Citations

BACKGROUND: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for treatment of relapsed/refractory (R/R) large B-cell lymphoma and is associated with high response rates and durable remissions. Recent data show that axi-cel is effective across various adverse prognostic features, namely cell of origin, disease bulkiness, and extranodal disease, among others. Hypoalbuminemia is a known adverse prognostic factor in lymphomas. It is unknown if axi-cel overcomes the adverse prognostic feature of hypoalbuminemia in R/R large B-cell or transformed follicular lymphoma. METHODS: We conducted a retrospective analysis of patients treated with axi-cel across three Mayo Clinic campuses (Rochester, Jacksonville, and Phoenix) from 06/01/2018 until 04/01/2019. The primary objective of this analysis was to assess the impact of hypoalbuminemia (defined at day 0, prior to infusion) on outcome after axi-cel therapy. RESULTS: A total of 50 (male=37, 74%) patients (pts), median age of 53 (26-67) years received axi-cel. The median number of prior lines of therapy was 3 (2-8) (Table 1). Two pts had no available serum albumin levels at time of axi-cel infusion. Seven (15%) of 48 pts had serum albumin levels lower than 3.5 g/dL (median= 3.3 g/dL (range 2.6-3.4)) and the median follow up of survivors was 7.6 (1.9-14.3) months. The best overall response rate (ORR) and complete remission (CR) rates in these pts were 57% and 57%, respectively. One (14%) patient had stable disease and 2 (29%) had disease progression. The median overall survival (OS) for pts with hypoalbuminemia was not reached. On the other hand, 41 (85%) pts had a normal serum albumin level (median=4.0 (range 3.5-5.1) g/dL) and the median follow up for survivors was 6.3 months. The best objective response rate (ORR) and complete remission (CR) rates in these pts were 82% and 44%, respectively. The median OS for pts with normal serum albumin was 14 (95%CI=6.3-29.6) months. There was no significant difference at 6-months and 1-year OS between pts with hypoalbuminemia vs. those with normal baseline serum albumin levels [6-month=100% vs. 79%(95%CI=64-93%); 1-year (100% vs. 54% (95%CI=26-82%), p=0.17] (Figure 1). All grades cytokine release syndrome (CRS) was diagnosed in all 7 pts with hypoalbuminemia (100%) and in 38 of 41 (92%) pts without hypoalbuminemia. There was no difference in the median duration of CRS between pts with or without hypoalbuminemia [6 (range 1-11) days vs 5 (range 1-19) days, p=0.89]. Neurotoxicity (all grades) was observed in 5 (71%) pts with hypoalbuminemia compared 26 (63%) with normal albumin levels. There was no statistically significant difference in median duration of neurotoxicity between pts with hypoalbuminemia and those with normal baseline albumin levels [9 (range 1-10) days vs. 3 (range 0-25) days, p= 0.72]. CONCLUSIONS: Hypoalbuminemia does not have a significant impact on the outcomes of axi-cel therapy, including the incidence of CRS or neurotoxicity. These results need to be validated in a large collaborative multicenter study. Further investigation is needed to assess the prognostic impact of severe hypoalbuminemia (<3g/dL) on axi-cel therapy. Disclosures Ansell: Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Mayo Clinic Rochester: Employment; Affimed: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Trillium: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding. Bennani:Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board. Paludo:Verily Life Sciences: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Celgene: Research Funding. Tun:DTRM Biopharma: Research Funding; Mundi-pharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Foran:Agios: Honoraria, Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Introduction and Purpose IRAK4 kinase activity is essential for signaling downstream of toll-like receptors (TLR) and the interleukin-1 receptor (IL-1R) family in a variety of myeloid and lymphoid cell types. Dysregulated signaling in these pathways is frequently observed in NHL, particularly in ABC-subtype of Diffuse Large B-Cell Lymphoma (DLBCL) and Waldenström macroglobulinemia (WM). A phase 1 trial in patients with NHL is being conducted to determine safety, pharmacokinetics, and preliminary efficacy of CA-4948 as monotherapy. Patients and Methods At the 18-Jul-2019 data cut-off date, 22 patients have been treated with single-agent CA-4948. Five dose-escalation cohorts from 50 mg QD to 200 mg BID have been tested and cleared; a cohort of patients treated at 400 mg BID dose is currently being evaluated. Patients were diagnosed with relapsed or refractory NHL, including DLBCL (n=13), FL (n=5), HGBL with MYC and BCL2 and/or BCL6 rearrangement (n=1), WM (n=1), LPL (n=1) and MCL (n=1), had a performance status of 0 or 1 (ECOG) at baseline, and were treated in 21-day cycles until progression of disease or unacceptable toxicity, lost to follow-up or death. 5 patients had prior autologous bone marrow transplants. Results CA-4948 has been generally well tolerated. Grade 3/4 treatment-related adverse events included amylase/lipase increased, diarrhea, neutrophil count decreased, rash, rhabdomyolysis. Pharmacokinetics has shown favorable characteristics with dose-proportional increases in exposure. Five patients have been on treatment through the end of Cycle 4, including one patient in Cycle 10 on study for over 7 months. Five patients experienced overall tumor burden decreases of ≥20% from baseline, including at least 2 of 4 patients treated at 200 mg BID. Downstream pharmacodynamic markers of IRAK4 activity are being evaluated. Molecular characteristics including cell-of-origin will be presented. Conclusion CA-4948 demonstrates preliminary clinical activity. Enrollment is on-going and the MTD has not been reached. These encouraging results warrant further clinical testing in patients with advanced hematological malignancies. Clinical trial: NCT03328078. Disclosures Younes: Roche: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Biopath: Consultancy; Xynomics: Consultancy; Celgene: Consultancy, Honoraria; HCM: Consultancy; BMS: Research Funding; AstraZeneca: Research Funding; Syndax: Research Funding; Abbvie: Honoraria; Epizyme: Consultancy, Honoraria. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Tun:Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding; Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding. Lunning:Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Martell:Curis, Inc.: Employment. Patel:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Sunesis: Consultancy.

Background: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting 1% of the population, and characterized by deficient or defective von Willebrand factor (VWF). Among women with VWD, up to 80% have heavy menstrual bleeding (HMB), many of whom have depleted iron stores and iron deficiency anemia with reduced physical functioning, anxiety, depression, and poor quality of life. HMB is a serious problem causing significant health burden for those affected. The lack of effective therapies for menorrhagia is a major unmet healthcare need in women with VWD: in up to 30% desmopressin (DDAVP), combined oral contraceptives (COCs) hormones, or the recommended non-hormonal agent, tranexamic acid (Lysteda®, TA) may be ineffective or poorly tolerated. VWF concentrates, including plasma-derived VWF (pdVWF, Humate-P®) and recombinant VWF (rVWF, Vonvendi®) safely reduce bleeds in VWD, but few data exist on VWF use in menorrhagia, and no prospective trials are available to guide treatment. As rVWF has higher purity, potency, and a longer half-life than pdVWF, this phase III trial will compare rVWF with TA in reducing menorrhagia in women with type 1 VWD. Methods: This is an NHLBI-funded U01 phase III multicenter, prospective, randomized, crossover trial in to compare IV rVWF vs. po TA in reducing menorrhagia in type 1 VWD, clinicaltrials.gov, NCT02606045. Women with type 1 VWD, VWF:RCo<0.50 IU/dL and menorrhagia, defined as pictorial blood assessment chart score (PBAC)>100 in at least one of the last two cycles, are eligible. Exclusions include hypothyroidism, past thrombosis, and renal disease. Subjects are randomized to rVWF 40 IU/kg IV day 1 vs. TA 1300 mg po three times daily days 1-5 in each of two consecutive cycles. The order of treatment is determined by randomization: in Group 1, rVWF is given in cycles 1 and 2, and TA in cycles 3 and 4; while in Group 2, TA is given in cycles 1 and 2, and rVWF in cycles 3 and 4. A rescue dose day of rVWF 40 IU/kg may be given day 2 of cycles in which rVWF is given. The primary endpoint is a 40-point reduction in PBAC, a validated measure of menstrual loss, after 2 cycles. As rVWF is a greater burden (IV, cost), to show it is superior to TA, it should improve PBAC 40 points more from baseline than TA. Secondary endpoints are cycle severity, cycle length, QoL (SF-36, Ruta, CDC-HRQ0L-14, CES-D), and satisfaction survey. Treatment response will also be compared with VWF assays and VWF genotype. Safety is assessed by number of rescue doses, other bleeding, thrombosis, and allergic reaction. Our research hypothesis is that rVWF will be superior, producing a greater improvement, by at least 40 points, in PBAC, than TA. We also hypothesize that rVWF will be as safe, tolerable, and acceptable as TA, and that VWF assays and VWF genotype will predict response to treatment. A sample size of 60 (inflated to 66 for 5% attrition) will provide 84% power to detect a difference in improvement of 40 points between rVWF and TA. Analysis will be by intent-to-treat analyses, with a two-tailed alternative hypothesis with type 1 error rate of 0.05, a 4-period 2-group (AABB/BBAA) crossover design, and an estimated between-subject standard deviation (SD) of 63 points and within subject SD of 100 points. Results: A total of 442 potential subjects have been identified at 19 participating HTCs, of whom 33 (7.5%) are eligible, and 2 enrolled. The most common reason for ineligibility is use of an IUD (15.6%), COCs (9.4%), age <18 years (6.2%), pregnancy (6.2%), breastfeeding (6.2%), and VWF prophylaxis (3.1%). Nursing services have been contracted for weekend rVWF infusions. In-person site visits include hands-on web portal training, including a password-protected, FDA-validated data entry system, eSYSDM, use of real-time data form completion by tablet, infusion tracking and training, real-time cycle reporting, patient-training checklists, and protocol training and monitoring. Local gynecologists have been invited to refer potentially eligible patients. Discussion: In conclusion, rVWF is a high-purity VWF concentrate with a longer half-life than pdVWF. In this multicenter phase III trial, rVWF is being compared to the current non-hormonal standard, TA, to reduce menorrhagia in adult women with type 1 VWD. rVWF is safe and effective in prevention and treatment of bleeds, and this trial will determine if rVWF reduces menorrhagia to a degree sufficient to justify its IV route and cost. Disclosures Ragni: Sangamo: Research Funding; Alnylam/Sanofi: Consultancy, Research Funding; ICER: Consultancy; OPKO: Research Funding; Bioverativ/Sanofi: Consultancy, Research Funding; Bayer: Consultancy; Biomarin: Consultancy, Research Funding; Shire/Takeda: Consultancy, Other: Study drug; Spark Therapeutics: Consultancy, Research Funding. Seaman:Spark Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees. Kuriakose:Alexion: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy. Malec:Hemostasis and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria; CSL: Honoraria. Rodgers:AstraZeneca: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy. Wheeler:Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background The phase 3 trial A041202 solidified the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib as a standard of care for older patients with previously untreated CLL by showing superior progression-free survival (PFS) as compared with bendamustine plus rituximab. While ibrutinib is highly effective in previously untreated CLL, there do remain disadvantages to this therapy, specifically the low rate of complete response (CR) and therefore the need for continuous administration, which increases cost and toxicity. In older patients especially, toxicities with ibrutinib are common; 17% of patients had atrial fibrillation and 29% had grade 3 or higher hypertension on the A041202 study. Thus, strategies to decrease the exposure time to ibrutinib are of interest. Venetoclax is an inhibitor of BCL2 that has shown efficacy as a single agent and in combination with monoclonal antibodies, specifically the anti-CD20 monoclonal antibody obinutuzumab for patients with previously untreated CLL. One significant advantage to venetoclax is the ability to produce CRs and minimal residual disease negative (MRD-) responses. In this study, we compare ibrutinib plus obinutuzumab (IO) to ibrutinib plus venetoclax plus obinutuzumab (IVO) with a response-dependent discontinuation. While other studies have been designed with the goal of discontinuation of ibrutinib through combinations with venetoclax, no other study has been presented using a response-dependent discontinuation strategy. Study Design and Methods A041702 is a randomized phase 3 study led by the Alliance for Clinical Trials in Oncology that is currently enrolling through the NCI National Clinical Trials Network (NCTN). CLL patients age 70 years or older who are previously untreated and in need of therapy are eligible. Previous treatment of autoimmune complications with steroids or rituximab is allowed. Patients must have intermediate- or high-risk Rai stage, ECOG performance status 0-2, ANC ≥ 1000/mm3 unless due to marrow involvement, and platelets ≥ 30,000/mm3. CrCl must be ≥ 40 mL/min and AST/ALT ≤ 2.5x upper limit of normal. Patients with hepatitis B must have undetectable viral load, and patients must not have an intercurrent illness that is expected to limit survival to < 5 years. Warfarin and strong inhibitors or inducers of CYP3A4/5 are not permitted. Patients are initially preregistered to the study and submit a peripheral blood sample for central FISH analysis of del(17p). Patients who are registered are randomized 1:1 to Arm 1 (IO) or Arm 2 (IVO), and are stratified by Rai stage and presence of del(17p). IO consists of I daily starting cycle 1 day 1, and O dosed as standard starting cycle 1 day 1 and continuing to cycle 6 day 1. IVO consists of IO as in Arm 1, with V starting cycle 3 day 1 with standard 5-week ramp-up and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and bone marrow MRD testing. Patients on IO then continue I indefinitely. Patients on IVO who are in a bone marrow MRD- CR discontinue all therapy, and those who are not continue I indefinitely. The primary objective of the study is to compare PFS between IO and IVO using the strategy of response-dependent discontinuation. There is 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes two interim analyses for superiority when 50% and 75% of the expected number of events have been observed and three interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed. Conclusions A041702 is an ongoing phase 3 clinical trial using a novel response-dependent discontinuation method. Results of this study have the potential to change the standard of care for older patients with previously untreated CLL. The study is expected to accrue for 3 years beginning January 2019, and we welcome participation from sites throughout the NCTN. Support: U10CA180821, U10CA180882, UG1CA189823, U24CA196171; U10CA180820 (ECOG-ACRIN); https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifier: NCT03737981 Disclosures Woyach: Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Lozanski:Beckman Coulter: Research Funding; Boehringer Ingelheim: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Ding:Merck: Research Funding; DTRM Biopharma: Research Funding. Hill:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stone:Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding; AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy. Byrd:Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; Genentech: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Gilead: Other: Travel Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Other: Travel Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel Expenses, Speakers Bureau; Ohio State University: Patents & Royalties: OSU-2S; Acerta: Research Funding; Novartis: Other: Travel Expenses, Speakers Bureau; BeiGene: Research Funding; Ohio State University: Patents & Royalties: OSU-2S; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Acerta: Research Funding; Genentech: Research Funding; BeiGene: Research Funding; Genentech: Research Funding; Acerta: Research Funding; TG Therapeutics: Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau.

Introduction Waldenstrom macroglobulinemia (WM) is a rare, incurable, indolent non-Hodgkin lymphoma that is preceded by an IgM monoclonal gammopathy of undetermined significance (IgM MGUS). In recent years, better understanding of the pathobiology of WM and IgM MGUS has strengthened the hypothesis that they may represent different stages of the same disease. Studying the relationship between these two conditions is the essential first step to understanding the mechanisms driving the malignant transformation from IgM MGUS to WM. Recently long non-coding RNAs (lncRNAs) have garnered significant recognition for their roles in the regulation of gene expression and cellular function. lncRNA can regulate gene expression of neighboring protein-coding genes through multiple mechanisms such as by recruiting chromatin modifiers and increasing accessibility of genes to transcription proteins, or by directly binding to enhancers or promoters. Here we present the first analysis of the lncRNA expression profile in patients with WM compared to IgM MGUS. Methods Twenty-one patients with untreated WM (n=14) and IgM MGUS (n=7) seen at Mayo Clinic were included in this analysis. Malignant cells were isolated from bone marrow samples using CD19 and CD38 positive selection. Total RNA was extracted and sequencing was performed using the Illumina HiSeq4000 NGS platform. Differentially expressed lncRNAs in WM compared to IgM MGUS were defined as log2 fold change (FC) > 1.0 (upregulated) or < -1.0 (downregulated) and a false discovery rate (FDR) < 0.05. The nearest gene to each lncRNA was also identified and their gene expression was detected. Using the Ingenuity Pathway Analysis software and taking into account the transcriptional expression and known function of these genes, a correlation between cell function and disease analysis was performed. Results A total of 119 lncRNAs were differently expressed between WM and IgM MGUS (17 transcripts were upregulated in WM, while 102 were downregulated in WM). Sixteen unique genes were identified as the nearest gene to 17 upregulated lncRNAs, while 18 genes were identified as the nearest genes to the top 18 downregulated lncRNAs in WM compared to IgM MGUS. Several of the upregulated lncRNA in WM were in proximity to known oncogenes. The well-known oncogenic lncRNA PVT1 was found to be upregulated in WM compared to IgM MGUS (log2 FC 1.35, FRD 0.04). PVT1 is overexpressed in several malignancies and associated with inhibition of apoptosis and increased cell proliferation. PVT1 is in close proximity to MYC and co-expression of PVT1-MYC has been described in multiple cancers. PVT1 also potentiate MYC amplification by increasing MYC protein stability, therefore promoting malignant cell growth. The lncRNA TCB1D27, also upregulated in WM compared to IgM MGUS, is located in close proximity to the oncogene TNFRSF13B (TACI), which was found to be overexpressed in WM patients (log2 FC 1.61, FDR <0.001). TACI is a receptor for BLyS/BAFF, which modulates the development of normal B-cells and plays a role in various B-cell malignancies. In fact, BLyS/BAFF level is known to be increased in WM and to promote survival and proliferation of WM B cells. The upregulated lncRNA RP11-25K21.1 in WM is located in close proximity to the oncogene FCGR2B (CD32B), which was also upregulated in WM compared to IgM MGUS (log2 FC 1.59, FDR 0.001). Overexpression of CD32B was previously shown to be associated with inferior outcomes in DLBCL and FL patients, presumably secondary to an increased internalization and clearance of rituximab due to increased CD32B expression on malignant cells. Several other upregulated lncRNAs in WM compared to IgM MGUS are also in proximity of other oncogenes such as PCED1B, POLD3, CLLU1, and SMAD7. Finally, we considered the expression of the nearest genes and their reported cell function and association with diseases. Several genes that are known to have a role in the cell proliferation and/or neoplasm development were noted to be upregulated in WM (figure 1). Conclusion We present the first report of lncRNAs expression in WM and IgM MGUS in addition to a concurrent analysis of the gene expression of the nearest protein-coding genes. Several known oncogenes are in proximity of overexpressed lncRNAs in WM compared to IgM MGUS that could indicate potential implications in the pathobiology of these diseases and the mechanism driving the malignant transformation to WM. Disclosures Paludo: Celgene: Research Funding; Celgene: Research Funding; Verily Life Sciences: Research Funding; Verily Life Sciences: Research Funding. Dasari:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kapoor:Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Glaxo Smith Kline: Research Funding. Ailawadhi:Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Cellectar: Research Funding; Celgene: Consultancy. Gertz:Amyloidosis Foundation: Research Funding; i3Health: Other: Development of educational programs and materials; Medscape: Consultancy, Speakers Bureau; Ionis/Akcea: Consultancy; Celgene: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Teva: Speakers Bureau; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Physicians Education Resource: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Springer Publishing: Patents & Royalties; International Waldenstrom Foundation: Research Funding. Novak:Celgene Coorperation: Research Funding. Ansell:Affimed: Research Funding; Regeneron: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; Trillium: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Mayo Clinic Rochester: Employment; Seattle Genetics: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mayo Clinic Rochester: Employment; LAM Therapeutics: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Affimed: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Mayo Clinic Rochester: Employment; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding.

AbstractThe public image of nursing is important because it can facilitate or create barriers to achieving an adequate supply of nursing human resources. This study sought to gain a better understanding of nursing’s professional image within the Republic of Georgia. The Nursing Human Resources Systems model was used to guide the study’s exploratory, qualitative approach. Data collection occurred over a 2‐week period in the Republic of Georgia, and thirty‐three participants formed the final study sample. Participants included healthcare professionals, key informants from nonprofit and research institutions, and patients. Data analysis occurred using directed content analysis techniques, and three themes emerged: (a) gender dimension; (b) the nursing service recipient experience; and (c) historical legacies. Themes revealed the complexities of nursing’s image in the country. Findings from this study serve as baseline data for understanding nursing’s image in the Republic of Georgia which could assist with improving pre‐entry nursing production issues.

Exercise-induced hypertension is a predictor of cardiovascular events in patients with coarctation of aorta (COA). However, it is unclear whether mild COA diagnosis is an independent risk factor of exercise-induced hypertension. We hypothesized that for every unit increase in exercise, patients with COA (without hemodynamically significant coarctation) will have a higher rise in systolic blood pressure (SBP) compared with matched controls. One hundred forty-nine patients with COA (aortic coarctation peak velocity <2 m/s) who underwent exercise testing were matched 1:1 to controls using propensity score method based on age, sex, body mass index, hypertension diagnosis, and SBP at rest. We compared exercise-induced change in SBP between patients with COA and controls and also assessed the correlation between Doppler-derived aortic vascular function indices (effective arterial elastance index and total arterial compliance index) and exercise-induced changes in SBP. Compared with controls, patients with COA had a greater change in SBP per unit metabolic equivalent (β=2.86; 95% CI, 1.96–4.77 versus 1.07, 95% CI, −0.15 to 1.75; P =0.018) and per unit oxygen pulse (β=4.57; 95% CI, 2.97–7.12 versus 1.45, 95% CI, −0.79 to 2.09, P <0.001). There was a correlation between SBP peak −SBP rest and elastance index ( r =0.38, P =0.032) and between SBP peak −SBP rest and total arterial compliance index ( r =−0.51, P =0.001), suggesting an association between vascular dysfunction and exercise-induced BP changes. Patients with COA, without significant obstruction, had higher exercise-induced changes in SBP after adjustment for other risk factors for hypertension. Considering the already known prognostic importance of exercise-induced hypertension, the current study highlights the potential role of exercise testing for risk stratification of patients with mild COA.

Abstract Introduction Cardiopulmonary exercise testing (CPET) is an important diagnostic method to evaluate athletes and non-athletes, however we do not have widely accepted normal values for correct evaluation and interpretation in the young. Goals Our aim was to compare CPET parameters of young athletes and non-athletes and determine reference values. Methods Exercise tests were performed in young non-athletes, aged <18 years between 2011 to 2016 at Mayo Clinic. Athletes underwent detailed sports cardiology screening including CPET at Semmelweis University Heart and Vascular Center between 2016 and 2018. Individuals with cardiovascular disease were excluded. We created 2 subgroups in both sexes: 12–14 years (Group 1), 15–17 years (Group 2). Statistical analysis was performed using SAS with analysis of variance under the general linear model adjusting for age, body mass index and test effort based on peak respiratory exchange ratio (RER). Results A total of 212 athletes (92% male, 15.5±0.6ys) and 207 non-athletes (68% male, 15.0±0.7ys) were included in the analysis. In Group 1 boys, athletes have higher peak HR (200.0±9.2 vs 188.5±16.8 bpm, p<0.0001), HR reserve (117.1±14.5 vs 108.9±19.8 bpm p<0.05), VO2 max (53.7±6.6 vs 44.7±9.1 mL/kg/min p<0.0001), ventilation (VE) (120.3±25.0 vs 70.7±21.6 L/min p<0.0001) and RER (1.12±0.0 vs 1.07±0.08, p <.001) compared to controls. In Group 2 boys, there was no difference in peak HR and HR reserve, but athletes have higher VO2 max (57.2±4.7 vs 45.3±9.3 mL/kg/min, p<0.0001) and VE (150.7±23.7 vs 104.1±25.9 L/min, p<0.0001), similarly as Group 2 girls: VO2 max (46.3±3.6 vs 34.9±8.5 mL/kg/min p<0.0001), VE (118.7±12.5 vs 68.4±20.6 L/min, p<0.0001). In male athletes, peak HR (200.6±9.2 vs 196.5±7.4 bpm p<0.05) and HR recovery (34.2±9.8 vs 29.8±11.1 bpm p<0.05) decreases with age, while VO2 max (53.7±6.6 vs 57.2±4.7 mL/kg/min, p<0.001) and VE (120.3±24.9 vs 150.7±23.7 L/min, p<0.0001) increases. Lower cut-off values were determined in each group (Figure). Lower-cut off values Conclusion We created a unique Mayo-Semmelweis database of young athletes and non-athletes. As a result of intensive training, athletes show higher levels of CPET variables vs non-athletes. Our study provides CPET reference values in the pediatric age group, applying them could contribute to correct evaluation and interpretation of CPET, increasing its diagnostic potential.