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Acute myeloid leukemia (AML) is fatal in majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting IQGAP1-GRD domain, and conducted SAR of ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, G2/M arrest, and colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. IQGAP1/F-actin showed co-localization and UR778Br induced filopodia formation in U937 cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows dependency on IQGAP1 and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.

PDF file, 62K, Newly acquired unpublished clinical data for cases previously described by our group.

Context.— Unicentric Castleman disease (UCD) is a dynamic entity with a wide spectrum of morphologic findings. UCD can be further subdivided into hyaline-vascular and mixed/plasmacytic variants. Hyaline-vascular UCD has both follicular and interfollicular (stromal) changes, and occasionally these lesions show a skewed representation of either the follicular or stromal compartments. Plasmacytosis is usually minimal in hyaline-vascular variant. Mixed/plasmacytic variant of UCD is composed of sheets of plasma cells often associated with a variable number of follicles with regressive changes. Objective.— To illustrate the differential diagnosis of UCD, as it is quite broad and includes lymphomas, plasma cell neoplasms and stromal neoplasms such as follicular dendritic cell sarcoma and vascular neoplasms, immunoglobulin G4–related disease, infections, and other rare lesions. An additional objective is to enhance awareness of the morphologic features of UCD in excisional and in small core-needle biopsy specimens, the latter of which may inadvertently target follicle- or stroma-rich areas, causing diagnostic challenges. Data Sources.— In this review, we provide the readership a concise illustration of the morphologic spectrum of UCD that we have encountered in our practice and a brief discussion of entities in the differential diagnosis. Conclusions.— UCD exhibits a broad spectrum of morphologic changes, and awareness of these morphologic variations is key to avoid misdiagnosis.

T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.

Acute eosinophilic leukemia (AEL) is a rare form of acute myeloid leukemia (AML) that requires prompt exclusion of reactive etiologies of eosinophilia and identification of an underlying acute myeloid neoplasm. Myeloid neoplasms with prominent eosinophilia often have rearrangements in the platelet-derived growth factor receptor α (PDGFRA) or β (PDGFRB) or are associated with core-binding factor AML. In this report, we describe a 35-year-old male presenting with chest discomfort and altered mental status, found to have marked leukocytosis with eosinophilic predominance and an elevated blast count. Bone marrow aspirate and biopsy findings were morphologically consistent with AEL. Fluorescence in situ hybridization (FISH) and standard karyotype analysis did not reveal any abnormalities, and mutation analysis using next generation sequencing (NGS) revealed a pathogenic mutation in PHF6. Cardiac work-up revealed findings suggestive of eosinophilic myocarditis. High-dose glucocorticoid therapy was initiated followed by standard intensive induction chemotherapy with cytarabine and idarubicin. He experienced a rapid reduction in peripheral blood eosinophil and blast count and was found to be in a complete remission at the time of his postinduction bone marrow examination. He underwent allogeneic stem cell transplantation with a matched sibling donor after consolidative high-dose cytarabine and remains in remission at the time of this report, 6 months following his initial diagnosis. The rarity of this condition has resulted in a paucity of data to guide management. Additional studies are needed to better characterize this entity and inform optimal management strategies to attain a long-term sustained remission in these patients.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) with unusual features, including some that can overlap morphologically with classic Hodgkin lymphoma (CHL), have been described. Herein, we describe 12 cases of NLPHL with fibrous bands and capsular fibrosis resembling, in part, nodular sclerosis (NS) CHL. Seven of 12 cases harbored Reed-Sternberg-like cells, further suggestive of CHL, but all cases lacked associated eosinophils and/or plasma cells in the background. In this cohort, all cases had areas of so-called pattern D (nodular T-cell rich) as a sole component in 7 (58%) cases or as a hybrid pattern along with pattern E (diffuse T-cell/histiocyte-rich) in 5 (42%) cases. The immunophenotype of the large neoplastic cells in these cases supported their being lymphocyte predominant cells of NLPHL, positive for CD20, CD79a, and OCT2, and negative for CD15 and CD30. However, PAX5 was weak in 9 of 11 cases similar to Hodgkin/Reed-Sternberg cells in CHL. We conclude that some cases of NLPHL are associated with fibrous bands and capsular fibrosis and resemble, in part, NS CHL. In our experience, NLPHL with NS-like features occurs in 10% to 15% of cases of NLPHL and is associated with a variant pattern (D and/or E). In addition, all patients in this cohort were not treated before biopsy, suggesting that the prominent sclerosis in these cases is inherent to disease biology. Recognition of NLPHL with NS-like features further expands the morphologic spectrum of NLPHL and helps avoid potential misdiagnosis as CHL.

Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a case of donor-derived, transient Alpha Beta (αβ) T-cell large granular clonal lymphocytosis and cytopenia that emerged post-HSCT in a patient with a history of gamma delta (γδ) T-cell large granular lymphocytic leukemia (T-LGLL). Clonal unrelatedness of post-transplant T-LGL lymphocytosis to the patient's pretransplant T-LGLL was first identified by T-cell receptor (TCR) PCR showing different sized fragments of rearranged gamma chains, in addition to shift from γδ to αβ TCR expression by flow cytometry analyses. Donor-derivation of the patient's post-transplant clonal lymphocytosis was confirmed by serial chimerism analyses of recipient's blood specimens demonstrating 100% donor DNA. Moreover, oncogenicDNMT3AandRUNX1mutations were detected by next-generation sequencing (NGS) only in post-transplant specimens. Intriguingly, despite continued increase inDNMT3AandRUNX1mutation load, the patient's clonal lymphocytosis and anemia eventually largely resolved; yet, the observed mutation profile with persistent thrombocytopenia indicated secondary clonal cytopenia of undetermined significance (CCUS) in the absence of overt morphologic evidence of myeloid neoplasm in the marrow. This case illustrates the utility of longitudinal chimerism analysis and NGS testing combined with flow cytometric immunophenotyping to evaluate emerging donor-derived hematolymphoid processes and to properly interpret partial functional engraftment. It may also support the notion that driver mutation-induced microenvironmental changes may paradoxically contribute to reestablishing tissue homeostasis.

Hepatic involvement by a T-cell neoplasm is rare and often challenging to diagnose in liver biopsies. We collected 40 cases of T-cell neoplasms diagnosed in the liver from five large academic institutions to assess the clinicopathologic features. The patients included 11 women and 29 men, with a median age of 54 (range: 2-75) years and a high mortality rate (31/37, 83.8%). Fourteen (35%) patients were diagnosed with hepatosplenic T-cell lymphoma (HSTCL), 13 (32.5%) peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 (32.5%) other types of T-cell neoplasms. Patients with HSTCL were much younger and had worse survival than PTCL-NOS and other T-cell neoplasms (P 0.05). On imaging studies, 20 cases (50%) showed abnormalities, including 10 with mass lesions that correlated with normal or cholestatic pattern enzyme elevation. Histomorphological analysis revealed four main patterns; with the exception of mass forming lesions (pattern 4; n = 8), cases with sinusoidal predominant (pattern 1; n = 12), portal predominant with sinusoidal infiltrates (pattern 2; n = 13) or lobular aggregates (pattern 3; n = 5) demonstrated small to medium lymphocytes resembling a reactive/inflammatory process. In addition, we described two cases of T-cell large granular lymphocytic leukemia that mimicked HSTCL, and a case of aggressive post-transplant lymphoproliferative disorder that developed after chronic Epstein-barr virus (EBV) infection, suggesting the importance of EBV testing in some lymphoma cases. As the largest cohort of T-cell neoplasms in liver, our study provides critical data on disease frequency, distribution, and clinicopathologic features that are essential for accurate diagnosis.

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is associated with increased risk for certain cancers, but relatively little is known about the risk for these patients to develop additional B cell malignancies. Here, we review the available epidemiological data on multiple B cell malignancies in CLL, discuss diagnostic methods and proper pathologic evaluation to distinguish CLL from other B cell malignancies, and address clinical challenges and unmet needs in caring for CLL patients with unrelated B cell malignancies and disease transformation. Considerations include CLL patients with unrelated monoclonal B cell lymphocytosis, biclonal CLL, secondary B cell non-Hodgkin lymphomas, and Richter syndrome - both clonally related transformation and de novo large B cell lymphoma. We address the challenges that remain in order to better understand the underlying risk factors and biology that may put CLL patients at increased risk of developing multiple B cell neoplasia.

Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (∼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.

Phosphoinositide-3-kinase (PI3K) inhibitors have efficacy in lymphoid malignancies; however, inflammatory and infectious toxicities can compromise the treatment course. An improved understanding of these toxicities will guide clinical use and further development. We evaluated the occurrence of treatment-related adverse events (AEs) in a retrospective review of 79 patients treated in standard fashion with PI3K inhibitor monotherapy or with anti-CD20 monoclonal antibodies or as part of a novel combination regimen. Patients treated with a novel combination were at a higher risk of developing a severe AE compared to those treated with standard therapy (HR 1.89, 95% CI 1.02, 3.49

Benign or malignant diseases confined to the liver can be associated with inflammation, including lymphoid or plasmacytic infiltrate, and can rarely mimic neoplastic hematopoietic disorders. These differential diagnoses have received limited attention in the literature. Understanding the patterns of liver histology caused by lymphoma and various non-neoplastic inflammatory pathologies is essential, as the differential diagnosis varies depending on whether an inflammatory infiltrate primarily involves portal tracts, primarily involves sinusoids, or forms a discrete mass lesion.

Key Clinical Message We present the case of a 30‐year‐old woman with a history of perinatal complications as well as bladder and urinary disease through her childhood and adult life. Microarray comparative genomic hybridization (aCGH) analysis revealed a 1.3 megabase duplication at chromosome 8q21.11 encompassing the CASC9 and HNF4G genes.

OBJECTIVES: Myeloid proliferative disorders associated with Down syndrome (MPD-DS), including transient abnormal myelopoiesis and myeloid leukemia associated with Down syndrome (DS), harbor mutations of GATA1, a transcription factor essential for erythroid and megakaryocytic development. These mutations result in a N-terminally truncated GATA1 (GATA1s) and prohibit the production of the full-length GATA1 (GATA1f). Here, we demonstrate the utility of immunohistochemical GATA1f reactivity in diagnosing MPD-DS. METHODS: Immunohistochemical studies for GATA1f expression were performed on bone marrow biopsy specimens. RESULTS: In all cases of MPD-DS, megakaryocytes lacked GATA1f expression. In contrast, GATA1f expression was detected in megakaryocytes in all specimen types from patients without DS (normal bone marrows, pediatric myelodysplastic syndrome, juvenile myelomonocytic leukemia, adult acute megakaryocytic leukemia [pediatric and adult; without trisomy 2]), as well as normal bone marrows from patients with DS. CONCLUSIONS: The lack of GATA1f expression is a sensitive and specific immunohistochemical marker for MPD-DS.

Introduction ALK-negative anaplastic large cell lymphoma (ALK- ALCL) is an uncommon type of T-cell non-Hodgkin lymphoma (T-NHL) with worse prognosis compared to ALK-positive (ALK+) ALCLs. Most published studies on the genomics of T-NHL have focused on peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and previous studies of ALCL described rearrangements in DUSP22 and TP63 and mutations in genes comprising the JAK/STAT pathway as common genetic drivers in ALK- ALCL. The degree to which these drivers affect survival or other molecular features of ALK- ALCL remains unknown. Here, we describe novel subgroups of ALK- ALCL that exhibit distinct survival. One subgroup appears molecularly similar to ALK+ALCLs and is associated with favorable survival while the second subgroup is quite distinct from ALK- ALCLs and associated with poor outcomes. Methods and Results Eighty-two ALK- ALCL patients were recruited to the Atlas of Blood Cancer (ABC) genomes project, a worldwide consortium established to define the molecular origins of blood cancers. Tumor biopsies from these patients, as well as 10 ALK+ ALCL samples for comparison were obtained from participating institutions. Each case was subjected to centralized pathology review by an experienced panel of hematopathologists to ensure the accuracy of the diagnosis. All cases, along with paired normal tissues, were subjected to DNA and RNA (whole exome-level) sequencing on the Illumina platform to identify mutations and expression changes for each of these cases using methods well established in our group and described previously. We first examined the genetic alterations in ALK- ALCLs. In addition to frequently described genetic alterations such as TP63 and DUSP22 rearrangements, as well as mutations in JAK1, STAT3 and TP53, we also detected mutations in ERBB4, SETD2 and KMT2D, which may serve as potential novel drivers and have not been described previously to our knowledge. We next performed comparative gene expression analysis of the ALK- and ALK+ ALCLs. Surprisingly, a proportion of ALK- ALCL cases (38%) clustered together with ALK+ ALCLs and had a signature resembling ALK+ cases, which we designated as "ALK-like ALCL" here. Both the ALK-like ALCLs and the other ALK- ALCL cases showed decreased ALK expression compared to the ALK+ ALCLs by gene expression analysis. These results point to downstream pathways that are common among ALK+ALCLs and ALK-like ALCLs, but different from the other ALK- ALCLs. Gene set enrichment analysis revealed that the ALK-like ALCLs overexpressed genes in pathways related to monocyte and fibroblast activation, whereas the remaining ALK- ALCLs overexpressed genes in the T follicular helper cells, memory T cells and adaptive immune response-related pathways (P Conclusion Our data indicate that ALK- ALCLs represent a heterogeneous group of diseases and comprise at least two distinct subgroups that can be identified based on their similarity to the ALK+ ALCLs. The ALK-like ALCLs demonstrated distinct molecular features and favorable outcomes. Our results provide a potentially new approach to patient risk-stratification and pathological classification of this disease. Disclosures Kwong: Celgene: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Jaye: Stemline Therapeutics: Honoraria. Behdad: Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau; Lilly: Speakers Bureau. Hsi: AbbVie Inc, Eli Lilly: Research Funding. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

INTRODUCTION Naked nuclei (NN) are observed upon examining bone marrow aspirate slides from healthy individuals and from those with hematologic malignancies, but are not well understood. Without characteristic findings like cytoplasm or plasma membrane, NN are considered remnants of slide preparation or are discounted as cells of undetermined significance. NN have been associated with poor prognosis in several solid cancers. Understanding the significance of NN in hematologic malignancies such as acute myelogenous leukemia (AML) may elucidate valuable diagnostic and prognostic knowledge. Decellularized Wharton's jelly matrix (DWJM) is an extra cellular matrix (ECM)-based in vitro model that shares similar elements with the bone marrow ECM and can be used as scaffolding to culture leukemia cells. We hypothesize that NN exist in AML and interact with other cells, suggesting potential biological relevance within the bone marrow microenvironment. METHODS Primary AML samples obtained by leukapheresis were cultured in suspension with growth media or in the presence of DWJM submerged in growth media. In samples grown with DWJM, cells that were non-adherent to the matrix were collected first and then adherent cells were isolated by treating DWJM with collagenase. Live cells were stained with CellVue Maroon (CVM) for membrane, CellTracker Green (CTG) for cytoplasm, and Hoechst 33342 for nucleus, followed by analysis with Amnis/Luminex ImageStream-X imaging flow cytometer (Figure 1A). NN were defined as events positive for nuclear stain and negative for cytoplasmic and membrane stains (Figure 1B). 3-D movement of adherent AML cells in DWJM was captured in real time using confocal microscopy. Fixed cells from leukemia cell line K562 served as a control for movement. NN (Hoechst positive only), non-nucleated (Hoechst negative/CTG positive), and nucleated cells (Hoechst and CTG positive) were identified by fluorescent labeling. NN were also observed after isolation by cell sorting. Cell speed, cell displacement from origin, and change in distance to closest neighboring cell over time were measured. Additionally, flow sorted NN were examined by immunohistochemistry (IHC). RESULTS Adherent populations contained significantly more NN than non-adherent and suspension populations. The frequency of NN in matrix adherent cells ranged from 0.4-2.4% at day 3 and 0.5-5.4% at day 7 of culture (Figure 1C). Through confocal microscopic analysis, we observed NN, nucleated, and non-nucleated cells moving at speeds ranging from 0.002-0.08 µm/sec. Fixed cells showed no discernible movement in DWJM. The average speed of NN [0.019 mm/s, SD 0.011] significantly differed from the average speed of nucleated and non-nucleated cells [0.027 mm/s, SD 0.016] (p=0.004) (Figure 1E). To demonstrate directional movement, we measured change in distance between NN and closest neighboring nucleated or non-nucleated cells over time. Cells (nucleated and non-nucleated) and NN moved closer to each other over time suggesting directional movement (p=0.001) (Figure 1D). NN also showed movement in DWJM after isolation by cell sorting. IHC analysis showed sorted NN stained positive for nuclear lamin A/C, which are considered markers of nuclear membrane (Figure 1F). CONCLUSIONS Our findings confirm that NN are present in primary AML cells cultured in vitro using ourECM-based model and that they can be isolated using flow cytometry. Additionally, NN display directional movement in DWJM suggesting that they interact with other cells and may be biologically relevant structures in the bone marrow microenvironment. Figure 1 Figure 1. Disclosures Baran: AstraZeneca/Acerta: Research Funding. Chu: Pfizer: Current equity holder in publicly-traded company; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding.

Introduction Blood cancers are collectively common and strikingly heterogeneous diseases both clinically and molecularly. According to the WHO taxonomy, there are over 100 distinct myeloid and lymphoid neoplasms. Genomic profiling of blood cancers has been applied in a somewhat ad hoc fashion using diverse sequencing approaches including the use of targeted panels, whole exome sequencing, whole genome sequencing, RNA sequencing, etc. The lack of data uniformity has made it difficult to comprehensively understand the clinical and molecular spectrum within and across diseases. Systematic genomic approaches can address the central challenges in the diagnosis and treatment of blood cancers. For the diagnosis of blood cancers, the incorporation of genomics could greatly enhance the accuracy and speed of clinical diagnostics. Genomics could also inform their pathology classification. However, these applications must be preceded by a clear understanding of the particular genetic aberrations and expression profiles that unite and distinguish different leukemias and lymphomas. Therapeutic development can also be aided by genomic approaches through identification of new targets and establishing the relevance of existing targets and treatments. Targeted therapies including those directed at specific surface markers (e.g. CD19, CD30 and CD123) or molecular targets (e.g. BCR-ABL fusions, IDH1 mutations and EZH2 mutations) are rarely restricted to a single disease, with most occurring in multiple blood cancers. A systematic understanding of the presence or overlap of these targets within or across blood cancers would significantly expand the therapeutic possibilities and better enable the use of existing therapies in both common and rare cancers. However, such therapeutic possibilities need to be established through a rigorous, data-driven approach. We initiated the Atlas of Blood Cancers Genomes (ABCG) project to systematically elucidate the molecular basis of all leukemias and lymphomas by building upon advances in genomic technologies, our capabilities for data analysis and economies of scale. Using a uniform approach to systematically profile all blood cancers through DNA and RNA sequencing at the whole exome/whole transcriptome level, we aim to link genomic events with clinical outcomes, disease categories and subcategories, thereby providing a complete molecular blueprint of blood cancers. Methods/Results The ABCG project consists of collaborators from 25 institutions around the world who have collectively contributed samples from 10,481 patients comprising every type of blood cancer in the current WHO classification. The samples include thousands of myeloid leukemias and mature B cell lymphomas, hundreds of Hodgkin lymphoma and plasma cell myeloma, as well as every rare type of hematologic malignancy (along with case-matched normal tissue). All cases were de-identified and their associated pathology and detailed clinical information entered into a purpose-built web-based system that included disease-specific data templates. All cases were subjected to centralized pathology review and clinical data review by experienced hematopathologists and oncologists. All 10,481cases are being sequenced at the DNA and RNA level, and are being profiled to define the genetic alterations and expression changes that are characteristic of each disease. Analysis will include translocations, copy number alterations, and viral status. These molecular features will be examined in conjunction with genetic events, pathologic factors, and the clinical features. We have already generated results for ALK-negative anaplastic large B cell lymphoma and primary mediastinal B cell lymphomas (N=210). These data demonstrate novel subgroup and molecular discoveries that are enabled by integrative DNA and RNA sequencing analysis and the examination of molecular features across different diseases as well as within individual entities. In addition, other disease entities and the collective data will be presented in the meeting. Conclusion The ABCG project will comprehensively study the genetic and clinicopathological features of all blood cancers using systematic genomic approaches. We anticipate our data, approaches and results will serve as a lasting resource for the molecular classification and therapeutic development for leukemias and lymphomas. Disclosures McKinney: Novartis: Research Funding; Nordic Nanovector: Research Funding; Molecular Templates: Consultancy, Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Incyte: Research Funding; Genetech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Celgene: Consultancy, Research Funding; BTG: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Verastem: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau.

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rare non-Hodgkin lymphoma subtype that occurs predominantly in young adults, with an overall favorable prognosis. The cell of origin is presumed to be thymic medullary B-cells and the gene expression profile of PMBL is similar to classic Hodgkin lymphoma. Recent studies have begun unravelling the genomic alterations underlying PMBL. Frequent, recurrent mutations (e.g. B2M, TNFAIP3, SOCS1, STAT6, GNA13) have been reported, but most of the studies have analyzed a small number of cases. To gain further insights into disease biology, we recruited 63 cases of PMBL as part of the Atlas of Blood Cancer Genomes (ABC-G) initiative, a consortium consisting of 25 institutions. Methods: Formalin-fixed paraffin-embedded (FFPE) biopsies and clinical data were collected. All cases were subjected to centralized review by an experienced panel of hematopathologists to ensure accurate diagnosis. Whole-exome DNA and RNA sequencing was performed using the Illumina platform and the DNA and RNA reads aligned to the GRCh38 genome and transcriptome respectively. Exonic variants were filtered using a set of paired normal samples and population-based databases to identify putative driver mutations, which were then aggregated at the gene level. Mutational analysis was performed on 56 samples that passed quality filtering and expression analysis on 45 samples. RNAseq data was normalized using DESeq2. Results: The cohort included samples from 16 males and 24 females, with a median age of 33 years (range 16 - 72) at the time of diagnosis. The majority of patients were treated with R-CHOP (47%) or R-EPOCH (43%), with 93% of patients surviving through the end of follow-up (median follow-up: 60.1 months). Besides the known recurrent mutations involving the JAK-STAT (STAT6 -21%, SOCS1 - 26%), NFKB (TNFAIP3 - 27%, NFKB1A - 7%), immune escape (B2M - 20%, LTB - 11%, IRF8 - 9%, IRF4 -9%), and chromatin modification (ZNF217 - 16%, CREBBP - 11%, KMT2D -11%) pathways , we discovered recurrent somatic variants in novel candidate driver genes in this disease, including NOTCH4 (7%), DICER1 (11%), MCL1 (7%), amongst others. EZH2, EP300, and XPO1 mutations were not detected. CIITA mutations and fusions were observed in 14% and 11% of cases, respectively, with novel partner genes (IGHA2, IGHG1, CDC6) detected in 67% of the fusion positive cases. Copy number alterations included gains at 2p16.1 (REL - 20%) and 9p24.2 (JAK2/PDL1/PDL2 - 24%), as well as loci not previously implicated in PMBL, 8q24.3 and 9q34.3 (each in 20%). Of note, CIITA alterations and 9p24 gains were virtually mutually exclusive, highlighting diverse mechanisms of immune escape in this entity. The transcriptomes of cases harboring CIITA alterations demonstrated differential enrichment of genes involved in protein glycosylation. The PMBLs in our series showed significant enrichment of the reported PMBL genetic classifier score, compared to nodal diffuse large B cell lymphoma (DLBCL) (p=0.0003). Finally, the gene expression profile of thymic B cells was more similar to that of PMBL than nodal DLBCL (p=0.0144). Conclusions: Our study, representing one of the largest comprehensive genomic and transcriptomic analyses of PMBL, expands the mutational landscape of PMBL, provides evidence for biologically distinct disease subsets and suggests an origin of PMBLs from thymic B-cells. Disclosures Hsi: AbbVie: Research Funding; Eli Lilly: Research Funding; Cytomx: Honoraria; Seattle Genetics: Honoraria. McKinney: BTG: Consultancy; Celgene: Consultancy, Research Funding; Epizyme: Consultancy; Genetech: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria, Speakers Bureau; Molecular Templates: Consultancy, Research Funding; Nordic Nanovector: Research Funding; Novartis: Research Funding; Pharmacyclics: Consultancy; Verastem: Consultancy; Beigene: Research Funding; ADC Therapeutics: Consultancy, Speakers Bureau. Jaye: Stemline Therapeutics: Honoraria. Cohen: Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding; Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy. Behdad: Lilly: Speakers Bureau; Roche/Foundation Medicine: Speakers Bureau; Thermo Fisher: Speakers Bureau. Dave: Data Driven Bioscience: Current equity holder in publicly-traded company.

Although most patients (pts) with newly diagnosed stage III or IV Hodgkin lymphoma (HL) will be cured with initial therapy (tx), about 20-25% of pts will have relapsed or refractory (R/R) HL. The standard initial tx for adults with advanced stage HL, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), is associated with pulmonary toxicity due to bleomycin. Recent studies have demonstrated that in pts with a negative interim PET scan, the omission of bleomycin after 2 cycles is non-inferior with regards to survival. However, a significant proportion of pts have a positive interim PET scan and require escalation to BEACOPP - an effective but toxic regimen associated with secondary malignancies and infertility. Recently, the addition of brentuximab vedotin (BV) to AVD chemotherapy (BV-AVD) demonstrated improved modified and traditionally-defined progression-free survival (PFS) compared to ABVD. However, the BV-AVD regimen was associated with higher rates of neutropenia, sepsis, and peripheral neuropathy compared to ABVD, and there still was a ~20% failure rate. In adolescent and young adult pts with advanced stage HL, there is a similar ~20% failure rate using ABVE-PC (AB, vincristine, etoposide, prednisone, cyclophosphamide) and response-adapted radiation therapy (RT) - with RT use in a majority of pts. There remains room to improve outcomes in pediatric and adult pts with newly diagnosed advanced stage HL. The PD-1 pathway plays a critical role in the pathogenesis of HL and the disease is exquisitely sensitive to PD-1 blockade, as demonstrated in clinical trials of nivolumab and pembrolizumab in pts with heavily treated R/R HL. A phase II trial evaluating nivolumab combined with AVD (N-AVD) demonstrated promising safety and efficacy in pts with newly diagnosed HL. The incorporation of PD-1 blockade into front-line tx represents a clear opportunity to potentially improve the outcomes and tolerability of initial tx for pts with newly diagnosed advanced stage HL. A meeting was convened between the North American cooperative group Lymphoma Committee chairs, expert HL researchers and physicians, representatives from the Cancer Therapy Evaluation Program (CTEP), and patient advocates with the goals of harmonizing treatment approaches in advanced stage HL across pediatric and adult pts and reaching consensus regarding the optimal study design for a randomized trial incorporating PD-1 blockade into frontline tx for pts with advanced stage HL. Study champions were identified from each of the North American cooperative groups (SWOG, ECOG-ACRIN, Alliance, Canadian Cancer Trials Group, and Children's Oncology Group) and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes were included in the study team. The resulting clinical trial - S1826, led by SWOG Cancer Research Network - represents the largest advanced stage HL study in the history of the North American cooperative groups and the first prospective collaboration between COG and the adult cooperative groups in HL. S1826 (NCT03907488) is a randomized, phase III study of N-AVD versus BV-AVD in pts with newly diagnosed advanced stage HL. Eligible pts must be 12 years or older and have stage III or IV HL. Pts are randomized 1:1 to receive 6 cycles of treatment with either N-AVD or BV-AVD. Pts randomized to BV-AVD are required to receive G-CSF prophylaxis for neutropenia. Pts are eligible to receive RT to residually metabolically active areas on the end of treatment (EOT) PET scan at the discretion of the treating investigator. Pts are stratified during randomization based on age, international prognostic score, and intention to use EOT RT. The primary endpoint is to compare the PFS in pts randomized to N-AVD versus BV-AVD. Secondary endpoints include overall survival, event-free survival, the EOT complete metabolic response rate, and the safety and tolerability of N-AVD compared to BV-AVD. Another key secondary endpoint will be a comparison of patient-reported symptoms and health-related quality of life (overall, fatigue, neuropathy) between the study arms. 940 eligible pts are expected to be accrued over 4 years with a total of 987 pts assuming an expected ineligible rate of 5%. The S1826 study represents an unprecedented effort across the North American clinical trial cooperative groups to improve the cure rate in advanced stage HL and harmonize treatment approaches across pediatric and adult pts. Figure Disclosures Herrera: Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Research Funding; Karyopharm: Consultancy; Immune Design: Research Funding; Pharmacyclics: Research Funding. Rutherford:Heron: Consultancy; Regeneron: Research Funding; Juno: Consultancy; Dova: Consultancy; Genentech/Roche: Research Funding; AstraZeneca: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy, Research Funding; Kite: Consultancy; LAM Therapeutics: Research Funding; Seattle Genetics: Consultancy. Parsons:Seattle Genetics: Consultancy. Prica:astra zeneca: Honoraria; seattle genetics: Honoraria; Gilead: Honoraria. Shipp:Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Merck: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Bayer: Honoraria. Crump:Kite/Gilead: Consultancy; Roche: Consultancy; Servier: Consultancy. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Research Funding. Leonard:Miltenyi: Consultancy; Roche/Genentech: Consultancy; BMS/Celgene: Consultancy; MEI Pharma: Consultancy; Gilead/Kite: Consultancy; Bayer: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; GenMab: Consultancy; Sutro: Consultancy; Karyopharm: Consultancy. Smith:Karyopharm: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding. Friedberg:Acerta Pharma - A member of the AstraZeneca Group, Bayer HealthCare Pharmaceuticals.: Other; Seattle Genetics: Research Funding; Roche: Other: Travel expenses; Astellas: Consultancy; Portola Pharmaceuticals: Consultancy; Kite Pharmaceuticals: Research Funding; Bayer: Consultancy.

Background The standard of care for diffuse large B-cell lymphoma (DLBCL) relapsing after front-line therapy is high-dose chemotherapy and autologous stem cell transplantation (ASCT). Evidence has suggested that early relapses (ie, within 1 year) after this approach portends exceptionally poor outcomes. However, data examining relapses > 1 year after ASCT for patients with refractory or relapsed DLBCL are limited, in particular, in the rituximab era. We sought to examine the effect of early (≤ 1 year) and late (> 1 year) relapse after ASCT in a single-institution cohort of patients with relapsed and refractory DLBCL treated with chemoimmunotherapy. Materials and Methods A retrospective analysis was performed on the data from 85 consecutive patients who had undergone ASCT for biopsy-confirmed relapsed or refractory DLBCL from 2001 to 2010 at the University of Rochester Medical Center. All patients had received rituximab as a part of treatment. Of the 85 patients, 35 developed relapse after ASCT. These 35 patients were divided into 2 groups according to the timing of the relapse (≤ 1 year and > 1 year after ASCT). Results The median follow-up period was 6.4 years. For all patients, the overall survival (OS) from post-ASCT relapse was 5.2 years. For the 27 patients developing relapse at ≤ 1 year after ASCT, the median OS was 0.6 year and progression-free survival was 0.4 year. For the 8 patients developing relapse at > 1 year after ASCT, the median OS was 5.9 years and progression-free survival was 2.9 years. Conclusion Patients with relapsed or refractory DLBCL experiencing relapse > 1 year after ASCT had good outcomes. Despite the relative rarity in incidence, a significant risk of relapse of DLBCL after ASCT remains, suggesting the need for continued monitoring because of the possibility of later progression.

AIMS Little has been written on the frequency and nature of incidental splenic lesions diagnosed on histopathological examination of pancreatosplenectomy specimens. METHODS AND RESULTS For 191 such specimens, incidental histological findings after haematopathologist re-review were tabulated. Cases suspicious for lymphoid malignancy underwent molecular analysis for immunoglobulin heavy and kappa light chain rearrangement. Follow-up was obtained on selected cases. In five cases (3%), the spleen was sampled but not mentioned in the original microscopic report; all were normal on re-review. Otherwise, most (171 of 186, 92%) were initially diagnosed as normal, with 160 (94%) remaining so on re-review. Findings on re-review not initially described (n = 11, 6%) included four cases with splenic morphology suspicious for possible leukaemia/lymphoma involvement. Additional findings included abscess formation, foamy macrophages, necrotising granulomas and simple cysts. Fifteen spleens were initially diagnosed as abnormal; the histopathological process was confirmed in all, including non-necrotising granulomas, cysts, Gamna-Gandy bodies, foamy macrophages, involvement by pancreatic neoplasm and involvement by known chronic lymphocytic leukaemia (CLL). Molecular analysis was performed on the five cases of known/suspected lymphoma and two were positive for monoclonal gene rearrangement, including the known CLL and a previously undiagnosed case with similar immunophenotype. CONCLUSIONS Incidental splenic findings are not uncommon in pancreatosplenectomy specimens. While most are of limited clinical significance, low-grade lymphoproliferative disorders may go undetected if the spleen is overlooked. We recommend careful observation of splenic findings in these specimens, with a low threshold for haematopathological consultation when in doubt.

This chapter consists of two categories of the less common yet important groups of breast lesions. Mesenchymal lesions consist of all types of benign and malignant mesenchymal lesions that can occur anywhere in the body, but the most common ones in the breast are often benign, including nodular fasciitis, benign vascular lesions, pseudoangiomatous stromal hyperplasia (PASH), myofibroblastoma, lipoma, etc. Lymphoma may arise in the breast as a primary tumor or present as breast involvement of a systemic lymphoma. One entity that needs to be mentioned here is breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), as it is a specific breast lesion and was provisionally classified as a novel lymphoma by the World Health Organization (WHO) in 2016.

Most patients with treatment naïve classical hairy cell leukemia (cHCL) have durable responses with purine nucleoside analogues. In contrast, options are limited for cHCL patients with co-morbidities, purine analogue intolerance, or resistant disease. We report the utility of targeted therapy for nine cHCL patients presenting with treatment naïve cHCL and severe neutropenia and infection (n = 3), purine analogue intolerance (n = 2), or purine analogue resistant disease (n = 4). BRAF inhibitor vemurafenib was started at 240-480 mg twice daily (planned 90-day treatment) and combined with rituximab in seven patients. Therapy was tolerable with no severe adverse events. All patients responded with rapid blood count recovery (median time 1.52 months, range 0.43-4.33). Median progression free and overall survival was not reached at a median follow up of 18.1 months (range 3.2-68.9). These data suggest targeted therapy could be an option for patients unable to be treated with purine analogues.

Background Castleman disease is a lymphoproliferative disorder that can present in multiple locations throughout the body. While considered a benign entity, Castleman disease in the pediatric head and neck can resemble other common childhood malignancies. Methods This report describes a case of Castleman disease in a 10-year-old male who presented with a progressively enlarging facial mass; work-up revealed aggressive histopathological and imaging features concerning for rhabdomyosarcoma. The patient ultimately required surgical resection for definitive diagnosis. Results The facial mass was successfully resected without complication. A diagnosis of unicentric Castleman disease was made based on final histopathological evaluation of the permanent specimen. The mass has not recurred one year postoperatively. Conclusions Castleman disease in the head and neck should be included in the differential diagnosis of a pediatric facial mass. Balancing the appropriate degree of diagnostic intervention and treatment is essential in ensuring the best possible outcome with the least morbidity.

In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival.

BACKGROUND: Transfusion-transmitted malaria (TTM) is a rare occurrence with serious consequences for the recipient. A case study is presented as an example of best practices for conducting a TTM investigation. CASE REPORT: A 15-year-old male with a history of sickle cell disease developed fever following a blood transfusion. He was diagnosed with Plasmodium falciparum malaria and successfully treated. The American Red Cross, New York State Department of Health, and the Centers for Disease Control and Prevention investigated the eight donors who provided components to the transfusion. The investigation to identify a malaria-positive donor included: trace back of donors, serologic methods to identify donor(s) with a history of malaria exposure, polymerase chain reaction (PCR) testing, microsatellite analysis to identify the parasite in a donor and match its genotype to the parasite in the recipient, and re-interview of all donors to clarify malaria risk factors. RESULTS: One donor had evidence of infection with P. falciparum by PCR, elevated antibody titers, and previously undisclosed malaria risk factors. Re-interview revealed that the donor immigrated to the US from Togo just short of 3 years prior to the blood donation. The donor was treated for asymptomatic low parasitemia infection. CONCLUSION: This investigation used standard procedure for investigating TTM but also demonstrated the importance of applying sensitive laboratory techniques to identify the infected donor, especially a donor with asymptomatic infection with low parasitemia. Repeat interview of all donors identified as having contributed to the transfused component provides complimentary epidemiologic information to confirm the infected donor.

Follicular Lymphoma (FL) is the most common indolent lymphoma derived from light zone germinal center B cells and characterized by a t(14;18) translocation resulting in upregulation of BCL2 in over 80% of cases. This translocation alone is not sufficient for tumorogenesis, and must be combined with additional genetic mutations to transform B cells. FL is incurable and the disease course can be highly varied, with survival ranging from a few months to decades following diagnosis and treatment with standard chemoimmunotherapy. The heterogeneity of FL poses major challenges to identifying the association of genetic alterations and clinical outcome. Current WHO guidelines recommend establishing grade for each FL case with grade 3 thought to be more aggressive than 1 and 2. The genetic basis and clinical implications of grade in FL are unclear. Recent sequencing studies have identified many genes found to be recurrently mutated in FL including KMT2D and CREBBP. However, the degree to which genetic alterations cooperate with each other or contribute to clinical outcome is unclear. Based on the observed mutational rates in follicular lymphoma, we estimated 900 cases were needed to comprehensively delineate the genetic alterations that underlie histologic grade and clinical outcome. Accordingly, we enrolled a cohort of 1042 patients with newly diagnosed FL. All treated patients received rituximab-containing standard regimens. To go beyond the identification of gene-coding events, we developed a very large panel of 110 Mbp covering exonic (~40Mbp) and non-exonic regions (~70Mbp) of interest to enable a wide range of genomic analysis including mutation calling in both coding and non-coding regions, rearrangement detection, viral identification, and copy number analysis. In addition to the whole exome, we extended coverage to include introns, promoters, and untranslated regions of all known driver genes in cancer. We included the entirety of the immunoglobulin loci, T-cell receptor loci and CD3 loci to detect clonotypes and rearrangements. We also included lymphoma-relevant long non-coding RNAs, microRNAs, enhancers, and breakpoint-prone regions. For viral detection, we targeted the genomes of eight cancer-related viruses: Epstein-Barr virus, human papillomavirus, human immunodeficiency virus, hepatitis B, hepatitis C, Kaposi's sarcoma-associated herpesvirus, human T-lymphotropic virus, and Merkel cell polyomavirus. In addition, to enable high resolution identification of copy number variation (CNV) calls, the entire genome was tiled with probes spaced 10kb apart. DNA and RNA were extracted from all tumors and their paired normal samples, prepared into DNA and RNA sequencing libraries and subjected to sequencing on the Illumina platform to a targeted coverage of 150X. Somatic events were identified and further filtered to identify driver events in both coding and non-coding regions. FLs demonstrated a significant degree of genetic heterogeneity with over 100 genes mutated with a frequency of at least 2%. Nearly 100% of FL cases had a mutation in at least one chromatin-modifying gene. The most frequently mutated genes in follicular lymphoma were KMT2D, BCL2, IGLL5 and CREBBP. In addition, we identified frequent mutations in SPEN, BIRC6 and SETD2. To our knowledge, this is the first description of alterations in these genes in FL. Transcriptome analysis indicated a strong correlation between BIRC6 mutations and the previously described immune response 2 signature that is associated with a poor prognosis. We further performed unbiased clustering of genetic alterations in these FL cases. We identified a cluster that was specifically enriched in BCL6 and TP53 alterations and was strongly associated with grade 3 FLs which are predicted to have poorer outcomes with low intensity therapies. We further examined the genetic profiles of 1001 DLBCLs in comparison to this cohort of FLs. Our data indicate a continuum of highly overlapping genetic alterations with DLBCL displaying more complex patterns that included alterations in MYC, TP53 and CDKN2A (mainly copy number losses), indicating shared pathogenetic mechanisms underlying FL and DLBCL, particularly those germinal center B cell origin. Disclosures Koff: Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; Lymphoma Research Foundation: Research Funding; American Association for Cancer Research: Research Funding. Leppä:Roche: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Gang:ROCHE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Hsi:Abbvie: Research Funding; Eli Lilly: Research Funding; Cleveland Clinic&Abbvie Biotherapeutics Inc: Patents & Royalties: US8,603,477 B2; Jazz: Consultancy. Flowers:AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; BeiGene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; Millenium/Takeda: Research Funding; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Neff:Enzyvant: Consultancy; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fedoriw:Alexion Pharmaceuticals: Other: Consultant and Speaker. Reddy:Genentech: Research Funding; BMS: Consultancy, Research Funding; Celgene: Consultancy; KITE Pharma: Consultancy; Abbvie: Consultancy. Mason:Sysmex: Honoraria. Behdad:Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Speaker. Burton:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dave:Data Driven Bioscience: Equity Ownership.

Background: Immunocompromised patients (pts) face an approximate 6-fold increase in lifetime risk of lymphoid malignancies compared with immunocompetent counterparts. Additionally, up to 80% of post-transplant lymphoproliferative disease (PTLD) cases are driven by EBV-associated mechanisms of tumorigenesis. Approximately 70% will express CD30 and over 80% will express CD20. Recent studies of chemoimmunotherapy (CIT) have reported median overall survival (OS) of 2-4 years and treatment-related mortality (TRM) rates of 13-50%. Moreover, solid organ transplant (SOT) pts are at significant risk of graft rejection when CIT is employed, possibly due to "off target" depletion of regulatory T-cell populations. R monotherapy induction, followed by response-stratified use of CIT, has been evaluated (Trappe, et al, JCO, 2016). However, ~75% of pts had an inadequate response to R alone and required subsequent CIT; 2-yr OS for the population as a whole was ~70%. BV is an anti-CD30 antibody-drug conjugate that received accelerated FDA approval for previously untreated CD30+ T-cell lymphoma and Hodgkin lymphoma. We hypothesized that a combination of BV and R would yield improved breadth and depth of response compared with R monotherapy induction, would spare pts subsequent exposure to CIT, and result in favorable OS. Methods: We report here results of a phase I/II multicenter study investigating the efficacy and safety of BV+R as frontline therapy in pts diagnosed with immunosuppression-associated CD30+ and/or EBV+ lymphoid malignancies. Induction consisted of R 375 mg/m2 given days 1, 8, 15, 22 and BV 1.2 mg/kg given days 1, 8, 15, of a 28-day cycle, followed by restaging. Those with progression were removed from study. Pts with stable disease were offered study discontinuation or completion of one consolidation cycle followed by repeat disease assessment. Pts with partial response or complete response (CR) could receive either consolidation followed by maintenance therapy (MT) or move directly to MT without consolidation. Consolidation was identical to induction dosing; MT consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to 1 year of therapy. Toxicity was defined using CTCAE 4.0 and response (Cheson, 2007) was assessed at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. Results: A total of 22 pts were entered in the trial. Toxicity and response data are available for 20 pts. Median age was 67 years (range, 30-79) and 14 pts (64%) were male (range, 30-79 years). Fourteen pts (64%) had received either a SOT or hematopoietic allograft requiring immunosuppression, 3 pts required immunosuppression for underlying rheumatologic conditions, and 3 pts were found to have EBV-associated lymphoid malignancies in the absence of iatrogenic immunosuppression (Table 1). Overall response rate was 70%, including a CR rate of 60%. With median follow-up of 26.1 month, the probability of progression-free survival at 1 year was 75.2% and 67.6% at 3 years (Fig 1). Probability of OS was 89.2% at both 1-year and 3-year follow-up (Fig 1). Median time to best response was 28 days. Three pts withdrew consent after induction, 2 pts died (1 death related to treatment), and 1 patient was lost to follow-up. Seven pts (31%) required dose adjustments or delay of medication administration during induction therapy and 45% required discontinuation of therapy due to toxicity within 1 year. The most frequent grade 3/4 toxicities were peripheral neuropathy, neutropenia, lymphopenia, and pancreatitis. The most frequent adverse events of any grade were fatigue, nausea, abdominal pain, pancytopenia, and peripheral neuropathy (Table 2). Conclusions: The combination of BV + R had an acceptable safety profile and appeared effective in achieving early remissions when used as frontline therapy for PTLD and other immunosuppression-related lymphomas. Specifically, over half of pts achieved CR, and 75% have been spared exposure to multi-agent cytotoxic chemotherapy. Furthermore, survival and PFS data were encouraging compared with historical controls. However, nearly half of pts discontinued therapy within 1 year due to toxicity suggesting poor long-term tolerance of the regimen and that earlier cessation of therapy may be warranted. Further studies are needed to confirm these efficacy results and to determine optimal BV+R dosing regimens and durations. Disclosures Pro: Seattle Genetics: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel Expenses; Celgene: Consultancy, Honoraria; Kyowa Hakka Kirin: Consultancy, Honoraria. Gordon:Gilead: Other: Advisory Board; Bayer: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Winter:Merck: Consultancy, Research Funding. Ma:Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Xeme: Research Funding; Bioverativ: Consultancy; Beigene: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy; Abbvie: Research Funding; Incyte: Research Funding; Juno: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Novartis: Research Funding. Behdad:Pfizer: Other: Speaker; Thermo Fisher: Membership on an entity's Board of Directors or advisory committees; Loxo-Bayer: Membership on an entity's Board of Directors or advisory committees. Petrich:AbbVie: Employment, Equity Ownership. Smith:Portola Pharmaceuticals: Research Funding.

Chimeric antigen receptors (CARs) are recombinant receptors composed of an antibody-derived extracellular single-chain variable fragment linked to a costimulatory signaling domain combined with the...

Fueled by the growing interest in stem cell biology and the promise of regenerative medicine, study of the hematopoietic stem cell (HSC) microenvironment has provided critical insights into normal and malignant hematopoiesis. Notch receptor signaling in this microenvironment is a critical regulator of HSC fate and differentiation. Notch signaling also has the potential to modulate the growth of various malignant cell types, as evidenced by the growing list of hematologic cancers and other malignancies associated with either mutations in Notch genes or alterations in Notch signaling. In both health and disease, activation of Notch signaling predominantly exerts influence through stromal cell interactions with the tumor or stem cell microenvironments. Definitive evidence from transgenic mouse models has shown that alterations in stromal cell signaling from the bone marrow niche can induce malignant outgrowth of preleukemic clones and leukemia. Understanding how Notch receptor signals in the bone marrow microenvironment govern stem cell behavior will advance our understanding of cancer pathogenesis in hematologic malignancies and may have implications for treating metastatic solid tumors involving bone. These microenvironmental interactions are potential therapeutic targets for treating and preventing a variety of diseases, including bone marrow failure disorders, myelodysplastic syndromes, leukemia, and lymphoma.

7547 Background: Outcomes remain poor for patients with relapsed refractory DLBCL and HGBCL, especially those ineligible for a stem cell transplant or CAR T-cell therapy. Lenalidomide has efficacy in these groups, most notably in the activated B-cell like (ABC) subtype when defined by gene expression profiling. We analyzed the outcomes of consecutive patients with DLBCL treated with lenalidomide, focusing on characteristics such as transformed histology and MYC translocation status. Methods: We performed a retrospective review of consecutive patients with transformed indolent NHL, DLBCL, and HGBCL treated with lenalidomide at the University of Rochester between 2011-2018. Cell of origin was determined by Hans algorithm and FISH was performed to detect MYC, BCL2, and BCL6 translocations. Kaplan Meier estimates and descriptive statistics were utilized for analysis. Results: 62 patients were identified with a median age of 76 years, the majority with > 2 prior therapies. ORR was 43.5%, including 14 patients with a CR. Median PFS was 4.6 months with 18 patients achieving a PFS > 1 year. Median OS was 14 months. No difference in PFS, OS, or ORR was observed between the de novo germinal center b-cell (GCB) and non-GCB populations (PFS 4 vs. 5 months, p = 0.87). 16 patients with transformed FL had a median PFS of 24 months and a median OS of 46.7 months (vs. de novo GCB OS of 7.8 months, p = 0.02). Notably, 6/7 MYC+ patients achieved an objective response, including 3 with a CR. All patients with double and triple hit disease had an objective response, including two PRs and one CR. Conclusions: Our experience confirms the clinical activity of lenalidomide in heavily pretreated older adults with DLBCL. Outcomes did not differ by cell of origin using the Hans immunohistochemistry algorithm and durable responses were observed, particularly in transformed FL. Nearly all of the MYC+ patients responded, including those with double/triple hit genetics, and almost half achieved a CR. Based on our data, lenalidomide may be an optimal bridge to consolidative cellular therapy in high-risk patients irrespective of genotype, particularly in transformed indolent histologies.

The secreted M1 protein of murine gammaherpesvirus 68 (MHV68) promotes effector Vβ4 + CD8 + T cell expansion to impact virus control and immune-mediated pathologies in C57BL/6 mice, but not BALB/c mice. We report a striking increase in the number of genome-positive, IgD − B cells during chronic infection of both mouse strains. This suggests a novel role for M1 in influencing long-term maintenance in a major latency reservoir irrespective of the degree of Vβ4 + CD8 + T cell expansion.