Citations

Background: Molecular genetic testing is increasingly utilized in clinical care, typically with peripheral blood as the preferred specimen. Despite the prevalence of therapeutic blood transfusions, whether donor DNA is present in a sufficient quantity to interfere with recipient genetic testing has not been systematically studied. Microchimerism secondary to transfusion of blood products with donor leukocytes has been well-documented in trauma patients receiving whole blood; however, most medical centers currently transfuse leukoreduced (LR) red blood cell products for non-trauma patients. The degree of leukoreduction varies among centers, but to meet AABB standards must be <5x106 white blood cells (WBC) in 95% of units tested. We sought to determine what quantity, if any, of infused LR or non-LR (NLR) products leads to detectable microchimerism that may impact genetic test results. Methods: We performed an in vitro spiking study utilizing four whole blood units collected from different anonymous donors. Three were leukoreduced at varying levels in order to establish a LR (per our institutional guidelines and standards), a partially leukoreduced (PLR) and a NLR unit, which were then considered "donors". The 4th unit was divided to generate two separate "recipients". The first half was left untreated simulating an immunocompetent recipient while the other was leukoreduced to mimic a leukopenic recipient. Based on a 70 kg patient, we calculated the volume of blood from each "donor" to mix with aliquots of each "recipient" to represent a transfusion of 2, 5, or 16 units, with 2 units corresponding to a double apheresis red blood cell (RBC) transfusion and 16 units corresponding to a near total volume transfusion. DNA was extracted from each individual unit as well as all "transfused" combinations within 24 hours of mixing. Chimerism analysis was then performed by STR analysis using the GlobalFiler PCR amplification kit followed by ChimerMarker analysis software. Results: None of the LR units, despite volume transfused, revealed any level of microchimerism in either the immunocompetent or leukopenic "recipients". The PLR transfused combinations displayed levels ranging from 0.14% to 1.52% of donor chimerism for the immunocompetent "recipient", which is below the limit of detection for most clinical assays evaluating germline genetic variation, and 6.3% to 27.78% of donor chimerism for the leukopenic "recipient", which would be expected to impact a subset of clinical genetic assays. The NLR transfused combinations displayed levels ranging from 13.28% to 95.66% of donor chimerism. Discussion:In vitro "transfusion" of LR RBCs into simulated immunocompetent or leukopenic samples does not lead to detectable donor DNA. However, "transfusion" of PLR and NLR units in an in vitro model reveals significant levels of microchimerism dependent on volume transfused and immune status of the "recipient" which implies possible risk for impact on clinical genetic tests. The minimum time required for clearance of donor leukocytes in the recipient is unknown; we were unable to fully evaluate this and other variables in our in vitro system, but follow-up in vivo studies addressing this question are planned. Disclosures No relevant conflicts of interest to declare.

Multiple myeloma (MM) is a neoplasm thought to arise from a damaged germinal center B-cell that progresses to a plasma cell clone arising in bone marrow. MM comprises 20% of all hematologic cancer deaths. Persons of African ancestry (AA) have a 1.5 to 2-fold higher risk compared to individuals of European ancestry (EA). Genetically driven differences in hematopoiesis may lead to variation in the levels white blood cell (WBC) subsets which could, in turn, be associated with MM etiology. There are differences in genetic determinants of WBC traits between EA and AA populations, with possible implications for the racial disparity in risk. We tested the above hypothesis using Mendelian randomization (MR), an approach that leverages genetic determinants of specific traits (i.e. WBC counts) to estimate their effects on the risk of an outcome; and a transcriptome-wide association study (TWAS), which utilizes genetic predictors of gene expression to identify susceptibility genes. These analytic approaches were applied to data from the African American Multiple Myeloma Study (AAMMS) consisting of 1813 cases and 8871 AA cancer-free controls to examine how differences in heritable WBC gene expression profiles influence MM risk. Genetic determinants of variation in WBC subsets in AA were obtained from the literature and supplemented with new genome-wide association findings in AA subjects from the UK Biobank cohort (n=6108). Odds ratios (OR) for MM per 1 standard deviation (SD) increase in each WBC phenotype were estimated using independent (linkage disequilibrium (LD) r2<0.10) variants with P<10-6 as genetic instruments. Analyses based on variants associated with WBC traits in AA populations did not identify any statistically-significant associations between MM risk and WBC overall (p=0.81, using 15 SNPs) or subsets (lymphocytes, monocytes, eosinophils, neutrophils and basophils, p>0.05 for each). However, when we applied genetic determinants of WBC identified in 330,000 cancer-free EA UK Biobank participants (P<10-8, replication P<0.05, LD r2<0.05), a statistically significant inverse relationship emerged between increasing lymphocyte counts and MM risk (OR=0.80, 95% CI: 0.66-0.97, p=0.02, using 385 SNPs), as well as increasing basophil counts (OR=0.63, 95% CI: 0.41-0.96, p=0.03, using 140 SNPs). Next, we examined the association between WBC gene expression profiles and MM risk in AAMMS data. We applied published and validated ancestry-specific models developed using the PrediXcan approach, which leverage germline genetic and transcriptomic data from the Multi-Ethnic Study of Atherosclerosis (MESA) (Mogil et al. PMID: 30096133). The primary TWAS used gene expression models trained in AA subjects (n=233), with sensitivity analyses using models developed in AA and Hispanic subjects (n=585). The TWAS significance threshold was based on the number of genes with significant germline prediction models (p<0.05 and R2 ≥0.05) in AA, corresponding to P < 0.05/2700 = 1.85×10-5. The expression of two genes was significantly associated with MM risk: KANK1at 9p24.3 (P = 1.01×10-5) and DNAJC27at 2p23.3 (P = 1.56×10-5). KANK1is a candidate tumor suppressor gene for renal cell carcinoma and has recently been associated with MM risk in AA [Du, Blood 2017 130:3058]. Here we provide additional evidence for its role in MM etiology via gene expression-mediated mechanisms. DNAJC27 (previously known as RBJ) is a novel MM risk gene linked to constitutive activation of ERK in solid tumors. We also identified two suggestively associated genes: PRR14 (P = 1.34×10-4; combined AA-Hispanic sample: P = 1.56×10-6), which has been linked to MM risk in EA populations, and PARP16 (P = 9.46×10-5). To our knowledge this is the first study to comprehensively examine variation in WBC traits and gene expression profiles with respect to MM risk in AA. Our TWAS analysis leveraged data from the largest collection of genetic and gene expression data in AA, enabling ancestry-matched inference and identification of two novel risk genes. Although the limited availability of genetic instruments for WBC limited the power of MR analysis, findings using variants identified in European populations may offer some insight into trans-ethnic etiologic pathways and contribute to risk stratification strategies using genetic and blood cell count biomarkers. Future studies, particularly with MGUS-free controls, are needed to validate these results. Disclosures Song: Millennium Pharmaceuticals Inc: Employment. Rand:Ancestry.com: Employment. Ailawadhi:Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy. Nooka:Takeda: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; GSK: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation. Singhal:Bureau of Millennium/Takeda, Celgene, Janssen, Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. van Rhee:Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy; Adicet Bio: Consultancy; Kite Pharma: Consultancy; Karyopharm Therapeutics: Consultancy. Mehta:Millennium/Takeda, Celgene; stock in Celgene, Bristol-Myers Squibb and Bluebird: Speakers Bureau. Wolf:Takeda: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy. Martin:Roche and Juno: Consultancy; Amgen, Sanofi, Seattle Genetics: Research Funding. Fiala:Incyte: Research Funding. Terebelo:Jannsen: Speakers Bureau; Celgene: Honoraria; Newland Medical Asociates: Employment. Anderson:Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding. Bernal-Mizrachi:TAKEDA: Research Funding; Kodikas Therapeutic Solutions, Inc: Equity Ownership; Winship Cancer Institute: Employment, Patents & Royalties. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Zonder:Celgene Corporation: Consultancy, Honoraria, 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; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees. Huff:Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees; Karyopharm, Sanofi, MiDiagnostics: Consultancy. Lonial:Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding; Genentech: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding.

Introduction: Non-endemic Burkitt lymphoma (BL) is a rare and highly aggressive B-cell malignancy, of whom a substantial number are adolescents and young adults (AYAs). In this particular group of patients, the balance between efficacy and long-term toxicities is of major concern, due to the long expected remaining lifetime. In this study, we investigated the outcomes for AYA patients treated with intensive immunochemotherapy. Patients and methods: Patients were identified through queries to clinic based and population-based lymphoma registries from six countries (Australia, Canada, Denmark, Norway, Sweden, and USA). All diagnoses were confirmed by local investigators; patients with classical BL histology plus detectable MYC translocation, were included. Patients between 18 and 39 years of age at diagnosis treated with intensive immunochemotherapy (DA-EPOCH-R or more intensively) were evaluated in pre-specified age groups. All treatment protocols included rituximab. Overall survival (OS) was defined as the time from diagnosis until death from any cause or censoring, while event-free survival (EFS) was defined as the time from diagnosis until unplanned re-treatment, progression/relapse, death, or censoring, whichever came first. Response evaluation was assessed using established response criteria based on CT and/or PET/CT imaging. Survival curves were computed using the Kaplan-Meier estimator. The cumulative incidence of relapse in patients reaching complete remission (CR) or CR unconfirmed (CRu) was computed by Aalen-Johansen estimator. The 5-year restricted loss of lifetime (RLOL) was defined as the area between the patient and general population survival curves until 5-years. The general population survival was retrieved from publicly available lifetables stratified on age, sex, calendar year, and country. Results: In total, 108 AYA BL patients were included. The median age was 30 years, ranging between 18 and 39 and 82% were male. The majority had advanced stage disease (Ann Arbor stage III-IV, 76%), extranodal involvement (87%), and elevated LDH (67%). Seven patients (6%) had CNS involvement at the time of diagnosis. The chemotherapy regimens used were CODOX-M/IVAC (51%), BFM/GMALL (34%), hyper-CVAD (7%), DA-EPOCH (5%), and others (3%). Among 74 patients for whom data on tumor lysis were available, 10 (14%) developed clinical tumor lysis upon start of chemotherapy, all presenting with advanced stage and extranodal disease. The response rate was 91% (89 in CR/CRu and 2% in partial remission). At a median follow-up of 53 months, 15 had an event and 10 died. The 2-year OS and EFS for the total population was 92% (87-97%, Figure 1) and 88% (82-94%), respectively. For 13 patients aged 18-21 2-year OS and EFS were both 100%, while 2-year OS and EFS for 43 patients aged 22-30 were 98% (93-100%) and 93% (85-100%), respectively. The 2-year OS and EFS for patients aged 31-39 were 86% (76-96%) and 80% (69-91%), respectively. For patients in CR/CRu and available date of response evaluation, the 2-year post-remission OS was 99% (97-100%) and the 2-year relapse risk was 2% (0-5%), with no relapses after 6 months. Compared to the general population, the RLOL was 0.8 months (-0.5-2.2 months). Nine patients did not respond to primary treatment (SD or PD), all which belonged to the age group 31-40 years (P<0.001 versus age group 18-30 years). The oldest age group had an inferior OS compared to younger patients (P=0.008), largely due to non-responders having poor subsequent survival with a 1-year OS of 33%. Conclusion: The outcomes of AYA BL patients following intensive immunochemotherapy are excellent with high remission rates and low risk of relapse in general. However, even among young patients age remained prognostic, with patients 31 years or older having inferior OS and lower response rate to first-line treatment. In patients achieving CR, survival was similar to that of the general population over the median follow-up of 4.5 years, illustrating the need to focus on survivorship issues in these individuals. Figure 1: Overall survival for BL patients following intensive immunochemotherapy for all patients and for age groups (18-21, 22-30, and 31-39 years). Figure 1 Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Holte:Novartis: Honoraria, Other: Advisory board. Molin:Roche Holding AG: Honoraria; Merck & Co., Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria. Ekstroem Smedby:Takeda: Honoraria, Other: Grant funding, Research Funding; Celgene: Honoraria, Other: Grant funding, Research Funding; Janssen Cilag: Honoraria, Other: Grant funding, Research Funding. Song:Takeda: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Gerrie:Lundbeck, Seattle Genetics: Consultancy, Honoraria. Cheah:Roche, Janssen, MSD, Gilead, Loxo Oncology, Acerta, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Travel expenses; Celgene, Roche, Abbvie: Research Funding. El-Galaly:Roche: Employment, Other: Travel support; Takeda: Other: Travel support.

Background Genome-wide association studies (GWAS) conducted in populations of European ancestry (EA) have identified and confirmed 23 germline susceptibility loci for multiple myeloma (MM). The effect sizes of single nucleotide polymorphisms (SNPs) at these loci are small, therefore combining them into a single summary measure, known as a polygenic risk score (PRS), may provide a more meaningful risk factor. We have previously shown a PRS comprised of the 23 SNPs for MM contributes to increased risk of MM, with a 2.7-fold increase for highest vs. lowest PRS quintiles. Whether the MM-PRS is also associated with overall survival (OS) in MM cases has not been evaluated. We examined the association between MM-PRS and OS in two EA studies. Methods The first study consisted of 2,179 EA MM cases from ten studies included in the Multiple Myeloma Working Group within the International Lymphoma Consortium (InterLymph). Cases were diagnosed between 1970 and 2015 and genotyped using multiple platforms (Oncoarray, Affymetrix, Human660W-quad Beadchip, and Illumina arrays); 885 cases also had stage [based on International Staging System (ISS)] available. Each of the GWAS was subjected to rigorous standard quality control independently (prior to imputation via the Michigan imputation server based on the Haplotype Reference Consortium (HRC). The second study consisted of 515 newly diagnosed EA MM cases from CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), diagnosed from 2011-2013, who had whole genome sequencing (WGS) performed on germline DNA. The WGS data was used to call common germline genetic variants through the Mayo Clinic bioinformatics pipeline. Briefly, genetic variants were detected with GenomeGPS, aligned to the hg19 reference genome, called using the GATK (V3.6) Haplotype Caller, and merged for multiple-sample joint calling. To reduce the false positive variants, variant quality score recalibration (VQSR) was applied for both SNPs and INDELs. After quality control, 458 EA samples remained. Follow-up was available for both studies and consisted of time from MM diagnosis date until death or date of last known follow-up. The PRS was constructed from the 23 MM SNPs using the published per allele odds ratio associated with MM risk. The published log odds ratios for each SNP were multiplied by the number of risk alleles (0, 1, 2) for the corresponding SNP, and summed, resulting in a unique score per person. Kaplan-Meier curves and Cox proportional hazard models were used to assess the association between PRS with MM OS considering two models: 1) adjusted for age, sex, study and 2) additional adjustment by stage (ISS). Hazard ratios (OR) and 95% confidence intervals (CI) were estimated. The PRS was evaluated both as a continuous variable, per standard deviation (SD), and as a categorical variable (quintiles). Results MM cases (N=2,179) in the InterLymph study were 59% male and 41% female and the median age was 61.0 years (26-90 years). Median follow-up time was 57.2 months (1.0-509.0 months) with 868 reported deaths. MM cases with stage information available consisted of 20% stage I (n=178), 53% stage II (n=466), and 27% stage III (n=241). No association was observed between PRS and OS in MM patients regardless of adjustment for stage (continuous PRS (HR: 1.03, 95% CI: 0.83-1.28, P=0.80) or by quintile PRS (p>0.05)) (Table). The CoMMpass EA MM cases (n=458) had similar distributions for sex (61% male and 39% females) but were slightly older 65 years (27-93 years) and had shorter follow-up time (median=39.75 months (0.13-77.2)) with 117 deaths. Stage was available for 96% of CoMMpass cases including 36% stage I (n=159), 33% stage II (n=146), and 31% stage III (n=134). We also observed no association of PRS and OS in the CoMMpass study (HR=1.02, 95% CI: 0.72 -1.46, P= 0.89), adjusted for age, sex, and stage (Table). Discussion A PRS score for MM risk is not associated with OS for MM cases in two EA populations. Given that prior studies have shown association of genetic variation with MM survival, efforts to identify additional loci associated with OS or MM specific survival are warranted. Future studies should also consider germline variants impact on molecular subtypes, specific therapies, and outcomes. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Background: The use of midostaurin in combination with standard induction chemotherapy has been shown to improve the outcomes in patients with newly diagnosed FLT3 mutated (FLT3m) AML (Stone et al) and allogeneic transplant is often recommended in first remission. While likely to achieve remission with standard induction, the majority of these patients will relapse and die of their disease. Gilteritinib, a potent FLT3 inhibitor, has been approved for use in patients with relapsed or refractory FLT3 mutated AML. In Phase I/II studies, when used as part of induction therapy, gilteritinib has shown promising CR rates. We have designed a trial comparing the outcomes of induction therapy with gilteritinib to those with midostaurin. The hypothesis is that gilteritinib, when added to induction chemotherapy, will produce more FLT3m negative composite complete remission (CRc). The Ratify trial combined midostaurin with daunorubicin 60 mg/m2/d X 3 days and cytarabine X 7 days Daunorubicin 90 mg/m2/d has however been shown to be superior during induction in patients with newly diagnosed FLT3 ITD mutated AML (Luskin et al, Burnett et al) While improved survival is the ultimate goal of any leukemia regimen, it is known that AML patients who proceed to allogeneic transplant with measurable residual disease (MRD) positive disease fare worse than those with MRD negative disease. As such, our goal is to increase the likelihood of an MRD negative state after induction. Study Design This is a randomized, open-label, multicenter phase II study comparing gilteritinib to midostaurin in combination with cytarabine 100 mg/m2 and daunorubicin 90 mg/m2 in newly diagnosed FLT3 mutated AML patients ages 18-65. Central confirmation of FLT3 mutation and other pretreatment studies are required. In order to identify patients without delay, all patients with suspected AML will be able to be prescreened without enrollment to the randomized treatment trial. Patients will be stratified according to TKD vs. ITD FLT3 mutation. Patients with FLT3-ITD mutation will undergo further stratification with NPM1 mutation status (positive vs. negative) and FLT3 ITD to FLT3 wild type signal ratio (high [≥ 0.5] vs. low [<0.5]). Patients will be randomized to receive standard induction treatment (cytarabine and daunorubicin) with either gilteritinib or midostaurin. Mandatory bone marrow samples are required after Induction and Consolidation. Patients who achieve CR or complete remission with incomplete hematologic recovery (CRi) will be assessed for MRD and be eligible at count recovery to go on to receive standard consolidation treatment of high-dose cytarabine with the study drug received during induction (gilteritinib or midostaurin). Patients may proceed to allogeneic transplant after induction or after 0-4 cycles of chemotherapy consolidation and may participate in BMT CTN 1506. Key Eligibility: Newly diagnosed FLT3m AML Primary Objective To evaluate the FLT3m negative (evaluated by polymerase chain reaction [PCR] and capillary electrophoresis) composite complete response (CRc) (includes CR or CRi)rate of patients with FLT3 mutated AML who receive gilteritinib compared to those who receive midostaurin in addition to standard therapy with cytarabine and daunorubicin during induction. Sample Size and Statistical design The accrual goal of this study will be 179 patients. Patients who achieve remission will be followed for survival and relapse. With an allocation ratio of 1:1 to the two arms, the study will have 80% power to detect an improvement of 20% in the FLT3 mutation negative CRc rate in the gilteritinib arm (i.e. from 40% to 60%) at the one-sided significance level of 0.05 based on Fisher's exact test. This study is conducted through PrECOG and is funded by Astellas Pharma. The study is slated to open in the summer of 2019 at 30 US sites. References: Stone R.M., Mandrekar S.J., Sanford B.L., et al. N Engl J Med 2017; 377:454-464 Luskin MR, Lee JW, Fernandez HF et al. Blood 2016 :blood-2015-07-657403; doi: https://doi.org/10.1182/blood-2015-07-657403 Burnett AK, Russell NH, Hills RK et al. Blood 2016; Blood 2016 128:449-452; doi: https://doi.org/10.1182/blood-2016-04-712091 Figure Disclosures Luger: Genetech: Research Funding; Jazz: Honoraria; Celgene: Research Funding; Pfizer: Honoraria; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Ariad: Research Funding; Biosight: Research Funding; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Daichi Sankyo: Honoraria. Loghavi:MDACC: Employment; GLG Consultants: Consultancy; AlphaSights: Consultancy. Lazarus:Genentech: Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; CSL Behring: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau. Rowe:BioSight: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Pratz:Astellas Pharma: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy. OffLabel Disclosure: In this study gilteritinib is being studies in newly diagnosed AML.

Introduction Tumor surface matrix metalloproteases ADAM10 and ADAM17 are associated with poor outcomes in multiple malignancies. We previously showed that these proteases shed PD-L1 from lymphoma cell line Karpas-299 to produce soluble PD-L1 (sPD-L1) that induces CD8+ T cell apoptosis (1). While higher levels of soluble PD-L1 are associated with worse prognosis in patients with non-Hodgkin lymphoma treated with standard chemoimmunotherapy (cutoff of 1.52 ng/ml, 3-year OS of 76% versus 89%) (2), it is unknown whether the loss of PD-L1 on the surface of B cell lymphoma cells affects clinical outcomes. We hypothesized that tumors expressing low PD-L1 levels despite high PD-L1 mRNA levels would (1) produce higher ADAM10 or ADAM17 transcript levels and (2) predict poorer prognosis in diffuse large B cell lymphomas. Methods We queried the cancer genome atlas (TCGA) public database for cases of diffuse large B cell lymphoma (DLBCL) for which PD-L1 (CD274) protein levels are reported by reverse phase protein array (RPPA). We then queried TCGA for RNA-Seq data for CD274, ADAM10, and ADAM17 expressed as transcripts per million (FPKM). We re-normalized RPPA data and calculated a PD-L1 protein-to-mRNA ratio for each tumor sample. We then compared groups of high and low PD-L1 protein-to-mRNA ratios for ADAM10 and ADAM17 mRNA expression. We further compared groups of high and low PD-L1 protein-to-mRNA ratios for survival (adjusted for age at diagnosis). All statistical analyses were performed using R Statistical Software (R Foundation). Unpaired student's t-test assessed statistical differences in experimental groups except where otherwise indicated. Figures comprise box plots showing quartile values and individual data points. P<0.05 was considered statistically significant. In figures, p values are denoted <0.05 with *, <0.01 with **, and <0.001 with ***. Results Data were available for a total of 33 diffuse large B cell (DLBC) lymphomas. 18 of those samples were categorized as having low PD-L1 protein-to-mRNA ratios (cutoff 6.38e-6) with the remaining categorized as high ratio. DLBCL tumors demonstrating low PD-L1 protein-to-mRNA ratios expressed significantly higher ADAM10 (p=0.0237) and ADAM17 (p<0.0001) transcripts than tumors expressing low PD-L1 protein-to-mRNA ratios (Figure 1). Furthermore, patients with tumors demonstrating low PD-L1 protein-to-mRNA ratios experienced significantly poorer survival according to likelihood ratio (6.6, p=0.01) and log rank (4.67, p=0.03) tests (Figure 2). Conclusions Our findings may explain a crucial phenomenon seen in diffuse large B cell lymphoma, namely that many purportedly PD-L1-positive tumors appear to express PD-L1 but do not respond to PD-(L)1 inhibitor therapy (3,4). This may be caused by the activity of ADAM10 and ADAM17 to cleave PD-L1, which we previously showed in lymphoma cell line Karpas-299 (1). This posits pre-treatment ADAM10/ADAM17 inhibition to "boost" PD-(L)1 inhibitor therapy in lymphoma. Our results contrast with previous findings that PD-L1-positive DLBCL progression free survival is inferior to PD-L1-negative DLBCL (5). This may be due to different methods of protein detection (immunohistochemistry versus RPPA) and the lack of localization of PD-L1 expression in tumor cells versus the microenvironment. Notably, this study is only correlative with a limited case number. Larger prospective studies will be needed to further elucidate this relationship. Acknowledgments The results shown here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. References 1. Orme et al. AACR Adv Malig Lymphoma 2018. Pres 423 2. Rossille et al. Leukemia 2014. 28:2367-75. 3. Moskowitz et al. Blood 2014 124:290. 4. Armand et al. J Clin Oncol 2013. 31:4199-206. 5. Kiyasu et al. 2015.126:2193-201. Figure Disclosures No relevant conflicts of interest to declare.

Background: Despite treatment advances, multiple myeloma (MM) remains a condition with high unmet medical need as patients (pts) relapse and become resistant to therapy. MM pts experience a range of serious disease-related symptoms and side effects impacting their functioning and health-related quality of life (HRQL). The median overall survival (OS) has improved with the advent of new treatments in the last two decades, however, the impact of newer combination treatments on pt quality of life remains unknown (Beckner, N et al. Cancer Res. 2011;183:25; Bharat, N et al. J Clin Oncol 2019;37:15(suppl):8039). Venetoclax is a novel, orally bioavailable small molecule inhibitor of BCL-2 activity in MM. In the Phase 3 double-blind, randomized clinical trial (M14-031, BELLINI) progression free survival (PFS) was studied in relapsed/refractory (RR) MM pts receiving venetoclax or placebo in combination with bortezomib and dexamethasone. In addition, patient-reported outcomes (PRO) data focused on physical functioning, pain, and fatigue from BELLINI were evaluated to better understand the overall impact on pt HRQL of adding venetoclax to bortezomib and dexamethasone-based doublet therapy. Methods: The BELLINI Phase 3 study (NCT01794520) enrolled patients ≥18 y old with R/R MM who had received 1-3 prior lines of therapy. The study met its primary endpoint of PFS (HR 0.63, 95% CI=0.44-0.89) but higher risk of death (HR 2.027, 95% CI=1.04-3.95) was observed in the treatment arm compared with placebo, although the OS data are not yet mature (Kumar, S et al. EHA Library. Jun 16 2019;273254:LB2601). The secondary HRQL endpoints included in this study were pain severity, fatigue, physical functioning (PF), and global health status, which were measured using the Brief Pain Inventory-Short Form (BPI-SF), PROMIS Fatigue Short Form surveys, and the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Change from baseline to day 1 of each cycle visit (up to 25 cycles or last treatment visit) was assessed for each measure in both the treatment and placebo groups. Summary analyses compared mean and median scores between arms at each cycle. The treatment effect was evaluated in a mixed effect model controlling for the patient's baseline score, total visits (or cycles of treatment), age (<65 or ≥65), prior therapy lines, and prior proteasome inhibitor exposure. The model also included an interaction term examining treatment by visits. Results: The intention-to-treat (ITT) dataset included 194 pts (median age: 66y; 53% with 2 or 3 prior lines of therapy) in the treatment group and 97 pts (median age: 65y; 55% with 2 or 3 prior lines of therapy) in the placebo group (2:1 randomization). There was no clear evidence for an independent effect of treatment on PF (P=0.522). Pain scores across multiple measures showed a similar trend, with a statistically non-significant improvement of unadjusted average "Worst Pain" scores for the venetoclax group (P=0.289; Figure B). Non-inferiority in pain results were replicated by the pain subscale of the QLQ-30 (P=0.778), the BPI pain severity index (P=0.418), and the related BPI pain interference subscale score (P=0.603). Fatigue scores likewise demonstrated no significant differences between treatment arms whether using PROMIS Cancer Fatigue t-scores (P=0.442), raw scores (P=0.568), or the 3-item QLQ-C30 subscale (P=0.959), although there was a positive trend across cycle summary scores for the treatment group compared with the placebo group. Unadjusted QLQ-C30 PF subscale scores showed declines from baseline that were generally worse in the placebo group across 25 treatment cycles, although differences were smaller and non-significant in the adjusted model (Figure A). Conclusions: Comparable HRQL in pain severity, fatigue, and PF was observed in RRMM pts receiving venetoclax in combination with bortezomib and dexamethasone compared to pts receiving bortezomib and dexamethasone. The summary scores showed outcomes that were comparable or slightly improved for those randomized to the venetoclax combination. Results of concurrent measures of the same or associated concepts reinforced confidence in these results. Additional analyses of subgroups are ongoing (eg, t(11;14), BCL-2 expression status) and may provide further insights surrounding HRQL in these populations. Figure Disclosures Gasparetto: BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Popat:Takeda: Honoraria, Other: travel, accommodations, expenses; GSK: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses; Janssen: Honoraria, Other: travel support to meetings; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salwender:Sanofi: Honoraria, Other: Travel or accommodations; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; Celgene: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations. Suzuki:Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Maciel:Amgen: Other: funding for travel, teaching, participation in advisory boards; Janssen: Other: funding for travel, teaching, participation in advisory boards. Moreau:Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Harrison:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jia:AbbVie: Employment, Other: Stock/stock options. Karve:AbbVie: Employment, Other: stock/stock options. Ma:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Devine:Genentech: Employment, Other: stock options; AbbVie: Other: Alliance Partner. Benjamin:AbbVie: Employment, Other: stock/stock options.

Gluteus minimus disorders are a potential source of greater trochanteric or anterior hip pain. Disorders of the gluteus minimus tendon most commonly occur in conjunction with gluteus medius tendon abnormalities but can also occur in isolation. Understanding the sonoanatomy of the gluteus minimus muscle‐tendon unit is a prerequisite for recognizing and characterizing gluteus minimus tendon disorders, which, in turn, guides treatment for patients with greater trochanteric or anterior hip pain syndromes.

Abstract Stigma in patients suffering from chronic disease is associated with worse clinical outcomes and secondary medical issues such as depression, anxiety, and decreased quality of life. We believe various forms of stigma can have different clinical significance in patients with inflammatory bowel disease (IBD). With further insight and research, we suggest that these forms of stigma could be identified and targeted by researchers or clinicians to lessen the psychological disease burden in patients and to potentially improve their physical well-being. In the current review, we discuss public perceptions, knowledge, and stigmatization of IBD, the prevalence of various forms of IBD stigma, and the impact of such stigma on patient outcomes. We also discuss IBD disclosure, its association with stigma, and the tendencies and effects of such disclosures among youth and adult patient populations. We finish the review by highlighting possible modalities and research areas for future IBD interventions.

Importance Objectively measuring how Mohs defect reconstruction changes casual observer attention has important implications for patients and facial plastic surgeons. Objective To use eye-tracking technology to objectively measure the ability of Mohs facial defect reconstruction to normalize facial attention. Design, Setting, and Participants This observational outcomes study was conducted at an academic tertiary referral center from January to June 2016. An eye-tracking system was used to record how 82 casual observers directed attention to photographs of 32 patients with Mohs facial defects of varying sizes and locations before and after reconstruction as well as 16 control faces with no facial defects. Statistical analysis was performed from November 2018 to January 2019. Main Outcomes and Measures First, the attentional distraction caused by facial defects was quantified in milliseconds of gaze time using eye tracking. Second, the eye-tracking data were analyzed using mixed-effects linear regression to assess the association of facial defect reconstruction with normalized facial attention. Results The 82 casual observers (63 women and 19 men; mean [SD] age, 34 [12] years) viewed control faces in a similar and consistent fashion, with most attention (65%; 95% CI, 62%-69%) directed at the central triangle, which includes the eyes, nose, and mouth. The eyes were the most visually important feature, capturing a mean of 60% (95% CI, 57%-64%) of fixation time within the central triangle and 39% (95% CI, 36%-43%) of total observer attention. The presence of Mohs defects was associated with statistically significant alterations in this pattern of normal facial attention. The larger the defect and the more centrally a defect was located, the more attentional distraction was observed, as measured by increased attention on the defect and decreased attention on the eyes, ranging from 729 (95% CI, 526-931) milliseconds for small peripheral defects to 3693 (95% CI, 3490-3896) milliseconds for large central defects. Reconstructive surgery was associated with improved gaze deviations for all faces and with normalized attention directed to the eyes for all faces except for those with large central defects. Conclusions and Relevance Mohs defects are associated with altered facial perception, diverting attention from valuable features such as the eyes. Reconstructive surgery was associated with normalized attentional distraction for many patients with cutaneous Mohs defects. These data are important to patients who want to know how reconstructive surgery could change the way people look at their face. The data also point to the possibility of outcomes prediction based on facial defect size and location before reconstruction. Eye tracking is a valuable research tool for outcomes assessment that lays the foundation for understanding how reconstructive surgery may change perception and normalize facial deformity.