Cases Of Peripheral T-cell Lymphoma Research Articles

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

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

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

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

Expression of telomerase reverse transcriptase in peripheral T-cell lymphoma.

Telomere length is maintained by the activation of telomerase, which causes continuous cell division and proliferation in many carcinomas. A catalytic reverse transcriptase protein (TERT) encoded by the TERT gene plays a critical role in the activation of telomerase. We performed a molecular and pathological analysis of the TERT against three different peripheral T‐cell lymphoma (PTCL) subtypes: PTCL, not otherwise specified (PTCL‐NOS), angioimmunoblastic T‐cell lymphoma (AITL), and adult T‐cell leukemia/lymphoma (ATLL). Immunohistochemical analysis demonstrated TERT expression in 31% of AITL, 11% of PTCL‐NOS, and 5% of ATLL. Among them, AITL frequently showed high TERT expression with statistical significance. TERT promoter mutation analysis and genomic copy number evaluation were performed. TERT promoter mutation was observed in two cases of PTCL‐NOS (2/40) and not in other PTCLs. Genome copy number amplification was detected in 33% of PTCL‐NOS, 33% of AITL, and 50% of ATLL cases. We evaluated the relationship between the analyzed TERT genomic abnormalities and protein expression; however, no apparent relationship was observed. Furthermore, immunostaining showed TERT expression in the PTCL cytoplasm, suggesting the existence of mechanisms other than the maintenance of telomere length. Statistical analysis of the effect of TERT expression on the prognosis in PTCL cases revealed that TERT expression tended to have a poor prognosis in PTCL‐NOS. Since TERT expression was not an independent factor in multivariate analysis, further research will be needed to clarify the poor prognosis of PTCL‐NOS in TERT expression.

Expression of GATA3 and bcl-11b in peripheral T-cell lymphoma and their clinical significance

Objective: To study the expression of GATA3 and bcl-11b in peripheral T-cell lymphoma (PTCL) and their correlation with clinicopathological features. Methods: The Oncomine and GEO databases were used for analyzing the expression levels of GATA3 and bcl-11b mRNA in PTCL. Immunohistochemistry was used to detect the expression of GATA3 and bcl-11b proteins in 127 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2010 to June 2020, as well as 40 cases of lymph node with reactive hyperplasia. Results: The data in Oncomine and GEO databases showed that the expression of GATA3 and bcl-11b mRNA in PTCL was lower than that in normal tissues (P<0.05). Immunohistochemistry showed that the positive rates of GATA3 in PTCL and lymph nodes with reactive hyperplasia were 60.6% (77/127) and 85.0% (34/40, P<0.05), respectively. The expression rates of bcl-11b in PTCL and lymph nodes with reactive hyperplasia were 55.1% (70/127) and 75.0% (30/40, P<0.05), respectively. The expression of GATA3 was related to the pathological classification of the patients with PTCL, and was inversely related to the Ann Arbor stage of the patient, while the expression of bcl-11b was inversely correlated with the IPI score of the patient (P<0.05). The expression of GATA3 and bcl-11b was related to the patients' age, gender, LDH level, and B symptoms. Other clinicopathological characteristics were irrelevant. Spearman correlation analysis shows that the expression of GATA3 protein was associated with that of bcl-11b protein in PTCL. Conclusion: GATA3 and bcl-11b are closely related to the prognosis of PTCL, and may be important factors involved in the occurrence and development of PTCL.

Clinical Outcomes of Patients with Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-Negative (ALCL, ALK-): Analysis of 203 Patients Prospectively Registered in the International T-Cell Project

Introduction: Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-negative (ALCL, ALK-) is a clinically aggressive lymphoid neoplasm with characteristic histologic and genetic features. The analysis from a retrospective International T-cell Lymphoma Project reported intermediate outcomes for ALCL, ALK- patients with 5-year event-free survival (EFS) and overall survival (OS) rates of 39% and 46%, respectively (Savage et al. Blood 2008 ). In this analysis, we sought to study clinical features and outcomes of 203 patients prospectively enrolled into the international T-cell lymphoma registry, the T-cell Project (TCP).Methods: The T-Cell Project prospectively registered consecutive patients with newly diagnosed peripheral T-cell lymphomas (PTCL) from 74 centres, in 14 countries, across 4 continents from Sep 2006 -Dec 2015. Demographic, clinical, and pathologic characteristics at the time of diagnosis, as well as treatment details and survival outcomes were collected. A key aim of this global collaborative project was to more precisely define clinical characteristics and outcome of patients with various subtypes of PTCL.Results: From a total of 1,429 evaluable PTCL cases, 203 (14.8%) were confirmed as ALCL, ALK- following international histopathologic panel review. As anticipated, these cases, as a proportion of all PTCL cases, varied across geographical regions (Asia 4.6%, South America 29.3%, U.S.A 12.7%, and Europe 14.7%). The median age at diagnosis was 55 (range, 18-89) years with a slight male predominance (63%). Stage III/IV disease was identified in 61% of patients, whilst bulky disease >5cm (25%) and BM involvement (9%) were uncommon. 65% of patients presented with low IPI score. Data on therapy was available in 155 (76%) patients, of whom 142 (92%) received chemotherapy (CHT) as part of first-line treatment. 23 (14.8%) patients additionally received concurrent or sequential radiotherapy (RT), whilst 12 patients (7.7%) underwent high-dose therapy as consolidation. Eleven (7%) patients received palliative care only. Of 142 patients treated with chemotherapy, 137 (96.5%) received anthracycline-containing regimens. There was no significant variation in anthracycline use by global geographic regions. The investigator-assessed overall response rate was 72%, with 84 (58%) patients achieving complete remission. With a median follow-up of 41 (range, 31-51) months, the median PFS (n=114) was 35 (95% CI 16-53) months, and 3-year and 5-year PFS rates were 48% and 40%, respectively. The median OS (n=203) was 52 (95% CI, 29-76) months, and 3-year and 5-year OS rates were 57% and 47%, respectively (Fig.1). At the time of data cut off, 84 (41%) patients died. Cause of death was most commonly attributable to lymphoma (72%) and infection (8%).Conclusions: This is the largest-to-date prospective international registry study of ALCL, ALK- patients describing epidemiology, clinical features, treatment approaches, and outcomes. With a mature follow-up, we report comparable results to previously reported from the retrospective International T-Cell Lymphoma Project. The long term survival rates after modern treatment approaches are disappointing with more than half of the patients not surviving past 5 years from diagnosis. This study underscores the urgent need for improved frontline therapies for ALCL, ALK- patients, and provides a robust platform for designing and interpreting future clinical trials. Recent results of incorporating novel CD30-targeting agent into initial therapy protocols are encouraging, and confirmatory randomized trial analysis is underway.Figure 1. Kaplan Meier estimates of overall (A) and progression-free (B) survival among ALCL, ALK- patients enrolled into the prospective TCP registry. [Display omitted] DisclosuresShustov:Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Horwitz:ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; HUYA: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; BMS: Consultancy. Radford:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Novartis: Speakers Bureau; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Speakers Bureau; Seattle Genetics: Speakers Bureau; GSK: Equity Ownership; AstraZeneca: Equity Ownership. Chiappella:Nanostring: Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Speakers Bureau; Celgene: Speakers Bureau; Roche: Speakers Bureau; Teva: Speakers Bureau; Janssen: Speakers Bureau. Federico:takeda: Honoraria, Research Funding.

Clinical Outcomes of Patients with Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-Positive (ALCL, ALK+): Data from 119 Patients Prospectively Registered in the International T-Cell Project

Introduction: Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase-positive (ALCL, ALK+) is a clinically aggressive lymphoid neoplasm with reported outcomes that compare favorably to other peripheral T-cell lymphoma (PTCL) subtypes. Pathogenesis of ALCL, ALK+ has been linked to perpetual activation of the ALK-kinase and numerous downstream signaling molecular events, that result from the recurrent genetic alteration, t(2;5)(p23;q35), in the majority of cases. In this study, we sought to analyze demographic characteristics, presenting clinical features, and treatment outcomes of 116 patients with ALK+ ALCL prospectively enrolled into the international T-cell lymphoma registry, the T-cell Project (TCP).Methods: The T-Cell Project prospectively registered consecutive patients with newly diagnosed PTCLs from 74 centers, in 14 countries, across 4 continents from Sep 2006 -Dec 2015. A key aim of this global collaborative project was to more precisely define clinical characteristics and outcomes of patients with various PTCL subtypes.Results: From a total of 1,429 evaluable PTCL cases, 119 (8.3%) were confirmed as ALCL, ALK+ following international histopathologic panel review. As anticipated, these cases, as a proportion of all PTCL cases, varied across geographical regions (Asia 4.4%, South America 8.0%, U.S.A 9.3%, and Europe 9.1%). The median age at diagnosis was 34.5 (range, 18-84) years with a slight male predominance (58%). Stage III/IV disease was found in 68.7% patients, whilst bulky disease >10cm (8.4%) and bone marrow involvement (14.5%) were uncommon, and 78.6% of patients had low risk IPI score (0-1). Data on therapy was available in 81 (68%) patients, of whom 80 (99%) received chemotherapy (CHT) as part of first-line treatment. Ten patients (12.3%) additionally received concurrent or sequential radiotherapy (RT), whilst 4 patients (4.9%) underwent high-dose therapy as consolidation. One patient (1.2%) received palliative care only. Of 80 patients treated with chemotherapy, 76 (91%) received anthracycline-containing regimens. The investigator-assessed overall response rate was 82.6%, with 57 patients (71%) achieving complete remission. With a median follow-up of 28 (range, 19-37) months, the median PFS for (n=114) ALK+ ALCL patients was not reached, and 3-year and 5-year PFS rates were 66% (95% CI, 55-75) and 59% (95% CI, 47-70), respectively. The median OS (n=116) was not reached, and 3-year and 5-year OS rates were both 77% (95% CI, 66-85) (Fig.1). At the time of data cut off, 20 patients died. Cause of death was most commonly attributable to lymphoma (65%) and infection (15%).Conclusions: This is the largest prospective international registry study to-date of ALCL, ALK+ patients, describing epidemiology, clinical features, treatment approaches and clinical outcomes. The use of anthracycline-based CHT regimens remains a standard of care front-line approach across global geographic regions. With a median follow up of >2 years, we observed favorable OS outcomes compared to other PTCLs despite presence of advanced stage disease in the majority of patients. However, the rates of PFS leave room for improvement. These findings are consistent with previous report from the retrospective International T-cell Project. Incorporation of recently developed CD30-targeting and ALK-kinase targeting agents into front-line regimens is underway to further improve outcomes for high-risk patients.Figure 1. Kaplan-Meier estimates of overall (A) and progression-free survival (B) among ALCL, ALK+ patients enrolled into the prospective TCP registry. [Display omitted] DisclosuresShustov:Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Pileri:Takeda Pharmaceuticals: Speakers Bureau. Horwitz:Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; HUYA: Consultancy. Carson:Seattle Genetics: Honoraria. Federico:takeda: Honoraria, Research Funding.

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

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

Comprehensive Genomic Profiling (CGP) Informs Molecular Diagnosis, Prognosis, and Therapeutic Decision-Making for Patients with Angioimmunoblastic T-Cell Lymphoma (AITL)

Background: AITL, under the 2016 WHO umbrella classification of nodal peripheral T cell lymphomas (PTCL) with a T follicular helper (TFH) phenotype, accounts for ~20% of all PTCL cases. Genomic analysis has revealed recurrent somatic mutations, such as RhoA G17V, that are hallmarks of AITL. Overlapping genomics have been observed in other PTCL subgroups, such as PTCL not otherwise specified (PTCL-NOS). We and others have reported frequent co-occurrence of RhoA G17V with mutations in the epigenetic regulators TET2 and IDH2R172 in AITL (Morley Blood 2015). Since treatment for the disease remains unsatisfactory, efforts are underway to assess the clinical utility of genomic information to guide therapy. The current study aimed to comprehensively assess the genomic landscape of AITL further, including identification of diagnostically and therapeutically relevant alterations.Methods: We explored the FoundationCORE™ database (Foundation Medicine Inc, Cambridge, MA) for cases assigned as AITL or harboring RhoA G17V positivity irrespective of disease ontology. This led to the inclusion of 42 cases: confirmed AITL (concordant diagnoses by internal and external pathologists, 29), suspected AITL (discordant diagnoses, 9), lymph node lymphoma NOS (PTCL, 1), or other neoplasm [pleomorphic myxofibrosarcoma (MFS), 1; marginal zone lymphoma (MZL), 1; cutaneous T-cell lymphoma (CTCL), 1]. Median cohort age was 65.5 years, 65 years for the AITL-specific subset; range for both, 34-88y. Pathology reports indicated Epstein-Barr virus positivity in 16/38 of AITL cases and prior autologous stem cell transplant in 4/38. DNA and RNA were extracted from formalin-fixed paraffin embedded samples or peripheral blood, and CGP performed using the CLIA-certified, NYS-approved, CAP-accredited FoundationOne® Heme assay (He Blood 2016).Results: RhoAG17V was seen in 57% (24/42) of cases in the cohort, including 53% (20/38) of AITL samples and in 1 case each of MFS, MZL, CTCL, and PTCL. Confirmed AITL harbored RhoAG17V in 52% (15/29), and suspected AITL in 56% (5/9), of samples. TET2 mutations (m TET2) were found in 89% of AITLs (26/29, confirmed; 8/9, suspected), and in 1/1 PTCL; as reported previously, m TET2 was not identified in the MFS, MZL, or CTCL. IDH2 mutations (m IDH2), all occurring at R172, were seen in 16% (6/38) of AITL cases, with all 6 co-occurring with RhoAG17V plus m TET2 . DNMT3A mutations (m DNMT3A) were seen in 32% (12/38) of AITLs (9/29, confirmed; 3/9, suspected) and in the single PTCL. RhoAG17V co-occurred with m TET2 (but notm DNMT3A orm IDH2) in 26% (10/38), m TET2 plus m DNMT3A in 7.9% (3/38), and m TET2, mDNMT3A, plus m IDH2 in 7.9% (3/38) of cases; all RhoAG17V cases(20/20) co-occurred with m TET2 . TP53 mutation was seen in 21% (8/38) of AITL cases. Other recurrent somatic mutations included BRCA1 or BRCA2 in 7.9% (3/38), CTNNB1 in 7.9% (3/38), and KRAS, ATM or STAT3 in 2.6% (1/38), of AITL samples. Assessment of tumor mutational burden (TMB), a biomarker for checkpoint inhibitor efficacy in solid tumors, revealed low TMB (<6 mutations/Mb) in 8/10 AITL cases and intermediate TMB (TMB-Intermediate, 6-19 mutations/Mb) in 2/10.Conclusion: This study utilized CGP to explore alterations of diagnostic and therapeutic potential in AITL. Confirming prior studies, in a significant proportion of AITL cases RhoAG17V co-occurred with m TET2 and m IDH2 ; all AITL cases positive for RhoAG17V had concurrent m TET2. We also found RhoAG17V, but not m TET2 or m IDH2, in solitary cases of MZL, MCL, and CTCL.Taken together, co-occurrence of RhoAG17V and m TET2 may provide greater specificity for AITL diagnosis than RhoAG17V alone. We also detected putative actionable targets in AITL. While predictors of response to hypomethylating agents (e.g. m TET2, m IDH2) were seen in most cases, a subset were found to have mutations in BRCA1/2 (3 pts), KRAS (1 pt), CTNNB1 (3 pts), or STAT3 (1 pt). These findings suggest alternative therapeutic opportunities in AITL (e.g. inhibitors of PARP, MEK, mTOR, and STAT3). We further report that mutational burden in AITL is generally low; however, a subset of cases (2/10) were TMB-Intermediate. Although the predictive power of TMB in lymphoma is unclear, in some solid tumors TMB-Intermediate status predicts response to immune checkpoint inhibition. In total, our findings highlight the utility of CGP to identify alterations that may influence the clinical management of AITL. DisclosuresMorley:Foundation Medicine: Employment, Other: Stock. He:Foundation Medicine, Inc: Employment, Other: Stock. Bailey:Foundation Medicine: Employment, Other: stock. Nahas:Foundation Medicine inc: Employment, Other: stockholder. Heilmann:Foundation Medicine, Inc: Employment, Other: Stockholder. Chudnovsky:Foundation Medicine, Inc: Employment, Other: Stockholder. Fabrizio:Foundation Medicine, Inc: Employment, Other: Stockholder. Ali:Foundation Medicine, Inc: Employment, Other: Stock. Lipson:Foundation Medicine: Employment, Other: stock. Stephens:Foundation Medicine Inc.: Employment, Equity Ownership. Ross:Foundation Medicine Inc: Employment, Other: stockholder. Miller:Foundation Medicine: Employment, Other: Stock. Severson:Foundation Medicine: Employment, Other: Stock. Vergilio:Foundation Medicine: Employment, Other: Stock. Erlich:Foundation Medicine: Employment, Other: stock. Mughal:Foundation Medicine, Inc: Employment, Other: Stock.

T-NHL subtypes and clinical perspective

Peripheral T-cell lymphomas (PTCL) are a distinct pathological entity with clinical advancements lagging behind its B-cell lymphoma counterpart. A significant proportion (15–20%) of PTCL cases are misdiagnosed as reactive or a different lymphoma subtype. An accurate diagnosis routinely requires analysis of the immunophenotype in conjunction with cellular morphology, analysis of lymph node architecture and molecular genetic analysis. Recent major advances in genomic studies examining gene expression profiling (GEP) and the genetic landscape of T-cell and NK-cell neoplasms have resulted in diagnostic, prognostic and therapeutic implications and has consequently led to revisions in the classification of PTCLs and introduction of new provisional entities. Incorporating these molecular and genetic markers, the latest 2016 WHO classification, an update of the current fourth edition, has identified 25 definitive and 6 provisional entities and further groups these lymphomas according to their usual presentation into disseminated disease (leukaemias), predominantly nodal, predominantly extra-nodal or cutaneous lymphomas. Nodal PTCLs represent the most prevalent PTCL subtype and include peripheral T-cell lymphoma - not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell lymphoma (FTCL), nodal PTCL with T follicular helper (TFH) phenotype, and systemic anaplastic large cell lymphoma (sALCL) either ALK-positive or ALK-negative. Due to better understanding of the cell of origin in T-cell lymphomas, AITL, FTCL and PTCL with TFH phenotype have been recognised as being derived from TFH cells as these neoplastic cells express at least two or three TFH cell antigens which include CD279/PD1, CD10, BCL6, CXCL13, ICOS, SAP and CCR5. In addition to the common cell of origin, these lymphomas share pathological and clinical features as well as recurrent genetic abnormalities such as mutations in TET2, IDH2, DNMT3A, RHOA and CD28, and gene fusions such as ITK-SYK and CTLA-CD28. Such features suggest that these lymphomas belong to the same spectrum of disease and are therefore now unified under a common heading. PTCL-NOS encompasses those which do not match the classification of other PTCL categories. This subtype mostly has a CD4+/CD8– phenotype and shows extreme cytological and phenotypical heterogeneity but GEP have identified at least three subgroups characterised by overexpression of GATA3, TBX21 and cytotoxic genes associated with varied clinical behaviour. Systemic ALCLs have a primarily aggressive nodal presentation and are further subdivided to ALK-positive or ALK-negative based on whether they carry the nucleoplasmin (NPM) anaplastic lymphoma kinase (ALK) translocation between chromosome 2 and 5, designated as t(2;5). We now know that a subset of ALCL, ALK-negative cases harbour rearrangement at the locus containing DUSP22 and IRF4 in chromosome 6p25, which induces down regulation of DUSP22, a dual specific phosphatase that inhibits TCR signalling. Another subset of ALK-negative ALCL has rearrangements in TP63. Clear distinction of PTCL with high CD30 expression from ALCL, ALK-negative have also been possible through GEP and as such, the former is no longer considered a provisional entity. Breast implant associated ALCL, a unique form of ALCL, ALK-negative arising in association with breast implants, is increasingly being recognised and has been included as a provisional entity. Cutaneous ALCL (cALCL), ALK-negative, the fourth subtype, is an indolent form limited to the skin. Whilst notorious to have an aggressive clinical course and an extremely poor overall prognosis, clinicians are constantly challenged with low rates of complete remissions, early relapses and failures to achieve long-term remissions despite aggressive first-line chemotherapy, in the majority of patients. More recently, improved understanding of disease biology and the molecular profile of specific PTCL subtypes has opened the door to the potential of more targeted therapies with a number of new biological therapies approved by regulatory agencies in the last few years.

Fusion transcripts FYN-TRAF3IP2 and KHDRBS1-LCK hijack T cell receptor signaling in peripheral T-cell lymphoma, not otherwise specified

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with poor prognosis. Up to 30% of PTCL lack distinctive features and are classified as PTCL, not otherwise specified (PTCL-NOS). To further improve our understanding of the genetic landscape and biology of PTCL-NOS, we perform RNA-sequencing of 18 cases and validate results in an independent cohort of 37 PTCL cases. We identify FYN-TRAF3IP2, KHDRBS1-LCK and SIN3A-FOXO1 as new in-frame fusion transcripts, with FYN-TRAF3IP2 as a recurrent fusion detected in 8 of 55 cases. Using ex vivo and in vivo experiments, we demonstrate that FYN-TRAF3IP2 and KHDRBS1-LCK activate signaling pathways downstream of the T cell receptor (TCR) complex and confer therapeutic vulnerability to clinically available drugs.

SUBTYPES OF MATURE T AND NK CELL LYMPHOMAS ACCORDING TO 2016 WHO CLASSIFICATION. PRELIMINARY REPORT OF THE INTERNATIONAL PROSPECTIVE T‐CELL PROJECT 2.0

Introduction: Mature T and NK-cell lymphomas represent a heterogeneous group of lymphoid disorders (29 subtypes according to the 2016 WHO classification) arising from mature T cells of post-thymic origin with different morphological characteristics, phenotypes, and clinical presentation. Following the success of the T Cell Project (TCP), which allowed the analysis of more than 1,500 cases of peripheral T-Cell lymphomas (PTCLs) collected prospectively in 18 Countries, in 2018 the TCP 2.0 was launched. Here we report the global distribution of PTCLs, from the cases registered so far based on the locally established histological diagnosis. Methods: The TCP2.0 (ClinicalTrials.gov Identifier: NCT03964480) is a prospective, international, observational study which adapts to changes made in the new WHO classification. Results: Since the beginning of the study (October 2018), 648 patients with newly diagnosed PTCL were registered by 75 active centers across 14 countries. Of these data, 594 patients have been validated by the centralized trial office. Overall, PTCL-NOS, Anaplastic large cell lymphoma (ALCL) ALK-negative, and Angioimmunoblastic T-cell lymphoma (AITL), represent the most frequent subtypes, representing 31.3%, 18,9% and 13,5% of cases, respectively. As reported in Table 1, PTCL-NOS represents the most frequent subtype worldwide, whereas Adult T-cell leukemia/lymphoma was more frequent in Brazil, AITL and ALCL ALK-negative in Australia/ India, and ALCL ALK-positive in North America and Europe. Extranodal NK/T-cell lymphoma, nasal type was relatively frequent in Brazil and quite rare in the other Latin America Countries. Finally, many sub-types represent less than 5% of cases in all geographic areas. Conclusions: The TCP2.0 continues to recruit very well, despite the difficulties linked to the COVID-19 pandemic, and may represent a useful resource for the prospective study of this group of rare lymphomas.

Mechanisms of Therapeutic Response to Tipifarnib in a Mouse Model of Angioimmunoblastic T-Cell Lymphoma

Angioimmunoblastic T-cell lymphomas (AITLs) are aggressive non-Hodgkin lymphomas arising from malignant transformation of follicular helper T-cells (Tfh) and are associated with limited response to intensified chemotherapy and poor prognosis. The genomic landscape of AITL is characterized by loss of function mutations in epigenetic regulators, including TET2, and the highly prevalent RHOA G17V mutation identified in almost 70% of AITL cases (Palomero et al., 2014). Using a combination of loss of TET2 and expression of RHOA G17V in CD4+ T-cells, our group developed a new mouse model of AITL, which accurately recapitulates the features of the human disease (Cortes et al., 2018). Our model constitutes a relevant platform for studying AITL pathogenesis and developing experimental therapeutic approaches for the treatment of this disease. Tipifarnib is a farnesyltransferase inhibitor that has been linked to reduced cell proliferation and increased apoptosis in a variety of solid tumors and leukemias (Alsina et al., 2004; Kirschbaum et al., 2011). Interestingly, a phase II study of tipifarnib in patients with relapsed/refractory lymphoma indicated that, while tipifarnib had a modest anti-lymphoma activity within the whole cohort, it elicited an overall response rate of 31% within the Peripheral T-cell Lymphoma cases, particularly AITL (Witzig et al, 2011). However, the molecular bases for the therapeutic activity of tipifarnib in AITL are still unknown. To understand the role and the mechanisms of action of tipifarnib in AITL, we have used our TET2-/-RHOA G17V mouse AITL lymphoma model. Using this model, we first identified that treatment in vitro with increasing doses of tipifarnib showed limited effect on the viability of AITL lymphoma cells; however, when mouse lymphoma cells were co-cultured in the presence of splenocytes as supporting cells, tipifarnib induced a strong decrease in cell viability and proliferation, suggesting that tipifarnib might be exerting its therapeutic effects not only on the tumor cells, but also indirectly by regulating the tumor microenvironment. Indeed, tipifarnib treatment in a lymphoma model in vivo led to significantly decreased tumor load and substantial reduction of lymphoma cell infiltration in solid organs, demonstrating a consistent and strong anti-tumor effect of tipifarnib in AITL in vivo. Mechanistic analysis of signaling pathways regulated by tipifarnib indicated that tipifarnib induced downregulation of surface expression of the CXCR4 receptor in tumor cells and increased the circulating levels of its ligand, CXCL12, resulting in an effective increase of the CXCL12/CXCR4 ratio. In addition, our data revealed a significant tipifarnib-induced decrease in the levels of IFN-G, TNF-A, IL-10 and IL-17 cytokines. We also performed gene expression profiling in sorted AITL lymphoma cells and sorted stroma splenocytes from mice that had been treated with tipifarnib or vehicle control. Interestingly, most of the genes specifically affected by tipifarnib were expressed in stromal cells, where we detected an upregulation of Fas-L and, more notably, of multiple genes associated with NK cell function and differentiation (CD226, CD244a, Klre1, Xcl1 and Eomes). CYBERSORT analysis of hematopoietic cell populations indicated that treatment with tipifarnib in our mouse lymphoma model is associated with enrichment in NK signatures and a potential decrease of monocytes and neutrophils within the tumor microenvironment. In summary, we have demonstrated that tipifarnib has a strong anti-lymphoma effect on a mouse model of AITL and that this effect might be mediated by the recruitment and/or activation of different hematopoietic cell populations in the tumor microenvironment that can alter the survival and proliferation of lymphoma cells. Disclosures Palomero: Kura Onclology: Research Funding.

Adult T-Cell Leukemia/Lymphoma: A Cohort of 41 Cases Recorded in the Brazilian T-Cell Project

Introduction:Adult T cell Leukemia/Lymphoma (ATLL) is a mature T-Cell-neoplasm related to human T-cell lymphotropic virus type 1 (HTLV-1) infection that shows variable clinical presentation and adverse prognosis with shorter overall survival (OS) when compared to other peripheral T-cell lymphomas (PTCL). Previous epidemiological studies estimated cumulative incidence in endemic regions around the world. In Brazil, mainly due to its vast dimension, data collection has limitations and is subject to bias. In April 2015 theBrazilianT-cell longitudinal project initiative was launched. One of the primary purposes was the collection of epidemiological and clinical data from the most frequent subtypes of newly diagnosed PTCL. Among them, 41 cases of ATLL were recorded. Objectives:The aim of this study is to describe clinical features, frequency and overall survival (OS) of 41 cases of ATLL registered in the ongoingBrazilianT-Cell Project. Methods:This is an ambispective observational study design collecting baseline characteristics, clinical features including date of diagnosis, clinical subtypes, B symptoms, performance status, Ann-Arbor staging, HTLV-1 status, number of sites, nodal and extra nodal presentation and types of skin lesions, peripheral blood counts and biochemical tests, front-line treatment and best response after first-line treatment. REDcap Platform has been used to collect and store data and for descriptive analysis the IBM-SPSS version 24 was applied. Kaplan-Meier method estimated the OS, whereas Log-Rank tests to compare its curves. OS period was calculated from diagnosis date until death or last seen date, and event was death by any cause. Results:Out of 281 cases of PTCL registered so far, 41 were ATLL cases. The median age was 50 years (34-88), 25 (64%) female; a higher incidence of lymphoma subtype was observed (46%), followed by acute (29%), chronic (17%) and smoldering (8%). Most of the patients (85%) had advanced-stage disease (III-IV, Ann-Arbor) and 56% had B symptoms (Table 1); 73% received chemotherapy with anthracycline-based regimens (46.5% CHOEP; 33.5% CHOP; 20% others) whereas 17% were managed with immunotherapy and antiviral therapy. The overall response rate was 30%; no response or progression 46%; stable disease 9% and 15% no data available yet (Table 2). Median follow-up was 13 months and 25 months for 41% of alive patients. Two year OS was 39% (95%CI: 23-55%) (Figure 1). Smoldering and Chronic subtypes showed better OS when compared with acute and lymphoma (100% smoldering, 86% chronic; 30% lymphoma type and 13% acuteP=0.04) (Figure 2). The multivariate Cox Regression analysis found male gender (HR 10.9 95%CI: 3.0-39.7, P&amp;lt;0.0001) and albumin (HR 0.23 Beta -1.45 95%CI: 0.10-0.55, P=0.001) as significant prognostic factors for OS. Discussion:ATLL prognosis remains poor regardless of the type of treatment regimen and may be associated with the high incidence of lymphoma and acute subtypes, as well as advanced stage disease presentation. Despite the high number of cases seen in southeastern region of Brazil, it is important to emphasize there are still limited data from other regions. Albeit the sample size is small, these findings confirmed literature review data so far, with poor overall survival in a short time and gender and albumin as predictors of OS in the multivariate analysis. Conclusion:This study highlights the poor prognosis associated with ATLL. Moreover, it seems relevant to expand this study to all Brazilian regions. Hence, the need for early diagnosis and new treatment strategies, able to reduce mortality is warranted, that could possibly change the nature and spectrum of disease. Disclosures Federico: Spectrum:Consultancy, Membership on an entity's Board of Directors or advisory committees;Sandoz:Consultancy, Membership on an entity's Board of Directors or advisory committees;Cephalon/Teva:Research Funding;Mundipharma s.r.l.:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Millennium/Takeda:Research Funding;Roche:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Takeda:Consultancy, Membership on an entity's Board of Directors or advisory committees.

S2854 Peripheral T-Cell Lymphoma, Not Otherwise Specified (PTCL, NOS) Presenting With Gastrointestinal Bleeding in an HIV Patient

INTRODUCTION: Peripheral T-Cell lymphomas (PTCL) are a rare type of Non-Hodgkin’s Lymphoma (NHL) with an incidence of < 1 case per 100,000 people in the USA. PTCL, not otherwise specified (NOS) is an EBV-associated malignancy, encompassing a spectrum of disorders that do not fulfill the criteria of other PTCL subtypes. Presentation of PTCL, NOS with gastrointestinal bleeding has only been described in rare case reports. CASE DESCRIPTION/METHODS: A 32-year-old female with congenital HIV, on highly active anti-retroviral therapy (HAART), presented with multiple episodes of hematochezia, diffuse abdominal pain and hypotension. After hemodynamic stabilization with multiple units of packed red blood cells and intravenous fluids, esophagogastroduodenoscopy and colonoscopy were performed revealing no obvious source of bleeding. Subsequently, CT scan and MRI of the abdomen delineated two segments of small bowel wall thickening, luminal narrowing and mesenteric lymphadenopathy. Capsule endoscopy showed scattered patches of erythematous mucosa in the small bowel without active bleeding or stigmata of bleeding. Afterwards, she underwent a small bowel push enteroscopy revealing a large, non-obstructing, infiltrative mass in the mid-jejunum which was successfully biopsied (Figure 1). Biopsy was consistent with PTCL, NOS with a high Ki-67 proliferation index (80-90%) and positive Epstein-Barr encoding regions-in situ hybridization (EBER-ISH) (Figure 2, 3). Further staging workup showed a normal bone marrow biopsy. PET-CT scan demonstrated intense FDG uptake in jejunum and small bowel segments in the left and right lower quadrants but no distant metastases. During the preparation for chemotherapy, she developed acute small bowel perforation. Given the rapid deterioration, definitive treatment was not feasible. After family discussions, she was transferred to inpatient hospice where she passed away. DISCUSSION: Push enteroscopy is an effective tool for the diagnosis of small bowel malignancies like PTCL. The presence of HIV increases the risk of PTCL by 15 times and adversely impacts the prognosis, with a median survival of around 1 year. Around 30% cases of PTCL, NOS are EBV positive and the presence of EBER-ISH portends worse outcomes. Induction with anthracycline-based chemotherapy regimens along with brentuximab vedotin (an antibody-drug conjugate against CD30) for CD30 + PTCL, and early consolidation with autologous stem cell transplant (ASCT) are the cornerstones of PTCL, NOS treatment.Figure 1.: Small bowel push enteroscopy: Panel (A) and (B) show a prominent mass lesion in the mid-jejunum. Panel (C) and (D) show the same area after biopsy and tattooing.Figure 2.: Small bowel mucosa with large pleomorphic cells infiltrating the lamina propria. Surface ulceration and extensive areas of punctate necrosis are also present. Figure (A) is X10 and Figure (B) is X25 magnification.Figure 3.: The large pleomorphic cells are positive for (A) CD3 (B) CD7 and (C) CD8 immunostains as well as (D) EBER-ISH (X25).

Expression of CDK6 and FOXM1 in peripheral T-cell lymphoma and their significance

Objective: To investigate the expression of CDK6 and FOXM1 in peripheral T-cell lymphoma (PTCL), and its correlation with clinicopathologic features and patient prognosis. Methods: The Oncomine was used for data mining and analyzing the expression levels of CDK6 and FOXM1 in PTCL. Immunohistochemistry (IHC) of EnVision method was used to detect the expression of CDK6 and FOXM1 proteins in 166 cases of PTCL diagnosed at Shanxi Provincial Cancer Hospital from January 2016 to December 2018, and 30 cases of lymph node with reactive hyperplasia as control. Results: Among the PTCL patients, 104 were male and 62 were female, aged from 3 to 85 years, with an average age of 53 years. Analyses of the Oncomine 4.5 database showed that mRNA expression of CDK6 and FOXM1 in PTCL tissues was significantly higher than that in normal tissue (P<0.05). IHC staining showed the positive rates of CDK6 and FOXM1 proteins in PTCL tissues were 27.7% (46/166) and 80.7% (134/166), respectively. The expression was mainly present in the nuclei of tumor cells, showing a diffuse, strongly positive pattern. The positive rates of CDK6 and FOXM1 proteins among the 30 cases of lymph-node reactive hyperplasia were 0 (0/30) and 30% (9/30), respectively. The expression of FOXM1 was mainly found in the lymphoid follicle germinal center, and not present in the T-zone cells. CDK6 protein, FOXM1 protein and the co-expression of CDK6 and FOXM1 proteins in PTCL were associated with higher Ann Arbor staging and international prognostication index score (P<0.05), and inversely associated with overall survival (P<0.05). Meanwhile, CDK6 protein expression was positively correlated with FOXM1 protein expression (P<0.05). Conclusions: CDK6 and FOXM1 may be new targets for the diagnosis and treatment of PTCL. The overexpression of CDK6 may lead to enhanced function of the transcription factor FOXM1, while the overexpression of CDK6 and FOXM1 also promotes the development and progression of PTCL.

Peripheral T cell lymphoma, NOS with aberrant αβ and γδ T cell receptor expression in a post-heart transplant patient

Three main patterns of T cell receptor (TCR) expression are identified in peripheral T cell lymphoma (PTCL): TCR-αβ type, TCR-γδ type, and TCR silent type. Cases of PTCL that express both αβ and γδ receptors are rare. Here, we report a case of PTCL-NOS (not otherwise specified) with dual αβ and γδ expression in a 61-year-old female 6 years after orthotopic cardiac transplant. The patient presented with fatigue, fever, worsening anemia, and thrombocytopenia. A chest CT showed multiple irregular lung nodules and diffuse lymphadenopathy. Cytology evaluation of the lymph nodes revealed large atypical lymphocytes with immunopositivity for CD3, CD8, CD56, TIA1, and granzyme B and immunonegativity for CD5 and CD30. Epstein-Barr virus (EBV) was not detected by EBV-encoded RNA (EBER) in situ hybridization study. The corresponding flow cytometry demonstrated abnormal T cells with TCR-αβ and TCR-γδ expression and loss of CD5 expression. A TCR gene rearrangement study demonstrated the presence of a clonal lymphoid population with TCRβ and TCRγ rearrangements. The patient was deceased within 2 months despite aggressive treatment. The findings were consistent with an EBV-negative, monomorphic T cell post-transplant lymphoproliferative disorder (PTLD) with features of PTCL-NOS. A literature review of T cell lymphoma with co-expression of TCR-αβ and TCR-γδ was performed. A case of aggressive PTCL with dual expression of TCR-αβ and TCR-γδ in a post-transplant setting has not been previously reported.

Hepatosplenic T Cell Lymphoma: A Rare Disease

Hepatosplenic T cell lymphoma (HSTCL) is an uncommon neoplasm comprising 5% of peripheral T-cell lymphomas. We report an uncommon case of Peripheral T-cell lymphoma that is characterized by primary extranodal disease with malignant T cell proliferation in spleen, liver and bone marrow. 19 year old male patient presented with fever, weakness and pain abdomen for 2 months. On clinical examination he was pale and had massive hepatosplenomegaly. The diagnosis was quite challenging as thorough clinical, hematological and immunophenotypic correlation was required.

Prognostic significance of Twist, ZEB1 and Slug in peripheral T-cell lymphomas

ABSTRACT Objectives: To investigate the protein expression of the epithelial-mesenchymal transition-inducing transcription factors (TFs) Twist, ZEB1 and Slug in peripheral T-cell lymphomas (PTCL) and their correlation with clinical parameters. Methods: The expression of these TFs was studied in 53 diagnostic biopsy specimens of several different PTCL subtypes with immunohistochemistry. Patient data were retrospectively collected from patient records and a statistical analysis was performed. Results: All three TFs were widely expressed. ZEB1 and Slug had correlations with clinical outcome. In all PTCL cases, high nuclear ZEB1 percentage correlated with a favorable progression-free survival (PFS) (3-year PFS: 70% vs. 34%; P = 0.010) and strong nuclear Slug intensity correlated with an unfavorable PFS (3-year PFS: 17% vs. 62%; P = 0.036). Discussion: The correlations between PFS and ZEB1 or Slug protein expression have not previously been established in PTCLs. The impact of ZEB1 and Slug expression on prognosis differed from our findings in DLBCL and the impact of ZEB1 expression was in line with current studies on mycosis fungoides and sézary syndrome. The findings may be explained by the roles these TFs play in hematopoiesis. Conclusion: ZEB1 and Slug may have potential clinical value for evaluating prognosis in PTCLs. The study size was small and heterogenous, and larger studies are warranted.

Present and future perspective of the treatment of peripheral T-cell lymphoma

Peripheral T-cell lymphoma (PTCL) is a kind of aggressive lymphoma with a poorer prognosis than mature B-cell lymphoma. Presently, the standard of care for PTCL is considered to be the CHOP regimen, yet clinical outcomes remain insufficient. The intensification of chemotherapy and front-line high-dose chemotherapy have been examined as potential therapeutic strategies by several clinical trials. A recent double-blind phase III trial examining the effects of brentuximab vedotin (BV) when incorporated into front-line chemotherapy involved CD30-positive PTCL cases and found that a progression-free survival benefit was observed by adding BV to the therapeutic regimen, especially in the context of anaplastic large-cell lymphoma. Other molecular target agents, i.e., antibodies and small molecules, have also actively been developed. Investigators should conduct further clinical trials to establish the next standard treatment by the optimization of classic chemotherapeutic agents and molecular target agents.

Expansion of PD1-positive T Cells in Nodal Marginal Zone Lymphoma: A Potential Diagnostic Pitfall.

The diagnosis of nodal marginal zone lymphoma (NMZL) can be challenging, with the differential diagnosis including other low-grade B-cell lymphomas, reactive hyperplasia, and even some cases of peripheral T-cell lymphoma (PTCL). PTCL may have a perifollicular growth pattern mimicking NMZL. We and others have noted an atypical distribution of T-follicular helper (TFH) cells in some cases of NMZL. This study was prompted by the diagnosis of NMZL in several cases in which a marked increase of TFH cells, as determined by staining for programmed death-1 (PD1), had prompted suspicion for a diagnosis of PTCL. We analyzed PD1 staining in 48 cases of NMZL to characterize the extent and pattern of the PD1-positive infiltrate. Three main patterns of PD1 staining were identified: follicular pattern (peripheral, n=16; central, n=9; mixed, n=3), diffuse pattern (n=4), and a reduced or normal staining pattern in residual follicles (n=16). A comprehensive analysis of other TFH markers was undertaken in 14 cases with a high content of PD1-positive cells that were confirmed as B-cell lymphoma by clonality analysis. We describe in detail 5 of these cases in which PTCL was an initial consideration. This study illuminates the diverse immunohistochemical patterns encountered in NMZL and highlights a diagnostic pitfall important for diagnostic accuracy.