Abstract: Background: The histone deacetylase inhibitor (HDACi) romidepsin (Coiffier 2010) and other HDACi such as belinostat (O'Connor 2015) are management options for relapsed peripheral T-cell lymphoma (PTCL), and HDACi have also shown benefit for B-cell lymphomas (Younes 2012). The aurora A kinase (AURKA) inhibitor alisertib has shown promising results in aggressive lymphomas including Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and PTCL (Friedberg 2011, Barr 2014), and a registration trial in PTCL has recently completed enrollment. Given preclinical evidence for synergy when combining an AURKA inhibitor plus an HDACi (Zullo 2015, Muscal 2011, Kretzner 2008), we initiated a Phase I trial (NCT01897012, supported by CTEP-NCI) combining alisertib plus romidepsin in patients with multiple lymphoma subtypes. Methods: 12 patients have been enrolled to date, 3 at each of 4 escalation dose levels with patients treated with alisertib on days 1 to 7 and romidepsin on days 1 to 8 of 21 day cycles. Of the eligible histologies there was 1 patient with BL, 3 with DLBCL and FISH positive for translocations of MYC and BCL2 (double-hit lymphoma, DHL), 4 with DLBCL with other unfavorable features (FISH-positive for c-myc alone; 90% Ki-67 positive; high protein staining for MYC and BCL2, but not FISH-positive; and transformed from follicular lymphoma), 3 with PTCL, and 1 with composite PTCL and DLBCL (Fanale 2014). Tumor core biopsies were performed at baseline and at the end of 1 cycle of therapy, part of which was collected in RNAlater for gene expression profiling (GEP) using Illumina HT12v4.0 arrays. Whole peripheral blood was also collected at these and other time points in PAXgene tubes for future GEP. Results: Dose escalation and safety data have been previously presented (Fanale 2014). Responses to date are CR (PTCL, dose level 1), SD (PTCL, dose level 3, composite PTCL/DLBCL, dose level 4), PD (3 DHL, 1 HG DLBCL, 1 DLBCL with c-Myc, 1 PTCL). 4 of the patients with PD have died from continued refractory disease and 1 has been transitioned to hospice. The CR patient received 7 prior lines of treatment and had a duration of remission of 10 month. The PTCL patient with SD underwent an allogeneic stem cell transplant (SCT) but developed further PD 5 months after completion of SCT. Technically-satisfactory GEP results were obtained for 9 pairs of baseline (pre-Rx) and post-cycle 1 (post-Rx) tumor biopsies. Hierarchical clustering of highly-variant genes across all samples, including additional samples from 2 patients (pre-Rx only), showed appropriate grouping of samples according to B- or T-cell lineage. For all but one sample pair, pre-Rx and post-Rx samples from the same patient clustered as nearest neighbors, indicating that treatment had less effect on GEP data than did patient origin, and that "subtraction" (comparing post-Rx to pre-Rx samples) would be necessary for comparing treatment effects. To identify treatment-induced GEP changes associated with response to alisertib plus romidepsin, log2-transformed and subtracted data for the lone patient (with PTCL) who reached CR were compared to those for the other 8 pairs. There were 160 gene probes that were upregulated by log2 〉 =1.5 in the lone responder, but by 〉 =0.75 in 2 or fewer of the other patients; similarly, 163 probes were downregulated by log2 〈 =-1.5 in the lone responder, but by 〈 =-0.75 in 2 or fewer of the other patients. The hypergeometric distribution test showed that upregulated genes were enriched with high significance for genes involved in cell cycle progression, including both AURKA and AURKB (more than 4-fold); interpretation is uncertain, but could indicate compensation for functional inhibition of aurora kinases. Individual, uniquely-upregulated genes suggested induction of an anti-tumor immune response: 〉 5-fold induction of TMSB15A, repressed by TGF-beta, and BATF3, essential for CD8a+ dendritic cells in animal models of anti-tumor immune response; and 〉 3-fold induction of TNFRSF18 (GITR), upregulated by T-cell activation. Conclusions: Based on toxicity and response profile thus far, an amendment is under review to modify dosing schema for alisertib and romidepsin, and once the MTD is reached a potential cohort expansion for PTCL patients is planned. GEP changes suggest that induction of an antitumor response may underlie clinical responses, and will be investigated further by other studies of tumor biopsies and whole-blood GEP. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: CNS relapse is a rare but fatal complication of patients with peripheral T-cell lymphoma (PTCL). Several large studies have identified risk factors for CNS relapse in PTCL, such as elevated serum lactate dehydrogenase (LDH), 〉 1 extranodal sites of involvement and high International Prognostic Index (IPI) score. We performed an analysis of histologic type of PTCL to identify additional risk factors for CNS relapse. Patients and Methods: A total of 616 patients with PTCL diagnosed between 1999 and 2014 were analyzed retrospectively including: 174 not otherwise specified (NOS), 144 angoimmunoblastic T-cell lymphoma (AITL), 76 ALK+ anaplastic large cell lymphoma (ALCL), 103 ALK-ALCL, 55 nasal type T/NK cell lymphoma (NK/T), 23 hepatopslenic T-cell lymphoma (HSTL), 16 enteropathy-type T-cell lymphoma (EATL), 13 adult T-cell leukemia/lymphoma (ATLL), and 12 subcutaneous panniculitis-like T-cell lymphoma (SPTL). Patients with CNS involvement at diagnosis (n=15) were excluded from this study. Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes by hazard ratio (HR). Cumulative incidence of CNS relapse was calculated by competing risk (death without CNS relapse) regression analysis. Results: The median age of the patients was 56 years (range, 17-93 years). With a median follow up of 57 months, 15 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 NK/T, and 2 ATLL) experienced CNS relapse, and 321 patients (52%) died without having had CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.8% (95%CI: 1.0-3.1%), 2.4% (95%CI: 1.3-3.8%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.3% in ALK+ALCL, 2.1% in ALK-ALCL and 3.6% in NK/T (Figure). All patients with CNS relapse eventually died, with median OS duration from CNS relapse of 1.6 months. Extranodal sites of involvement 〉 1 (HR: 6.0, 95%CI: 2.0-17.4) and higher IPI score (HR: 1.8, 95%CI: 1.1-3.1, by one increase in IPI score) were risk factors of CNS relapse by univariate analysis. ALK+ALCL patients who had 〉 1 extranodal site of involvement (N=19) had very high risk of CNS relapse with one year cumulative incidence of 15% (95%CI: 3.7%-33.5%), with all occurring within six months after diagnosis. Summary: CNS relapse in patients with PTCL is rare as reported previously. However, the risk varies by histologic type. Specifically ALK+ALCL patients with 〉 1 extranodal site of involvement have a very high risk of CNS relapse in early phase of treatment, and CNS evaluation at the time of diagnosis and possibly CNS targeted prophylaxis may be appropriate. Figure Figure. Disclosures Westin: ProNAi: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fayad:Seattle Genetics: Consultancy, Research Funding. Wang:BeiGene: Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Dava Oncology: Honoraria; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; Juno Therapeutics: Research Funding. Fowler:Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Infinity: Consultancy, Research Funding; TG Therapeutics: Consultancy. Oki:Novartis: Research Funding.

Abstract: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive neoplasm derived from CD4+ T-cells with HTLV-I infection, and its mechanisms of tumorigenesis still remain to be elucidated. The fact that tumor cells rarely proliferate in vitro is one of the most important problems to be solved. The establishment of cell line from ATLL patient samples has been difficult even in the presence of interleukins. Previously we established one cell line (HU-ATTAK) from acute or lymphoma types of 10 ATLL cases which did not proliferate in the presence of IL-2 and/or IL-4. HU-ATTAK is critically dependent on IL-2 and human umbilical cord vein endothelial cells (HUVEC) as feeder cells. In HU-ATTAK, adding anti-OX40 ligand antibody into the culture system completely inhibited its proliferation. So, OX40 ligand as well as L-2 and/or IL-4 is suggested be necessary for the proliferation of ATLL cells, and feeder cells may also confer the favorable environment. As the substitute of HUVEC, follicular dendritic cell like cell line HK which expresses OX40 ligand was used by introducing human OX40 ligand cDNA (HK-OX40L). When 9 ATLL patient samples were co-cultured with HK-OX40L in the presence of L-2 and/or IL-4, two ATLL cells proliferate vigorously only in the presence of both IL-2 and IL-4 simultaneously. These cell lines were confirmed to be derived from original tumor cells by array CGH analysis, and continued the growth for more than a year. Depletion of IL-2 and IL-4 made these cell lines stop growing within 6 days even on HK-OX40L. In the presence of IL-2 and IL-4, the conditions such as HK alone without OX40 ligand or OX40 ligand alone without HK made the cell lines growing for three months at most. In the presence of IL-2 and IL-4 without HK-OX40L, these cell lines vigorously proliferated for more than three months but finally stopped growing. These data suggested that for the growth of these two cell lines, the cell division is dependent on IL-2 and IL-4, and the maintenance of immortalization is dependent on OX40 ligand and HK cells. This culture analysis would provide important factors for cell growth of ATLL which will explore new targets for ATLL treatment. *HK cells are kindly provided by Dr. Young S Choi at Ochsner Cancer Center, New Orleans. Disclosures: No relevant conflicts of interest to declare.

Abstract: BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type, (ENKTCL) is a rare and aggressive peripheral T-cell lymphoma associated with Epstein-Barr virus infection of neoplastic cells. The current standard-of-care for patients (pts) with localized disease is combined modality with radiation and systemic chemotherapy, while advanced disease is treated with asparaginase-based combination chemotherapy or chemoradiation. To date, there is limited real-world data regarding the clinico-pathological markers, survival patterns, and long-term outcomes ENKTCL in the United States. METHODS: We conducted a retrospective study of pts with ENKTCL. We reviewed clinical variables, pathological characteristics, treatment patterns and outcomes. Patients who were treated/referred to our instituition from 2009-2020 were included in the analysis. We excluded cases with missing treatment and/or no follow up information. Fisher's exact test or Chi-square test was used to evaluate the association between two categorical variables. Kaplan-Meier method was used to estimate the time-to-event endpoints including progression free survival (PFS) and overall survival (OS). RESULTS: A total of 69 patients met diagnostic criteria and were included in this retrospective analysis. Forty (60%) patients were & lt;60 years of age at diagnosis with median age of 53 years (range 13-94); 38 (57%) were men. Thirty-five (50%) patients had early-stage, 28 (40%) advanced-stage disease among whom all but one had stage 4 disease, and 6 (10%) were unknown. Extranodal sites involved were cutaneous/ subcutaneous (n=16), CNS (n=5) and bone/ bone marrow (n=5). Of the cases with CD30 testing done, 54% (20/36) were positive. In early-stage disease, 10 pts received either radiation alone (n=4) or chemotherapy alone (n=6), while 24 received combined modality therapy. Only 15 patients with advanced-stage disease received frontline asparaginase based therapy. Five patients received CHOP based therapy all prior to 2014. Among the 53 patients evaluable for response, the overall response (OR) to first line treatment was 67.92% (95% CI: 53.68 ~ 80.08%) with complete response (CR) rate of 66.04% (95% CI: 51.73 ~ 78.48%). In those with early stage, 77% had a CR, whereas only 47 % with advanced disease had CR to frontline treatment (p=0.0327). Eight patients with advanced-stage disease underwent consolidation high dose chemotherapy and autologous stem cell transplant, with 2 relapses post-therapy. The the median PFS to frontline treatment was 12.48 months (95% CI: 7.23-38.63), for stages I/II 19.15 months, and for stages III/IV 7.23 months . The PFS rate at 2 years was 35% (95% CI: 0.24-0.51) for the entire cohort, 46% (95% CI: 0.3-0.71) for stage I/II, and 21% (95% CI: 0.09-0.47) for stage III/ IV (p=0.0264) (Figure 1A). Extranodal involvement of the skin / subcutaneous tissue was associated with worse outcomes (Figures 1B and C), with a median PFS to frontline treatment at 3.52 months versus 14.22 months (P=0.0025), and a 2-year PFS of 14% (95% CI: 0.04-0.52). The median OS (Figure 1D) for the entire cohort was 33.94 months (95%CI 14.22 - NA), with OS at 2 years (Figure 1A) of 54% (95% CI: 0.42 -0.71) for the whole cohort, 72% (95% CI: 0.56 -0.92) for stage I/II and 33% (95% CI: 0.18 - 0.6) for stage III/ IV (p=0.0055). The most common second line regimen was SMILE (n=7, 5CRs and 1PR). Novel therapies included brentuximab vedotin (n=4), pembrolizumab (n=6), and EBV-directed T cell infusion (n=5). Analysis of molecular predictive markers, clinical correlates and toxicity data is currently ongoing and will be presented at the meeting. CONCLUSION: ENKTCL has poor prognosis especially in advanced stages. In this large single institution cohort, we evaluated the clinical and treatment patterns of this disease over a 12-year period. Our cohort was characterized by younger age and early stage. Higher response rates and improved survival were seen in those with early stage. In advanced stage; the presence of skin/ subcutaneous involvement was identified as a high-risk feature for worse survival. Furthermore, this trend was maintained for PFS and OS for those with advanced stages and skin/ subcutaneous involvement. A better understanding of targetable pathways and a unified treatment approach is needed to improve the outcomes for patients with high-risk features. Figure 1 Figure 1. Disclosures Huen: Rhizen: Research Funding; Elorac: Research Funding; Kyowa Kirin: Research Funding; Tillium: Research Funding; Innate: Research Funding; Galderma: Research Funding; Miragen: Research Funding. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Steiner: BMS: Research Funding; Seattle Genetics: Research Funding; Rafael Pharmaceuticals: Research Funding. Chihara: Astrazeneca: Honoraria. Jain: Lilly: Consultancy; kite: Consultancy. Nastoupil: Caribou Biosciences: Research Funding; Novartis: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; MorphoSys: Honoraria; Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; ADC Therapeutics: Honoraria; TG Therapeutics: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; IGM Biosciences: Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; Denovo Pharma: Other: DSMC. Pinnix: Merck Inc: Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Flowers: 4D: Research Funding; TG Therapeutics: Research Funding; Adaptimmune: Research Funding; Morphosys: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Kite: Research Funding; Ziopharm: Research Funding; Iovance: Research Funding; Nektar: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Celgene: Consultancy, Research Funding; Biopharma: Consultancy; Bayer: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Denovo: Consultancy; Janssen: Research Funding; Takeda: Research Funding; Burroughs Wellcome Fund: Research Funding; Genmab: Consultancy; BeiGene: Consultancy; Amgen: Research Funding; Xencor: Research Funding; Novartis: Research Funding; Genentech/Roche: Consultancy, Research Funding; National Cancer Institute: Research Funding; EMD: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Sanofi: Research Funding; Acerta: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Allogene: Research Funding; Pfizer: Research Funding; Guardant: Research Funding; Pharmacyclics: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Wang: OMI: Honoraria; Celgene: Research Funding; BGICS: Honoraria; Moffit Cancer Center: Honoraria; Genentech: Consultancy; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Bayer Healthcare: Consultancy; Imedex: Honoraria; Juno: Consultancy, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Scripps: Honoraria; InnoCare: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Mumbai Hematology Group: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; CAHON: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; VelosBio: Consultancy, Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; BioInvent: Research Funding; CStone: Consultancy; Newbridge Pharmaceuticals: Honoraria; Physicians Education Resources (PER): Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Vega: i3Health, Elsevier, America Registry of Pathology, Congressionally Directed Medical Research Program, and the Society of Hematology Oncology: Research Funding; CRISPR Therapeutics and Geron: Research Funding. Iyer: CRISPRX: Research Funding; Seattle Genetics: Research Funding; Rhizen: Research Funding; Merck: Research Funding; Legend: Research Funding; Innate: Research Funding; Spectrum: Research Funding; Trillium: Research Funding; Astra Zeneca: Research Funding; Yingli: Research Funding; Cyclacel: Research Funding.

Abstract: Patients with hematologic malignancies have both an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and higher morbidity/mortality. They have lower seroconversion rates after vaccination, potentially leading to inferior coronavirus disease 2019 (COVID-19) outcomes, despite vaccination. We consequently evaluated the clinical outcomes of COVID-19 infections in 243 vaccinated and 175 unvaccinated patients with hematologic malignancies. Hospitalization rates were lower in the vaccinated group when compared with the unvaccinated group (31.3% vs 52.6%). However, the rates of COVID-19–associated death were similar at 7.0% and 8.6% in vaccinated and unvaccinated patients, respectively. By univariate logistic regression, females, older patients, and individuals with higher modified Charlson Comorbidity Index scores were at a higher risk of death from COVID-19 infections. To account for the nonrandomized nature of COVID-19 vaccination status, a propensity score weighting approach was used. In the final propensity-weighted model, vaccination status was not significantly associated with the risk of death from COVID-19 infections but was associated with the risk of hospitalization. The predicted benefit of vaccination was an absolute decrease in the probability of death and hospitalization from COVID-19 infections by 2.3% and 22.9%, respectively. In conclusion, COVID-19 vaccination status in patients with hematologic malignancies was associated with a decreased risk of hospitalization but not associated with a decreased risk of death from COVID-19 infections in the pre-Omicron era. Protective strategies, in addition to immunization, are warranted in this vulnerable patient population.