Citations

Objective: The ε4 allele of the APOE gene ( APOE4 ) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear. Approach and Results: Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice. Conclusions: ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.

Abstract A trait of inflammation pathogenesis in human atherosclerosis: inflammasome driven interleukin-1 signalling in complex atherosclerotic plaques via hyperlipidemia trained innate immunity Objectives We aimed to investigate interleukin (IL)-1 generation and the regulatory role of inflammasome in human advanced atherosclerosis. Background IL-1β is key contributor to the inflammatory process associated with atherosclerosis and its complications. Recent studies suggested that IL-1β blockade reduces the burden of inflammation and recurrence of cardiovascular events. Yet, other cytokines in IL-1 family and the regulation of IL-1 generation in patients with atherosclerosis remains poorly understood. Methods and results A focused transcriptomic analysis in human atherosclerotic specimens discovered that human atherosclerotic plaques host a broad reservoir of inflammasome components, characterised by expression of canonical inflammasome gene NLRP6, NLRP12, NLRC4, NLRP3 and non-canonical inflammasome gene caspase 4 significantly elevated in the symptomatic plaques versus the asymptomatic plaques. Upregulation of NLRP3 inflammasome expression in plaque validated by immunohistochemistry staining suggested it as a distinctive characteristic of plaque vulnerability and complexity. Functional studies on atherosclerotic explants obtained from patients undergoing carotid endarterectomy revealed constitutive generation of IL-1β accompanied by secretion of comparable levels of IL-1α from the majority of the plaques, while IL-18 and IL-33 generation from some of the plaques. Stimulation of the plaques with inflammasome activators showed an inducible generation of both IL-1α and IL-1β, not IL-18 or IL-33, mediated by specific canonical and non-canonical inflammasome pathways. Analysis on the medication records of these patients indicated that plaques from patients with suboptimally controlled hyperlipidemia, imaging signs for plaque instability and inadequate statins therapy possessed higher recruitable production of IL-1β, suggesting the conventional atherogenic factor in regulation of inflammasome immunity and disease activity. Mechanistic studies on tissue and cells isolated from atheromatous plaques demonstrate that generation of mature IL-1β is via a mechanism controlled by NLRP3 and the effector caspase-1. Conclusions The study supports a profound canonical and non-canonical inflammasomes mediated plaque IL-1α/β generation, via a key mechanism by NLRP3 and caspase-1. The results provide biological insights into the clinical merit of high-intensity cholesterol lowering and anti-IL-1 signalling-directed therapies in high-risk patients with atherosclerosis. Acknowledgement/Funding KI-Mayo collaboration project, the Swedish Research Council, the Swedish Heart-Lung Foundation, European Union FP7 projects, the NIH

AbstractNF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.

Abstract Introduction REGN1979 is an anti-CD20 x anti-CD3 bispecific IgG4 antibody (Ab) modified to reduce Fc binding. Engaging both targets results in CD20-specific, local T-cell activation and cytotoxicity, a mechanism of action distinct from standard anti-CD20 Abs. We report updated promising efficacy results of a Phase 1 trial of REGN1979 in patients (pts) with relapsed/refactory (R/R) B-NHL previously treated with anti-CD20 Abs. Methods The primary objectives of the study are to determine safety, tolerability, and occurrence of dose limiting toxicities (DLTs). Other objectives include assessment of preliminary antitumor activity, pharmacokinetics (PK), and pharmacodynamics. Eligible pts with R/R NHL must have received at least 1 prior CD20-directed therapy. Treatment consists of 12 weekly doses of REGN1979 followed by every 2 week dosing for 12 doses for a total of 36 weeks. Guidelines are provided for management of cytokine release syndrome (CRS) and include steroids and/or tocilizumab at investigator discretion. Results As of June 1, 2018, 54 pts with B-NHL were treated with REGN1979 monotherapy: DLBCL (pt number [n]=30), FL (n=16), MCL (n=5), MZL (n=2), and WM (n=1). The median number of prior regimens was 3 (range, 1-11); 41 pts were refractory to their last prior systemic therapy, 18 had bulky disease, and 6 had prior HSCT. Pts were treated with REGN1979 0.03-27 mg and received a median of 7 (range, 1-24) doses. Eight pts remain on treatment, 13 completed treatment, and 33 discontinued therapy prior to the planned 36 wks (majority [n=22] due to progressive disease [PD]). There have been no DLTs to date. The most common treatment-related treatment-emergent adverse events (TR-TEAEs) included infusion-related reactions (IRR) or CRS; 26 pts experienced CRS (Grade 1-2, n=23; Grade 3, n=3) with a median duration of CRS of 2 (range 1-15) days. Six pts received tocilizumab. The severity of CRS symptoms declined through optimized pre-medication even with REGN1979 dose escalation. Other common Grade ≥3 TR-TEAEs were lymphocytopenia/ decreased lymphocyte count (n=8); neutropenia/ decreased neutrophil count (n=7); and thrombocytopenia/ decreased platelet count, hypotension, hypophosphatemia, and anemia (each n=3). Seventeen pts experienced a nervous system event including headache, dizziness, paraesthesia, dysgeusia, and peripheral neuropathy with no Grade ≥3 events; no neurologic event required termination of study drug. Seven pts died on study: PD (n=5), gastric perforation (n=1), and cardiac arrest (n=1). TEAEs leading to premature discontinuation of REGN1979 were Grade 3 fatigue (n=1), Grade 3 hemolysis (n=1), and Grade 2 pyrexia/Grade 2 tachycardia (n=1). Among 27 pts treated with REGN1979 ≥5 mg (dose associated with tumor killing in pre-clinical data), the overall response rate (ORR) was 55.6% (5 complete response [CR] and 10 partial response [PR]; Table/Figure). Responses were seen in 7/7 FL Grade 1-3a pts (5 CR, 2 PR), 6/15 DLBCL pts (all PR), 2/2 MCL pts (all PR). At 18 mg and 27 mg of REGN1979, 4 of 4 pts with DLBCL had best response of PR. Post data cut-off, 1 pt with a DLBCL best response of PR converted to CR. PK and pharmacodynamic assessments suggest that for pts treated with REGN1979 5-18 mg, best exposures in the first 3 weeks appear to linearly increase with dose. In pts treated with up to REGN1979 18 mg, a maximum mean Ctrough of 1.6 mcg/mL was observed in the first 3 weeks of weekly dosing. Studies of peripheral blood biomarkers demonstrated depletion of peripheral B lymphocytes, transient margination of circulating T-cells, and elevated circulating cytokines following REGN1979 dosing. Increased peak cytokine levels (IL-6, IL-10, and TNF-alpha) were observed in pts with CRS. Immunohistological analysis of malignant lymph node tissue demonstrated a decrease of CD20 expression in responding pts; among the responders, subsequent relapse was associated with either maintenance of CD20 expression or further CD20 loss, suggesting antigen-dependent and independent disease escape mechanisms. Conclusions REGN1979 displays efficacy and an acceptable safety profile in pts with R/R B-NHL. Most TR-TEAEs were IRR/CRS and have been well managed with supportive care. No significant neurological toxicity has been observed. At doses of 5-27 mg of REGN1979, the preliminary ORR was 100% in pts with FL Grade 1-3a and 40.0% in pts with DLBCL. This promising efficacy warrants further clinical investigation. Disclosures Bannerji: Regeneron Pharmaceuticals, Inc.: Consultancy; AbbVie, Inc.: Consultancy. Arnason:Regeneron Pharmaceuticals, Inc.: Consultancy. Advani:Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Millenium: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Agensys: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Kura: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Kyowa: Other: Consulting/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role. Brown:Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Pharmacyclics: Consultancy; Celgene: Consultancy; Genentech: Consultancy; TG Therapeutics: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Abbvie: Consultancy; Gilead: Consultancy, Research Funding; Sun Pharmaceutical Industries: Research Funding; Sunesis: Consultancy; Loxo: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Invectys: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy; Boehringer: Consultancy. Allan:Genentech: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy. Ansell:Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. O'Brien:Kite Pharma: Research Funding; Aptose Biosciences Inc.: Consultancy; Pharmacyclics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Astellas: Consultancy; Sunesis: Consultancy, Research Funding; Alexion: Consultancy; Amgen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Chavez:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Humanigen: Consultancy. Lowy:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Charnas:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Sternberg:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ambati:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Adriaens:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Ufkin:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Li:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Navarro:Regeneron Pharmaceuticals, Inc.: Employment. Gasparini:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Jankovic:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Fiaschi:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Zhang:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Hamon:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Thurston:Regeneron Pharmaceuticals, Inc.: Employment, Equity Ownership. Topp:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding.

Abstract The first two authors and last two authors contributed equally. Genome-wide association studies (GWAS) have identified risk loci for Acute Lymphoblastic Leukemia (ALL), Chronic Lymphoblastic Leukemia (CLL) and Non-Hodgkin Lymphoma, however an Acute Myeloid Leukemia (AML) GWAS has not been published to date. We performed a GWAS to identify AML and Myelodysplastic Syndrome (MDS) risk loci using a nested case-control study design in the DISCOVeRY-BMT cohorts which includes almost 2000 AML and MDS patients as cases and 2813 unrelated donors as controls. Genotyping was performed using the Illumina Human OmniExpress BeadChip and imputed using the Haplotype Reference Consortium, yielding > 8 million high-quality variants for statistical analysis. Logistic regression models with AML (de novo AML with normal cytogenetics, de novo AML with abnormal cytogenetics and therapy-related AML) and MDS cases and European American healthy donor controls adjusted for age and sex were used to test the association of each SNP with disease status. To identify the strongest association signal with disease we conducted a summary statistic SNP-based association analysis (ASSET) using non-overlapping AML and MDS cases implemented in R statistical software. ASSET uses an exhaustive search for SNPs with small but common pleiotropic effects across groups of traits while accounting for the multiple tests required by the subset search, as well as any shared controls between groups. This approach allowed us to further investigate the heterogeneity within AML subtypes and to gain increased power by pooling subtypes that show pleiotropic effects. ASSET genome wide (GW) significance is defined as P<5.0x10-8, however, we present results of each subset analysis. ASSET analyses identified an association of T allele at rs12203592, Interferon Regulatory Factor 4 (IRF4), with increased risk of de novo AML and MDS (Figure 1) (OR=1.37; 95% CI, 1.25-1.51, Pmeta=1.59x10-10). The variant has been reported significant in GWAS of skin pigmentation, hair color, non-melanoma skin cancer, squamous cell carcinoma, actinic keratosis, and childhood ALL; GW case-control studies of neuroblastoma and breast cancer show suggestive association signals (P<5 x 10-6). IRF4 belongs to the IRF family of transcription factors and is a key regulator of differentiation stages in hematopoiesis. The T allele at rs12203592 is associated with significantly increased expression of IRF4 in whole blood and lung tissue and in vitro mouse studies have shown the T allele to be associated with higher levels of IRF4 transcription. rs12203592 is <80bp from an IRF4 transcription start site and in an important position within NF-κB motifs in multiple blood and immune cell lines, supporting the hypothesis that this SNP modulates NF-κB repression of IRF4 expression. Another variant in the IRF4 regulatory region, rs62389423 (A allele), showed a putative association with subsets of de novo AML and MDS (OR=1.36; 95% CI,1.21-1.52, Pmeta=1.2x10-7). Although not in linkage disequilibrium with rs12203592, the A allele has also been previously associated with susceptibility to skin cancer and melanoma in multiple GWAS. Analysis of 596 UKbiobank CLL cases and >300,000 controls, shows the A allele correlates with a 50% increased risk of CLL (95% CI, 1.32-1.73, P= 2.4x10-9).Several other GWAS also show an association between additional IRF4 variants and CLL. Analyses in individual subtypes also revealed an intronic variant, rs10098598, in RAD21 to be associated with de novo AML (OR=2.18; 95% CI, 1.60-2.97; Pmeta=8.9x10-7). RAD21, on8q24, a region known to be associated with multiple cancer types, is involved in DNA double-stranded break repair and in chromatid cohesion in mitotic cells. Loss of function would theoretically lead to chromosomal instability and tumorigenesis. Components of the cohesion complex (including RAD21) are somatically mutated in ~12% of de novo AML and MDS patients, where it is frequently an early event. We provide the first GW evidence of association between a common variant and AML susceptibility. This SNP has been shown to be associated with multiple phenotypes, suggesting that there are pleiotropic effects at work. Our RAD21 finding is consistent with the role of cohesion in leukemogenesis and provides some evidence of its role in de novo AML susceptibility. Replication and further subset analyses with genome-wide data in >2000 AML cases are ongoing. Disclosures Griffiths: Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. McCarthy:Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Abstract Introduction: Given the established role of PD-1 in mediating immune suppression in chronic lymphocytic leukemia (CLL), we tested and reported the efficacy of PD-1 blocking antibody pembrolizumab in relapsed and transformed CLL patients. A selective response of pembrolizumab (~40%) in patients with RT, particularly after prior ibrutinib, was observed (Ding, Blood, 129:3419). Correlative analysis showed PD-1 expression in tumor B-cells of patients with RT and aggressive CLL after progression on ibrutinib. PD-1, an inhibitory receptor expressed on CLL T-cells, inhibits the immune synapse and cytotoxic T cell functions via the interactions with its ligands. However, the expression pattern and role of PD-1 in tumor B-cells is not well defined. In this study we investigated the functional implication of the PD-1 signaling axis in B-cell pathobiology in CLL and RT patients. Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). For in vitro study, we checked PD-1 expression in 11 lymphoma cell lines and 1 CLL cell line by both flow cytometry and Western blot (WB) analysis. Effect of PD-1 knockdown using CRISPR/Cas9 system (Addgene) and over-expression of PD-1 using pLEX-lentiviral (Thermoscientific) or pRetro-retroviral (Clonetech) system were evaluated on pro-survival and apoptotic signaling pathways by Western blot analysis. Gene expression signatures in CLL and RT patients were also evaluated by Illumina-based RNA sequencing using FFPE-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL). Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN. (mean ± SEM in RT vs. CLL, 30.6 ± 4.7 vs. 11.5 ± 2.8, p < 0.001). PD-1 expression was highest in patients with RT where the immediate prior CLL therapy was ibrutinib (Figure 1A). Among all cell lines tested for PD-1 expression, the expression of PD-1 by WB and flow was highest in Mino (mantle cell lymphoma line), followed by moderate expression in Jvm2 (B-PLL line) and Mec1 (CLL line), and very low-level expression in both Jeko-1 (B-NHL line) and lymphoma line 'Karpas299'. CRISPR/Cas9 mediated depletion of PD-1 in Mino cells inhibited constitutively active Akt, p70S6K and mTOR pathway, accompanied by significant downregulation of the anti-apoptotic proteins, Bcl-2, Mcl-1 and XIAP, but P-ERK1/2 was not affected. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in Jeko-1 and doxycycline regulated inducible retroviral (pRetro-PD-1) mediated overexpression of PD-1 in Karpas299 activated Akt, mTOR and p70S6K pathway. Overexpression of PD-1 in Jeko-1 significantly increased Bcl-2 and Mcl-1 and in Karpas299 increased Bcl-2, Mcl-1 and XIAP expression (Figure 1B). A parallel genetic analysis using RNA sequencing was performed on 5 nodal tissues involved by either RT or progressive CLL after these patients developed clinical progression after prior ibrutinib therapy. In all 5 patients, overexpression of PD-1 was associated with increased expression of Bcl-2 and mTOR regardless of the genetic mutations detected (including TP53, ATM, BTK, NOTCH1, XPO1, SF3B1, TET2 etc). However, in 2 patients who received prior chemoimmunotherapy, similar overexpression of gene signature was not observed by RNA sequencing analysis, alternative pathways including Met or NFkB overexpression was detected. Given these clinical and laboratory findings, we have treated 2 RT patients with a combination of BTK and Bcl-2 inhibitors (ibrutinib and venetoclax, respectively) whose CLL transformed after prior ibrutinib. Significant reduction of tumor burden was observed in both cases with one complete response and one mixed response. Conclusion: An increased expression of PD-1, Akt/mTOR and Bcl-2 gene signature was first observed in RT patients after prior ibrutinib therapy. PD-1 overexpression in the tumor B-cells of RT and progressive CLL patients likely regulate AKT/mtOR to upregulate Bcl-2. Targeting both BTK and Bcl-2 pathways in addition to PD-1 blockade appear to be a promising strategy to treat these aggressive diseases. Disclosures Parikh: Gilead: Honoraria; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding. Ansell:Takeda: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Ding:Merck: Research Funding.

Abstract Monoclonal gammopathies, including multiple myeloma (MM), represent a group of plasma cell (PC) disorders that comprise of mostly incurable hematopoietic malignancies with an increasing incidence in the US. Previous epidemiological studies demonstrated a 2-3 fold higher incidence of monoclonal gammopathy of undetermined significance (MGUS) and a similarly higher incidence of MM along with a ~4-year younger age of onset among African Americans (AA) compared to European Americans (EAs) (Fonseca, Leukemia, 2017). This suggests a possible ancestral-associated genetic predisposition of AAs to the development of monoclonal gammopathies (Landgren, Blood, 2006). When access to care is equal, AAs have a better overall survival compared to EAs suggesting that AAs may have a genetic predisposition that renders them better responders to treatment or have more favorable cytogenetic subtypes of MM (Waxman, Blood, 2010). Previous efforts to understand this disparity have relied on self-reported race rather than genetic ancestry. We hypothesize that quantifying genetic ancestry is necessary to fully understand the genetic mechanisms of racial disparities of monoclonal gammopathies. We describe our study of 881 patients with monoclonal gammopathies who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from the bone marrow samples was genotyped on the Precision Medicine Research Array. Biogeographical ancestry was assessed using the Geographic Population Structure Origins tool, which provides the ancestral breakdown of 36 admixture components for each individual representing different geographic regions and outputs admixture proportions corresponding to those ancestries (Elhaik, Nat Commun, 2014). We evaluated whether an increase in the percentage of African Ancestry altered the odds of any primary cytogenetic abnormality. We demonstrated that a 10% increase in the percentage of African ancestry was associated with a 6% increase in the odds of detecting either an t(11;14), t(14;16) or t(14;20) (odds ratio = 1.06, 95% CI: 1.02 - 1.11; p-value = 0.05). Although we observed an increase in the odds of each of the individual translocations with 10% increase in African ancestry, l t(11;14) (OR=1.03) t(14;16) (OR=1.11) and t(14;20) (OR=1.10), these three abnormalities were combined to achieve greater statistical power. The differences in cytogenetic abnormalities were most striking among individuals with ≥80.0% African (n=120) compared to individuals with <0.1% African ancestry (n=235). Using these cutoff values comparing the ≥80.0% and <0.1% African ancestry cohorts, there was a higher prevalence of t(11;14), t(14;16) and t(14;20) (51% vs. 33%, respectively, p-value=0.008) and a lower prevalence of trisomies (with or without IgH translocations) (48.3% vs. 61.3%, respectively, p-value=0.066). In addition, the ≥80% African ancestry cohort also displayed a slightly lower prevalence of monosomy 13/13q deletion compared to the cohort with <0.1% African ancestry (34.2% vs. 38.7%, respectively, p-value=0.021). Further, we observed a significantly higher prevalence in the proportion of females with monoclonal gammopathies among the ≥80% African ancestry cohort compared to the cohort with <0.1% African ancestry (56.7% vs. 42.1%, respectively, p-value=0.028). We complement our past studies that relied on self-reported race and characterized patients' demographic and uniformly collected cytogenetic data in relation to genetically defined African ancestry. We demonstrate the prevalence of having one of three specific subtypes (i.e., t(11;14), t(14;16), or t(14;20)) was significantly higher in those with highest (≥80%) compared to lowest (<0.1%) African ancestry demonstrating African ancestry is associated with a subtype distribution of MM that differs from non-African individuals. These differences were only revealed after analysis of individuals with the highest and lowest percentage of African ancestry. Since 38.3% of the individuals with ≥80% African ancestry have the favorable t(11;14) translocation (in comparison to 26.8% of <0.1% African individuals), this finding may explain improved survival with equal access to care. Understanding the genetic mechanisms of this disparity is a fundamental step to understanding differences in incidence and outcomes of patients with monoclonal gammopathies. Disclosures Elhaik: DNA Diagnostics Center: Consultancy. Baird:DNA Diagnostics Center: Employment. Cerhan:Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Stewart:Amgen Inc., BMS, Celgene, Takeda, Roche, Seattle Genetics, Janssen, Ono: Consultancy; Amgen Inc., Celgene, Roche, Seattle Genetics: Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Kumar:Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding.