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Background The most common subtype of B-cell lymphomas presenting in the conjunctiva is extranodal marginal zone lymphoma (EMZL), accounting for ~80% of cases. Most patients (pts) present with localized disease, and radiation therapy (RT) is the preferred treatment strategy. We aimed to retrospectively analyze our single-institution experience to provide further insight into the characteristics and long-term outcomes of conjunctival EMZL. Methods We evaluated 72 pts diagnosed with conjunctival EMZL between 01/1995 and 12/2020 at the University of Miami. Pts' characteristics included age, sex, TNM-AJCC ocular lymphoma and Ann Arbor staging systems, MALT-IPI score, treatment (RT, chemotherapy, rituximab), and treatment response (complete response (CR), partial response, stable disease, progression of disease). Primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated using the Kaplan-Meier method, and compared using the log rank test and the univariable Cox regression analysis. We also performed a competing risk univariable analysis (UVA) assessing predictors of cumulative incidence of relapse/progression, with death without relapse as a competing risk, using the Fine and Gray regression analysis. Results Among all 72 pts, mean age was 59.9 yrs (7-93) with 38 (52.8%) being >60 yrs old, 46 (63.9%) were female, 56 (77.8%) had unilateral conjunctival disease, localized disease (T1N0M0 and Ann Arbor stage I) was present in 63 (87.5%), 6 (8.3%) had disseminated disease with more than 1 extranodal site involved, and 29 (40.3%) had a MALT-IPI of 1 or 2. After biopsy and surgical removal, 65 (90.2%) received additional treatment, while 6 (8.3%) were followed only, and in one case therapy information was not available . RT was the most common treatment (53 pts [73.6%], with 46 [86.8%] of those treated with ≥ 30 Gy). In two of these patients RT was combined with chemotherapy. Other treated pts received immunochemotherapy (12 [16.7%], including rituximab in 8). Five pts with stage II-IV disease received systemic therapy. CR was achieved in 63 (87.5%) after first line treatment, and no high-grade lymphoma transformation was seen. With a median follow up of 6.67 yrs (0.56-24.13), there were 14 relapses (19.4%). Among 53 pts treated with RT there were 8 relapses (15.1%), only one (1.9%) within the RT field. There were 23 progression events (31.9%, 14 relapses and 9 deaths without documented relapse), and a total of 14 deaths (19.4%). Mean PFS and OS were 6.69 yrs (0.49-20.37, SD 4.95) and 7.81 yrs (0.56-24.13, SD 5.40), respectively. The 10-yr PFS and OS were 68.4% (95%CI 52.8, 79.8%) and 89.4% (95%CI 77.4, 95.2%), respectively. Variables associated with shorter PFS in UVA Cox model were age > 60 yrs (HR=2.93, 95%CI 1.08, 7.95; p=0.035), high MALT-IPI (1-2) (HR=2.42, 95%CI 1.01, 5.78; p=0.048), and use of chemotherapy only (HR=2.73, 95%CI 1.13, 6.56; p=0.025). Variables associated with shorter OS included age >60 yrs (HR=9.07, 95%CI 1.17, 70.26; p=0.035) and high MALT-IPI (HR=6.19, 95%CI 1.35, 28.33; p=0.019). CR after frontline therapy was associated with longer PFS (HR=0.13, 95%CI 0.04, 0.45; p=0.001) but not OS. PFS of MALT-IPI 0 vs 1-2 was significantly longer (p=0.042), with 10-yr PFS 80.9% (95%CI 63.4%, 90.6%) vs 55.6% (95%CI 32.1%, 73.8%). Similarly, longer OS was observed in MALT-IPI 0 pts (p=0.0077; 10-yr OS 95.2% [95%CI 82.2%, 98.8%] vs 80.6% [95%CI 55.6%, 92.4%]) (Figure). A subset UVA Cox analysis of patients with Ann Arbor stage I showed longer PFS associated with CR after frontline therapy (HR 0.15, 95%CI 0.04, 0.58; p=0.006) with no significant association with age >60 yrs, high MALT-IPI or use of chemotherapy. Variables associated with shorter OS were age >60 yrs (HR 8.01, 95%CI 1.00, 63.98; p=0.05) and high MALT-IPI (HR 13.41, 95%CI 1.67, 107.99; p=0.015), similarly to the primary analysis. On univariable Fine and Gray regression models with death without relapse/progression as a competing risk, RT (SHR=0.33, 95%CI 0.12, 0.96; p=0.041) and CR-post frontline therapy (SHR=0.11, 95%CI 0.03, 0.36; p Conclusion Patients with conjunctival EMZL exhibit excellent long-term survival, and RT remains the most effective frontline therapy. MALT-IPI appropriately identifies patients at risk for treatment failure. Figure 1 Figure 1. Disclosures Alderuccio: ADC Therapeutics: Consultancy, Research Funding; Oncinfo / OncLive: Honoraria; Puma Biotechnology: Other: Family member; Inovio Pharmaceuticals: Other: Family member; Agios Pharmaceuticals: Other: Family member; Forma Therapeutics: Other: Family member. Lossos: Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; NCI: Research Funding; Stanford University: Patents & Royalties; Verastem: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; NIH grants: Research Funding; University of Miami: Current Employment.

Background: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive malignancy with dismal prognosis and associated with clonal T-cell expansion driven by Human T-Lymphotropic Virus 1 (HTLV-1) infection. Comprehensive genomic studies in Japan have identified recurrent alterations affecting TCR-NF-kB signaling (i.e. PRKCB, PLCG1, CARD11, VAV1, and IRF4), T-cell trafficking pathways (i.e. CCR4 and CCR7), and the tumor suppressor genes CDKN2A and TP53. HTLV-1 endemic regions include Africa, the Caribbean, and South America in addition to Japan. Retrospective studies from the Western population have reported distinctive features from the Japanese cohort, e.g. younger age, more common lymphomatous presentation, and worse outcomes. Our group sought to evaluate the unique molecular features of ATLL in a large cohort of patients from the Caribbean and South America. Methods: We performed a multimodal genomic study on specimens from 169 patients encountered in the United States (Miami), Peru, Brazil, France, and Spain. Data types included Oncoscan/Copy Number Variation (CNV) data for 129 patients, RNA-seq data for 97 patients, and whole exome sequencing (WES) data for 125 patients. Patients were ethnically classified based upon single nucleotide polymorphisms, under 3 main groups: African (n=80), native American (n= 32), or South Asian/Islander (n=12). 46 specimens without WES data could not be ethnically classified. Somatic variants were called using Mutect. Putative driver mutations were identified by frequency-based criteria. CNV significance was determined using GISTIC2.0. Data were compared to whole exome and targeted sequencing data published by Kataoka et al. Results: Our cohort replicated trends reported in Japanese datasets but included several distinctive findings. South American and Caribbean patients had fewer mutations in CCR4 and CD58. Three putative tumor suppressors not previously implicated in ATLL were identified based on recurrent damaging mutations. These included ANKRD11 (n=3), DGKZ (n=3), and PTPN6 (n=3). Both ANKRD11 and PTPN6 were only mutated in Afro-Caribbean patients with aggressive (acute and lymphomatous) cases. CNV analysis revealed ANKRD11 deletions in a significant portion of cases (n=16). As previously reported, STAT3 mutations were more common in indolent subtypes. IRF4 mutations (n=14) or amplifications (n=19) were only observed in aggressive ATLL subtypes. L70V was the most common IRF4 variant (n=5). Among Japanese samples, K59R mutations were seen twice as often as L70V mutations. Both K59R and L70V are located within the IRF4 DNA binding domain. In samples from patients with disease relapse (N = 10), IRF4 was the only gene mutated significantly more often (p = 0.03). 3 of 10 patients who were previously treated with interferon (IFN)-based therapy relapsed with new IRF4 mutations (L70V n=2, and K59R n=1), suggesting IRF4 may be associated with IFN resistance. A total of 11 patients in the Western cohort had FOXO3 mutations including R177W (n=7) and D199N (n=3) variants. These only occurred in Afro-Caribbean patients with aggressive subtypes. R177W is located within the FOXO3DNA binding domain, suggesting that dysregulation of its transcriptional targets may contribute to disease. In the Japanese cohort, only one patient had a FOXO3 mutation, (D199N). The majority of primary ATLL samples analyzed by Western Blot showed significantly reduced or no expression of FOXO3, or ANKRD11. Conclusion: The genomic landscape of ATLL encountered in patients from South America and the Caribbean resembles that of ATLL in Japanese patients. However, our study identified novel variants and tumor suppressor genes not previously implicated in ATLL that differ from the Japanese population. Furthermore, we correlate our genomic analysis with clinical findings to implicate ATLL driver genes in IFN resistance and disease prognosis. Functional Studies to determine the prognostic and functional roles of the gene alterations we identified in ATLL are ongoing. Disclosures Gru: StemLine: Honoraria, Research Funding, Speakers Bureau; CRISPT Therapeutics: Research Funding; Innate Pharma: Research Funding.

Introduction: Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) and has prognostic and, potentially, therapeutic implications in AML.Advances in the biological understanding of AML pathogenesis have led to the approval of new targeted agents that increase the therapeutic options for the treatment of AML. Despite these approvals, induction chemotherapy is still widely used for the treatment of patients newly diagnosed with AML. Unfavorable risk cytogeneticand secondary AML have been associated with low responses to induction chemotherapy. In the current study, we investigated the predictive role of molecular abnormalities detected with NGS related to responses to induction chemotherapy in newly diagnosed AML patients. Methods:We used the Medical Archival Retrieval System to identify newly diagnosed AML patients who had NGS analysis performed at our institution.. Patients treated with induction chemotherapy at AML diagnosis were included in the analysis. Response to therapy was evaluated two weeks after therapy was initiated and at count recovery. The difference in distribution of each mutation between the patients who responded to chemotherapy after one or two courses of induction chemotherapy and non-responders was analyzed using Fisher's exact test and the Cochran-Armitage Trend test. Findings with an expected false discovery rate ≤ 10% were reported as positive. The study was approved by the University of Pittsburgh IRB committee. Results: One hundred twenty-seven newly diagnosed AML patients (median age 61 years, interquartile range 51-68 years) were treated with induction chemotherapy. Sixteen patients (13%) had favorable risk cytogenetics, 73 patients (58%) had intermediate risk cytogenetics, and 36 patients (29%) had unfavorable risk cytogenetics. The most common molecular event was an NPM1 (28%) mutation followed by DNMT3A (25%), FLT3-ITD (22%), NRAS (13%), ASXL1 (12%), TET2 (12%), and TP53 (11%) as shown in Figure 1. Eighty-five of 127 patients (67%) achieved CR after one course of chemotherapy with idarubicin and cytarabine (7+3) and 17 patients (13%) responded after a second course with mitoxantrone and etoposide. Twenty-five patients (20%) did not respond to one or two courses of induction chemotherapy. From the 102 patients that responded, measurable residual disease (MRD) data were available in 59 (58%) patients. 29% patients were MRD positive and 71% patients were MRD negative. Secondary AML and poor cytogenetics were associated with poor response. Among the 17 genes with at least 5% prevalence, only TP53 mutations were associated with worse response. TP53 mutations increased monotonically with worse outcomes; TP53 mutations were present in only 2% of those responding to one course of chemotherapy, in 18% responding to two courses, and in 38% with no response to either course (p < 0.0001). Ninety-three percent of patients (13 of 14 patients) with TP53 mutations had poor cytogenetics. After induction chemotherapy, 21% of patients with TP53 mutations achieved CR and 14% achieved morphologic leukemia-free state (MLFS); 2 patients achieved CR after one course and, after the second course, 1 patient achieved CR and 2 patients MLFS. From the 5 patients that responded, 4 had available MRD data; 2 patients were MRD positive and 2 patients were MRD negative. NPM1 mutations were associated with higher response rates to induction chemotherapy (p =0.002). Ninety-four percent of patients (32 of 34 patients) with NPM1 mutations had intermediate cytogenetics. After induction chemotherapy, 92% of patients with NPM1 mutations achieved CR and 3% achieved MLFS; 32 patients (89%) achieved CR after one course. Two patients received a second course; one patient achieved CR and one MLFS. From the 34 patients that responded, 20 patients had available MRD data; 9 patients were MRD positive and 11 patients were MRD negative. Conclusion: Among 17 gene mutations detected using NSG at AML diagnosis, only TP53 and NPMI mutations were associated with responses to induction chemotherapy. Patients with TP53 mutations at AML diagnosis were associated with lower response rates to induction chemotherapy, whereas NPM1 mutations were associated with improved response. Disclosures Raptis: INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Hou:Genentech: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: PI. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Sehgal:TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Research Funding.

Background: Tumor-associated macrophages (TAMs) play a key role in cutaneous T cell lymphoma (CTCL) growth and neoplastic T cells escape immune surveillance via PD1-PD-L1 axis (Querfeld, C., et al., Blood 2019; Khodadoust, M.S., et al., J Clin Oncol, 2020). There remains a lack of knowledge about how cytokines regulate the mechanisms controlling tumor-growth and polarize the tumor microenvironment (TME). Methods and Results: To investigate PD-L1 and PD1 expression on TAMs and T cells in mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS) patients, we performed multiplex immunofluorescence (IF) staining of lesional skin samples of MF patients that demonstrated co-localization of PD-L1 on CD163+ M2 macrophages and PD1 expression on CD4+ and CD8+ T cells. In addition, significant enrichment of CD14+ and CD16+/CD14dim CD163+ M2-like monocytes/macrophages with upregulated PD-L1 expression in SS patients compared to healthy donors (HDs) was found via FACS analysis. We also performed 30-plex Luminex cytokine assay on plasma samples, which showed significantly increased IL-6, IL-10, IFNγ and TNFα levels in plasma of MF/SS compared to HDs. To investigate whether polarization towards an M2-like macrophage phenotype with increased PD-L1 expression correlated with the cytokine expression from CTCL-TME, we cultured total PBMCs from HDs with conditioned media (CM) from well established CTCL cell lines MyLa and HuT78 and analyzed PD-L1 mRNA, total PD-L1 protein and PD-L1 surface expression on M2-like macrophages. Significantly increased expression of PD-L1 protein in total PBMCs, especially on CD14+ and CD16+/CD14dim M2-like macrophages was seen. To understand whether distinct cytokines are associated with PD-L1 upregulation on CD163+ M2-like populations, total PBMCs from HDs were stimulated with human recombinant IL-6, IL-10, IFNγ or TNFα. Antibody blocking studies were conducted by adding anti human IL-6, IL-10, IFNγ or TNFα to the cultures with CM. TNFα stimulation significantly increased the CD14+ M2-like subset, but did not affect CD16+/CD14dim M2-like subset. We observed increased PD-L1 expression on both M2-like populations with TNFα compared to other cytokines. In contrast, blockade of TNFα significantly decreased the CD14+ M2-like subset with reduced PD-L1 expression and increased CD16+/CD14dim M2-like cells with upregulated PD-L1 expression. To explore whether the STAT pathway regulates PD-L1 expression through cytokines from CTCL TME, we incubated total PBMCs from HDs in CM of MyLa and HuT78 cells with/without a pan-STAT inhibitor, and in media alone. Inhibition of STAT signaling decreased CD14+ M2-like macrophage population, but did not alter the CD16+/CD14dim M2-like population. In addition, pan-STAT inhibition significantly reduced surface expression of PD-L1 on both CD14+ and CD16+/CD14dim M2-like macrophages. The effects of cytokines on STAT signaling components in regulating PD-L1 expression were also investigated by FACS and immunoblots. TNFα blockade significantly downregulated PD-L1, but also pSTAT1, pSTAT3 and pNF-κB levels, illustrating the role of TNFα on STAT1, STAT3 and NF-κB pathways in conjunction with PD-L1 expression. Stimulation with TNFα increased pSTAT3 level in CD14+ M2-like macrophages, while it did not significantly change pSTAT3 in CD16+/CD14dim M2-like macrophages. Anti-TNFα reduced pSTAT3 levels in CD14+ M2-like macrophages, but profoundly increased PD-L1 in CD16+/CD14dim M2-like macrophages, which aligns with our data of increased PD-L1 expression on CD16+/CD14dim M2-like macrophages following TNFα blockade. Conclusion: We profiled immune alterations of monocyte/macrophages populations and PD-L1 expression in CTCL regulated by selected cytokines. Our results support the dominant role of TNFα in the CTCL microenvironment. Here we show that TNFα potentiates the immunosuppressive TME through macrophage polarization and STAT-mediated PD-L1 regulation. Our results identify potential targets for combination immunotherapy. Disclosures Zain: Seattle Genetics: Research Funding; Mundai Pharma: Research Funding; Kyowa Kirlin: Research Funding. Abdulla:Johnson Johnson: Research Funding; Mallinckrodt: Consultancy, Speakers Bureau. Rosen:Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Querfeld:Trillium: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Helsinn: Consultancy; Celgene: Research Funding; Kyowa Kirin: Consultancy; MiRagen: Consultancy.

Rapidly proliferating hematopoietic cells are particularly prone to threats to genomic integrity through replication stress. The response to replication stress involves complex molecular machinery to prevent replication fork collapse, avoid accumulation of DNA damage, and ensure the completion of DNA synthesis. Smarcal1, a DNA remodeling enzyme, has been linked to the replication stress response through stabilization, repair, and restart of stalled DNA replication forks. In humans, complete loss of function of Smarcal1 leads to the pleiotropic disorder Schimke immuno-osseous dysplasia (SIOD), which is characterized, in part, by a severe lymphoid immunodeficiency that leaves patients susceptible to opportunistic infections. Currently, the mechanisms driving the clinical immunodeficient phenotype of SIOD and the in vivo functions of Smarcal1 in hematopoietic cells remain largely unexplored. We evaluated the contribution of Smarcal1 to normal and stressed/emergency hematopoiesis, using a Smarcal1 knockout mouse model and hematopoietic cell replication stresses such as low-dose radiation, 5-fluorouracil, bone marrow transplantation, and oncogene- driven proliferation. We determined that, while loss of Smarcal1 does not affect hematopoietic stem and progenitor cells (HSPCs) or mature hematopoietic cell populations at a normal "resting" state, Smarcal1 is required in these cells undergoing proliferative stress. Following DNA replication stress, we detected defects in multiple Smarcal1-deficient hematopoietic cell populations. We also observed that loss of Smarcal1 led to significantly increased levels of replication stress, DNA damage, and apoptosis in proliferating cells. Through bone marrow transplantation, we determined that the deficiencies observed were not due to a defect in the bone marrow environment or an inability of the HSPCs to home to the bone marrow. Thus, our results reveal that Smarcal1 is critical to maintaining hematopoietic cell survival and function under conditions of DNA replication stress. Our data also suggest that the immunodeficiency of patients with Smarcal1 mutations may be due to an inability of hematopoietic cells, especially HSPCs, to properly respond to replication stress and proliferate. Since wild-type bone marrow is able to fully reconstitute and function in a Smarcal1-deficient environment, bone marrow transplantation may be an effective therapy for immunodeficient SIOD patients. Disclosures Eischen: AbbVie Inc.: Research Funding.

Affiliation 1Muhimbili University of Health and Allied Sciences, Dar es salaam, Tanzania. 2Department of Oncology, University of Oxford, Oxford UK. 3Dar es salaam University College of Education, Dar es salaam, Tanzania. ABSTRACT. Background; SCD constitutes to be a major public health problem in Tanzania. NBS for SCD identify infants with SCD at birth and subsequently enroll them into SCD comprehensive care program and it has been reported to reduce early childhood mortality and morbidity due to SCD and increase life expectancy. There are different methods for Newborn screening for SCD such as HPLC, IEF, DNA analysis, sickle scan and hemotype SC that helps in early detection of SCD and other haemoglobinopathies but we are lacking sufficient information on alternative screening methods that can be used for NBS in Tanzania so this study is aiming at investigating the effectiveness and feasibility of NBS laboratory tests. Aim of the study; To evaluate newborn screening Laboratory assays for sickle cell disease and other haemoglobinopathies in Tanzania. Methodology; This will be a retrospective and prospective study which will be conducted in Dar es Salaam and Mwanza.1000 newborns and 100 children with SCD under five years old will be enrolled. DBS samples will be collected and analyzed by DNA Analysis, sickle scan, Hemotype SC, HPLC, and IEF. SPSS version 16.0 will be used to analyze data. Statistically, significant tests will be declared at a level of p-value < 0.05. Progress: Initially we have conducted a pilot of 12 individuals who were screened for SCD and turned out to be carriers ( Hb AS). However these individuals continuously reported to experience painful events. Initial analysis has include Hb subtyping and quantification by HPLC,Sickle scan and HemotypeSC to ascertain indicator for thalassaemia syndrome. Definitive analysis involved sequencing of thalassaemia and SCD associated regions by using Oxford Nanopore Technology and NGS Expected outcomes; The findings of this study will inform Newborn screening stakeholders on the best point of care screening test and definitive test, in terms of turnaround time and cost. Such findings will assist in planning and scaling up of newborn screening services across the country. Corresponding Author; HChristopher, Email; hchristopher@blood.ac.tz, Tel; +255762175732. Disclosures Schuh: AbbVie: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Speakers Bureau; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau; Verastem: Speakers Bureau.

EBV-immortalized B lymphocyte cell lines have been widely banked for studying a variety of diseases, including rare genetic disorders. These cell lines represent an important resource for disease modeling with the induced pluripotent stem cell (iPSC) technology. Here we report the generation of iPSCs from EBV-immortalized B-cell lines derived from multiple inherited disease patients via a nonviral method. The reprogramming method for the EBV cell lines involves a distinct protocol compared with that of patient fibroblasts. The B-cell line–derived iPSCs expressed pluripotency markers, retained the inherited mutation and the parental V(D)J rearrangement profile, and differentiated into all 3 germ layer cell types. There was no integration of the reprogramming-related transgenes or the EBV-associated genes in these iPSCs. The ability to reprogram the widely banked patient B-cell lines will offer an unprecedented opportunity to generate human disease models and provide novel drug therapies.

Introduction: Thirty-day readmission risk is widely accepted as an indicator of quality of care. Sickle cell disease (SCD) has one the highest hospital readmission risk with a wide variation between different studies. In recent studies, older age, insurance status, and systemic complications including sepsis, renal and liver disease increased the risk of readmission whereas blood transfusion reduced the risk. During hospital stay, patients experience a variety of changes in their symptoms and laboratory measures. Evidence on the role of these changes on readmission risk is limited. In the current study, we aimed to assess the clinical and laboratory predictors of 30-day readmission risk in SCD adult patients in a tertiary health care system. Methods: Medical record discharge abstract files which cover visits for the SCD patients at the University of Pittsburgh Medical Center (UPMC) were extracted from electronic health records. Laboratory test results were obtained for each admission and were linked to discharge data. For each admission ICD 9/10 codes were used to identify the comorbidities. Blood transfusion information was recorded during each the admission. Natural language processing was used to extract medical concepts from chest X-ray and CT scan reports during patient's admission. Acute chest syndrome/pneumonia were identified from a combination of ICD codes and radiologic reports. For each laboratory value, a single rate of change (trajectory) was calculated with a random coefficient model from any measures during the hospital stay. Rate of changes were categorized to negative and positive trajectory. We used Generalized Estimating Equations models to assess predictors of 30-day readmission risk including the relationship between negative trajectory of any laboratory values duration the admission. Results: During January 2010 to May 2016, data for 2,108 hospital admissions in 173 SCD unique adult patients (median age of 32, 57% female and 59% SS genotype) were extracted. Risk of 30-day readmission was 41.2%. Older age (P Conclusions: These results support that cardiopulmonary comorbidities are unexpectedly common in adult SCD patients. Blood transfusion in younger SCD patient reduced the readmission risk. Renal complications and leukocytosis in these patients contributed to health care utilization. Using advanced predictive models can help us to define patients who are at higher risk of readmission and generate strategies to reduce hospital readmission. Disclosures No relevant conflicts of interest to declare.

Background: Classic Hodgkin lymphoma (CHL) is currently highly curable. Surveillance guidelines have been extrapolated largely from an era where sophisticated staging techniques were lacking, radiotherapy alone was the mainstay of therapy, and cure rates were lower. While the lack of a role for surveillance imaging for patients (pts) in complete remission (CR) at end of therapy (EOT) is well established, there is paucity of data regarding role of laboratory testing. Current NCCN guidelines recommend complete blood counts (CBC), chemistry panels, and erythrocyte sedimentation rate (ESR) "as clinically indicated," while ESMO recommends testing be performed at each clinic visit. To assess the utility of surveillance laboratory testing in detecting relapse, we conducted a retrospective analysis. Methods: Newly diagnosed CHL pts, uniformly treated with the Stanford V regimen from 1998-2014 and in CR for at least 3 months, were identified from our institutional lymphoma database. Post EOT, follow up included; a clinic visit and laboratory tests (CBC, metabolic panel, ESR) every 2-3 months for years 1-2 and at 6-12 month intervals thereafter for years 3-5. Data at surveillance visits were abstracted from electronic medical records for up to five years after EOT. Laboratory tests categorized by CTCAE v4.03 as Grade 2 or higher were considered abnormal. Values outside the normal range were considered abnormal for non-categorized tests. Primary analysis included sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of surveillance laboratory tests for predicting relapse in first three years after EOT. Secondary objectives included assessment of subsets of higher risk pts defined as early stage (ES) unfavorable [GHSG or EORTC criteria], early stage bulky disease, ESR > 30 mm/hr and advanced stage disease with an international prognostic score (IPS) 3-7. Results: 235 pts were identified. Characteristics included median age 32 (range 18-82), 92 (39.1%) ES favorable, 66 (28.0%) ES unfavorable, and 61 (25.9%) advanced stage. 16 (6.8%) of ES pts could not be classified as favorable or unfavorable due to missing data. 24 (10.2%) pts relapsed at a median time from EOT of 8 months (range 3.4-80.5). In the first three years after EOT among 234 pts (one did not undergo laboratory testing), the mean number of surveillance blood draws per patient was 7.1, range (1-13). These 1661 surveillance blood draws included 4684 individual laboratory tests, comprising 1609 CBCs, 1578 metabolic panels, and 1497 ESRs. 180 (77%) of pts had at least one abnormal test result over five years. None of the biopsies confirming relapses were prompted by any abnormal laboratory finding. Relapses were detected on basis of surveillance imaging (n=15, 65.2%), patient symptoms and/or abnormal physical exam (n= 8, 34.8%). The sensitivity of any surveillance laboratory test for detecting relapse within 3 years of EOT was 72.7% (95% CI: 49.8-89.3%), specificity 22.6% (17.2%-28.9%), yielding a PPV of 8.9% (95% CI: 7.0%-11.3%) and NPV of 88.9% (79%-94%). Similar results were seen in higher risk subsets (Table 1). Conclusion: Our study found no utility of routine surveillance laboratory testing in detecting relapse in pts with CR at EOT including higher risk subsets. Our results support modifications of current practice guidelines. Disclosures Lynch: Johnson Graffe Keay Moniz & Wick LLP: Consultancy; Rhizen Pharmaceuticals S.A.: Research Funding; Takeda Pharmaceuticals: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding. Advani:Agensys: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Millenium: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Merck: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Forty Seven, Inc: Other: Institutional Research Support; Janssen Pharmaceutical: Other: Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Cell Medica: Other: Consultancy/Advisory Role; Autolus: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support.

Background: The anti-apoptotic protein BCL2 is expressed in most non-Hodgkin lymphomas (NHL) including chronic lymphocytic leukemias (CLL), mantle cell lymphomas (MCL), follicular lymphomas (FL), diffuse large B cell lymphomas (DLBCL) and marginal zone lymphomas (MZL). BCL2 expression is associated with an inferior survival when co-expressed with MYC, an oncogene that induces cellular proliferation, especially in high-grade lymphomas with translocations in MYC and BCL2(HGBL-DH). Venetoclax, a selective BCL2 inhibitor, is effective in CLL, but has modest clinical activity in other NHLs. CLL has been shown to be "primed" and BCL2-dependent, predicting for a favorable response to venetoclax using BH3 profiling. This technique measures mitochondrial outer membrane depolarization (MOMP) after exposure to synthetic pro-apoptotic BH3 peptides that have different affinities to anti-apoptotic proteins BCL2, BCLXL, MCL1 and BCLW. Cells with functional BAX/BAK undergo MOMP after exposure to pro-apoptotic proteins BIM/BID. "Primed" cells undergo MOMP after exposure to BIM, BID and PUMA, where the latter inhibits all anti-apoptotic proteins. Thus, inhibiting the anti-apoptotic proteins would initiate apoptosis. We hypothesized that BH3 profiling of NHLs could help us understand the mechanisms of venetoclax-resistance in BCL2+ NHL. This has not yet been performed due to the rarity of samples archived as a viable cell suspension. Methods: We performed BH3 profiling on 138 B-cell NHLs (36 CLL/SLL, 42 FL, 38 DLBCL, 10 HGBL-DH, 13 MCL, and 3 MZLs) and 34 controls (14 tonsils and 20 peripheral blood mononuclear cells). NHLs were taken prior to (n=107) or after therapy (n= 31). A T-test and ANOVA were performed to determine the differences in MOMP between NHLs subtypes and normal B cells. We also profiled HGBL-DH cell lines to determine if chemotherapy (cyclophosphamide, doxorubicin, vincristine, dexamethasone and bendamustine) could potentiate venetoclax-responses. We measured the levels of anti-apoptotic proteins and MYC by immunoblot, speculating that proteins with short half-lives (MYC and MCL1) may fall upon cell-cycle arrest. Results: Normal B and T lymphocytes were primed and depended on BCL2, MCL1 and BCL-XL. NHLs were primed in 85% (121/138) of cases, 5% (6/138) were unprimed (no PUMA response) and 10% (14/138) were incompetent to undergo MOMP (no BIM/BID response), indicating dysfunctional BAX/BAK. The latter apoptotic defect was mainly seen in DLBCL (10/14). CLL and HGBL-DH had significantly higher venetoclax responses than DLBCL, MCL and FL (all p Conclusion: CLL and HGBL-DH were the most BCL2-dependent NHLs and had the highest responses to venetoclax. Venetoclax-resistance in our NHLs was due to the presence of MCL1, the lack of BCL2 expression and dysfunctional BAX/BAK. In the former scenario, resistance may be overcome by combining venetoclax with vincristine and doxorubicin, two drugs used in standard RCHOP. Disclosures Johnson: Seattle Genetics: Honoraria; Merck: Consultancy, Honoraria; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria, Other: travel, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, Research Funding. Steidl:Juno Therapeutics: Consultancy; Roche: Consultancy; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding. Scott:Janssen: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Celgene: Consultancy, Honoraria; Roche: Research Funding. Letai:Flash Therapeutics: Equity Ownership; Vivid Biosciences: Equity Ownership; AbbVie: Consultancy, Other: Lab research report; Novartis: Consultancy, Other: Lab research report; AstraZeneca: Consultancy, Other: Lab research report.

The survival of patients with Waldenstrom macroglobulinemia (WM) varies enormously. The development of prognostic models in WM has been fraught by limited follow-up in current studies. Here, we update the outcome of a prospective WM trial with a median follow-up of 10 years for live patients. Of the 59 previously untreated patients who initially were observed, only 12 patients (21%) required therapy at a median follow-up of 100 months. Multivariate analysis among the 183 patients requiring therapy reaffirmed age 70 years or greater, previous nonprotocol therapy, and β-2 microglobulin (B2M) of 3 mg/dL or greater as prognostic factors. Importantly, increased serum lactate dehydrogenase (LDH) was identified as an additional independent variable, which improved risk assessment beyond the recent WM international prognostic scoring system (ISSWM). By using age, previous therapy, B2M, and LDH, we identified 3 risk groups with 8-year survival estimates of 55%, 33%, and 5% (P < .001). These data provide novel insights into factors predicting long-term outcome in WM. This trial has been registered with www.cancer.gov under ID 4852904.

It is well established that the stromal niche exerts a protective effect on chronic lymphocytic leukemia (CLL) cells, thereby also affecting their drug sensitivity. One hallmark of malignant cells is metabolic reprogramming, which is mostly represented by a glycolytic shift known as the Warburg effect. Because treatment resistance can be linked to metabolic alterations, we investigated whether bone marrow stromal cells impact the bioenergetics of primary CLL cells. In fact, stromal contact led to an increase of aerobic glycolysis and the cells' overall glycolytic capacity accompanied by an increased glucose uptake, expression of glucose transporter, and glycolytic enzymes. Activation of Notch signaling and of its direct transcriptional target c-Myc contributed to this metabolic switch. Based on these observations, CLL cells' acquired increased glucose dependency as well as Notch-c-Myc signaling could be therapeutically exploited in an effort to overcome stroma-mediated drug resistance.

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+) T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemogenesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the expression of distinct cellular genes. Alterations in the expression levels of unknown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked to Tax transformation and ATL leukemogenesis, this study systematically compared the gene expression of cultured cells from patients with acute ATL with that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These include a dual-specific protein phosphatase (PAC1), an interferon-inducible factor (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) signaling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309--specific antiapoptotic activity and the proapoptotic effect of inhibitors of I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apoptosis in ATL cells and could substantially contribute to their growth. (Blood. 2001;98:1150-1159)