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With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p

Summary Peripheral T‐cell lymphomas (PTCL) and natural killer (NK)/T‐cell lymphomas (NKTCL) are a heterogeneous group of aggressive malignancies with dismal outcomes and limited treatment options. While the phosphatidylinositol 3‐kinase (PIK3) pathway has been shown to be highly activated in many B‐cell lymphomas, its therapeutic relevance in PTCL and NKTCL remains unclear. The aim of this study is to investigate the expression of PIK3 and phosphatase and tensin homolog (PTEN) in these subtypes of lymphoma and to identify potential therapeutic targets for clinical testing. Therefore, the expression of PIK3α, PIK3β, PIK3γ, PIK3δ and PTEN was analyzed in 88 cases of PTCL and NKTCL samples by immunohistochemistry. All PTCL and NKTCL samples demonstrated high expression of PIK3 isoforms. In particular, high PIK3α expression was significantly associated with poor survival, even after adjustment for age, International Prognostic Index (IPI) score and anthracycline‐based chemotherapy in first line. Notably, copanlisib, a pan‐class I inhibitor with predominant activities towards PIK3α and PIK3δ isoforms, effectively inhibited phosphorylation of AKT, 4E‐BP‐1 and STAT3, causing G0/G1 cell cycle arrest and resulting in suppression of tumour cell growth in vitro and in vivo. This study provides evidence that targeting the PIK3 pathway, particularly simultaneous inhibition of PIK3α and δ, could be a promising approach for the treatment of PTCL and NKTCL.

Key Points Whole genomic and transcriptomic analyses of MEITL revealed multiple potential therapeutic targets. Synergistic effects of pimozide and romidepsin are shown in a well-characterized MEITL PDX model.

Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.

Introduction While combination therapy is the standard of care for relapsed/ refractory non-Hodgkin lymphoma (RR-NHL), the choice of combinations for an individual patient is empirical, and response rates remain poor. Here we explore the use of a hybrid experimental/analytic method termed Quadratic Phenotypic Optimization Platform (QPOP), for prediction of optimal drug combinations from limited clinical material. This high-throughput platform identifies optimal drug-combinations on ex-vivo biopsies using an orthogonal array composite design to maximise search space. These features are potentially useful to assess personalized efficacious combinations among a set of drugs with single agent pre-clinical or clinical activity in lymphoma. Methods We performed a prospective cohort study of QPOP analysis in RR-NHL. Participants included RR-NHL patients across two tertiary oncology centres in Singapore, with disease amenable to biopsy or blood/ marrow aspiration, recruited between 1 st November 2017 and 5 th May 2021 - with a median follow up of 24.5 months. CD20, CD3 or CD56 selection was performed to enrich for B, T or NK cells respectively, depending on the specimen type. QPOP drug combination scores were derived from lymphoma samples (approximately 1,000,000 cells/ patient) using a matrix of drugs with known pre-clinical or clinical efficacy against NHL. Results were shared with the treating physician, and off-label QPOP-guided therapy was offered in the absence of standard options. The primary outcomes were feasibility and turnaround time of QPOP analysis. The secondary outcomes were identification of recurrent 2 and 3 drug-combinations, and concordance of QPOP results with clinical responses. Results In this interim analysis period, we recruited 63 patients comprising 36 B-NHL and 27 T/NK-NHL, with a median age of 57 years and median 2 prior lines of treatment. Successful QPOP analysis (Z' score >0.5) was feasible in 56/63 cases with an average turn-around time of 6 (±2.1) days. QPOP predicted frequent sensitivities to Copanlisib- and Venetoclax-based combinations in B-NHL, and Romidepsin-based combinations in T/NK-NHL. Importantly, efficacy of specific combinations was not entirely dependent on single agent dose responses. Greater variability in ex-vivo responses was seen with combinations of targeted therapy and cytotoxic therapy compared with combinations of cytotoxic agents. Clinical responses were evaluable for 29 independent treatments in 26 patients. QPOP had a positive predictive value of 60% and a negative predictive value of 78.6% with an area under the curve of 0.672 (95%CI 0.47-0.87; p=0.12) for partial response or better (n=29, p= 0.06). Complete responses were achieved with novel QPOP derived drug combinations in patients refractory to standard therapy. Examples include Palbociclib-Everolimus for diffuse large B-cell lymphoma (figure 1) and Romidepsin-copanlisib for extra nodal natural killer T-cell lymphoma. Conclusions Prediction of sensitivity to drug-combinations in a clinically applicable time-frame is feasible for RR-NHL cases through QPOP analysis. The relatively small number of patients treated with QPOP directed regimens makes a definitive conclusion on concordance with clinical outcomes difficult at this stage. QPOP was however able to identify novel clinically effective combinations in patients refractory to standard therapy. These data provide the basis for a prospective clinical trial evaluating QPOP based therapy in RR-NHL. Figure 1 Figure 1. Disclosures Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria. OffLabel Disclosure: everolimus palbociclib for diffuse large B cell lymphoma and rhomidepsin Bortezomib for extra nodal NK T cell lymphoma

Background and aims: Angioimmunoblastic T-cell lymphoma (AITL) is currently classified amongst an umbrella group of diagnoses referred to as nodal peripheral T-cell lymphoma (PTCL) with T-follicular helper (TFH) phenotype. In this entity, it is recognized that the presence of atypical B-cell blasts mimicking Hodgkin-Reed-Sternberg cells may lead to misdiagnosis as Hodgkin lymphoma (HL), resulting in suboptimal management and poorer outcomes. This diagnostic complexity has been acknowledged by the World Health Organization classification of lymphoid neoplasms. In this study, we aim to investigate the clinical features and outcomes of such cases of diagnostic ambiguity (HL/PTCL). Methods: A total of 379 patients from the Singapore Lymphoma Study database across three tertiary cancer centers (National Cancer Centre Singapore, Singapore General Hospital, National University Cancer Institute) were included in this study, including those diagnosed with AITL (n=169), HL (n=178) and HL/PTCL (n=32). Median follow-up was 47.5 months. Relevant demographical and clinical characteristics were collected. Survival analyses were performed using the Kaplan-Meier method. Results: The 32 patients with HL/PTCL were identified from three distinct clinical scenarios. In the first group (n=18), an initial histological diagnosis of HL was revised upon independent pathological re-assessment following a second opinion consultation (revised diagnoses to AITL, n=10; PTCL-TFH, n=7; PTCL-NOS, n=1). In the second group (n=11), the histological diagnoses were different at diagnosis and at relapse (mostly HL relapsed as AITL/PTCL-TFH, n=9). The third group consisted of patients with synchronous or composite features of both HL and AITL/PTCL at diagnosis (n=3). In the overall cohort, most were male (62.5%), and the majority had excellent performance status with ECOG 0-1 (96.9%). The median age was 45 years (range, 20 to 77), which is older than the HL cohort (28 years, p=0.0012) but younger than the AITL cohort (62 years, p=0.0005). In terms of disease staging, most were Ann Arbor stage 3-4 (62.5%), which is comparable to the AITL cohort (78.3%), but significantly more advanced than the HL cohort (32%, p=0.001). HL/PTCL represented a group with worse prognostic risk scores by IPI as compared to HL (p=0.0038), but better as compared to AITL (p=0.0418). Accordingly, the median overall survival was 8.4 years for HL/PTCL, compared to 5.5 years (AITL) and not reached (HL) (logrank p Conclusion: We describe a significant and clinically distinct group of HL and AITL/PTCL-TFH cases which are challenging to diagnose. Further studies on the molecular characteristics of this ambiguous disease entity may be required to resolve the diagnostic difficulties. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Natural-killer/T-cell lymphoma (NKTL) is a rare subset of non-Hodgkin lymphoma that demonstrates a unique geographic distribution, with higher prevalence in Asia compared to the West1. While cure remains achievable in early-stage disease, the prognosis for advanced-stage NKTL is dismal2. Recently, some progress has been made in uncovering the molecular pathogenesis of NKTL. In a genome-wide association study, strong correlations between HLA-DPB1 single-nucleotide polymorphisms and NKTL susceptibility were discovered, implicating altered antigen processing and presentation to CD4-positive T-lymphocytes in this Epstein-Barr virus (EBV)-associated malignancy3. Next generation sequencing also revealed recurrent somatic mutations such as TP53, JAK3, STAT3 and DDX3X in NKTL4,5. In this paper, we report a pair of male siblings from a non-consanguineous Chinese family who were diagnosed with NKTL, and provide initial evidence for novel recessive germline mutations in FAM160A1 identified through next-generation sequencing. The index patient was 35 years old, when he presented with nasal blockage in March 2013. 18-FDG-PET/CT imaging revealed an 18-FDG-avid nasal mass infiltrating into the palate, as well as enlarged cervical lymph nodes. Biopsy of the mass showed abnormal lymphoid cells positive for CD56 by immunohistochemistry (IHC) as well as EBV-encoded RNA (EBER) by in-situ hybridization. He was diagnosed with stage IIA extranodal NKTL, nasal type, and treated with 4 cycles of bortezomib-GIFOX (gemcitabine, ifosfamide and oxaliplatin) as part of a clinical trial followed by radiotherapy to the nasal region. He had primary-refractory disease and was further treated with 4 cycles of SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) followed by high-dose chemotherapy and autologous stem cell transplantation. He progressed and received ruxolitinib off-label, followed by RAD001 (mTOR inhibitor) and LBH589B (histone deacetylase inhibitor) as part of another clinical trial. He then had radiotherapy to an ulcerating penile lesion before he died of progressive disease 27 months after diagnosis (Supplementary Table 1). His younger brother was 18 years old, when diagnosed with NKTL affecting the nasal floor in 1998 following a bout of epistaxis. He received 6 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with high-dose methotrexate and went into complete remission. Three years later he was diagnosed with chronic myeloid leukemia, for which he received hydroxyurea. In 2004, he had a relapse of NKTL and received ESHAP (etoposide, prednisolone, cytarabine and cisplatin), total body irradiation and allogeneic bone marrow transplant. He died of transplant-related complications 6 years from diagnosis. These siblings have an older brother unaffected by any hematological malignancy. Their father died of a non-malignant condition in his fifties and their mother remains well at the age of 68 years. Among their first-degree relatives, none were known to be inflicted with hematologic malignancies (Fig. ​(Fig.11). Open in a separate window Fig. 1 Clinical characterization of brothers with familial NKTL. a 18-FDG-PET/CT image depicting a large nasal mass infiltrating into the palate, of which biopsy showed abnormal lymphoid cells positive for Epstein-Barr virus encoded RNA (EBER) by in situ hybridization. b, c Inheritance modelling identified homozygous germline mutations of FAM160A1 c.2827 C > T in both affected brothers, heterozygous carriage in their mother and paternal aunt, and homozygous wildtype in their healthy older brother. d, e The non-synonymous substitution at FAM160A1 c.2827 C > T results in an amino-acid alteration from arginine to cysteine (p.R943C). Patterns and frequencies of known mutations in other cancer types are shown

Mature T-cell lymphomas, including peripheral T-cell lymphoma (PTCL) and extranodal NK/T-cell lymphoma (NKTL), represent a heterogeneous group of non-Hodgkin lymphomas with dismal outcomes and limited treatment options. To determine the extent of involvement of the JAK/STAT pathway in this malignancy, we performed targeted capture sequencing of 188 genes in this pathway in 171 PTCL and NKTL cases. A total of 272 nonsynonymous somatic mutations in 101 genes were identified in 73% of the samples, including 258 single-nucleotide variants and 14 insertions or deletions. Recurrent mutations were most frequently located in STAT3 and TP53 (15%), followed by JAK3 and JAK1 (6%) and SOCS1 (4%). A high prevalence of STAT3 mutation (21%) was observed specifically in NKTL. Novel STAT3 mutations (p.D427H, E616G, p.E616K, and p.E696K) were shown to increase STAT3 phosphorylation and transcriptional activity of STAT3 in the absence of cytokine, in which p.E616K induced programmed cell death-ligand 1 (PD-L1) expression by robust binding of activated STAT3 to the PD-L1 gene promoter. Consistent with these findings, PD-L1 was overexpressed in NKTL cell lines harboring hotspot STAT3 mutations, and similar findings were observed by the overexpression of p.E616K and p.E616G in the STAT3 wild-type NKTL cell line. Conversely, STAT3 silencing and inhibition decreased PD-L1 expression in STAT3 mutant NKTL cell lines. In NKTL tumors, STAT3 activation correlated significantly with PD-L1 expression. We demonstrated that STAT3 activation confers high PD-L1 expression, which may promote tumor immune evasion. The combination of PD-1/PD-L1 antibodies and STAT3 inhibitors might be a promising therapeutic approach for NKTL, and possibly PTCL. ASTAR (Agency for Sci., Tech. and Research, S’pore) NMRC (Natl Medical Research Council, S’pore) MOH (Min. of Health, S’pore)

The genetic landscape of Natural killer/T-cell nasal-type lymphoma (NKTL) has been recently unraveled by discoveries describing recurring mutations altering the JAK-STAT pathway, epigenetic modifiers, the DDX3X gene and genetic predisposition in the HLA-DPB1 gene but none has employed whole-genome sequencing (WGS). Whole-genome sequencing was performed for 11 pairs of tumor-blood samples to study the association between somatic mutations and response to pembrolizumab. Interestingly, recurrent PD-L1 SRs were validated in four of the seven complete responders (CR) cases. JAK3-activating (p.A573V) mutations were also validated in another two pembrolizumab-treated patients who have achieved CR. Lastly, we also found a homozygous 3 bp insertion (p.Q131_H132insQ) in the ARID1B gene, a chromatin remodeler gene and a subunit in the SWI/SNF complex in the last remaining CR case. A recent study has also reported PBRM1-deficient and ARID2-deficient tumors correlated with better response to anti-PD1/PD-L1 therapy renal cell carcinoma. There seems to be a relationship between truncating alterations in the subunits of the SWI/SNF complex and response to PD1/PD-L1 therapy. However, the exact mechanisms behind these associations remain to be elucidated for NKTL. Analysis of the WGS data from the four remaining progressive disease (PD) patients' tumors did not reveal similar alterations in the PD-L1 and JAK3 genes. A careful inspection was also carried out on the genes associated with major histocompatibility complex and interferon gamma pathways, which are known to associate with resistance to immune checkpoint blockade in melanoma, but no further mutation in these groups of genes was found in our cohort. Furthermore, a TP53 (p.W14X) stop-gain mutation, a hallmark tumor suppressor gene, was detected in a patient who had progressive disease after given pembrolizumab. We went on to check if PD-L1 IHC staining could explain the response of these NKTL patients to pembrolizumab. In this study, tumors were stained and assessed for PD-L1 positivity by the same pathologist. All cases, except two cases, have greater than 20% of tumor cells stained positive for PD-L1. Interesting, both cases are CR. In addition, all four PD cases were strongly stained for PD-L1 with an average of 69% PD-L1 positive cells (range, 50% - 90%) but their outcomes were dismal. This suggests that there could be a companion biomarker that could be added to PD-L1 IHC positivity for better predictive power of response to PD1 blockade therapy. Here we report retrospectively, for the first time, the genomic mutational profiles of anti-PD1 blockade in 11 relapsed/refractory NKTL patients using WGS data, which provide proof-of-concept data that the response to anti-PD1 is relevant and correlates with recurrent PD-L1 and JAK3 genomic alterations in this malignancy. Disclosures No relevant conflicts of interest to declare.

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.

Non-Hodgkin lymphomas (NHL) are a diverse group of blood cancers on the rising trend both worldwide and in Singapore. Better understanding of the pathogenesis and biology of these tumors is urgently required to improve the diagnosis and prognostication. Moreover, the outcome using currently available therapies is poor and there is an immediate need for better treatment options. With an increasing number of genomic studies published, there is a growing demand to bring these discoveries into in vitro and in vivo models. However, the lack of publicly available cell lines and/or animal models for the majority of the NHL subtypes makes these studies difficult to proceed. With that objective, we have started collecting fresh NHL tumor samples and implanting them into NOD scid gamma (NSG) mice to generate patient-derived xenograft (PDX) models. After tumor dissemination, the cells are injected either subcutaneously or intraperitoneally into 6-10 week old mice. Each passage is thoroughly immunohistochemically characterized by a senior hematopathologist and contrasted to the primary patient specimen. Whole exome sequencing (WES) is performed and compared to the primary patient data where possible. A model is considered stable if it has not changed its phenotype for at least 3 passages. A full list of currently available stable models is listed in Table 1. Efforts are also under way to generate stable cell lines based on these models. Strategies tested are spontaneous immortalization, human telomerase reverse transcriptase (TERT), Herpesvirus saimiri (HVS) or Epstein-Barr virus (EBV) transduction and feeder culture. We have recently reported a comprehensive molecular profiling of monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL; previously also known as type II enteropathy-associated T-cell lymphoma; Nairismagi et al., Leukemia, 2016). MEITL, a newly recognized WHO entity, is a rare aggressive primary intestinal disease with poor prognosis and a median overall survival of only 7 months. Frequent alterations were identified in the JAK-STAT and G-protein-coupled receptor signaling pathways and a number of epigenetic regulators. Specifically, 60-30% mutation frequencies were found in the STAT5B, JAK3, SETD2, GNAI2 and CREBBP genes. Tumor tissue was collected from a 55 year old Chinese male with relapsed MEITL. The cells have been propagated in the NSG mouse by subcutaneous or intraperitoneal injection up to 6 and 3 passages, respectively. All passages have been histologically characterized and maintained their CD3+ CD8alpha-alpha+ cytotoxic granules+ MATK+ and EBER- phenotype with aberrant expression of both TCR beta and gamma. WES was performed both in the patient primary sample and in passage 1 (P1) PDX sample. There were 83 somatic mutations present in the primary sample, all of which were also identified in the P1 PDX sample. Furthermore, Sanger sequencing was used to validate the presence of all 83 mutations in the remaining passages. There was only 1 mutation lost in the P6 subcutaneous PDX model compared to the primary patient specimen demonstrating the outstanding stability of this model. Using peritoneal fluid cells from P2 we have previously performed ex vivo studies and identified novel treatment modalities for this deadly disease (Nairismagi et al., Leukemia, 2016). Efforts are currently under way to test these regimens also in in vivo setting. In summary, we have generated a number of NHL PDX models with the objective to enhance drug testing. MEITL presents a real life situation where clinical trials are not possible due to the rarity of the disease; however, the availability of PDX models allows for efficient testing of novel therapies and can lead to improved patient outcome. Efforts are under way to further characterize the existing models and tissue collection is ongoing to establish more models. Table 1 List of available stable non-Hodgkin lymphoma models. AITL, angioimmunoblastic T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; GC, germinal center; MCL, mantle cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; NK/TCL, natural killer/T-cell lymphoma and PTCL NOS, peripheral T-cell lymphoma not otherwise specified. Table 1. List of available stable non-Hodgkin lymphoma models. AITL, angioimmunoblastic T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EBV, Epstein-Barr virus; GC, germinal center; MCL, mantle cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; NK/TCL, natural killer/T-cell lymphoma and PTCL NOS, peripheral T-cell lymphoma not otherwise specified. Disclosures No relevant conflicts of interest to declare.