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Enteropathy-associated T-cell lymphoma (EATL) is a rare lymphoma arising in the setting of celiac disease. Multiagent anthracycline-based chemotherapy alone is associated with poor long-term outcomes with a median overall survival of only 7 months. In patients who achieve a response to firstline therapy and are eligible for autologous stem cell transplantation (SCT), 5-year median overall survival can be improved to 50% to 60%. Because ~50% of patients with EATL express the CD30 antigen, targeted therapy with brentuximab vedotin has been explored with promising outcomes. We have recently completed a phase 1/2 study showing safety and efficacy of chimeric antigen receptor (CAR)–modified T cells targeting the CD30 molecule (CD30 CAR T cells) in CD301 Hodgkin lymphoma. Here we describe a patient with multiply relapsed EATL after previous allogeneic SCT (allo-SCT) who achieved a durable remission with CD30 CAR T cells.

Large granular lymphocytic leukemia (LGLL) is a heterogenous group of disorders. The clinical presentations of LGLL are highly variable; it may present with neutropenia or anemia, complicated with recurrent infections, autoimmune diseases such as rheumatoid arthritis, and neurological symptoms, requiring therapeutic interventions. It may present only with indolent laboratory changes without any symptoms. The cytological phenotypes of LGLL also vary and they commonly include CD8+TCR αβ-type, CD4+TCR αβ-type, and NK cell-type. NK cell-type LGLL is designated as chronic lymphoproliferative disorder of NK cells (CLPD-NK). TCR γδ-type LGLL (γδT-LGLL) is even rarer and it often confers cytopenia. The genetic backgrounds of LGLL with CD8+TCRαβ-type, CD4+TCRαβ-type and NK cell-type have been elucidated with the recent sequencing technologies. JAK/STAT signaling genes and chromatin-modifying genes were frequently mutated in the non-leukemic counterpart of the lymphoid malignancies with γδ TCR immunophenotypes, such as hepatosplenic T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma and primary cutaneous gamma delta T-cell lymphoma. However, the genetic basis of γδT-LGLL and the genetic-phenotypic associations remain unclear. The aim of this study is to identify clinical and genetic characteristics of γδT-LGLL in comparison with other LGL leukemias. In total, 56 LGLL patients were recruited; six patients with γδT-LGLL, 25 CD8+ TCRαβ type, 8 CD4+TCR αβ type and 17 CLPD-NK, in this study. All cases were negative for EBV. The median age of patients with γδT-LGLL was 48 years old and five of them were male. The median LGL counts and hemoglobin level were 1.81 ×109/L (range; 0.60-4.42) and 5.8 g/dL (range; 3.0-11.2), respectively. All patients with γδT-LGLL had anemia and/or neutropenia, although no patients were thrombocytopenic. 4 patients presented with pure red cell aplasia. Common immunophenotypes of γδT cells were CD2+ CD3+ CD4-CD7+. 3 patients were CD8+. CD16, CD56 and CD57 were positive in 3, 0, and 1 patient, respectively. γδT cells of all patients showed a monoclonal pattern of TCRγ gene rearrangements with BioMed 2 protocol. We performed amplicon sequencing of entire coding regions of STAT3, STAT5B and TNFAIP3 genes and allele-specific PCR for several hot spot regions of STAT3 and STAT5B genes using extracted DNA from mononuclear cells of peripheral blood. Mutations in STAT3 and TNFAIP3 were identified in 100% (6/6) and 17% (1/6), respectively. Among the10 STAT3 mutations identified, 5 were located in the SH-2 domain, while other 3 were in coiled-coiled domain and the other 2 were in the DNA binding domain. The median variant allele frequencies of STAT3 was 2.0% (0.7-22.6) and STAT3 mutations were restricted to sorted γδT cells in all 3 patients examined. No patient was positive for STAT5B mutations, including N642H and Y665F with allele specific PCRs. One of 5 patients who were treated with cyclosporin A was refractory. Two patients were treated with cyclophosphamide, showing clinical improvements. The patients with γδT-LGLL were younger than those with other types of LGLL (P=0.048) and anemia and STAT3 mutations were significantly more frequent in γδT-LGLL (P value; 0.003 and 0.02, respectively). PRCA was a consistent cause of anemia in γδT-LGLL. Low frequency of STAT5B mutations among γδT-LGLL patients was in contrast to other aggressive γδT cell lymphoma in which STAT5B frequently mutated. The clinical characteristics of γδT-LGLL patients may be defined by younger age and the anemia due to pure red cell aplasia, and the frequent STAT3 mutations might be a novel molecular marker for γδT-LGLL. Disclosures Yamane: Pfizer: Research Funding; Celgene: Honoraria; Bristol-Meyers Squibb: Research Funding; Chugai Pharmaceutical: Consultancy, Research Funding; Astellas Pharma: Research Funding; Eli Lily and Company: Research Funding. Ishida:Eli Lily and Company: Research Funding; Astellas Pharma: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding; Chugai Pharmaceutical: Consultancy, Research Funding; Celgene: Honoraria.

Background: Central nervous system (CNS) involvement by peripheral T cell lymphoma (PTCL) is a rare condition. Among primary CNS lymphomas, only 2% are secondary to PTCL, while the risk of CNS relapse in all cases of PTCL is estimated at 2% to 6%. Little is known about the presentation and outcomes of PTCL patients with CNS involvement given the rarity of this entity. In this study, we describe patient characteristics, histology, and clinical course of patients with CNS involvement by PTCL. Methods: The Mayo Clinic Lymphoma Database was used to identify PTCL patients with primary or secondary CNS involvement seen at our institution between 2000 and 2018. A total of 12 patients were identified and their medical records were reviewed for patient and disease characteristics, CNS-directed treatment modality, and outcomes. The Kaplan-Meier method was used for time-to-event analysis. Results: The median age at CNS diagnosis was 63 years (range 41 to 76) and 11 (93%) patients were male. The histological diagnoses were PTCL, NOS in 9 (75%) patients, enteropathy-associated T-cell lymphoma in 2 (17%) patients, and angioimmunoblastic T-cell lymphoma in 1 (8%) patient. Five patients presented with primary T-cell CNS lymphoma (all with a PTCL, NOS histology), while the remaining 7 (58%) patients also had systemic involvement. All patients presented with neurologic symptoms at the time of CNS involvement diagnosis including: focal motor deficits in 6 patients (unilateral upper extremity weakness, gait impairments, and hemiparesis), cognitive decline in 5 patients (memory impairments, reduced attention, and confusion), headache in 4 patients, and seizure in 3 patients. The CNS disease location included the brain parenchyma in 9 (75%) patients, leptomeninges in 1 (8%) patient, and lumbar plexus in 1 (8%) patient. One patient (8%) had positive CSF finding only without radiologic evidence of involvement. CSF analysis was performed in 11 patients. Elevated protein levels were noted in 3 (27%) patients, malignant cells in 2 (18%), and no clear abnormalities in the remaining 6 (55%) patients. Concomitant bone marrow involvement was seen in only 1 patient. Elevated LDH was seen in 2 patients. The a median LDH was 195 U/L (range 139 to 4,360) The most common CNS-directed therapies were: high-dose methotrexate (MTX)-based regimens in 8 (67%) patients, including high-dose MTX in combination with temozolomide (n=2), or cytarabine and thiotepa (n=2). Intrathecal MTX, temozolomide and dexamethasone, lenalidomide, high-dose steroids, and surgical resection were the treatment modality used for one patient each. At a median follow up of 18 months, eight (75%) out of 12 patients were not alive at the time of last follow up. The median overall survival (OS) from diagnosis was 16 months (95% CI: 2.8-173). The median progression free survival (PFS) from initiation of CNS-directed therapy was 9 months (95% CI: 1.6-33) (figure). Four patients had a PFS longer than 12 months. These 4 patients were treated with: temozolomide/dexamethasone, high-dose MTX, lenalidomide, and high-dose MTX followed by cytarabine/thiothepa. Conclusion: CNS involvement by T-cell lymphoma is a rare complication that carries a poor prognosis. Early onset of neurologic symptoms should trigger prompt investigation of CNS involvement. Despite the short OS and PFS, some patients may achieve a relatively longer disease free interval. Disclosures Bennani: Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Cerhan:Celgene: Research Funding; NanoString: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Nowakowski:Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees. Ansell:Mayo Clinic Rochester: Employment; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Affimed: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding. Paludo:Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding.

Introduction Historically, the GI tract is involved in 10-15% of patients with newly diagnosed NHL. Despite being the predominant extranodal site for lymphoma involvement little is known about its pathophysiologic presentation given its overall rarity. Nonetheless its evaluation, diagnosis, prognosis and management is distinct from lymphomas at other sites hence their recognition irrespective of whether being the primary site is prudent. Methods We performed a single center retrospective study of patients to describe clinical characteristics and outcome of newly diagnosed NHL presenting with GI involvement defined by tissue biopsy between January 2003 and April 2019. Descriptive statistics were calculated by Fisher's exact test and Chi2 test for categorical variables and rank-sum analyses for continuous variables. Results We identified 91 patients with one patient presenting with 2 different GI NHL involvement. The median age at presentation was 70 years (range 33-92) and 61 were male. 41 (45%) patients had diffuse large B cell lymphoma (DLBCL) and 5 had concomitant low grade component, 28 (30.8%) mucosal associated lymphoid tissue (MALT) lymphoma, 10 (11%) mantle cell lymphoma (MCL), 4 (4.4%) enteropathy associated T cell lymphoma (EATL), 3 (3.3%) follicular lymphoma, 2 (2.2%) Burkitt's lymphoma and 2 (2.2%) EBV driven lymphoproliferative disorder (LPD). There were 1 case each of plasmablastic lymphoma and extranodal NK/T-cell lymphoma, nasal type. 37 with DLBCL and 2 with MCL had primary GI involvement. Gastric involvement was the commonest site, 43 (55.8%) cases followed by the large intestine, 22 (28.6%). PET-CT scan was done in 42 cases with high grade NHL; GI involvement by FDG avidity was noted in 23 cases and negative in 19 (45.2%). Serum albumin at presentation was available in all patient. Patients with presenting serum albumin < 25 g/L were more likely to die in the first 30-days post diagnosis; p Conclusions Despite the relatively small sample size this real-world data of GI lymphomas outlines some of its recognized features; advanced age at diagnosis, male prevalence and gastric involvement as the commonest site of involvement. Presenting serum albumin Disclosures No relevant conflicts of interest to declare.

Introduction: Aggressive T cell lymphomas (TCL) are a heterogenous group of lymphomas that are frequently associated with poor outcomes. Autologous stem cell transplantation (ASCT) is recommended according to the NCCN guidelines and by practice standards for most subtypes as a consolidation for patients in first remission. A large prospective study of up-front ASCT by the Nordic Lymphoma group identified age, ECOG performance status Methods: We retrospectively analyzed data from consecutively treated patients (pts) with aggressive T-cell lymphomas who underwent ASCT at our institution from July 2009 to February 2019. Patient and disease characteristics were summarized using descriptive statistics. Kaplan-Meier analysis was used to estimate progression free survival (PFS) that was defined as the time from SCT to the first evidence of recurrence, and overall survival (OS) that was defined as the time from SCT to death or last institutional follow up with a hematologist. We collected data on age, co-morbidities, disease subtype, stage, response to therapy and treatment both pre and post SCT. Flow cytometry was obtained at diagnosis and phenotype of atypical circulating cells was compared with immunophenotype from tumor biopsy specimens. Results: 50 pts with TCL who received ASCT were identified for this analysis. Of this population, 41 (80%) of pts had peripheral blood flow available at the time of initial diagnosis. T-cell lymphoma types included peripheral T cell lymphoma not otherwise specified (PTCL NOS, 17 pts), angioimmunoblastic T cell lymphoma (AITCL, 15pts), ALK negative anaplastic large cell lymphoma (ALCL, 1pt), enteropathy-type T-cell lymphoma (EATL, 2pts), extranodal natural killer T-cell lymphoma (NKTCL, 2pts) and panniculitis like T cell lymphoma (2 pts) (Table 1). Median age of the cohort was 62 years (range 20-75 years) and all patients included had an ECOG PS 0-1 at the time of diagnosis. The majority had stage 4 disease (36/41, 87.8%), but analysis included a small number of patients with stage 2 (1/41, 2.4%) and stage 3 (4/41,9.7%) disease. Bone marrow involvement by morphologic criteria was noted on bone marrow biopsy in 8/41 (19.5%) pts; bone marrow was negative in 28/41 or 61% pts and not evaluated in 8/41 or 19.5% pts. Flow cytometry of peripheral blood performed as part of initial staging was positive for circulating malignant cells in 13/41 pts (31.7%) at the time of diagnosis. All patients underwent ASCT in first remission. The median PFS and OS were 15.2 and 29.9 months respectively in the flow positive group, while neither median PFS nor OS were reached in the flow negative group (Figures 1 and 2). Flow cytometry results from time of diagnosis was not strongly associated with PFS (log rank, p = 0.39), however, it was associated with overall survival (log rank, p = 0.012). There were 11 deaths in the cohort- 4 in the flow negative group and 7 in the flow positive group. Further, when bone marrow involvement was evaluated, 7 of 13 pts with positive flow cytometry (53.8%) and 5 of 28 (17.8%) pts with negative flow cytometry had BM involvement, suggesting a correlation between positive bone marrow and detection of lymphoma cells in the peripheral blood at the time of diagnosis. Conclusions: We demonstrate in our cohort of patients that detection of circulating lymphoma cells at diagnosis by flow cytometry was associated with a worse outcome in patients with aggressive T cell lymphomas undergoing ASCT as a consolidation in first remission. Larger cohorts will be needed to validate these findings, but these results suggest peripheral blood involvement by sensitive flow cytometry may identify patients with worse outcomes who might benefit from a more aggressive strategy such as allogeneic stem cell transplantation or alternative consolidation strategies. Disclosures Huntington: Bayer: Consultancy, Honoraria; Pharmacyclics: Honoraria; Celgene: Consultancy, Research Funding; DTRM Biopharm: Research Funding; Genentech: Consultancy; AbbVie: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Foss:Seattle Genetics: Consultancy, Other: fees for non-CME/CE services ; Mallinckrodt: Consultancy; miRagen: Consultancy; Spectrum: Other: fees for non-CME/CE services ; Eisai: Consultancy; Acrotech: Consultancy.

Enteropathy-associated T-cell lymphoma (EATL) is a complication of celiac disease (CD). This tumor derives from the neoplastic transformation of aberrant intraepithelial T lymphocytes emerging in celiac patients unresponsive to a gluten-free diet. Poor adherence to a gluten-free diet, HLA-DQ2 homozygosity, and late diagnosis of CD are recognized as risk factors for malignant evolution of CD. Recurrence of diarrhea, unexplained weight loss, abdominal pain, fever, and night sweating should alert physicians to this complication. The suspicion of EATL should lead to an extensive diagnostic workup in which magnetic resonance enteroclysis, positron emission tomography scan, and histologic identification of lesions represent the best options. Treatment includes high-dose chemotherapy preceded by surgical resection and followed by autologous stem cell transplantation, although biologic therapies seem to be promising. Strict adherence to a gluten-free diet remains the only way to prevent EATL.

Introduction: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 WHO classifications of the lymphoid neoplasms, as it was found that features of MEITL differed from those of enteropathy-associated T-cell lymphoma. It is now considered that MEITL is more prevalent in Asia, and almost all cases of intestinal T-cell lymphoma in Asians might be MEITL. To further elucidate the clinicopathologic features of this new disease entity, we carried out a multicenter, retrospective analysis from 9 tertiary institutes in Korea. Patients and methods: A total of 38 patients who were diagnosed with MEITL between 2002 and 2017 from 9 institutes were included in the analysis. Medical records including age, sex, stage, presenting symptoms, laboratory findings, primary sites, and treatment outcomes were collected. The histopathologic diagnoses were centrally-reviewed by experienced lymphoma histopathologists. The primary end-point of the analysis was overall survival (OS). Results: The median age of the patients was 59 (range, 20 - 84) and 27 patients (71.1%) were male. None of the patients had prior history of Celiac disease. Thirty one patients (81.5%) were stage I-II by the Ann-Arbor classifications, and 28 patients (73.7%) were stage I-II1&2 by the Lugano classifications. The most frequent site of involvement was jejunum (N = 20) followed by ileum (N = 17), and 11 patients had multiple site involvement. In line with the previous reports, most cases expressed CD8 (77.1%) and CD56 (92.1%), and did not expressed CD30 (5.3%), and EBER (6.9%). T-cell intracellular antigen was positive in 14 out of 17 cases (82.4%). The median progression-free survival was 6.9 months (95% CI 4.2 - 9.6), and the median OS was 14.8 months (3.0 - 26.6). Thirty one patients (81.6%) received surgery, and 34 patients (89.5%) received chemotherapy. CHOP (N = 28) was the most frequently used regimen followed by CHOEP (N = 3), and ICE, IMVP-16, and EPOCH (N = 1 each). Complete response (CR) rate was 47.1%, and 14 patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 22 cases, and the most frequent site was the primary site (N = 20). Of note, relapse at central nervous system was found in 4 cases. Older age (≥ 55 years), advanced Lugano stage (IIE~IV), not achieving CR, and not receiving ASCT were associated with adverse OS. Conclusion: Although most patients had limited stage, the clinical outcomes of MEITL patients were dismal. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem to be essential. In addition, considering the frequent local failure, as well as the CNS relapse, novel therapeutic approaches are required to improve survival. Figure. Figure. Disclosures Kim: Mundipharma: Research Funding; Merck: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Roche: Honoraria, Research Funding; Kyowa-Kirin: Research Funding; Eisai: Honoraria, Research Funding; J&J: Research Funding; Celltrion: Honoraria, Research Funding; Novartis: Research Funding.

Introduction: Red blood cell distribution width (RDW) has emerged as a potential prognostic factor in solid tumors and lymphomas. Previous studies have shown an association between increased levels of RDW and inflammatory diseases, being a surrogate marker of inflammation and a predictor of poor outcome. Data on the impact of RDW in outcomes of patients with aggressive peripheral T-cell lymphoma (PTCL) are scarce. Methods: We performed a retrospective study on consecutive patients with a de novo diagnosis of aggressive PTCL diagnosed and treated at our institution between 2010 to 2016. All patients included were treated with chemotherapy with a curative intent. The RDW was collected from the hemogram of PTCL patients at diagnosis. RDW-CV >14% and RDW-SD >49 fL were our cut-offs for the categorical analysis. We fitted univariate and multivariate Cox proportional hazard regression models for overall survival (OS). P Results: A total of 101 patients with de novo aggressive PTCL were included. This study included 53 patients (52%) with PTCL, not otherwise specified, 16 patients (16%) with extranodal natural killer/T-cell lymphoma,15 (15%) with adult T-cell lymphoma/leukemia,14 patients (14%) with anaplastic large cell lymphoma, 2 patients (2%) with angioimmunoblastic T-cell lymphoma, and 1 patient (1%) with enteropathy-associated T-cell lymphoma. Median age was 57 with a male predominance (69%). Clinically, 45 patients (45%) were 60 years or older, 41 patients (34%) had ECOG ≥2, 63 patients (65%) had increased LDH levels, 68 patients (67%) had > 1 extranodal site, 65 patients (64%) had stage III/IV disease, and 55 patients (54%) had B symptoms. RDW-CV was >14% in 64 patients (64%). RDW-SD was >49 fL in 35 patients (35%). 38% of patients received CHOEP, 29% received CHOP, and 33% received other regimens. The overall response rate was 68%; 50% had a complete response and 18% had a partial response. At 5 years, median overall survival (OS) was 46%. In the univariate Cox regression analysis, ECOG ≥2 (p14% (p49 fL (p=0.007) and high neutrophil-lymphocyte ratio (NLR >4) (p=0.002) were associated with a worse survival. In the multivariate Cox regression analyses, ECOG ≥2 (HR 3.1 CI 1.6-6.0; p=0.001) and high RDW-CV >14% (HR 2.7, 95% CI 1.2-6.0; p=0.01) were independent predictors of poor survival. RDW-CV was an independent factor of survival when was compared with IPI and NCCN-IPI score. Conclusions: RDW is an independent marker for adverse prognosis in aggressive patients with aggressive PTCL treated with curative intent. Figure. Figure. Disclosures Castillo: Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Millennium: Research Funding.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a type of rare aggressive lymphoma accounting for 5.4% of primary intestinal peripheral T-cell lymphoma and 10-25% of all primary intestinal lymphoma. MEITL also has an extremely poor prognosis with the median overall survival of only seven months. No effective treatment or targeted therapies are currently available to manage this disease. Therefore, there is an urgent need to devise and establish an appropriate preclinical model for a better understanding of this disease and for new therapeutic strategies to be developed on it. Here, we present the first MEITL patient derived xenograft (PDX) as both orthotropic intestinal and as a subcutaneous model. The histological analysis demonstrated high similarity in the overall immunomorphologic features between the primary tumour and PDX tumours. Importantly, all the PDX tumors carried the distinctive MEITL immunophenotype; CD3+CD4-CD8+CD56+ and extensive nuclear expression of MATK. We also had Sanger sequenced 83 somatic mutations in the original tumour and rediscovered them in the 6th passage of our xenografts, which suggest that the generated MEITL PDX tumours were genetically stable. Moreover, whole exome sequencing results showed that the clonal architecture in the primary tumour was well preserved in the PDX tumours. The clonal architecture was further analysed with single cell whole genome amplification following by Sanger sequencing. We found that the most of heterozygous mutations in the primary tumour were a mixture of wild type alleles and heterozygous/homozygous mutations from separated clones, including DUPS14 heterozygous mutation (p.R300W) which was known to activate MEK pathway, and SETD2 mutations, (g.chr3:47061285_ 47061286insA and g.chr3:47127805C>A) which were the synthetic lethal partner of Wee1. Interestingly, we found that the two SETD2 mutations alone were able to differentiate three subclones. This result indicates that the tumour was highly subclonal, which could have a strong impact on the selection of drug resistant clones in the drug treatment. In order to verify this hypothesis, we proceeded to test the efficacy of MEK inhibitor, Trametinib and Wee1 inhibitor, AZD1775 both separately and combined treatment, in our PDX subcutaneous model. The results showed that both 1mg/kg/day of Trametinib and 60mg/kg/day of AZD1775 treatments significantly delayed 60-70% of tumour growth as compared with the vehicle group. The tumour growth was completely arrested in the combined treatment group. In addition, 20% and 40% of the mice exhibited Trametinib and AZD1775 resistance, respectively. From our genomic analysis, all DUPS14 and SETD2 mutations from the pretreated tumours were preserved in the treatment-resistant tumours but absent in the sensitive post-treated residual tumours. The clonality analysis from the sequencing data of the pretreated tumour supports and suggests that single-agent regimes will often not be able to induce a complete response in MEITL patients. Altogether, the current results demonstrated that our MEITL PDX model preserved the principal histological and genetic characteristics of its original tumour and is genomic stable across passages. The model also showed that MEITL could be highly subclonal and combined targeted therapy might achieve a higher efficacy for MEITL treatment. Disclosures No relevant conflicts of interest to declare.

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

Background: Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a disease involving the intestine and is often diagnosed in surgically resected specimens. The disease prognosis of MEITL is fatal because of rapid recurrence and leakage after excision. Recently, in microscopic finding of MEITL, intraepithelial lymphocytosis in mucosa that were grossly intact has been reported. In this study, we evaluated the intraepithelial lymphocytosis of the resection margin to determine the reason for the early recurrence or leakage in MEITL. Materials and Methods: We reviewed the medical records of all patients who were diagnosed with small intestine lymphoma from January 1995 to June 2018 at our medical center. We analyzed a tissue array from 8 patients diagnosed with MEITL. The expression of CD3, CD5, and CD8 were analyzed by immunohistochemistry. Results: A total of 8 cases of small intestine lymphoma were collected in this period. There were three men (37.5%) and five women (mean age 55 years). Two patients died without initiation of chemotherapy. Six patients received chemotherapy after resection of MEITL (4 patients received CHOP regimens, 2 patients received ProMACE-CyBOM regimens), but five patients died within 6 months (mean survival time 4.1 months, range 0.3-12.1 months). Only one patient survived for 5 years. On gross examination, the distance to the resection margin was 7.58 cm (3.8-14.0 cm) on average. Microscopic examination revealed intraepithelial lymphocytosis at least of one of the resected margins in all case. Immunohistochemical staining for CD3, CD5, and CD8 was performed on the resection margins. As a result, severe intraepithelial lymphocytosis accompanied by aberrant loss of CD5 was observed in 6 cases (75%). Conclusion: In the MEITL, an intraepithelial lymphocytosis accompanied by aberrant CD5 loss is frequently observed in the resection margin, even if the resection margin is grossly intact, and there is no clear microscopic involvement of the lymphoma especially on low power. This fact is thought to be related to the early recurrence or leakage of MEITL at the surgical site. Disclosures No relevant conflicts of interest to declare.

Introduction The CD30 antigen is expressed by a small number of cells in classical Hodgkin lymphoma (HL), by malignant cells in anaplastic large cell lymphoma (ALCL), and in several non-Hodgkin lymphomas (NHL). Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody (Ab) conjugated to chemotherapy, showed its efficacy in HL and ALCL. However, a correlation between response to BV and CD30 expression in NHL is difficult to establish by immunohistochemistry (IHC) since the count of dimly positive cells is difficult to standardize. Flow cytometry (FCM) is a standardizable tool which allows the multiparametric characterization of malignant NHL cells and the quantification of proteins at the cell surface. The objective of this multicentric study is to standardize CD30 expression in NHL by quantitative FCM. Materiel and methods The nine centers used one or two cytometers: BD Biosciences (BD) n=7, Beckman Coulter (BC) n=4. The standardization was conducted using the Euroflow strategy, the same operating procedure and the same reagents. Abs recognizing different CD30 epitopes were: BerH83 (BD), HRS4 (BC) and a specific AC10 (Ancell) similar to BV. If tissue was available, pathologists locally used BerH2 (Dako) for IHC. The CD30 expression was normalized using Mean Fluorescence Intensity (MFI) to MFI CD4 expression and expressed as a percentage (nMFI30). Three cell lines (SUDHL4, K562 and L82) with differential expression of CD30 were shipped to the different laboratories in order to validate the centers using a robust statistical method. Then, NHL cases including anaplastic lymphomas, T lymphomas, and large B cell lymphomas were collected using a website www.mfi30.fr. All FCM Abs were used on available cells when nMFI30 >1% using Ancell Ab. Results On cell lines, all centers obtained similar results: z-scores between -2 to +2. Mean of nMFI30 were SUDHL4 0.1% (SD=0.1), K562 69.8% (SD=16.9), L82 292.9% (SD= 45.7) with BD Abs and 0.6% (SD=0.1), 229.9% (SD= 47.9) and 2053.8 (SD= 282) with BC Abs , respectively, demonstrating that BD and BC Abs are not equivalent. Samples from 82 adult patients were included in the study: peripheral blood (n=39), lymph node suspensions (n=21), bone marrow (n=5) or different tissues (n=17, cerebrospinal, seroma, pleural and ascite fluid, spleen). The diagnoses included diffuse large B-cell lymphoma (DLCBL, n=33 with 4 DLBCL of central nervous system (CNS)), Sezary syndrome (SS, n=14), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS, n=11), T-cell prolymphocytic leukaemia (T-PLL, n=8), enteropathy-associated T-cell lymphoma (EATL-1, n=2), angio-immunoblastic lymphoma (AITL, n=5), primary effusion lymphoma (PEL, n=1), plasmablastic lymphoma (PBL, n=1), B-lymphoblastic lymphoma (B-LBL, n=1), breast implant associated anaplastic large cell lymphoma (BIA-ALCL, n=1), anaplastic large cell lymphoma (ALCL, n=1), mantle cell lymphoma (n=1), T-cell large granular lymphocyte leukemia (T-LGLL, n=2) and chronic lymphoproliferative disorders of NK cells (CLPD-NK, n=1). Four groups are defined: (1) a negative group (n=60) presents nMFI30 10% with the 3 FCM Abs and positive in IHC (2 ALCL, 1 DLBCL, 1 EATL). This group shows a more intense nMFI30 with BC Ab; (3) a dim positive group (n=8) presents nMFI30 between 1-10% with the 3 FCM Abs. In this group, IHC is negative in 2 out of the 3 tested cases; (4) a discordant group (n=10) presents nMFI30 >1% with at least 1 Ab and discordant with another one. In this group, 8 IHC were tested: 2 IHC positive 1% with Ancell Ab and 1 case shows a high discrepancy between 2 FCM Abs. Regarding lymphoma entities, T-PLL, DLBCL-CNS, and T-LGLL are always negative and the ALCL are positive. Seven out of the 33 DLBCL are in the positive or discordant groups (21%). Conclusion As previously reported in literature using IHC, CD30 is positive in all ALCL, in some DLCBL (20%) and only rarely in other NHL using FCM. Therefore these first results emphasize the feasibility of FCM in CD30 determination and quantification in NHL subtypes and mainly its multicentric standardization. The inclusion of FCM with relevant Abs in clinical trials using BV should be now validated in larger series to better understand clinical results. Figure. Figure. Disclosures Pruvot Debliquis: Alexion: Consultancy, Honoraria; Takeda Oncology: Honoraria. Baseggio:Takeda Oncology: Honoraria. Jacob:Takeda Oncology: Honoraria. Drenou:Takeda Oncology: Honoraria, Research Funding; Alexion: Consultancy, Honoraria.

Background: Positron emission tomography combined with computed tomography (PET-CT) has been widely used for initial staging and monitoring of treatment response in patients with malignant lymphomas. The predictive value of interim PET-CT (iPET) and end-of-treatment PET-CT (ePET) is well-established for patients with Hodgkin lymphoma, diffuse large B-cell lymphoma, and follicular lymphoma. However, there are limited data on their prognostic values in patients with mature T-cell and NK-cell lymphomas. In this study, we aimed to assess the value of iPET and ePET in the prediction of progression-free survival (PFS) and overall survival (OS) in patients with mature T-cell and NK-cell lymphomas. Methods: Data of 99 patients with mature T/NK-cell lymphomas who underwent iPET (after 2-4 cycles of chemotherapy; performed just before the next cycle) or ePET at the Kameda Medical Center were retrospectively analyzed. PET-CT scans were scored as positive or negative based on the Deauville score using a 5-point scale. While a Deauville score of 1-3 was considered to indicate complete metabolic response (CMR) (negative), a score of 4-5 was considered as persistent or progressive disease (positive). Standardized uptake value (SUV) was normalized relative to the injected dose and lean body mass and was measured for all lesions. The highest SUV for each scan was recorded as maximum SUV (SUVmax). To quantitatively interpret iPET scans, we determined the rate of reduction in SUVmax between baseline and iPET (ΔSUVmax). Survival was calculated using the Kaplan-Meier method and compared using the log-rank test. Results: In total, 99 patients, including patients with peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (n = 36), angioimmunoblastic T-cell lymphoma (AITL) (n = 28), anaplastic large cell lymphoma (ALCL) (n = 6), adult T-cell leukemia/lymphoma (ATLL) (n = 14), enteropathy-associated T-cell lymphoma (EATL) (n = 2), cutaneous T-cell lymphoma (CTCL) (n = 3), and NK/T-cell lymphoma (NKTCL) (n = 10), participated in this study. Of all patients, 55 (56%) were men, and the median age was 48 (range: 22-78) years. The majority of patients, except those with ATLL and NKTCL, were treated with CHOP or CHOP-like chemotherapy. After a median follow-up of 26 months, the 5-year PFS and OS rates for all patients were 24% and 41%, respectively. While 98 patients (99%) underwent iPET, 60 of them (61%) underwent ePET. Baseline PET-CT scan was positive in all cases, and the median SUVmax was 12.8 (range: 2.6-37.4). Using the ROC curve, ΔSUVmax values between baseline and iPET of >79% and >73% were predictive of better PFS and OS, respectively (PFS: sensitivity 77%, specificity 69%, area under the curve [AUC] 0.82, 95% confidence interval [CI] = 0.68-0.88 and OS: sensitivity 78%, specificity 63%, AUC 0.78, 95% CI = 0.62-0.83). While iPET results were negative in 49 of 98 (50%) cases, ePET results were negative in 35 of 60 (59%) cases. The proportion of patients with PTCL-NOS, AITL, ALCL, ATLL, EATL, CTCL, and NKTCL who achieved CMR with iPET or ePET were 53% (19/36), 82% (23/28), 67% (4/6), 36% (5/14), 50% (1/2), 67% (2/3), and 80% (8/10), respectively. The 5-year PFS and OS were significantly longer in patients with negative results on both iPET (PFS: 41% vs. 7%, p < 0.0001; OS: 67% vs. 15%, p < 0.0001) and ePET (PFS: 39% vs. 0%, p < 0.0001; OS: 72% vs. 11%, p < 0.0001). Conclusion: These results indicate that iPET and ePET are good predictors of PFS and OS in patients with mature T-cell and NK-cell lymphomas. Furthermore, our findings highlight the significance of iPET findings in the early identification of potential candidates for an intensive therapeutic strategy, with the aim of improving clinical outcomes. Risk-adapted treatment strategies based on iPET and ePET findings should be investigated in larger and prospective clinical trials. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Enteropathy associated T-cell lymphoma (EATL) is a rare type of peripheral T-cell lymphoma. At present, there are no standardized diagnostic or treatment protocols for EATL. We describe EATL in a population-based setting and evaluate a new treatment with aggressive chemotherapy and autologous stem cell transplantation (ASCT). From 1979 onward the Scotland and Newcastle Lymphoma Group prospectively collected data on all patients newly diagnosed with lymphoma in the Northern Region of England and Scotland. Between 1994 and 1998, records of all patients diagnosed with EATL were reviewed, and 54 patients had features of EATL. Overall incidence was 0.14/100 000 per year. Treatment was systemic chemotherapy (mostly anthracycline-based chemotherapy) with or without surgery in 35 patients and surgery alone in 19 patients. Median progression-free survival (PFS) was 3.4 months and overall survival (OS) was 7.1 months. The novel regimen IVE/MTX (ifosfamide, vincristine, etoposide/methotrexate)–ASCT was piloted from 1998 for patients eligible for intensive treatment, and 26 patients were included. Five-years PFS and OS were 52% and 60%, respectively, and were significantly improved compared with the historical group treated with anthracycline-based chemotherapy (P = .01 and P = .003, respectively). EATL is a rare lymphoma with an unfavorable prognosis when treated with conventional therapies. The IVE/MTX-ASCT regimen is feasible with acceptable toxicity and significantly improved outcome.

Introduction: Peripheral T-cell lymphoma (PTCL) encompasses a group of rare and aggressive lymphomas. PTCL, unspecified (PTCLU) is the most common subtype of PTCL, and carries a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCLU (PIT) scoring systems are powerful risk-stratification tools in patients with PTCL. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with advanced stage PTCLU (Beltran Leuk Lymphoma 2016). The aim of this study was to evaluate whether the NLR is a prognostic factor in patients with early stage PTCLU. Methods: We included patients with a pathological diagnosis of PTCLU who were diagnosed and treated at our institution between 2001-2016. We excluded cases with stage 3 or 4 disease. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review, and are presented using descriptive statistics. The NLR was calculated by dividing the neutrophil by the lymphocyte count, and dichotomized in NLR>=4 and NLR Results: 48 patients with a diagnosis of early stage PTCL were included in this analysis. Histologically, 40 patients (83%) were PTCL, unspecified, 7 (15%) were anaplastic large cell lymphoma, and 1 (2%) was enteropathy-associated T-cell lymphoma. The median age at diagnosis was 60 years (range 18-83 years) with a slight male predominance (82%). Clinically, 49% of patients were 60 or older, 34% presented with ECOG>1, 36% with elevated LDH, and 65% with extranodal disease; 44% had stage II and 56% had stage I disease. No patient had bone marrow involvement. 30% of patients presented with high/high-intermediate IPI score and 34% with high/high-intermediate PIT score. 27% of patients had a NLR >=4. There were no differences in age, LDH levels, extranodal involvement and stage between NLR>=4 and NLR=4 patients (p=0.06). The 3- and 5-year OS rates were 67% (95% CI 50-80%) and 52% (95% CI 29-71%), respectively. High/high-intermediate IPI score was associated with a worse outcome (HR 4.9, 95% CI 1.7-14.2; p=0.004), as well as high-high-intermediate PIT score (HR 3.9, 95% CI 1.2-12.7; p=0.03). According to NLR, NLR>=4 patients had a higher risk of death (HR 9.9, 95% CO 3.2-30.1; p=4 was the only independent factor associated with a worse survival (HR 6.2, 95% CI 1.9-20.9; p=0.003). Conclusion: The NLR appears as a novel and easy to use prognostic factor for OS in previously untreated patients with early-stage PTCL. Our findings support the need for validation of the NLR in larger retrospective or prospective studies in patients with PTCL. Disclosures Castillo: Otsuka: Consultancy; Pharmacyclics: Honoraria; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Honoraria; Biogen: Consultancy.

Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs) that accounts for approximately 10% of all aggressive NHLs in Western countries. The optimal management remains unclear, however, given the poor outcome, allogeneic transplant (allo-SCT) has been integrated into the front-line treatment for some rare extranodal subtypes as well in relapsed/refractory setting. We report our provincial experience of the outcome of patients with PTCL who have undergone allo-SCT at the British Columbia Cancer Agency (BCCA). Methods: The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with PTCL who have undergone allo-SCT between November 1990 and January 2016. Overall survival and relapse free survival were estimated using the Kaplan-Meier method. Results: We identified 36 cases of PTCL patients who have undergone allogeneic transplant from a median time of 11 months from primary diagnosis (range 4-64) with the following clinical features: median age at transplant was 45 years (range 16-58 years); 24 (67%) were male; 32 (89%) patients had advanced stage disease; 22 (61%) had B-symptoms at diagnosis. Bone marrow involvement detected in 13/34 (38%) patients. Histological diagnosis based on the WHO 2008 classification were: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) n=15 (42%); anaplastic large cell lymphoma (ALCL) n=7 (19%) out of which three were ALK positive, angioimmunoblastic T-cell lymphoma (AITL) n=6 (17%), hepatosplenic T-cell lymphoma n=5 (14%), enteropathy associated T-cell lymphoma type I n=1, advanced primary cutaneous gamma-delta T-cell lymphoma n=1 and Sezary syndrome n=1. Ten patients (28%) underwent allo-SCT as part of planned primary therapy after achieving their first remission [6 were in complete remission 1 (CR1) and 4 were in partial remission 1 (PR1)], whereas 26 patients (72%) underwent allo-SCT for relapsed/refractory disease. CHOP was administered in 19 patients (53%) as the primary therapy. 17 (47%) patients received alternative chemotherapy regimen due to patient and/or physician preference. The clinical status at the time of transplantation was CR in 12 patients (33%), relapsed sensitive disease n=10 (28%), relapsed untreated n=5 (14%), partial remission (PR) in 5 (14%), primary progressive disease n=3 (8%) and relapsed resistant disease n=1 (3%). Thirty two patients (89%) underwent myeloablative conditioning, 4 (11%) underwent reduced intensity conditioning (RIC). The conditioning regimens included: cyclophosphamide/TBI n=24 (67%), busulfan/cyclophosphamide n=5 (14%), fludarabine containing reduced intensity n=4 (11%), and other regimens n= 3 (8%). With a median follow-up of alive patients from the time of allo-SCT of 69 months (range 1-186 months). At last follow-up, 17 (47%) patients have died, 6 from disease relapse, 5 from graft vs host disease (GVHD), 2 from regimen related toxicity and 4 from other causes. Nineteen patients (53%) still alive at last follow up post-transplant of which 14 (39%) still in remission. The 5-year event free survival (EFS) and overall survival (OS) from the time of allo-SCT of all patients were 43% and 63%, respectively. For PTCL-NOS the 5-year EFS and OS were 52% and 69%, respectively. Table 1 summarizes the patients' characteristics. Figures 1 and 2 shows the Kaplan-Meier curves for OS and EFS respectively. Conclusion: Allo-SCT can be effective strategy in select patients with relapsed/refractory PTCL and those with high risk histologies in the upfront setting PTCL with an acceptable toxicity. Disclosures Toze: Roche Canada: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Connors:NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Millennium Takeda: Research Funding. Song:Janssen: Honoraria; Otsuka: Honoraria; Celgene: Honoraria, Research Funding.

Background Peripheral T-cell lymphomas (PTCLs) encompass ~10-15% of aggressive non-Hodgkin lymphomas. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or variations thereof, are the most commonly used treatment regimens with complete remission (CR) rates ranging from 39-55% (Reimer 2009, d'Amore 2012). With the exception of low international prognostic index (IPI)-anaplastic lymphoma kinase (ALK)-positive ALCL, with 4-year progression-free survival (PFS) and overall survival (OS) ranging from 25-35% and 30-40%, respectively (Ellin 2014). We previously reported the results of this phase 1 trial that evaluated brentuximab vedotin (BV) administered in sequence with CHOP, or in combination with CHP (CHOP without vincristine) in treatment-naive patients (pts) with CD30-expressing PTCL (NCT01309789). The combination therapy (BV+CHP) showed safety and activity at standard doses, with an objective response rate (ORR) of 100% and complete response (CR) rate of 88% (Fanale 2014). The most common adverse events (AEs) experienced by pts were nausea and peripheral sensory neuropathy (69% each). Four-year durability data and updated results on peripheral neuropathy (PN) resolution from the BV+CHP combination treatment arm are presented herein. Methods Adults with CD30-expressing PTCL, including systemic ALCL (anaplastic large cell lymphoma, ALK-negative, or ALK-positive with IPI score ≥2) were eligible for this study. CD30 expression for non-ALCL pts was defined as ≥1% CD30 expression in malignant cells. Pts on the combination treatment arm received 1.8 mg/kg BV and standard-dose CHP q3wk for up to 6 cycles. Pts who achieved at least a partial response (PR) following treatment could receive continued BV 1.8 mg/kg q3wk as single-agent for up to 10 additional cycles. Antitumor response was assessed by the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Twenty-six previously untreated pts received BV+CHP. Disease diagnoses included systemic ALCL (n=19; including ALK-negative, n=16 and ALK-positive, n=3), PTCL-NOS (n=2), angioimmunoblastic T-cell lymphoma (AITL, n=2), adult T-cell leukemia/lymphoma (ATLL, n=2), and enteropathy-associated T-cell lymphoma (EATL, n=1). Twenty-one of the 26 pts who achieved remission with combination treatment continued on to receive single-agent BV. Overall, the 26 pts received a median of 13 cycles (range, 3 to 16) of BV. After a median observation period of 52 months (range 4.6 to 58.3) from first dose, 18 pts remain on study. The estimated 4-year PFS and OS rates are 52% (95% CI: 31, 69) and 80% (95% CI: 59, 91), respectively. The median PFS has not been reached (95% CI: 12.3, -). To date, 15 of 19 ALCL (3/3 ALK-positive, 12/16 ALK-negative), and 6 of 7 non-ALCL pts were alive at last follow-up. Five pts (19%) received subsequent treatment with single-agent BV in long-term follow-up and 3 pts received stem cell transplants (1 autologous, 2 allogeneic) for relapsed disease. There were no pts who underwent a consolidative stem cell transplant. Of the 26 pts treated with combination therapy, 19 (73%) experienced PN. Of these pts, 95% (18 of 19) experienced complete resolution (8 pts), or some resolution or improvement (defined as a decrease by at least 1 grade from worst grade, 10 pts). Of the pts who experienced improvement, 1 pt each improved from Grade 3 to a lowest Grade 2 and from Grade 3 to a lowest Grade 1, and 5 pts improved from Grade 2 to a lowest Grade 1. The median time to resolution of PN symptoms was 5.7 months. Eleven pts had ongoing neuropathy at last follow-up, of which, 9 pts had Grade 1 severity and 2 pts had Grade 2. Conclusions These 4-year durability results demonstrate that among pts with PTCL, initial therapy with BV in combination with CHP can induce long-term remissions with a tolerable safety profile. A phase 3 randomized trial comparing BV+CHP with CHOP for the frontline treatment of CD30-expressing PTCL is ongoing (NCT01777152). Progression-free Survival Figure Figure. Disclosures Horwitz: Celgene: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Research Funding; Infinity: Research Funding; Huya: Consultancy; FortySeven: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Spectrum: Consultancy, Research Funding. Forero-Torres:Seattle Genetics: Research Funding; Genentech/Roche: Research Funding; Juno: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Bartlett:Gilead: Consultancy. Pro:Takeda: Honoraria; Seattle Genetics: Honoraria; Celegene: Honoraria. Chen:Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Merck: Consultancy, Research Funding. Davies:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodation, expenses, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel to scientific conferences, Research Funding; GSK: Research Funding; Mundipharma: Honoraria; Janssen: Honoraria; Bayer: Research Funding; Karyopharma: Honoraria, Research Funding; Pfizer: Research Funding. Illidge:Seattle Genetics: Consultancy, Research Funding; Takeda Pharmaceuticals International Co.: Consultancy, Honoraria. Uttarwar:Seattle Genetics: Employment, Equity Ownership. Huebner:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Ren:Seattle Genetics: Employment, Equity Ownership.

Loss of response to a gluten-free diet (refractory sprue) and ulcerative jejunitis are complications of celiac disease that may progress to enteropathy-associated T-cell lymphoma (EATL). Both conditions are characterized by the presence of a nonlymphomatous monoclonal T-cell population in the enteropathic mucosa. In EATL, a similar monoclonal population that shows clonal identity with the lymphoma itself is also present in the enteropathic mucosa. In this study we show that in all three circumstances the monoclonal T-cell population is constituted by cytologically normal, noninvasive intraepithelial T lymphocytes that share an identical aberrant immunophenotype with EATL. Patients with refractory sprue and/or ulcerative jejunitis are, therefore, suffering from a neoplastic T-cell disorder for which hematological treatment strategies need to be devised.

Introduction: Enteropathy-associated T-cell Lymphoma (EATL) is a rare lymphoma of the GI tract accounting for less than 1% of all non-Hodgkin's lymphomas (NHL). EATL type I is seen predominately in patients (pts) from parts of Europe associated with a high incidence of celiac disease; type II is less frequently associated with celiac disease and thus a more worldwide distribution. EATL is difficult to treat with very poor prognosis. The purpose of this study is to understand the epidemiology and outcomes of this rare lymphoma in a North American multicultural setting at a tertiary cancer care centre. Methods: All pts with EATL who were assessed and treated at Princess Margaret Cancer Centre in Toronto, Canada, between January 1, 1996 and January 30, 2015 were retrospectively reviewed with case ascertainmentfrom a pathology database as well as a prospectively populatedlymphoma database. Pathological diagnoses were made according to the WHO classification and central pathology review was undertaken when available. Staging procedures included CT scans and bone marrow biopsy. Simple descriptive statistics were calculated as well as progression-free survival (PFS) and overall survival (OS). Results: 4852 new NHLs were seen for primary treatment at our centre during this time period, of which 287 were T cell lymphomas; 11 had EATL (0.23% of all NHL cases and 3.8% of all T-cell lymphomas). Median age at presentation was 61 years (range 51-85) with the majority being male (64%) (Table 1). All 11 pts presented with abdominal pain from small bowel perforation or obstruction. The most common site of EATL was jejunum (55%). Four pts (36%) had EATL type 1 and three had positive celiac serology. None had a history of celiac disease prior to diagnosis. 46% and 36% of pts presented with a high Ann Arbour stage (stage III or IV) and high Lugano stage (stage III or IV) respectively. No pt had a high ECOG score at presentation. Central pathology review was available for 8 patients (table 1). Interestingly, only 36% of cases had an intermediate-high risk International Prognostic Index (IPI) score of 3 and no pts had a high risk score of 4 or 5. Only one pt had an elevated LDH. All type 1 pts were CD56-, while type 2 pts were all CD8+ and most (86%) were CD56+. Ten pts (91%) received CHOP chemotherapy (one with the addition of etoposide and one of an IL2 receptor antibody) and one pt received palliative therapy. Only 5 of 11 responded to therapy (45%), with 2 patients achieving complete remission. All patients have progressed through treatment or relapsed (6 pts primary refractory and 5 responders), with one late relapse 14 years post response. At relapse, patients often presented with another bowel perforation. Upon relapse, four (36%) pts received salvage chemotherapy and 1 patient received an autologous stem cell transplant but progressed 16 months later and died from his disease. Ten patients (91%) have died, all from lymphoma; one patient (the late relapser) is presently undergoing salvage chemotherapy. Both median PFS and OS for all pts were 7 months. Two year OS and PFS were 18% and 9% respectively. Table 1 provides PFS and OS for EATL type separately. Conclusions: EATL is an aggressive form of lymphoma with unique presentation and very poor prognosis despite frequently presenting with limited disease and low IPI score. In our centre, type II EATL was more common, potentially underlying the multicultural composition of our city. CHOP with or without etoposide remains inadequate therapy for this aggressive lymphoma, and alternative induction regimens are needed. Few patients are stem cell transplant candidates at relapse due to age and poor performance status. Table 1. Patient characteristics Feature EATL1 (N=4) EATL 2 (N=7) Age (yrs) median (range) 65 (55-71) 61 (51-85) Gender (%) male 1 (25) 6 (86) Celiac status (%) positive 3(75) 0 Pathology CD3+ 4(100) 7(100) CD7+ 3(75) 5(71) CD4+/CD8- 1(25) 0 CD4-/CD8+ 2(50) 7(100) CD4-/CD8- 1(25) 0 CD56+ 0 6(86) T-cell receptor clonal gene rearrangement 1/2(50) 4/4(100) Symptoms (%) abdominal pain 4(100) 7(100) constitutional symptoms 3(75) 1(17) lymphadenopathy 2(50) 1(14) bone marrow 1 (25) 0 Primary Location (%) duodenum 2 (50) 3 (43) jejunum 1 (25) 5 (71) ileum 3 (75) 0 Monofocal (%) yes 3 (75) 3 (43) Anne Arbor Staging (%) III or IV 2 (50) 3 (43) Lugano Staging (%) III or IV 2 (50) 2 (29) IPI (%) score 3-5 1(25) 3 (43) Response to tx CR/CRu/PR 1(25) 4 (57) PFS median (mo) 6 7 2 year PFS 25% 0% OS median (mo) 7 8 2 year OS 25% 14% Disclosures Prica: Janssen: Honoraria; Celgene: Honoraria. Crump:Celgene: Consultancy; Seattle Genetics: Consultancy; Roche Canada: Consultancy. Kukreti:Celgene: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen Ortho: Honoraria. Kuruvilla:Lundbeck: Honoraria; Karyopharm: Honoraria; Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy; Seattle Genetics: Consultancy, Honoraria; Hoffmann LaRoche: Consultancy, Honoraria, Research Funding.

Introduction Enteropathy-associated T cell lymphoma (EATL) is an intestinal tumor of the intraepithelial T lymphocytes, with a median survival time of less than 1 year. It is a rare disease in general and has two main subtypes described. Type 1 EATL is a complication in patients with celiac disease, a chronic gluten-sensitive enteropathy. Type 2 EATL, characterized by smaller monomorphic lymphocytes, typically occurs sporadically in patients without celiac disease. Very little is known about the genetic mutations and gene expression signatures that define this disease, or the extent to which the two types of EATL are genetically distinct. It has been suggested that the two types of EATLs should be reclassified as separate diseases in future WHO categories. Methods In this study, we performed whole exome sequencing to 100-fold depth of 41 EATL tumors including 23 type 1 cases and 18 type 2 cases. Both alpha-beta (65%) and gamma-delta (35%) T cell receptor rearrangements were seen among these cases. Paired normal DNA was sequenced in most (N=30) cases. We defined somatic mutations, copy number alterations, and HLA genotypes in these cases from sequencing data. Additionally, we generated RNA sequencing data on the same EATL tumors. Corresponding clinical and outcome data was collected on the same cohort. Results We found that both type 1 and type 2 EATLs had overlapping patterns of mutations and similar overall survival. The most commonly mutated genes were chromatin modifier genes (34%) including ATRX and ARID1B. We also identified recurrent somatic mutations in signal transduction genes, including JAK1 and BCL9L. TP53 mutations were also recurrent (12%). Copy number amplifications in 9q, 1q, and 8q occurred most frequently and were present in both subtypes. We further compared the mutational profiles to peripheral T cell lymphoma, angioimmunoblastic T cell lymphoma, cutaneous T cell lymphoma, natural killer/T cell lymphoma, diffuse large B cell lymphoma, and Burkitt lymphoma. These comparisons identify EATL as a genetically distinct disease with a very different pattern of mutations. RNAseq identified the gene expression patterns that are unique to EATL and also identified gene expression signatures that distinguish the two types of EATL. The DQ2 or DQ8 HLA genotype is present in the majority of type 1 cases (73%) while occurring infrequently in type 2 cases (27%). Conclusions Our study defines the genetic landscape of enteropathy associated T cell lymphoma and highlights the genetic and clinical overlap between the two types. While the two types have differences in mutations and gene expression patterns, they have more in common with each other compared to other lymphoma types. Our data may inform future decisions regarding the potential separation of the two EATL types as distinct entities. Disclosures No relevant conflicts of interest to declare.

Background: Peripheral T-Cell lymphomas (PTCLs) constitute approximately 10% of lymphoid malignancies and consist of several distinct entities based on pathologic and clinical characteristics. With the exception of a few subtypes (e.g., ALK-positive anaplastic large cell lymphoma (ALCL) and some primary cutaneous or leukemic forms of PTCL), a majority of PTCLs are aggressive as characterized by poor treatment response, rapid disease progression and poor overall survival. We have shown that landmark timepoints of event-free survival after diagnosis can stratify subsequent overall survival (OS) in diffuse large B-cell and follicular lymphoma. Here we evaluate this approach in newly diagnosed aggressive PTCLs treated with anthracyline-based or related chemotherapy. Methods. Newly diagnosed PTCL patients were prospectively enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE Molecular Epidemiology Resource (MER) from 2002-2012. Clinical data were abstracted from medical records using a standard protocol. For this analysis, we included patients receiving anthracycline-based or other multiagent chemotherapy for the following PTCL subtypes: ALK-negative ALCL (N=24); angioimmunoblastic T-cell lymphoma (AITL, N=34); PTCL, not otherwise specified (NOS; N=60); enteropathy-associated T-cell lymphoma (EATL, N=8); extranodal NK/T-cell lymphoma, nasal type (ENKTL, N=11); and hepatosplenic T-cell lymphoma (HSTCL, N=1). Patients were prospectively followed, and event-free survival (EFS) was defined as time from diagnosis to progression, re-treatment, or death due to any cause. Landmark EFS timepoints were assessed at 12 (EFS12) and 24 (EFS24) months after the date of diagnosis. Subsequent OS was defined as time from a specific endpoint (diagnosis, event or EFS landmark). Replication was performed in a population-based cohort of T-cell lymphomas diagnosed from 2000-2009 from the Swedish Lymphoma Registry. Results. 138 eligible patients were enrolled in the MER from 2002-2012, the median age at diagnosis was 58 years (range, 19-88), 66% were male, 73% had Stage III-IV disease, and 33% had IPI 0-1. At a median follow-up of 47 months (range 11-120), 87 patients (63%) had an event and 70 patients (51%) had died. From diagnosis, only 60 patients were event-free at 12 months (EFS12 45%). Patients who failed to achieve EFS12 had a poor subsequent OS from event (median OS = 6.8 months, 95% CI: 5.3-14.0, figure 1). In contrast, patients who achieved EFS12 had a favorable subsequent OS (median unreached, figure 2). Of the 427 eligible patients in the Swedish registry, the median age at diagnosis was 66 years (range, 18-88), 63% were male, 68% had Stage III-IV disease, and 25% had IPI 0-1. PTCL subtypes were: ALK-negative ALCL (N=89); AITL (N=80); PTCL, NOS (N=183); EATL (N=44); ENKTL (N=24); and HSTCL (N=7). At a median follow-up of 86 months (range 40-158), 333 patients (79%) had an event and 316 patients (74%) had died. From diagnosis, 183 patients were event-free at 12 months (EFS12 44%). Similar to the MER cohort, Swedish patients failing EFS12 had poor subsequent survival (median OS = 3.7 months, 95% CI: 2.9-5.3, figure 1). Swedish patients achieving EFS12 had a favorable subsequent OS (median OS = 89 months, figure 2). Similar results were obtained when conducting landmark analysis at 24 months after diagnosis (EFS24). Conclusion. Relapse and re-treatment events within the first 12 months of diagnosis are associated with very poor OS in PTCL treated with anthracyclines or related chemotherapy, while patients achieving EFS12 have encouraging subsequent OS. Stratifying patients into prognostically distinct subsets using EFS12 may help focus biologic and biomarker studies. EFS12 has potential as an early endpoint for studies of newly diagnosed PTCL. Further investigation of determinants related to post-EFS12 survival is needed. Disclosures Maurer: Kite Pharma: Research Funding. Cerhan:Kite Pharma: Research Funding. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Link:Genentech: Consultancy, Research Funding; Kite Pharma: Research Funding. Thompson:Kite Pharma: Research Funding. Relander:Respiratorius: Patents & Royalties: valproate for DLBCL.

[Figure][1] A 70-year-old Hispanic woman with history of coronary arterial disease presented with dull abdominal pain and weight loss for ∼2 weeks. A computed tomography scan of the abdomen revealed a large mass occupying the proximal jejunum. The patient had no history of celiac disease

Introduction Enteropathy-associated T-cell lymphoma (EATL) is an intestinal tumor of intraepithelial T lymphocytes. The 2008 WHO classification distinguishes two types of EATL: the first type of EATL (type I), the most frequent (80-90%) is strongly associated with celiac disease (CD) and the HLA-DQ2/DQ8 haplotypes. The tumor cells are CD3+CD8-/+CD4-CD56- and contain cytotoxic granules. In almost all cases, a varying proportion of the tumor cells express CD30. The second type of EATL (type II), the monomorphic form, has a distinct immunophenotype (CD3+CD4-CD8+CD56+). In two types, TCRgamma genes are often clonally rearranged. EATL may be preceded by refractory celiac disease (RCD), corresponding to CD refractory to gluten free diet (GFD). RCD is divided in two types based on the absence (type I) or presence (type II) of abnormal intraepithelial lymphocytes (IEL) showing down-regulation of CD8 and often TCRgamma genes rearrangement. RCD II is now considered as a small cell intraepithelial T-cell lymphoma that could be an intermediate stage between CD and EATL. The aim of the present study was to establish the pattern of CD30 expression in EATL. This could have therapeutic implications with the use of anti-CD30 monoclonal antibody like brentuximab vedotin (BV). Methods Consecutive adult patients (pts) diagnosed with EATL between 2007 and 2013 in two university hospitals in Paris (Necker University Hospital and Georges Pompidou European Hospital) were eligible for this study. Diagnosis was confirmed after histopathologic and immunohistochemical review. For the purpose of the present study, two expert hematopathologists (V.V. and N.B.) reviewed all EATL and extended the phenotypic analysis to reclassify them according to the 2008 WHO classification. A panel of antibodies directed against CD20, CD3, CD4, CD5, CD8, CD56, granzyme B and ALK1 was used. CD30 staining was performed with Monoclonal Mouse Anti-Human CD30, Clone Ber-H2 (Dako). Consecutive RCDI and RCDII cases with complete phenotype and clonality analyses diagnosed in the same period were used as control. Diagnosis of CD was based on HLA-DQ2/8 typing, detection of celiac specific antibodies and of villous atrophy with increased counts of IEL on normal diet. Pts were further classified in RCDI or II depending on their clinical and histological response to a GFD and the presence of abnormal IEL. Results Twenty five adults were diagnosed with EATL on consensus review (median age 53 years [range 34-76], M/F ratio 12/13). Twenty five RCDI pts (median age 51 years [range 16-75], M/F ratio 6/19) and 20 RCDII pts (median age 62 years [range 29-81], M/F ratio 7/13) were used as control. A clinical history of CD was found in 17/20 (85%) evaluable EATL pts. Histological features of CD/RCD were seen in all cases (20/20) of EATL in which the mucosa adjacent to the tumor could be investigated (half of these were RCDII). Primary sites of EATL were small intestine (20/25), mesenteric lymph nodes (3/25), peritoneal nodules (1/25) and spleen (1/25). Phenotypic analysis showed that EATL cases were all WHO type I (25/25). ALK1 was constantly negative. IEL were CD3+ in all 70 cases. CD8 was normally expressed in all RCDI IEL and downregulated in all RCDII IEL and 35% of EATL. In all cases of EATL (25/25), CD30 was strongly expressed by all large tumor cells. In RCDI and II, CD30 was negative in most cases (∼90%), and was rarely expressed by dispersed atypical lymphocytes (IEL or in lamina propria) in some cases. TCRgamma genes were clonally rearranged in 11/14 (79%) EATL, 3/25 (12%) RCDI and 18/20 (90%) RCDII. Based on these results, we initiated in 2012 a pilot study combining BV with chemotherapy followed by autologous stem-cell transplantation (ASCT) as frontline treatment of EATL. Five pts have currently been treated. The associated chemotherapy regimen was IVE/MTX (Sieniawski M, Blood 2010) for the first two pts. After presentation at ASH 2012 Annual Meeting of preliminary results of a phase 1 study combining BV with CHP regimen as frontline treatment of systemic ALCL and other CD30-positive mature T–cell and NK–cell lymphomas (Fanale MA, Abstract #60), we replaced IVE/MTX by CHP regimen, and treated 3 other pts. The treatment was well tolerated, and the 5 pts reached CR and underwent ASCT. Conclusion CD30 is strongly expressed in EATL type I. Promising results of the combination of BV with CHP led us to plan a phase 2 study of BV and CHP followed by ASCT as frontline treatment of EATL. Disclosures: Off Label Use: Brentuximab vedotin was used in enteropathy-associated T-cell lymphoma (EATL).

Abstract 1607 Background: Lymphoid malignancies derived from T and NK cells (PTCLs) constitute a heterogeneous group of uncommon disease entities, with marked geographic variation in their distribution. The most recent data from the International T-cell Lymphoma Project based on a retrospective analysis of PTCLs diagnosed between 1990 and 2002 (Blood. 2011;117(25): 6756–67) indicate that PTCL, not otherwise specified (PTCL,NOS) represents the most common PTCL worldwide (25,9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (18,5%). Over the last few years, a better characterization of the cellular origin and pathophysiology of PTCLs has led to the development of new diagnostic markers. Aim of the study: To characterize the epidemiology of mature T/NK-cell malignancies in Western Europe (France and bordering countries) and to examine whether the availability of new tools/antibodies and changing concepts over the past years might have translated into an apparent change in the relative distribution of PTCL entities. Materials and methods: The histopathological diagnosis of PTCL entities according to the 2008 WHO classification were collected through two independent sets of PTCLs in France and bordering countries. Results: Over the past two years (2010–2011), 933 newly diagnosed non-cutaneous PTCLs were reviewed in reference centers through the prospective network “Lymphopath” aiming to review any newly diagnosed lymphoma in France. According to the 2008 WHO classification, the 933 PTCLs comprised: 314 AITL (33,6%), 239 PTCL,NOS (25,6%), 78 ALK-positive anaplastic large cell lymphoma (ALCL) (8,3%), 72 ALK-negative ALCL (7,7%), 59 extranodal NK/T-cell lymphomas (ENKTL 6%), 33 enteropathy-associated T-cell lymphoma (4%), 32 HTLV1+ adult T leukemia/lymphoma (3%), 7 hepatosplenic T-cell lymphoma (1%) and 99 cases of other entities or unclassifiable (11%). A high prevalence of AITL was also found in an independent set of PTCLs retrospectively collected in the framework of a multicentric T-cell lymphoma research consortium “Tenomic” where non-cutaneous PTCL with frozen material available (n=623) from 1999 to 2009 in France and Belgium were retrieved and collegially reviewed for consensus diagnosis. In this collection, AITL (n=288, 46%) also outnumbered PTCL, NOS (n=215, 35%). Of the 196 AITL cases extensively investigated for CD10, TFH markers (PD1, CXCL13), CD21/CD23 follicular dendritic cells (FDC) and EBV, the initial diagnosis was recorded in 178 cases as: AITL in 155 cases (87%), PTCL, NOS in 21 cases (12%), and intermediate between PTCL,NOS and AITL (PTCL,NOS/AITL) in 2 cases, indicating the impact of additional stainings for the diagnosis of AITL. The 107 PTCL,NOS cases also extensively immunostained included 9 follicular variant of PTCL,NOS, 8 PTCL,NOS/AITL cases, 5 cases intermediate between PTCL,NOS and ALK-negative ALCL (of which 2 had been diagnosed as such and two as PTCL,NOS), and 85 remaining cases truly unspecified. Of these, 60 had been initially diagnosed as PTCL,NOS; 2 as PTCL,NOS/AITL; 4 as ALK-negative ALCLs and 1 as ENKTL. Conclusion: This study based on two independent large cohorts of non-cutaneous PTCLs highlights AITL as the most prevalent entity in Western Europe. It shows that extensive studies including investigation for CD10, TFH markers, FDC and EBV can at least partly contribute to the reclassification of some PTCL, NOS into the AITL spectrum category. Disclosures: No relevant conflicts of interest to declare.

Abstract 5101 Introduction: Enteropathy associated T-cell Lymphoma(EATL) is a distinctive clinicopathological entity but knowledge about potential prognostic factors in this disease is very limited. Aim: Clinicopathological and immunohistochemical analysis of single center EATL cohort focusing especially on stromal components, activation molecules and potential loss of TCR receptors. Methods: Detailed clinical analysis of a cohort of 21 patients from the southern-west Germany was performed. Additionally broad panel of immunohistochemical staining including MUM1IRF4, Blimp-1, FoxP3, TCR γ, TCRβ, CD11c was done. Univariate statistical analysis of survival was performed. Results: The study group comprised of 12 males and 9 females, aged 37–86, with the median survival time of 5 months after the initial diagnosis. Following clinical factors turned out to be connected with longer overall survival (OS): age ≤ 60years (p=0, 007), Ann Arbor Stadium I+II (p =0, 048), good general condition (p = 0, 0068), IPI 1–3 (p=0, 004), usage of anthracycline in the chemotherapy regimen (p=0, 0504). Longer event free survival(EFS) was connected with good general condition (p=0, 023) usage of anthracycline (p=0, 047). There was 17 Type I cases (81%) and 4 Type II (19%). EATL type, histological variants of neoplastic cells, perivascular and angiocentric growth pattern as well as tissue eosinophilia did not influence survival. There was a strikingly strong infiltration of the neoplastic infiltrate by CD11c+ dendritic cells in 9/21 cases, but it was prognostically irrelevant. MUM1/IRF4 expression was observed in 8/19(42, 1%), Blimp-1 in 5/14 (35, 7%) and FoxP3 in 7/20 (35%), but only FoxP3 positivity was connected with longer EFS. There was a trend toward worse OS (p=0, 18) and EFS (p=0, 12) in Blimp-1 positive cases. Expression of TCRβ was observed in 4/21(19%), of TCRγ in 3/21(14, 3%) while the majority of cases (14/21), showed loss of expression of both proteins. There was a trend toward longer OS (p=0, 19) and EFS (p=0, 16) in TCR β+ than in TCRγ+ and TCR γ-β- cases. TCRβ expression was statistically significant more frequent in patients that achieved complete remission (3/7) than in group that did not achieve CR (1/14, p=0, 049). Conclusions: In EATL several clinical factors can provide relevant prognostic information. Immunohistochemical expression of FoxP3, Blimp-1 and TCRβ seems also to be prognostically usefull. TCRβ is the only marker that can predict response to the chemotherapy in this very aggressive neoplasm. Disclosures: Finke: Fresenius Biotech GmbH: Honoraria, Research Funding.

Abstract 3105 Background: EATL is a rare subtype of peripheral T-cell lymphomas characterized by primarily intestinal localization and a frequent association with celiac disease. The prognosis is considered to be poor with conventional chemotherapy. Limited data is available on the efficacy of ASCT in this lymphoma subtype. Primary objective was to study the outcome of ASCT as a consolidation or salvage strategy for EATL. The primary endpoint was overall survival (OS) and progression-free survival (PFS). Eligible patients were > 18 years who had received ASCT between 2000–2010 for EATL that was confirmed by review of written histopathology reports, and had sufficient information on disease history and follow-up available. The search strategy used the EBMT database to identify patients potentially fulfilling the eligibility criteria. An additional questionnaire was sent to individual transplant centres to confirm histological diagnosis (histopathology report or pathology review) as well as updated follow-up data. Patients and transplant characteristics were compared between groups using X2 test or Fisher's exact test for categorical variables and t-test or Mann-Whiney U-test for continuous variables. OS and PFS were estimated using the Kaplan-Meier product-limit estimate and compared by the log-rank test. Estimates for non-relapse mortality (NRM) and relapse or progression were calculated using cumulative incidence rates to accommodate competing risk and compared to Gray's test. Results: Altogether 138 patients were identified. Updated follow-up data was received from 74 patients (54 %) and histology report from 54 patients (39 %). In ten patients the diagnosis of EATL could not be adequately verified. Thus the final analysis included 44. There were 24 males and 20 females with a median age of 56 (35–72) years at the time of transplant. Twenty-five patients (57 %) had a history of celiac disease. Disease stage was I in nine patients (21 %), II in 14 patients (33 %) and IV in 19 patients (45 %). Twenty-four patients (55 %) were in the first CR or PR at the time of transplant. BEAM was used as a high-dose regimen in 36 patients (82 %) and all patients received peripheral blood grafts. The median follow-up for survivors was 46 (2–108) months from ASCT. Three patients died early from transplant-related reasons translating into a 2-year non-relapse mortality of 7 %. Relapse incidence at 4 years after ASCT was 39 %, with no events occurring beyond 2.5 years after ASCT. PFS and OS were 54 % and 59 % at four years, respectively. There was a trend for better OS in patients transplanted in the first CR or PR compared to more advanced disease status (70 % vs. 43 %, p=0.053). Of note, patients with a history of celiac disease had superior PFS (70 % vs. 35 %, p=0.02) and OS (70 % vs. 45 %, p=0.052) whilst age, gender, disease stage, B-symptoms at diagnosis or high-dose regimen were not associated with OS or PFS. Conclusions: This study shows for the first time in a larger patient sample that ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. Patients transplanted in first CR or PR appear to do better than those transplanted later. ASCT should be considered in EATL patients responding to initial therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 331 Background and aims: Systemic peripheral T-cell lymphomas (PTCL) are malignancies responding poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by upfront high-dose chemotherapy supported by autologous stem-cell transplantation (HDT/ASCT) in PTCL, the Nordic Lymphoma Group conducted the, so far, largest PTCL-restricted prospective phase II study in previously untreated systemic PTCL. This is the final report of the NLG-T-01 study with a 5-years median follow up. Methods: Patients with previously untreated systemic PTCL aged 18–67 years were included. ALK-positive anaplastic large cell lymphoma (ALCL) cases were excluded. An induction regimen of six cycles of bi-weekly cyclophosphamide, doxorubicin, etoposide, vincristin and prednisone (CHOEP) was given. Age-based (>60 yrs) omission of etoposide was recommended. If in complete or partial remission, patients received high-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan/cyclophosphamide (BEAM/BEAC) followed by HDT/ASCT. Results: A total of 166 patients with previously untreated PTCL were enrolled. Of these, 160 were histopathologically confirmed and included the following subtypes: PTCL-not otherwise specified (PTCL-NOS) (n=62; 39%), ALK-negative ALCL (n=31; 19%), angioimmunoblastic lymphoma (AIL) (n=30; 19%), enteropathy-associated T-cell lymphoma (n=21; 13%), panniculitis-like (n=6; 4%), T/NK nasal-type (n=5; 3%), and hepatosplenic (n=5; 3%). The M/F ratio was 2.0 and the median age 57 yrs (range 22–67 yrs). The majority of the cases presented with advanced-stage disease (81%), B-symptoms (59%) and elevated s-LDH (62%). Nevertheless, 71% of all patients had a good performance score (PS) (WHO 0–1) at inclusion. With regard to the International Prognostic Index (IPI), risk factor distribution was as follows: 1 factor n=45 (28%), 2 factors n=52 (32%), 3 factors n=30 (19%), 4–5 factors n=33 (21%). Of the 160 patients, a total of 114 (71%) underwent HDT/ASCT with 90 in complete remission at 3 months post-transplant. Early failures occurred in 26% of the patients. The treatment related mortality was low (4%). At a median follow-up of 60 months, 83 patients were alive. The median follow-up for deceased patients (N=77) was 9 months. The consolidated 5-yr overall (OS) and progression-free survival (PFS) values for the entire cohort were 51% and 44%, respectively. Best results were obtained in ALK-negative ALCL with 5-yr OS and PFS of 70% and 61%, respectively. IPI was a useful overall prognostic discriminator for the low/low-intermediate vs. intermediate-high/high groups with regard to 5-yr OS (p=0,047) and 5-yr PFS (p=0,029). If applied separately to each of the four major subtypes, IPI had a predictive value for OS in AIL (p=0,02) and for PFS in both AIL (p=0,02) and PTCL-NOS (p=0,03). The clinicopathological parameters that showed a significant impact on OS and PFS were: female gender (correlated with a better outcome), age (analyzed as continuous variable), PS≥2 (correlated with adverse outcome), and cytotoxic phenotype (correlated with adverse outcome in AIL). All these parameters retained their prognostic value at multivariate level, except for cytotoxic phenotype, where multivariate analysis could not be performed because of too small numbers. Conclusions: Dose-dense induction followed by HDT/ASCT is well tolerated and leads to long-term PFS in 44% of patients with systemic PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the present study population. Therefore, based on these results, dose-dense induction and HDT/ASCT should be considered in transplant-eligible PTCL patients. Disclosures: Jantunen: Genzyme: Honoraria.

Abstract 2722 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. Clinical outcome of patients with EATL is very poor, due to chemotherapy-resistance and high relapse rates. Therefore, new therapeutic options for EATL are urgently needed. Studies in other types of lymphoma have shown that inhibition of apoptosis may cause chemotherapy-resistance and that restoration of defective apoptosis can induce cell death in these lymphomas. Preliminary data in EATL samples have demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in EATL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In the present study, we evaluated if apoptosis is inhibited in EATL cells and if Bortezomib can restore apoptosis in EATL cells. Laser-capture microdissection was applied to 16 fresh frozen EATL samples to obtain purified tumor cells for RNA isolation. Intraepithelial lymphocytes (IEL) of healthy controls were obtained from fresh duodenal biopsies and isolated by cell sorting. RT-MLPA analysis revealed that the pro-apoptotic BH3-only gene Noxa was significantly downregulated in most EATL samples compared to healthy donor IEL. Induction with etoposide resulted in caspase-9 mediated apoptosis in EATL cells with relatively high Noxa expression, whereas in EATL cells with low Noxa expression no apoptosis was induced, suggesting an inhibition in the intrinsic apoptosis pathway. Treatment with Bortezomib resulted in induction of apoptosis in EATL cells. The lethal dose (LD50) varied between 7.5 nM and 15 nM. Bortezomib induced cell death in EATL cells was caspase-9 mediated. mRNA and protein expression analysis showed upregulation of Noxa after incubation with bortezomib. In conclusion, our study showed that bortezomib induces apoptosis by upregulation of Noxa in EATL cells. Bortezomib therefore may be a potential drug in the treatment of patients with EATL. Disclosures: No relevant conflicts of interest to declare.

Abstract 3115 Background: EATCL is a rare subtype of peripheral T-cell lymphoma frequently observed in patients with a history of celiac disease. EATCL is characterized by poor prognosis when treated with conventional chemotherapy with only 10–20 % of long-term survivors. Limited data are available on feasibility and efficacy of stem cell transplantation in this lymphoma entity. Patients and methods: The database of the EBMT was used to identify patients with EATCL who had received autologous and/or allogeneic stem cell transplantation in 2000–2007. All centres reporting these patients were contacted to receive confirmation to histopathology report/pathology review and to obtain information in regard to treatment prior to stem cell transplantation and more recent follow-up data. Results: Altogether 85 patients with EATCL were identified. Seventy-three patients had received ASCT and 12 patients allogeneic SCT. Histological report/review with additional follow-up data was available from 22 ASCT treated patients which are reported here. There were 14 females (64 %) and eight males with a median age of 55 years at the time of transplant. Half of the patients had a history of coeliac disease. The median number of treatment lines before ASCT was 1 and 50 % of the patients were in the first remission at the time of ASCT. BEAM was the most commonly used high-dose regimen (17 pts, 77 %) and all patents received blood stem cell grafts. The median time from the diagnosis to ASCT was 6 months. The median follow-up time for living patients was 45 months from ASCT. During the follow-up relapse has been observed in 13 patients (59 %), the median time was only four months from ASCT. The median disease-free survival and overall survival were nine months and 15 months, respectively. Two-year overall survival, disease-free survival, cumulative incidence of relapse and non-relase mortality (NRM) was 45%, 40%, 55% and 4%, respectively. Conclusions: ASCT is feasible in selected patients with EATCL with a low NRM. Of transplanted patients 40 % remained disease-free beyond 2 years. This seems to be superior when compared to historical experiences although selection factors should be taken into account. ASCT is a treatment option in transplant eligible EATCL patients who respond to initial therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 1665 EATL is an intestinal tumor of aberrant intraepithelial T-lymphocytes (IELs) and may be preceded by refractory celiac disease type II (RCD II). Current therapies include surgery, chemotherapy and autologous and/or allogeneic stem cell transplantation. Despite these therapies, the overall outcome of EATL is very poor with 1- and 5-year survival rates in the range of 31–39% and 8–20%, respectively. Therefore, new therapeutic options are needed. Human soluble tumor necrosis factor-related apoptosis-inducing ligand, hsTRAIL/Apo2L, a member of the TNF family, has proven to selectively kill tumor cells via an alternative, death-receptor mediated apoptosis pathway. In this present study we evaluated if hsTRAIL/Apo2L induces apoptosis in both isolated lymphoma cells of EATL biopsies and isolated cells of RCD II biopsies. hsTRAIL/Apo2L induced apoptosis in isolated EATL lymphoma cells. RCD II cells were less sensitive to hsTRAIL/Apo2L compared to EATL cells. hsTRAIL/Apo2L induced apoptosis in EATL cells was caspase-9 dependent, but unexpectedly active caspase-8 involvement could not be detected. RT-MLPA analysis on EATL samples confirmed this observation by showing increased levels of c-Flip in EATL cells, which suggests a blockage in the extrinsic apoptosis pathway. Both EATL and RCDII cells showed expression of TRAIL receptors R1 and R2 and almost no expression of R3 and R4. In conclusion, our study showed that hsTRAIL/Apo2L induces apoptosis in EATL cells through the intrinsic apoptosis pathway. Moreover, we showed that TRAIL receptor R1 and R2 are expressed in EATL cells. Based on these results, hsTRAIL/Apo2L may be a new therapeutic option for EATL patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 3092 Enteropathy-associated T-cell lymphoma (EATL) is a rare intestinal lymphoma that arises from intraepithelial lymphocytes. In Western countries EATL accounts for 5% of all gastrointestinal lymphomas and in 80–90% of all cases this lymphoma is associated with celiac disease (CD). Based on clinical presentation, EATL can be divided into two subtypes: primary and secondary EATL. Primary EATL develops without a preceding history of CD. The first presentation is often perforation or obstruction, which leads to diagnosis of both EATL and CD. Secondary EATL is diagnosed in patients with well-established CD or refractory CD. These patients deteriorate and eventually develop EATL. The current standard treatment for both types of EATL consists of surgery and chemotherapy, but overall survival (OS) is poor and new therapeutic strategies are urgently needed. For risk-based selection of patients for new therapies and clinical trials, prognostic models as the International Prognostic Index (IPI) are generally used. Since IPI is not predictive for EATL, we determined a prognostic model specifically for EATL, which can identify high-risk patients who need more aggressive therapy. Forty-one patients were diagnosed with EATL and retrospectively analyzed. Two- and 5-years OS were 18% and 10% respectively (range: 0 – 97 months). In multivariate analysis, 3 risk factors were predictive for survival: serum LDH > normal (P < 0.001; RR 6.65; 95% CI 1.96 to 9.89), presence of B-symptoms (P < 0.001; RR 4.41; 95% CI 2.73 to 16.18) and subtype secondary EATL (P = 0.036; RR 2.33; 95% CI 1.06 to 5.13). A weighted point score was assigned to each of these 3 factors and a prognostic model was constructed. Four risk groups were identified (P < 0.0001). Group I showed most favorable outcome: 2- and 5-years OS were 55% and 30% respectively. Although survival rates in groups II, III and IV were significantly different, in none of these groups 2-years survival was achieved. Therefore, the model was simplified to a low risk and a high risk group (P < 0.0001, Figure 1). The low risk group represented patients with no risk factors, i.e. primary EATL with no B-symptoms and normal LDH. In the high risk group, patients had 1 or more of the risk factors elevated serum LDH, B-symptoms or subtype secondary EATL. The new prognostic model showed superior predictive capacity as compared to IPI. In conclusion, our new prognostic model clearly identifies a high and a low risk group. Patients with one or more of the risk factors serum LDH > normal, B-symptoms or subtype secondary EATL are at high risk, and therefore new therapies for this group are urgently needed. Figure 1: Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH > normal, B-symptoms or subtype secondary EATL. Figure 1:. Survival in EATL. Low risk group = no risk factors. High risk group = presence of 1 or more of the following risk factors: serum LDH > normal, B-symptoms or subtype secondary EATL. Disclosures: No relevant conflicts of interest to declare.

Abstract 1660 Poster Board I-686 Background In the past two decades we have observed improvement in the outcome of patients diagnosed with some subtypes of lymphoma. However, the prognosis of patient with peripheral T-cell lymphoma (PTCL) still remains unsatisfactory. We prospectively evaluated aggressive chemotherapy and autologous stem cell transplantation (ASCT): IVE/MTX-ASCT in patients with de-novo PTCL. Patients and methods: The regimen was piloted from 1997 for new patients eligible for intensive treatment: first for pts with enteropathy associated T-cell lymphoma (EATL) and subsequently for other types of PTCL. This therapy delivers one cycle of CHOP, followed by 3 courses of IVE (ifosfamide, etoposide, epirubicin), alternating with intermediate dose methotrexate (MTX). Stem cells are harvested after IVE and complete remissions (CR) were consolidated with myeloablative ASCT. The patients were evaluated with an intent to treat analysis for feasibility, response, progression free survival (PFS) and overall survival (OS). Results 57 patients were treated with the aggessive regimen, 26 pts had EATL and 31 other types of PTCL: 17 peripheral T-cell lymphoma NOS, 6 anaplastic T-cell lymphoma ALK positive, 4 extranodal NK/T cell lymphoma nasal type, 3 anaplastic T-cell lymphoma ALK negative and 1 hepatosplenic gamma/delta T-cell lymphoma. The median age at diagnosis was 51 years (range 23 – 69), 36/57 (63%) pts were male and 27/55 (49%) presented with ECOG >1. Early stage disease was diagnosed in 22/57 (39%) pts and advanced disease in 35/57 (61%). Bone marrow was involved in 6/53 (11%) pts and LDH was elevated in 23/46 (50%). Among pts with primary nodal disease 14/26 (54%) had at least one extranodal site involved and 6/26 (23%) bulky disease. At present, 55 pts are available for response evaluation. Eight pts discontinued treatment prematurely; 4 due to toxicity (one severe sepsis and death, one severe encephalopathy, one bone marrow failure and one bleeding from the gastrointestinal tract), and four pts due to disease progression. Of the remaining 47 pts 33 went on to receive ASCT. ASCT was omitted due to: refractory disease in 5 pts, poor general condition in 4 pts, insufficient stem cell mobilisation in 4 pts and one pt declined further treatment. The most common severe toxicities were pancytopenia, infection, nausea/vomiting and obstruction/perforation. Complete remission was confirmed in 39/55 (71%) pts, partial remission in 3/55 (5%) pts and 13/55 (24%) pts failed the treatment. The remission rates were: CR-17/26 (65%) pts and PR-1/26 (4%) for EATL and 22/29 (76%) and 2/29 (7%), respectively for other PTCL. During the study time 17/57 (30%) pts died, 15 due to lymphoma. For all pts 3-years PFS was 59% and OS 67%. For pts with EATL the 3-years PFS and OS were 52% and 60% and for other types 65% and 72%, respectively. These results were unchanged after the exclusion of anaplastic T-cell lymphoma ALK positive: (61% and 72%, respectively). Conclusions For patients with PTCL, we propose that intensive chemotherapy and ASCT significantly improves outcome compared to CHOP-like regimens, and has acceptable toxicities. In conclusion, where feasible patients with PTCL should be considered for aggressive treatments, like IVE/MTX – ASCT as primary therapy. Disclosures No relevant conflicts of interest to declare.

Abstract 2937 Poster Board II-913 Enteropathy-associated T-cell Lymphoma (EATL) may complicate celiac disease (CD), refractory celiac disease type I (RCD I) characterized by normal intraepithelial lymphocytes (IEL) or refractory celiac disease type II (RCD II) defined by abnormal IEL (CD3s-,CD3i+ and CD8-) and a clonal rearrangement of the gamma or delta chain of the T cell receptor (TCRγ/δ). It remains unknown whether the type of the associated enteropathy, non clonal (CD or RCD I) or clonal (RCD II), may be a prognostic factor in EATL. We aimed to assess the prognosis of EATL according to the type of the associated enteropathy. Medical files of 29 patients with EATL were retrospectively studied. The type of associated enteropathy was confirmed by immunohistochemistry analysis in all cases and by flow cytometry phenotyping analysis of freshly isolated IEL and search for a TCR γ or δ clonal rearrangement by Multiplex PCR whenever possible. Kaplan-Meier curves and Logrank test were used to compare survival of EATL in the 2 groups of enteropathy (clonal or not). Mean age at EATL (13 women / 16 men) onset was 57 years. The associated enteropathy was CD (n=10) or RCD I (n=2) in 12 patients and RCD II in 17 patients. No statistical difference was found in lymphoma staging with localized (IE and IIE) versus disseminated stages (IV) found in 42% and 58% of patients with CD or RCD I and in 53% and 47% of patients with RCD II, respectively. Diagnostic or therapeutic surgery was practiced in 83% and 47% of patients with CD or RCD I and with RCD II, respectively and chemotherapy in 92% and 82% of the same groups of patients, respectively (n.s). Considering all the EATL, the two-year and five-year survival rates of EATL were 34.1% and 20.2%, respectively. In subgroup analysis, the two-year and five-year survival rates of EATL were 66.7% and 53.3% in case of CD and/or RCD I and 11.8% and 0% in case of RCD II, respectively (p=0.0007). In conclusion, the type of enteropathy significantly impacts the prognosis of EATL with a particular short survival in case of associated RCD II enteropathy. Disclosures: No relevant conflicts of interest to declare.

Enteropathy associated T-cell lymphoma (EATL) is a rare disease with dismal prognosis. At present there are no standardised diagnostic or treatment protocols. The SNLG collected 5yrs of prospective data which uniquely enables us to describe the disease in a population-based setting. Additionally, we introduce results from a novel approach with aggressive chemotherapy (CT) and autologous stem cell transplantation (ASCT). From 1994 – 1998 all pts diagnosed with lymphoma in Scotland and the Northern region of England were prospectively registered. Pts with a diagnosis of EATL were evaluated for clinical features, treatment and outcome. The novel regimen was piloted from 1997 for new pts eligible for intensive treatment. This therapy delivers one cycle of CHOP, followed by 3 courses of IVE (ifosfamide, etoposide, epirubicin), alternating with intermediate dose methotrexate (MTX). Stem cells are harvested after IVE and complete remissions (CR) are consolidated with myeloablative ASCT. During the study period, 4542 pts were diagnosed with non-Hodgkin-lymphoma and of these 54 pts (1.2%) had features of EATL. In the population of 7.6 million, this equates to an overall incidence of 0.14/100,000 per yr. The median age at diagnosis was 57 yrs, 61% of pts were male. 40% of pts presented with Lugano clinical stage (CS) IIE (serosal penetration involving adjacent organs and tissues), 17% CS IV (disseminated extranodal involvement or supradiaphragmatic nodal involvement), 15% CS I (confined to GI-tract), 15% CS II1 (local abdominal involvement) and 12% CS II2 (distant abdominal involvement). Two pts had bone marrow involvement. Diagnosis of EATL was made at laparotomy in 91% of pts. Tumour was arising from the small bowel in 96% of pts; in one case involved the duodenum and in another the iliocaecal region. Pain was the most common presenting symptom (81%), followed by weight loss, visceral perforation, nausea/vomiting, bowel upset and subacute obstruction. Symptoms were present less than a month before diagnosis in 33% of pts and between 1–6 months in 55%. 92% of pts had co-existing coeliac disease (diagnosed prior to diagnosis of EATL in 35% of pts and co-incidently in 58%). 30 pts (56%) were treated with surgery and CT, 19 pts (35%) with surgery alone and 5 pts (9%) with CT alone. Of those pts treated with CT the majority (31/35) received CHOP-like regimens. There were no statistically significant differences between treatment groups with the exception of higher number of elderly pts treated with surgery alone. 44 pts died, mostly due to lymphoma or complications. For all pts, median progression free survival (PFS) was 3.4 months and overall survival (OS) 7 months. 5yr PFS and OS for pts treated with CHOP-like CT was 20% and 22%, respectively and no pts treated with surgery alone survived. 18 pts were subsequently treated with the new regimen. The median age was 52.5 yrs, 67% of pts were male, 39% presented with Lugano CS II1, 22% CS I, 22% CS IV, 11% CS IIE, 6% CS II2+E. The bone marrow was involved in one pt. Site of disease was small bowel in 83% of pts and two patients had involvement of stomach and duodenum and one of small bowel and colon. In all except one pt the diagnosis was made at laparotomy. 12 pts (67%) completed all planned treatment, 3 pts had progressing disease during treatment, two other did not received ASCT due to poor general condition and one pt declined further treatment. Most common severe toxicities were pancytopenia, infection, nausea/vomiting and obstruction/perforation. Treatment results were compared with historical control group treated with CHOP-like CT. There was no difference between the groups according to age, sex and features at presentation. Compared to pts treated with CHOP-like CT, those in the IVE/MTX group had improved CR at final evaluation (42% vs 72%), 5yr PFS (20% vs 56%; p=0.008) and 5yr OS (22% vs 67%; p=0.001). Additionally, in the IVE/MTX group fewer patients died than in the CHOP-like CT group (33% vs 81%; p=0.002). There were no treatment related deaths. In a population-based study of EATL we describe the natural history of the disease in the context of current treatments. We propose a new protocol with significantly improved outcome and acceptable toxicities. In conclusion, pts with EATL should be treated with systemic CT and where feasible an aggressive treatment like IVE/MTX – ASCT. We recommend patients should be entered into national studies such as (NCRI 1418) to evaluate this approach further.

Combination chemotherapy has been the basis of treatment for peripheral T-cell lymphoma (PTCL) for many years, but relapses are frequent, often rapid and usually associated with a poor outcome. New treatment strategies are therefore required. Zanolimumab is a fully human monoclonal cytotoxic IgG1κ antibody, targeting the CD4 molecule on T-cells. The present open-labeled exploratory clinical trial investigated the efficacy and safety of Zanolimumab in 21 patients with biopsy-proven, treatment-refractory or relapsed CD4+ PTCL of non-cutaneous type. Zanolimumab was administered by i.v. infusion at a dose of 980 mg once weekly for 12 weeks. Patients (11 male, 10 female, median age 69 years) were enrolled with the following diagnoses: enteropathy-associated T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (ALTL, n=4, 3 ALKneg subtype, 1 unknown), angioimmunoblastic T-cell lymphoma (n=9) and PTCL-unspecified (n=7). Patients had received a median of 1 previous treatment (range, 1–5) and 3 had undergone high dose chemotherapy with autologous stem cell rescue. The primary endpoint was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Objective tumor response was obtained in 5 out of 21 patients (23.8%; 95% CI: [8.2; 47.2]). Three patients (1 Anaplastic Large T-cell lymphoma and 2 angioimmunoblastic T-cell lymphoma) obtained a partial response of 43 and 51 days duration, respectively, one had not relapsed after 182 days, no further data available. Two patients (PTCL-unspecified and angioimmunoblastic T-cell lymphoma) obtained a complete response (unconfirmed) of 46 days duration and in the latter no relapse after 252 days was observed. 27 serious AEs were reported of which 6 were assessed as related to Zanolimumab treatment. Four infusion related AEs, one transient thrombocytopenia, one febrile neutropenia in a patient that was neutropenic at trial entry. All patients with serious AEs had complete recovery. Two non-serious grade 3 infusion related AEs were reported and one joint pain. In conclusion, zanolimumab was found to be active and well tolerated in heavily pretreated patients with aggressive PTCL. Zanolimumab in combination with CHOP is now being investigated in the setting of previously untreated patients with nodal T-cell lymphoma.

Background: Enteropathy associated T cell lymphoma (EATL) accounts for less than 1% of all Non-Hodgkins lymphomas and ~5% of gastro-intestinal lymphomas, and is strongly associated with Coeliac disease. Treatment has traditionally involved Doxorubicin based combination chemotherapy such as CHOP although there is no consensus on guidelines for treatment. Patients are often emaciated due to malabsorbtion at diagnosis and often tolerate treatment poorly with death occurring due to perforation and gastro-intestinal bleeding. There appears to be a high relapse rate in those who complete treatment, and overall survival rates are agreed to be around 20% at 5 years. Methods: Consecutive patients with biopsy proven Enteropathy associated T cell lymphomas were treated in a single institution. All patients were made nil by mouth, and given intra-venous fluids with oral ciprofloxacin and metronidazole as gut prophylaxis 48 hours prior to chemotherapy. When the risk of perforation was considered to be over continuous NJ feeding was instituted with regular dietetic support. 2 cycles of a combination of Ifosphamide, Etoposide and Epirubicin (IVE) were given 4 weeks apart. Patients had peripheral blood stem cells mobilised with G-CSF support following the second cycle. After stem cell harvest 2 cycles of high dose methotrexate (3g/m2) with folinic acid rescue were given. Following this, patients were admitted for consolidation with autologous stem cell transplantation with BEAM conditioning. Results: The median age of the patients was 56 years (40–59). 5 were diagnosed following laporotomy and small bowel resection and one by lymph node biopsy. All but 1 patient had stage 1E disease. 3 were known to have coeliac disease previously while 3 were diagnosed post-operatively. All 6 patients were able to tolerate the planned treatment with no deviation from protocol and there was no transplant related mortality. There were no episodes of perforation or GI bleeding. One patient was unable to be harvested due to sepsis and was mobilised with G-CSF alone prior to methotrexate being given. All patients suffered with severe diarrhoea and weight loss ranging from 5–11 kilograms during their autograft, despite continuous parenteral feeding. Standard CT restaging showed five patients achieved a complete remission (CR) and one other a very good partial response (VGPR). Of the 6 patients, 2 had florid relapse at 0.21 and 1.71 years post PBSCT and subsequently rapidly died due to intestinal perforation. The other 4 remain alive and in CR at 1.83, 3.35, 3.67 and 4.32 years following transplant respectively. Conclusion: EATL is a rare extra-nodal T cell lymphoma with a very poor prognosis with standard treatment, and large case series take many years to build. EATL is also often added to series of other high-grade T cell lymphomas or GI non Hodgkin’s lymphomas, making it difficult to determine optimal management. In our series of patients there were no serious complications following gut sterilisation and induction and consolidation chemotherapy, and despite marked weight loss all were able to tolerate PBSCT. 4 out of 6 patients (66.7%) remain alive and in a sustained CR, while 2 suffered an early relapse and rapidly died. We conclude that this regimen appears to be extremely efficacious in the treatment of EATL.

Zanolimumab (previously referred to as HuMax-CD4) is a fully human monoclonal IgG1k antibody. It is specific for the CD4 antigen expressed on a subset of T cells and has been shown to possess cytotoxic and anti-proliferative effects. We report initial clinical efficacy and safety results following treatment with 980 mg of zanolimumab in 15 patients diagnosed with biopsy-proven, treatment-refractory or relapsed CD4+ systemic PTCL. The following PTCL subtypes were included : enteropathy-type T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (ALCL, n=3, 2 alk-negative, 1 alk-status unknown), angioimmunoblastic T-cell lymphoma (AIL, n=8) and PTCL-unspecified (PTCLu, n=3). The primary endpoint of the study was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Out of 15 patients enrolled, 4 responses have been seen; 2 PR (one patient later achieved a CRu) and 2 CRu verified by CT scan. Further, clinical improvements (marked decrease in the size of peripheral lymph nodes) were recorded in 2 additional patients. So far, a total of 21 SAEs has been reported. Of these, 4 were considered related to the study treatment: febrile neutropenia (n=1), thrombocytopenia (n=1), infusion related reaction (n=1) and hyperthermia (38.8° C) with hypotension (n=1). Eight unrelated deaths have been reported so far, all secondary to disease progression. In conclusion, in this heavily pretreated patient population, zanolimumab demonstrated a good tolerability profile and the present results indicate efficacy in the treatment of CD4-positive PTCL.

FDG-PET is emerging as a standard staging study for diffuse large B-cell lymphoma and Hodgkin’s disease. There is little experience with PET in staging T-cell lymphomas (TCL). TCL often involve extranodal sites not well imaged by standard CT. We hypothesized that PET would add to staging by detecting additional sites of disease. To address this question we reviewed our TCL database to identify patients (pt) who had PET as part of complete staging at initial diagnosis or at relapse. Each pt was included once. Staging included physical exam, CT scan of the chest/abdomen/pelvis alone or as part of a PET/CT combination, and bone marrow (BM) biopsy. Studies such as MRI of the sinus or ultrasound of the testes were done as clinically indicated. We reviewed 107 pt who met the above criteria. Histologies were as follows: peripheral T-cell lymphoma NOS (PTCL), angioimmunoblastic T-cell lymphoma (AILT), anaplastic large cell lymphoma, ALK-1-, (ALCL−), anaplastic large cell lymphoma, ALK-1+, (ALCL+), mycosis fungoides (MF), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), adult T-cell lymphoma (ATL), NK lymphoma nasal type (NK-Nas), lymphoblastic lymphoma (LL), enteropathy associated T-cell lymphoma (EATCL), blastic NK lymphoma (BLNK), primary cutaneous ALCL (ALCL-Cut), and hepatosplenic T-cell lymphoma (HSPTCL). All pt with MF had suspicion of extracutaneous disease. Overall 95/107 (89%) had a PET interpreted as positive by visual review. Standard uptake values (SUV) varied from 1.1–20.5 g/ml. Of the 12 pt with negative PET scans, 7(58%) had no evidence of disease on CT including PTCL (n=3, stage I resected), HSPTCL (n=2, liver, spleen, BM disease only), ALCL-Cut (n=2, skin only). | Histology | N | PET + | % positive | SUV Range (g/ml) | |:--------- | --- | ----- | ---------- | ---------------- | | ALL PT | 107 | 95 | 89% | 1.1–20.5 | | PTCL | 27 | 24 | 88% | 2–20 | | AILT | 19 | 16 | 84% | 2–11.7 | | ALCL− | 12 | 12 | 100% | 3–19.6 | | ALCL+ | 4 4 | 100% | 4–12 | | | MF | 12 | 10 | 83% | 1.8–17.6 | | SPTCL | 8 | 8 | 100% | 1.4–13.1 | | ATL | 5 | 5 | 100% | 2.9–19.7 | | NK-Nas | 5 | 5 | 100% | 3.4–13.1 | | LL | 3 | 3 | 100% | 5.5–20.5 | | EATCL | 3 | 3 | 100% | 3.5–9.9 | | ALCL-Cut | 5 | 3 | 60% | 1.1–1.4 | | BLNK | 2 | 2 | 100% | 1.929.5 | | HSPTCL | 2 | | | N/A | T-cell Lymphoma-PET Results PET detected additional sites of disease in 34/107 (32%). These sites detected by PET were skin/subcut (n=9), bone (n=7), lymph node (n=6), spleen (n=3), nasopharynx/sinus (n=2), liver (n=2), BM (n=1), bowel (n=1), muscle (n=1), kidney (n=1), tonsil (n=1), testes (n=1). Three new malignancies were incidentally detected by PET including lung cancer (n=1), metastatic renal cell to the parotid (n=1), and mantle cell lymphoma (n=1 in a pt with ALCL-cut). Despite these additional sites, stage was changed in only 10/107 (9%). We did not use negative PET to downstage. Sites resulting in higher stage included bone (n=3), lymph node (n=2), subcut/muscle (n=3), testes (n=1), liver (n=1). Skin lesions were noted on physical exam and therefore did not change stage. In conclusion, TCL are almost universally PET positive. PET often adds information by identifying extranodal disease. However, partly due to many pt being stage IV by other modalities, PET resulted in a change of stage in

Histone deacetylase inhibitors induce changes in gene expression that lead to cellular differentiation and reversal of the transformed phenotype. Interest in clinical development of these agents has been spurred by the responses observed in patients with T-cell lymphoma to romidepsin, previously FK228 and depsipeptide. To date, 61 patients with CTCL and 34 with PTCL have been accrued to our ongoing multiinstitutional trial of romidepsin for patients with recurrent or refractory cutaneous or peripheral T-cell lymphoma. Romidepsin is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m2. Complete and partial responses have been observed in patients with CTCL, with a complete response in a patient with Sézary syndrome ongoing for over 45 months and a partial response ongoing for over 60 months. Both complete and partial responses were observed in patients with various subtypes of PTCL, including PTCL, unspecified, ALK-/CD30+ anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma, with a complete response ongoing for over 34 months. Responses will be updated for presentation. Molecular endpoint analysis was performed in normal and malignant circulating peripheral mononuclear cells, PBMCs, and in tumor samples. Immunoblot analysis demonstrated increased histone acetylation in PBMCs of 2-fold or greater from 19 of 33 patients at 4 or 24 hrs. RT-PCR of RNA demonstrated a 2-fold or greater increased expression of MDR-1 in PBMCs from 27 of 45 patients, 11 of which were greater than 4-fold. Microarray performed on CTCL patient samples detected significant changes with treatment. In addition, changes in the 5 gene signature for CTCL previously published (Nebozhyn et al. Blood2006; 107:3189) were also detected when analyzed by QPCR. MDR1 expression was evaluated by RT-PCR in 30 patient’s tumors. MDR1 expression level was not significantly increased at the time of progression, mean 3.2 and 4.9 (s.d. 3.1 and 5.5, respectively) in MDR1 units as defined in Zhan et al. Blood 1997 89:3795. Since differentiating agents have been shown to induce expression of fetal hemoglobin in the laboratory, fetal hemoglobin levels were assayed in patients on this clinical trial. Increased circulating fetal hemoglobin of 2, 5, and 10 fold was observed in 34, 24, and 15 patients, respectively, from 44 patients evaluated. SNP analysis is being performed on the MDR1 gene for comparison with pharmacokinetics and induction of fetal hemoglobin and MDR1 itself. In conclusion, romidepsin has significant single agent activity in patients with CTCL or PTCL. Molecular effects can be assayed in patients treated with romidepsin and related agents. Further clinical development of these agents should include combination trials and the identification of molecular markers of response.

In an international retrospective clinical study of 1159 adult, non-cutaneous mature T-cell lymphomas, verified by an expert pathology panel, 62 cases of enteropathy-type T-cell lymphoma (ETTCL) were identified, representing 5.3%. Patients in this study were diagnosed at one of the participating centers in North America, Europe, and Asia between 1990 and 2002. ETTCL represented the 6th most common T-cell lymphoma, affecting predominantly the small bowel. Of interest, about a third of the cases of ETTCL were obtained from Norway, as the only participating center from Scandinavia. Twenty out of 52 cases (38%) were associated with celiac disease. As expected, abdominal pain was the most frequently recorded symptom, followed by general symptoms such as fatigue, weakness and anorexia. Overall as well as failure-free 5-year survival were poor, 20% and 4%, respectively. Univariate statistical analysis revealed that high T-IPI score (Gallamini, et al: Blood 103: 2474–2479, 2004) but not high IPI score, high CRP and LDH levels, and tumor size >5cm were adverse prognostic factors at p values 5cm were independent prognostic factors. In conclusion, ETTCL is a clinically aggressive and fatal disease for which, currently, no effective treatment exists. T-IPI score, CRP levels and tumor size can be used as prognostic factors.

Introduction: Enteropathy-type T-cell Lymphoma (ETL) is a highly aggressive extranodal T-cell non-Hodgkin’s lymphoma that is often associated with underlying celiac disease. In this study we used whole genome tiling resolution array comparative genomic hybridization (CGH) to delineate genomic changes that may be critical in disease pathogenesis in 30 well-characterized cases of ETL, among them 14 cases of CD56+ monomorphic small to medium-sized ETL, so-called small cell variant (CD56+smETL). Experimental Approach: Whole genome tiling array CGH was used to generate high resolution segmental copy number profiles of 30 ETL specimens, the array platform consisting of 26,819 bacterial artificial chromosome (BAC) derived amplified fragment pools spotted in duplicate. Results: Alignment of these profiles with the human genome map has resulted in the identification of both previously reported and novel regions of recurrent genomic alteration. The most frequently identified recurrent chromosomal gains were 9q34.11-qter (approx. 10.2 Mb; 70%), 9q33.2-q33.2 (6.6 Mb; 67%), 9q31.3-q33.2 (13.8 Mb; 60%), 5q34-q35.2 (6.5 Mb), 7q33-q34 (2.4 Mb, 47% each), 1q25.3-q31.2 (8.4 Mb), 1q32.2-q41 (7.9 Mb), 7q22-q31.1 (5.6Mb), 7q36.1-qter (9.6Mb, 43% each), 8q13.3–8q21.11 (3Mb), and 8q22.1-q24.3 (46.2 Mb, 40% each). Frequent recurrent chromosomal losses were observed on 8p22-p23.2 (15.3Mb, 37%), 10q26.2-q26.3 (5.5Mb, 27%), and 9p21.2-p21.3 (4.9Mb, 23%). Interestingly, the most frequent gains at 9q34.11-qter were inversely correlated with losses at 16q12.1 (2.5Mb, 23%, p=0.0139), suggesting these regions may accomplish similar biological effects. CD56-positive monomorphic small cell ETL were characterized by highly recurrent gains of 8q13.3-q21.11 and 8q22.1-q24.3 (71.4% in CD56+smETL vs 18.8% in non-monomorphic ETL, p=0.0086) and the rare occurrence of gains on 1q25.3-q31.2 and 1q32.2-q41 (21.4% in CD56+smETL vs 62.5% in non-monomorphic ETL, p=0.0329) and 5q34-q35.2 (21.4% in CD56+smETL vs 68.8% in non-monomorphic ETL, p=0.0136) which are common within non-monomorphic ETL. Conclusions: ETL show highly recurrent and characteristic gains and losses of chromosomal material. While gains of chromosome 9q (detected in 70% of ETL) appear to be the hallmark genetic alteration in ETL, ETL, in line with differences in morphology, immunophenotypes and clinical features, seems to be also genetically subdivided into two distinct sub-groups: CD56+monomorphic small to medium sized ETL characterized by gains of 8q and CD56-negative non-monomorphic ETL characterized by gains of 1q and 5q.

HuMax-CD4 (zanolimumab) is a fully human monoclonal IgG1k antibody, targeting the CD4 molecule on T-cells. It exhibits cytotoxic and anti-proliferative effects and has previously shown efficacy in cutaneous T-cell lymphoma. We report initial clinical efficacy and safety of treatment with 980 mg of HuMax-CD4 in 8 patients diagnosed with biopsy-proven, treatment-refractory or relapsed CD4+ peripheral T-cell lymphoma (PTCL) of non-cutaneous type. Patients were enrolled with the following diagnoses; enteropathy-type T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (n=3, 2 ALK− subtype, 1 unknown), angioimmunoblastic T-cell lymphoma (n=1) and PTCL, unspecified (n=3). Primary endpoint was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Out of the 8 patients enrolled, 2 responses have been seen; 1 PR and 1 CRu (verified by CT scan). Further, clinical improvements (marked decrease in the size of peripheral lymph nodes) were recorded by the physicians in 3 other patients. In total, 9 SAEs have been reported. Of these, 1 case of febrile neutropenia was judged related. 8 unrelated SAEs were recorded; knee pain, viremia (n=2), condition aggravated, and disease progression (n=4). Three unrelated deaths have been reported, all due to disease progression. In conclusion, HuMax-CD4 was well tolerated in heavily pre-treated patients and the present results indicate efficacy in the treatment of PTCL.