regarding this condition in Latin American countries, especially in those aged 60 years and older. The Latin American Group of Lymphoproliferative Disorders (GELL) has previously reported on the impact of serum albumin level in survival outcomes in PTCL-NOS. Therefore, we aim to evaluate the clinical, demographic, and outcome patterns of elderly patients with PTCL-NOS.Methods: We conducted an observational, retrospective study of newly diagnosed PTCL-NOS between January 2000 and December 2020. Patient must be aged 60 years and older. All clinical data were retrieved from clinical records at the different participating institutions. The study outcomes were overall survival (OS) and progression-free survival (PFS). The International Prognostic Index (IPI), the Prognostic Index for T-cell lymphoma (PIT), and the NCCN IPI scores were used for risk stratification. Kaplan-Meier and log-rank test were used for survival analysis. Univariate and multivariate Cox regression analysis were used to estimate hazard ratios (HR) with a 95% confidence interval (CI). Outcomes with a p-value <0.05 were considered statistically significant.Results: A total of 107 patients were included; median age at diagnosis was 72 years (range 60-92), 61% were male, 46% had an ECOG ≥2, 70% had stage III-IV, and 15% had more than one extranodal site. The IPI, PIT and NCCN-IPI scores stratified 51%, 69%, and 74% of patients as high- / high-intermediate risk, respectively. Seventy-four (69%) patients received first-line systemic therapy. Most patients (53%) were managed with CHOP/CHOP-like regimen, followed by CHOEP (19%). The overall response (OR) rate to first-line therapy was 61% (complete response, CR 41%). Salvage therapy was given to only 9 patients; the OR rate was 44% (CR 11%). With a median follow-up of 29 months (95% CI 13-45 months), the 2-year OS was 46% (95% CI 36-59), with median survival time of 16 months (95% CI 10-NR). In the multivariate analysis, patients with serum albumin levels <3.5 g/dL had median survival of 7 months (95% CI 3-20) and 2-year OS rate of 24% (95% CI 13-46%), while patients with albumin ≥3.5 g/dL did not reach the median survival time and had a 2-yOS rate of 67% (95% CI 36-65%) (p<0.0001) (Table 1, Figure 1). Patients with a lymphocyte-to-monocyte ratio (LMR) >7.6 had a median OS of 8 months (95% CI 6-NR) and a 2-year OS of 10% (95% CI 2-65), while patients with a LMR ≤7.6 did not reach the median OS and had a 2-year OS of 57% (95% CI 45-72) (p = 0.0108) (Table 1, Figure 1).Conclusions: This large cohort of Latin American PTCL-NOS patients aged ≥60 years showed overall response rates comparable to previously published data. However, survival rates were shorter compared to those reported in developed countries. In this study, we again confirmed low serum albumin level (<3.5 g/dL) as an adverse prognostic factor for OS in PTCL-NOS, and independent from the IPI, PIT and NCCN-IP scores. Additionally, we describe for first time in a Latin American cohort the impact of the LMR on survival, demonstrating poor outcomes in those with LMR >7.6. We are currently validating our findings in a prospective cohort of Latin American PTCL patients and to improve clinical decision-making in those deemed at high-risk for early mortality. [Display omitted] DisclosuresOtero: Astra Zeneca: Current Employment. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding.

Prognostic significance of serum β2-microglobulin levels in patients with peripheral T-cell lymphoma not otherwise specified

We aimed to investigate the prognostic value of serum β2-microglobulin in patients with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). A cohort study of PTCL-NOS patients (n = 147) was conducted. An elevated serum β2-microglobulin level was associated with the presence of previously identified predictors of a poor prognosis for PTCL-NOS. Patients with an elevated serum β2-microglobulin level exhibited a significantly worse progression-free survival (PFS) and overall survival (OS). Multivariate analyses revealed that an elevated serum β2-microglobulin level was independently associated with a shorter PFS and OS. A new prognostic index incorporating the serum β2-microglobulin level allowed for the stratification of patients into three distinct risk subgroups. The index was validated to stratify patients with distinct survival outcomes in an independent cohort of PTCL-NOS (n = 89). In conclusion, serum β2-microglobulin level is an independent prognostic factor in patients with PTCL-NOS. Our β2-microglobulin-based prognostic index for PTCL-NOS deserves further investigation and validation.

Novel Subtypes Based on Microenvironment Immune Signature Provides Prognostic Stratification and Therapeutic Strategy in Peripheral T-Cell Lymphoma

Peripheral T-cell Lymphoma Not Otherwise Specified (PTCL-NOS) is the largest group of peripheral T-cell lymphomas (PTCL) with dismal prognosis. PTCL-NOS does not correspond to any of the specifically defined entities of T-cell lymphoma in the World Health Organization classification and is referred to as the “waste-basket” category that contains heterogeneous disease entities. Its heterogeneity represents a major obstacle to development of standardized therapeutic strategies, and therefore classification of this “waste-basket” diagnosis is necessary. Although previous studies tried to classify PTCL-NOS from the viewpoint of Cell-of-Origin (COO) of tumor cells by utilizing histopathologic methods or gene expression profiling, the prognostic impact of COO-based stratification still remains controversial. In addition, recent studies revealed the prognostic importance and the therapeutic potential of tumor-microenvironment in various types of cancers. These situations prompted us to investigate microenvironment profile of PTCL-NOS.The aim of this study is to elucidate the microenvironment signatures of PTCL-NOS by gene expression profiling, and to establish a new stratification model. For this purpose, the expression levels of 770 genes related to phenotype and function of tumor T-cells and microenvironment immune cells (B-cells, macrophages (Mø), dendritic cells and granulocytes) were analyzed by employing nCounter system, digital RNA counting technology with high reproducibility for the measurement of even lowly-expressed genes from rare microenvironment components. Sixty-eight patients who were diagnosed as PTCL-NOS between 1993 and 2011 were included in this study. These patients were equally treated by anthracycline-based conventional chemotherapies,and the median survival period was 2.8 years (range, 0.2-11.0 years), which was comparable to historical controls.To explore the classifier genes for PTCL-NOS, principal component analysis was performed and 2 distinct clusters of microenvironment-derived genes, B-cell (CD19, CD20, PAX5) and Mø (CD68, CD163) related genes, were identified (Figure 1). By hierarchical clustering analysis based on the expression levels of these genes, 68 PTCL-NOS patients were classified into three groups as B-cell-rich, Mø-rich and unclassified type (Figure 2). We visually confirmed that CD20+ B-cells and CD163+ Mø were enriched in the tumor tissues of B-cell-rich and Mø-rich type, respectively utilizing multiplexed fluorescent immunostaining (Perkin-Elmer, Mantra quantitative pathology workstation). More importantly, this microenvironment-based classification was significantly associated with prognosis: B-cell-rich type patients had better overall survival compared with Mø-rich patients (2-year overall survival: B-cell-rich type, 77.7%; Mø-rich type, 39.3%; others, 55.5%; p = 0.02) (Figure 3). We also validated the impact of these microenvironment signatures on the prognosis by analyzing published microarray datasets of 123 PTCL-NOS patients (GSE58445). Thus, B-cell-rich type patients were expected to respond to conventional chemotherapies and classified as favorable subtype.We further investigated potential therapeutic targets for Mø-rich patients who were classified as unfavorable subtype, and found that gene expression levels of immune checkpoint molecules, such as PD-L1, PD-L2, TIM-3, LAG-3, IDO-1, were up-regulated in the Mø-rich type compared with the others (PD-L1, p < 0.01; PD-L2, p < 0.01; TIM-3, p < 0.01; LAG-3, p = 0.01; IDO-1, p < 0.01). Imaging analysis of Mø-rich type tissues with Mantra system revealed that PD-L1 was highly and exclusively expressed on the CD163+ Mø, suggesting that microenvironment Mø might negatively regulate tumor immunity via expression of immune-checkpoint molecules and that Mø-rich type patients were expected to respond to immunotherapeutic agents including immune checkpoint inhibitors.In conclusion, our findings collectively suggest that tumor microenvironment signature has significant prognostic impact, and novel microenvironment-based stratification model will contribute to the development of optimal therapeutic strategies for PTCL-NOS patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnostic Utility of SOX4 Expression in Adult T-Cell Leukemia/Lymphoma.

Differentiation between adult T-cell leukemia/lymphoma (ATLL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is often challenging based on pathological findings alone. Although serum anti-HTLV-1 antibody positivity is required for ATLL diagnosis, this information is often not available at the time of pathological diagnosis. Therefore, we examined whether the expression of SOX4 and p16 would be helpful for differentiating the two disease entities. We immunohistochemically examined SOX4 and p16 expression (which have been implicated in ATLL carcinogenesis) in 11 ATLL patients and 20 PTCL-NOS patients and classified them into four stages according to the percentage of positive cells. Among the ATLL cases, 8/11 (73%) were SOX4-positive, while only 2/20 (10%) PTCL-NOS cases expressed SOX4. The mean total score was 4.2 (standard deviation (SD): 0.61) in the ATLL group and 0.50 (SD: 0.46) in the PTCL-NOS group (p < 0.001). Positive expression of p16 was noted in 4/11 (36%) patients with ATLL and 3/20 (15%) patients with PTCL-NOS, with mean total scores of 1.9 (SD: 0.64) and 0.70 (SD: 0.48) in the ATLL and PTCL-NOS groups, respectively (p = 0.141). These results suggest that SOX4 may be strongly expressed in ATLL compared to PTCL-NOS cases. Therefore, it may be helpful to perform immunohistochemical staining of SOX4 when pathologists face challenges discriminating between ATLL and PTCL-NOS.

DNMT3A Mutations Identify a Prognostic Subgroup in Peripheral T-Cell Lymphoma

Background Mutational profiling of angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) has revealed recurrent mutations in DNMT3A, a de novo methyltransferase. DNMT3A catalyzes the conversion of cytosine to 5-methylcytosine (5-mC) while interacting with histones and transcription factors to influence gene expression. While the DNMT3A mutational profile in PTCL entities indicates loss-of-function, hotspot change-of-function mutations (e.g., DNMT3AR882H/C) have been observed with their frequency differing between PTCL entities. Despite the high occurrence of DNMT3A mutations in PTCLs (~30% of cases), their functional consequences have not been extensively studied. Herein, we examined DNMT3A mutations in AITL and the novel molecular subgroups of PTCL-NOS (i.e., PTCL-TBX21 and PTCL-GATA3) and observed distinct biological and prognostic significance associated with DNMT3A mutations in the PTCL-TBX21 subgroup. Methods PTCL-NOS cases (n = 141) were utilized following PTCL-TFH exclusion. Using previously described molecular classification methods, cases were classified as PTCL-TBX21 (n = 80) or PTCL-GATA3 (n = 61). A separate cohort of AITL cases (n = 176) were included for comparative purposes. Clinical outcome data were assessed with the Kaplan-Meier method. Mutation data were generated from DNA-sequencing (n = 224) or RNA-sequencing methods (n = 46). Gene expression comparisons were conducted using BRB-ArrayTools. Immune-cell signatures were generated from the CIBERSORT and/or xCell computational tools. 5-mC DNA immunoprecipitation sequencing (MeDIP-Seq) was performed on available PTCL-TBX21 cases (n = 7) or healthy tonsil controls (n = 2). Four of these cases carried DNMT3A mutations (n = 3 DNMT3AR882, n = 1 DNMT3AQ886) while the remaining cases (n = 3) were wild type for DNMT3A. In vitro analyses of ectopic expression of the DNMT3AR882H mutant or DNMT3A knockdown were conducted using healthy-donor CD3+ T-cells or the CD8+ T8ML1 PTCL cell line. Following corrections for false discoveries, p-values &amp;lt; 0.05 were considered significant. Results DNMT3A-mutated PTCL-TBX21 cases had an inferior overall survival, with DNMT3A mutated residues skewed toward the methyltransferase domain. In contrast to the DNMT3A mutation profile seen in AITL, PTCL-TBX21 featured DNMT3AR882H/C mutations at a frequency (30%) similar to other hematological malignancies. Gene expression profiling revealed that DNMT3A-mutant PTCL-TBX21 cases were enriched for activated CD8+ T-cell gene signatures and showed association with the previously described TH1/αβ cytotoxic T-cell lymphoma subgroup. Following MeDIP-Seq, assessment of differentially methylated regions comparing DNMT3AR882/Q886 PTCL-TBX21 cases to wild type found hypomethylation in pathways associated with T-cell activation, TCR signaling, and TH1 responses. In vitro analyses demonstrated that ectopic expression of the DNMT3AR882H mutant or DNMT3A knockdown lead to enhanced proliferation and NF-κB signaling in T8ML1 cells in comparison to control vectors. In primary CD3+ T-cell cultures, ectopic expression of the DNMT3AR882H mutant protein resulted in the preferential outgrowth of CD8+ T-cells. Conclusions Taken together, our findings establish mutations in DNMT3A as a novel prognostic marker in PTCL-TBX21. The integrated expression, methylation, and in vitro findings suggest that disruption of DNMT3A leads toward an activated and cytotoxic phenotype and could potentially drive oncogenic TCR signaling. Clinically, as these cases were associated with the TH1/αβ cytotoxic T-cell lymphoma subgrouping, these findings should be taken into consideration for future treatment strategies regarding PTCL-NOS patients as current standard-of-care treatments may be particularly inadequate in the treatment of PTCLs with cytotoxic phenotype. Disclosures No relevant conflicts of interest to declare.

Effects of stem cell transplantation in patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.

Serum Albumin Is an Independent Factor Predicting Survival in Patients with Peripheral T Cell Lymphoma: A Multi-Institutional Study from the Latin American Working Group for Lymphomas (GELL)

Introduction: Peripheral T cell lymphoma (PTCL) is a very heterogenous disease and corresponds to approximately 15% of all non-Hodgkin lymphoma cases. PTCL is divided into several subtypes, however, PTCL not otherwise specified (PTCL-NOS) is the most frequent, with a proportion of 26% of all PTCL cases. There is a lack of demographic and clinical data about PTCL-NOS in middle- and low-income countries, where patients' access to early diagnosis and otherwise standard care might be suboptimal. The objective of this study is to describe the population of PTCL-NOS patients in Latin America, specifically from the countries conforming the "Grupo Latinoamericano de Linfomas" (GELL), in order to better understand clinical behavior and find possible prognostic factors that might prognosticate overall survival (OS). We specifically evaluated the neutrophil/lymphocyte ratio (NLR) and serum albumin as potential prognostic factors. Methods: An observational, retrospective and analytical study was conducted during the period from January 2000 through January 2018. A total of 200 Latin American patients with a pathological diagnosis of PTCL-NOS were included. Clinical data were gathered from clinical records. NLR ≥4 and serum albumin ≤3.5 g/dl were considered adverse prognostic factors. Median Overall Survival (mOS) and 5-year Overall Survival (5y-OS) rates were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional-hazard regression analyses were performed to identify adverse prognostic factors for OS. Data were analyzed and interpreted using STATA 15. Results: A total of 200 patients with a diagnosis of PTCL-NOS were included. 50% of patients were ≥60 years, 57% were male, 50% had ECOG ≥2, 40% had elevated serum Lactate Dehydrogenase (LDH) level, 70% showed stage III/IV disease, bone marrow involvement was present in 37% of patients, B symptoms in 65%, 33% presented with hemoglobin levels &lt;10 g/dL. The International Prognostic Index (IPI) score was high-intermediate in 33% and high in 14% of cases. The Prognostic Index for PTCL-U (PIT) risk score was high-intermediate in 32% and high in 26% of cases. Serum albumin &lt;3.5 mg/dl was seen in 58%, and NLR ≥4 in 37% of patients. Median OS (mOS) for the entire cohort was 0.83 years (95% CI 0.58-1.75) and 5-year OS rate was 31% (95% CI 23-40%). Patients with serum albumin levels &lt;3.5 g/dL had mOS of 0.42 years (95% CI 0.25-0.75) and 5-year OS rate of 20% (95% CI 9-33%), while patients with albumin ≥3.5 g/dL had mOS of 5.1 years (95% CI 0.83-not reached) and 5-year OS rate of 51% (95% CI 36-65%) (log-rank p&lt;0.001). The mOS for NLR &lt;4 was 1.67 years (95% CI 0.75-4.92) with 5-year OS rate of 37% (95% CI 25-48%) while for NLR ≥4, the mOS was 0.58 years (95% CI 0.25-1.00) and 5-year OS rate was 23% (95% CI 12-36%) (log-rank p=0.02). Cox proportional Hazard regression multivariate analyses found serum albumin &lt;3.5 g/dL (HR 1.83, 95% CI 1.10-3.05; p=0.02) and ECOG ≥2 (HR 1.95, 95% CI 1.15-3.30; p=0,01) were associated with a worse OS. Serum albumin remained an adverse prognostic factor for OS after adjustment for the IPI and the PIT scores (HR 1.66, 95% CI 1.01-2.75; p=0.047, and HR 1.70, 95% CI 1.03-2.80; p=0.038, respectively). Conclusion: This multi-institutional Latin American study showed that serum albumin level &lt;3.5 g/dL was an adverse prognostic factor for OS, independent from the IPI and the PIT scores, in Latin American patients with a diagnosis of PTCL-NOS. The survival rates of Latin American patients with PTCL-NOS appear lower than in developed countries. Disclosures M: Merck-Sharp-Dome: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Roche-Mexico: Consultancy, Speakers Bureau. Peña:Novartis: Other: Congress inscription and flights; Tecnofarma: Other: Congress inscription and flights; Roche: Other: Congress inscription and flights; Biotoscana: Other: Congress inscription and flights; Janssen: Other: Congress inscription and flights; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paredes:Tecnofarma: Honoraria. Rojas:ROCHE: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Abello:Takeda: Other: Participation in advisory board meeting. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding.

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

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.

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.

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.

The Impact of Upfront Autologous Transplant on the Survival of Adult Patients with ALCL and PTCL-NOS According to Their ALK, DUSP22 and TP63 Gene Rearrangement Status - a Joined Nordic Lymphoma Group and Mayo Clinic Analysis

Introduction: Recent results from two independent patient series have shown that chromosomal rearrangements of DUSP22 (DUSP22r+) and TP63 (TP63r+) can predict outcome in ALK-negative anaplastic large cell lymphoma (ALK-ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) with morphologic features resembling ALK-ALCL (Parilla-Castellar E, Blood 2014; Pedersen MB, Blood 2017). While DUSP22r+ is predictive for excellent survival similar to that of ALK+ALCL after CHOP/CHOP-like therapy, the rarely occurring TP63r+ is associated with an aggressive clinical behavior and poor outcome. The largest subgroup, i.e. patients with neither ALK nor DUSP22 nor TP63 rearrangements (triple negative), show a 5 year (yr) overall survival (OS) intermediate between that of ALK-/DUSP22r+ and ALK-/TP63r+ patients.The aim of the present study was to assess the impact of upfront high-dose therapy with autologous stem cell transplant (HDT/ASCT) on outcome in adult ALCL and PTCL-NOS patients according to their ALK, DUSP22 and TP63 status. The survival results from the two published series were pooled with those of a Nordic Lymphoma Group trial, the NLG-T-01 (d'Amore et al, JCO 2012), where patients were treated with 1st line CHOEP/CHOP followed, in chemosensitive cases, by upfront HDT/ASCT.Methods: Fluorescence in situ hybridization was performed on sections of previously constructed tissue microarrays using break-apart probes for the DUSP22-IRF4 and TP63 loci and a dual-fusion probe for TBL1XR1/TP63 fusion [inv(3)(q26q28)]. Evaluation of DUSP22 and TP63 rearrangements was performed in a blinded fashion without knowledge of PTCL subtype, clinical course, or outcome. Three independent patient cohorts were included: (i) one from Mayo Clinic consisting of 31 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 25; TP63r+: 6); (ii) one from Denmark consisting of 93 DUSP22r-, ALK-ALCL and PTCL-NOS (triple negative: 90; TP63r+: 3); and one from the NLG-T-01 trial consisting of 46 ALK-ALCL and PTCL-NOS (triple negative: 37; TP63r+: 1; DUSP22r+: 8), leading to a total study population of 170 patients. ALK+ ALCL was not included in the analysis, since no patients with this histology entered the NLG-T-01 trial. Association of genetic subtype with OS was assessed using Kaplan-Meier curves and Cox proportional models for hazard rate ratios (HR). Significant differences were defined as P <0.05.Results: The eight DUSP22r+ patients (7 ALK-ALCL and 1 PTCL-NOS) from NLG-T-01 had a 5-yr OS of 83%, (95%CI 27-97), similar to that reported for DUSP22r+ in the Mayo and Danish cohorts (90% and 80%, respectively). No lymphoma-related events were observed in this subset. The only event was a septic death due to HDT-induced cytopenias in a patient who was in complete remission (CR). Among the 162 patients with DUSP22r-, ALK-ALCL and PTCL-NOS, those consolidated with HDT/ASCT (n=47) had a significantly better outcome (5-yr OS: 45%) than those treated with induction chemotherapy alone (5-yr OS: 30%) (n=115) (P=0.01). The patients in the HDT/ASCT group were younger (P<0.001) and had more advanced stage disease (P=0.002). The improvement in OS persisted when the analysis was limited to transplant eligible patients and adjusted for age and stage (HR 0.52 95%CI 29-91, P=0.023) or International Prognostic Index (IPI) groups (HR 0.49, 95%CI 20-82, P=0.006). Of the 10 TP63r+ patients found within the pooled cohort, 6 were transplant eligible. Of these, 5 were not transplanted (intention-to-treat) while one was (Nordic trial). The latter patient achieved a still ongoing long-term CR, while all others died of lymphoma progression.Conclusion: In ALK-ALCL and PTCL-NOS patients from the NLG-T-01 trial, DUSP22r+ was associated with a very good outcome, similar to that seen in DUSP22r+ patients who had not undergone upfront autologous transplant. This observation supports the impression that upfront HDT/ASCT may not be of benefit in these patients. TP63r+ predicted poor outcome in non-transplanted patients. The impact of HDT/ASCT in the TP63r+ setting could not be adequately evaluated, since only one patient from the NLG-T-01 trial cohort was found to be TP63r+. Notably, this patient was the only survivor of the TP63r+ subset. For DUSP22r-, ALK-ALCL and PTCL-NOS patients taken as one group, those who received upfront HDT/ASCT had a superior survival compared to their age- and IPI-matched non-transplanted counterparts. DisclosuresEllin:ROCHE: Consultancy, Research Funding; CTI: Consultancy. Mannisto:Roche: Honoraria, Other: Travel expence; Takeda: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Cerhan:Janssen: Other: Scientific Advisory Board (REMICADELYM4001); Janssen: Other: Multiple Myeloma Registry Steering . Toldbod:Takeda Pharma: Honoraria.

Clinicopathological analysis in PTCL-NOS with CADM1 expression.

Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS), is a heterogeneous disease with respect to clinicopathological features. Cell adhesion molecule 1 (CADM1) has been reported to be ectopically expressed in adult T cell leukaemia/lymphoma (ATLL). However, the frequency of CADM1 expression remains unknown in peripheral T cell lymphomas. In the current study, CADM1 expression was analysed in 88 PTCL-NOS patients. CADM1 was expressed in 14 of 88 (15.9%) PTCL-NOS cases, and its expression was associated with C-C chemokine receptor type 4 (CCR4) expression and nuclear atypia. CADM1-positive PTCL-NOS cases (10/74) had a significantly poorer prognosis than CADM1-negative cases (64/74) (P=0.001). Multivariate analysis confirmed that CADM1 expression was an independent prognostic factor in PTCL-NOS. These findings suggest that CADM1 expression is a novel prognostic factor for PTCL-NOS.

Comparison of clinicopathological characteristics between T-cell prolymphocytic leukemia and peripheral T-cell lymphoma, not otherwise specified.

T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.

Delineation of Novel Subtypes Based on Microenvironment Immune Signature Provides Prognostic Stratification Strategy in Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is the largest subgroup with dismal prognosis in peripheral T-cell lymphomas (PTCL) that do not fit into any of the specifically defined categories in the World Health Organization classification, and it comprises over 25% of PTCL. PTCL-NOS is sometimes referred to as the gwaste-basketh category because of the lack of specific features, and therefore contains heterogeneous disease entities. Its heterogeneity represents a major obstacle to elucidation of pathogenesis, development of novel therapeutic targets and establishment of standardized therapeutic strategies and results in its poor prognosis.The stratification strategy of PTCL-NOS still remains controversial, although previous studies tried to reclassify PTCL-NOS from the viewpoint of gCell-of-Originh of tumor cells (e.g. T helper 1/2 cells, regulatory T cells) by utilizing histopathologic methods or gene expression profiling. These situations prompted us to investigate microenvironment profile of PTCL-NOS and to develop the novel stratification strategy.For this purpose, we analyzed the expression levels of 800 of tumor microenvironment-related genes including the phenotypic markers, transcription factors and functional molecules of microenvironment cells in formalin fixed paraffin embedded (FFPE) samples derived from 33 PTCL-NOS patients utilizing nCounter system, which is novel RNA counting system based on a digital molecular barcoding technology and enables accurate quantification of genes with low expression levels. Thirty-three patients who were diagnosed as PTCL-NOS between 1993 and 2011 were included in this study. The median follow-up time was 796 days (range, 15-2973). The overall survival rate at 1 year after diagnosis (1yr OS) was 40%, and it was comparable to previous reports. Unsupervised hierarchical clustering analysis revealed three distinct clusters based on the gene expression pattern of the microenvironment-related genes: B-cell type (42.4 %), M2 macrophage type (24.2 %), and others (33.3 %) (Figure 1). On the other hand, the expression patterns of the major T-cell subset-associated genes were complicated and diverse depending on patients, and failed to form any distinct clusters. B-cell-related genes, such as CD19, CD79B and PAX5 were highly expressed in the B-cell type, and the M2 macrophage-related genes, such as CD68, CD163, CD14 and MARCO were highly expressed in the M2 macrophage type. More importantly, these microenvironment-based subgroups, B-cell type and M2 macrophage type, represent prognostically favorable and unfavorable subgroups, respectively (1yr OS: B-cell type, 84.8%; M2 macrophage type, 16.7%; others, 56.2%; log rank test, p = 0.01) (Figure 2). Interestingly, genes associated with immune checkpoint, such as PD-L1, TIM-3 and IDO-1, were highly expressed in the M2 macrophage type than the others (PD-L1, p = 0.02; TIM-3, p = 0.05; IDO-1, p < 0.01), indicating the existence of specific subgroup of PTCL-NOS patients as anticipated good-responder for immunotherapeutic agents including immune checkpoint inhibitors. Collectively, our findings strongly suggest that microenvironment immune signature, not gCell-of-Originh of tumor cells, could provide novel prognostic stratification method and therapeutic strategy of PTCL-NOS. [Display omitted] DisclosuresAkashi:Asahi Kasei Pharma Corporation: Research Funding; Shionogi & Co., Ltd: Research Funding; Astellas Pharma: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Sunitomo Dainippon Pharma: Consultancy; Bristol Meyers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding.

Clinical and prognostic differences between ALK-negative anaplastic large cell lymphoma and peripheral T cell lymphoma, not otherwise specified: a single institution experience.

Clinical differences between anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALK(-) ALCL) and peripheral T cell lymphoma, not otherwise specified (PTCL-NOS), remain unclear. The aim of this study was to compare the clinical and prognostic features of these two lymphoma types. We retrospectively analyzed 167 patients with ALK(-) ALCL (n = 48) and PTCL-NOS (n = 119). Compared with ALK(-) ALCL patients, PTCL-NOS patients exhibited distinct differences in clinical features with a propensity for more advanced stages, frequent extranodal involvement, and a poor performance status, leading to a higher risk group according to the International Prognostic Index or Prognostic Index for PTCL-NOS. Patients with ALK(-) ALCL were associated with a higher complete response rate (47.9 vs. 31.0%; P = 0.041) after initial chemotherapy than patients with PTCL-NOS. The prognosis was significantly different between two subtypes, with a 5-year overall survival (OS) rate of 57.9% for ALK(-) ALCL and 23.9% for PTCL-NOS (P = 0.002). The subgroup analysis showed significant differences in OS and progression-free survival between the two subtypes in early-stage diseases, but not in advanced-stage diseases. We conclude that patients with ALK(-) ALCL showed favorable clinical features, higher chemosensitivity, and a superior outcome than those with PTCL-NOS.

G17V Rhoa Mutation in Circulating DNA Is a Useful Marker for Diagnosis of AITL and AITL-Related Lymphoma

[Background] Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma. We and others reported that the G17V RHOA mutation is frequent and highly specific to AITL and AITL-like peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Thus, detection of this mutation serves as a novel diagnostic strategy for AITL and AITL-like PTCL-NOS.[Aim] Analysis of disease-specific mutations in serum DNA from AITL and PTCL-NOS patients.[Method] Genomic DNA was collected from tumors and sera from 16 AITL and PTCL-NOS patients and 11 B-cell malignancy patients. Seven out of 16 T-cell lymphoma and all B-cell malignancy patients did not receive prior treatment. Amplicon-based sequencing by Ion Torrent PGM was performed to analyze the G17V RHOA mutation as well as TET2 and DNMT3A mutations in these samples.[Result] Three out of 7 tumor samples of T-cell lymphoma patients whose serum was preserved prior to treatment were positive for the G17V RHOA mutation. In the serum of these 3 patients, allele frequencies of the G17V RHOA mutation were 0.006 - 0.072 (mean 0.015, SDV 0.026), while 0 (mean 0, SDV 0) in the serum of the remaining 4 T-cell lymphoma patients and all the 11 B-cell malignancy patients whose tumor samples did not show RHOA mutation. Because we set cut off value as 0.002 (0.2%) based on the ROC curve, RHOA mutation was segregated into positive and negative faithfully according to whether the mutation was identified in the tumor samples. Then, we analyzed TET2 and DNMT3A mutations in sera of 5 patients whose tumor samples were positive for TET2 (n=2; a single mutation in each sample) and DNMT3A (n=3; 5 mutations all together), respectively. TET2 and DNMT3A mutations were detected in all the 5 sera, although 2 out of the 5 DNMT3A mutations were undetectable. In the clinical courses, RHOA mutations became undetectable after the treatment in sera of all the 3 patients whose pre-treatment sera were positive, while TET2 mutations were detected even after the treatment in sera of both patients whose pre-treatment sera were positive.[Conclusion] Biopsy is sometimes difficult in lymphoma patients with progressed diseases. Identification of the disease-specific G17V RHOA mutation in serum may provide a non-invasive method to diagnose AITL and AITL-like PTCL-NOS, although inapplicable to detect minimum residual disease. Stable detection of TET2 mutations regardless of chemotherapy might indicate the presence of the mutations in the 'pre-cancerous cells' which are resistant to the chemotherapy. DisclosuresNo relevant conflicts of interest to declare.