bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surgery with Turoctocog Alfa: Efficacy and Safety in Bleeding Prevention During Surgical Procedures - Results From the guardian™ Trials.
Authors: Santagostino Elena , Lentz Steven R. , Misgav Mudi , Brand Brigitte , Chowdary Pratima , Savic Aleksander , Kilinc Yurdanur , Tuddenham Edward GD , Lindblom Anders 
Published: October 2019

Abstract
Abstract 2228

Introduction:
Novo Nordisk is developing turoctocog alfa, a human third generation recombinant FVIII for treatment of hemophilia A. During the pivotal trial in adult and adolescent previously treated patients with severe hemophilia A (guardian™1), subjects in need of surgery were able to participate in a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Pediatric (<12 years of age) previously treated patients in the guardian™3 trial were allowed to undergo minor surgery if needed during the trial. In addition, after completing these initial trials subjects were allowed to continue treatment with turoctocog alfa in the extension trial (guardian™2) which also includes a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding.

Methods:
We here describe surgeries performed within the guardian trials. For the ongoing guardian™2 extension trial, only cases included in the interim analysis (data cut-off 21NOV2011) are included.

Results:
In all, results from 10 major and 3 minor surgeries are included. Surgery indication was related to hemophilia joint disease in 8/13 cases. The hemostatic efficacy during and after surgery was rated on a 4-point scale (excellent, good, moderate and none) by the Investigator and/or Surgeon. Details and outcome of the individual surgeries performed are presented in Table 1. In addition, there were no safety concerns.

Discussion:
Prevention of surgical bleeding is an important aspect of hemophilia treatment. In the present 13 surgeries, including all surgeries performed with turoctocog alfa in the phase 3 guardian™ trials, hemostatic efficacy during and after was rated as either excellent or good in each case. The results support that turoctocog alfa has an excellent safety and efficacy profile for use in hemophilia A.

Disclosures:
Santagostino: Novo Nordisk and Pfizer: Research Funding; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau. Lentz:Novo Nordisk: Consultancy, Research Funding. Brand:Bayer: Travel support, Travel support Other; Novo Nordisk, Baxter, Pfizer: Advisory Boards, Advisory Boards Other; Novo Nordisk: Honoraria. Chowdary:Novo Nordisk: Consultancy. Savic:Novo Nordisk: Speakers Bureau. Lindblom:Novo Nordisk A/S: Employment.
Influence of Factor V G1691A or Prothrombin G20210A Mutation On Inhibitor Development in Patients with Severe Hemophilia A - an Israeli-German Database Study.
Authors: Kenet Gili , Bidlingmaier Christoph , Ettingshausen Carmen Escuriola , Gutsche Sven , Halimeh Susan , Janssen Verena , Kurnik Karin , Nowak-Gottl Ulrike 
Published: October 2019

Abstract
Abstract 2234
It has been reported that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V (FV) G1691A mutation and that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors, namely the FV or the factor II (FII) G20210A variant, is significantly later in life than in non-carriers. Until today many factors, such as a positive family history, the use of recombinant FVIII [rFVIII] concentrates, or high dose FVIII administration, are included as potential risk factors for inhibitor development. The present non-concurrent Israeli-German database study was performed to investigate the impact of FV and FII mutations on clinical meaningful inhibitor development (outcome variable) in patients with severe HA. 272 patients with HA < 1% consecutively ascertained from Israel (n=88) and four different German catchment areas (n=184) born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. To avoid family cluster effects [inhibitor; IT] in both countries only the first HA patient who presented for diagnosis at the treatment center was included in the present study. From the entire cohort 80% were tested for thrombophilia [IT]. 32 of 216 children (14.8%) carried either the FV or the FII variant. During the follow-up period of 200 exposure days 54 of 216 (26%) developed a clinical meaningful inhibitor: 14 out of 32 carriers of IT (44%) compared with 40 of 184 (22%) without IT [Hazard ratio [HR]/95% confidence intervals [CIs] 2.1/1.16–3.9]. In addition, univariate Cox regression analysis for patients treated with rFVIII products compared with plasma-derived [pdFVIII] showed a significant increased risk for inhibitor development [HR/CI: 2.1/1.3–3.6]. Multivariate analysis adjusted for patient's individual median single FVIII dose, administered during the first three months, first-line use of pdFVIII (n=82) versus rFVIII concentrations (n=134) and treatment periods [1980–2011] revealed that the presence of IT independently increases the risk of inhibitor development to a hazard of 2.5 [CI: 1.1–5.8]. In addition, the increase of FVIII per one IU/kgbw was significantly associated with the risk to develop a high responding inhibitor [HR/CI: 1.2/1.04–1.1]. In multivariate analysis neither rFVIII products, nor treatment periods showed a statistically significant influence on clinical important inhibitor development. Data presented here suggest that clinical meaningful inhibitor development is of multifactorial origin and that apart from a positive family history also FV and FII mutations should be included in the aetiology research.

Disclosures:
No relevant conflicts of interest to declare.
Increased Relapse Associated with Mixed Donor-Donor Chimerism Following Double Umbilical Cord Blood Transplantation (dUCBT)
Authors: Verneris Michael R. , Turcotte Lucie M. , Cao Qing , MacMillan Margaret L. , Miller Jeffrey S. , Weisdorf Daniel , Brunstein Claudio G , Wagner John E. 
Published: October 2019

Abstract
Abstract 358
We previously showed lower rates of relapse in recipients of dUCBT, compared to patients treated with single UCBT (Verneris, Blood, 2009). One unit predominates by D+100 in ∼90% of patients and recent studies show that single unit dominance is associated with T cell recognition of the rejected unit (Gutman, Blood, 2010). In addition, higher rates of acute graft-vs-host disease (aGVHD) have been observed after dUCBT compared to single UCBT, regardless of age (MacMillian, Blood, 2009). Thus, we hypothesized that graft vs. graft interactions that occur during dUCBT may drive both GVL and GVHD reactions. To test this hypothesis, we reviewed the records of patients with hematological malignancies transplanted with a dUCBT from 2000 to 2011 at the University of Minnesota. Myeloablative (MA) conditioning was with cyclophosphamide (Cy 120 mg/kg), fludarabine (Flu 75 mg/m2) and total body irradiation (TBI 13.2 Gy) (n=178) and non-MA conditioning was with Cy (50 mg/kg), Flu (200 mg/m2) and TBI (2 Gy) (n=282). Acute GVHD prophylaxis consisted of cyclosporine and mycophenolic acid. At D+100 316 patients were evaluable and had either BM (n=273) and/or PB (n=178) donor engraftment data. Engraftment was assessed using short tandem repeat analysis. “Mixed donor-recipient chimerism” was defined as >5% host cells and “dual chimerism” was defined as complete donor chimerism (donor 1 + donor 2), with a minimum contribution of 5% by each unit (5% is the lower limit of detection for this clinical test). As expected, patients with evidence of mixed donor-recipient chimerism in the blood or marrow at D+100 (n=35) had high rates of relapse (69% [95% CI, 49–89%] at 2 years) and were excluded from further analysis. Of the patients with evaluable peripheral blood chimerism data, 90.4% (n=161) had hematopoiesis derived from a single unit, while 9.6% (n=17) showed dual chimerism after dUCBT. In multivariate analysis, dual chimerism at D+100 was associated with higher relapse (HR=1.97 [95% CI, 1.08–3.59], p=0.01), less grade II-IV aGVHD (HR=0.36 [95% CI, 0.17–0.78], p=0.01) and a trend toward worse DFS (HR=1.68 [95% CI, 0.9–3.13], p=0.1). Dual chimerism was not associated with age (p=0.32), nor non-MA conditioning (p=0.15). Recipients of two HLA 6/6 matched units (with each other and the recipient), were more likely to have dual chimerism (p<0.01). Nearly identical results were obtained in a separate model examining BM engraftment (single (n=247) and dual chimerism (n=26)) and transplant outcomes. While these findings should be confirmed in a separate dataset, they suggest that an unexpected consequence of selecting well matched units for dUCBT is higher mixed donor-donor chimerim, less aGVHD and more relapse. Further study of dUCBT and GVL is needed.

Disclosures:
No relevant conflicts of interest to declare.
Targeting B-Cell Lymphoma with Idiotype-Specific Peptibodies: Toward a Personalized and Tumor-Specific Therapy
Authors: Torchia James A , Ng Patrick P , Chen Homer , Kohrt Holbrook E , Marabelle Aurelien , Alizadeh Ash A. , Levy Ronald 
Published: October 2019

Abstract
Abstract 3713

Background:
The complementarity determining region, or idiotype, of the surface immunoglobulin receptor is a tumor-specific marker on B-cell lymphomas that is unique to each patient. Antibodies against idiotype can induce complete regression of lymphoma in patients, but since this therapeutic approach requires the generation of a custom monoclonal antibody for each patient, it has not been practical.

Objective:
Here we describe a method for targeting the idiotype on the surface of a B-cell lymphoma by using synthetic idiotype-ligands covalently linked to a recombinant IgG Fc domain (Figure 1A). These peptide idiotype-ligands can be identified through oligopeptide library screens and produced inexpensively by automated solid-phase synthesis. Linkage of idiotype-ligands to the Fc domain serves two purposes: to enhance their pharmacokinetics and to augment their anti-tumor effect by activating immune effector functions. Since each patient-specific peptide can be chemically linked to a common IgG Fc domain, this modular construct design yields a patient-specific therapeutic that does not require the production of a custom biologic macromolecule for each patient.

Results:
Idiotype peptide-ligands were produced by solid-phase synthesis and covalently linked to the amino-terminus of a recombinant mouse IgG2a Fc domain by native chemical ligation, a method for site-selective polypeptide ligation. The resulting peptibody demonstrated targeted killing of a human lymphoma cell line in vitro by crosslinking surface immunoglobulin and triggering activation-induced death. Additionally, the peptibody triggered complement-mediated cytotoxicity of opsonized lymphoma cells in vitro and activated natural killer cells co-cultured with opsonized lymphoma cells. The peptibody exhibited a favorable pharmacokinetic profile and peptibody treatment was sufficient to clear tumor in SCID mice challenged intravenously with a luciferase-labeled human lymphoma cell line (p = 0.0018; Figure 1B-D).

Conclusions:
Idiotype-specific peptibodies demonstrate multimodal activity against lymphoma cells in vitro and clear human lymphoma in a disseminated xenograft model. The modular design of this therapeutic may enable a personalized and targeted therapy that is feasible to produce for patients with B-cell lymphoma.

Disclosures:
No relevant conflicts of interest to declare.
Targeting the Genetic Resistance of JAK2 and BCR/ABL by TG101348
Authors: Kesarwani Meenu , Azam Mohammad 
Published: October 2019

Abstract
Abstract 3765
The inherent preponderance of genetic resistance against tyrosine kinase inhibitor (TKI) therapy poses significant challenge for effective treatments. Recent approval of Janus kinase 2 (JAK2) inhibitor INCB018424 (Jakafi, ruxolitinib) for the treatment of myeloproliferative neoplasms (MPNs) prompted us to identify resistant mutations that may pose clinical challenge. In vitro drug selection screening against two leading JAK2 inhibitors (INCB018424 and TG101348) were performed. Here we show that like other kinase inhibitors, INCB018424 is prone to genetic resistance while TG101348 is recalcitrant to develop in vitro resistance. Sequencing of INCB018424 resistant clones identified 211 amino acid substitutions spanning across FERM, SH2, JH2 and the kinase domain. Biochemical and structural modeling studies of these mutants demonstrate that mutations within the active site confer resistance either by direct steric hindrance or destabilizing the architecture of the active site. And mutations from the allosteric sites destabilize the intermediary state of the active and inactive conformations of JAK2 to which INCB018424 preferentially binds. Furthermore, these resistant variants are cross resistant to other JAK2 inhbitors (Lestaurtinib, CYT-387 and AZD1480). In contrast, these resistant variants are fully sensitive to TG101348 supporting the lack of resistance against this compound as observed during in vitro screening. Structural modeling studies revealed that TG101348 stabilizes the active conformation of the kinase and binds to the substrate-binding pocket. Mutations affecting the substrate-binding pocket may either alter substrate binding/phosphorylation or encode an incompetent kinase that blocks the emergence of resistance. Because JAK2 and BCR/ABL share a common substrate, STAT5, they might have similar architecture of the substrate-binding pocket, which may allow the inhibition of BCR/ABL by TG101348. Indeed, TG101348 can inhibit both native and gatekeeper variants of BCR/ABL and in vitro drug resistant screening failed to develop emergence of resistant clones. These studies provide evidence that the patients developing resistant variants of JAK2 and BCR/ABL can be treated with TG101348 and support for future drug design geared towards targeting the substrate binding sites in other oncogenic kinases for better and sustained therapeutic response.

Disclosures:
No relevant conflicts of interest to declare.
Development of Inhibitory Antibodies to Therapeutic Factor VIII in Severe Hemophilia A Is Associated with Microsatellite Polymorphism in the HMOX1 promoter
Authors: Repesse Yohann , Peyron Ivan , Dimitrov Jordan , Dasgupta Suryasarathi , Moshai Elika Farrokhi , Borel-Derlon Annie , Costa Catherine , Guillet Benoist , d'Oiron Roseline , Aouba Achille , Rothschild Chantal , Oldenburg Johannes , Pavlova Ana , Kaveri Srinivas , Lacroix-Desmazes Sebastien 
Published: October 2019

Abstract
Abstract 38
The occurrence of inhibitory anti-factor VIII (FVIII) antibodies is the major complication of replacement therapy in patients with hemophilia A. Heme oxygenase-1 (HO-1) is a stress inducible enzyme with anti-inflammatory activity. Induction of HO-1 in hemophilic mice reduces the immunogenicity of therapeutic FVIII. Interestingly, polymorphisms in the promoter of the HO-1-encoding gene (HMOX1) modulate the expression of HO-1.
We investigated the relationship between polymorphisms in the promoter of HMOX1 in severe hemophilia A patients and the development of FVIII inhibitors.
We analyzed 362 patients with severe hemophilia A involving 99 patients with FVIII inhibitors and 263 patients who did not develop inhibitor within the first 150 cumulative exposure days to therapeutic FVIII. Direct sequencing and DNA fragment analysis were used to study the variable (GT)n polymorphism and single nucleotide polymorphisms located at −1135 and −413 in the promoter of HMOX1. We assessed associations between the individual allele frequencies and genotypes, and the development of inhibitors.
Our results demonstrate a higher frequency of alleles with large (GT)n repeat (n≥30, L, associated with a lesser expression of HO-1) in inhibitor-positive patients [odds ratio (OR) 2.31; 95% CI 1.46–3.66, p<0.001]. Six genotypes (L/L, L/M, L/S, M/M, M/S and S/S) of (GT)n repeats were identified (S: n<21; M: 21≤n<30). The genotype group including L alleles (L/L, L/M and L/S) was statistically more frequent among inhibitor-positive than inhibitor-negative patients, as compared to the other genotypes (33.3% vs 17.1%) [OR 2.21, 95% CI 1.30–3.76, p<0.01].
To our knowledge, this is the first association between HMOX1 promoter polymorphism and development of anti-drug antibodies. Modulating the endogenous anti-inflammatory machinery of hemophilia A patients appears as a plausible therapeutic option for reducing the risk of inhibitor development.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Utility of PET/CT Scanning in Patients with Chronic Lymphocytic Leukemia
Authors: Conte Michael J. , Bowen Deborah , Rabe Kari G. , Schwager Susan , Slager Susan L , Zent Clive S. 
Published: October 2019

Abstract
Abstract 3903
The clinical utility of 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET-CT) scans in the management of patients with chronic lymphocytic leukemia (CLL) has not been clearly defined. CLL cells typically have low FDG avidity and the addition of the PET component has not been shown to improve the utility of CT scans in the management of patients with CLL. However, patients with CLL are at increased risk of developing FDG avid complications including more aggressive lymphomas, other second malignancies, and infections for which FDG PET-CT scans are a useful imaging modality. We hypothesized that FDG PET-CT scans are sensitive tests for evaluation of these complications in patients with CLL.

Patients and Methods:
This observational study was performed with IRB approval. We studied all 4030 CLL patients seen at least once in the Division of Hematology at Mayo Clinic Rochester between January 1, 2006 and December 31, 2011 using data prospectively collected into the Mayo Clinic CLL database. We reviewed the clinical and radiological records of the 272 (7%) patients who underwent 526 FDG PET-CT scans of the trunk during this time period to determine the indication for PET-CT scan, results of imaging, and the effects of the use of PET/CT scan on management.

Results:
Four hundred and seventy two (90%) of the 526 PET-CT scans were reported as abnormal. Of these, 78 (17%) scans were useful in directing a tissue biopsy of high FDG avidity lesions. Of the 37 (8%) positive PET-CT scans that facilitated the diagnosis of new complications of CLL, 21 (4%) scans led to a diagnosis of diffuse large B cell lymphoma and 9 (2%) scans led to a diagnosis of a solid malignancy. The FDG component of 22 PET-CT scans done because of clinical suspicion of complications of CLL were negative, and thus useful in management of these patients. PET-CT scans showed progressive CLL in 138 (29%) studies but in these patients, the PET component of the scan did not provide additional information about the status of the patients' CLL compared to the CT component alone.

Conclusions:
FDG PET-CT scans are not of proven value in staging CLL or determining response to treatment. However, our data suggest that they could be of considerable value in evaluation for complications, especially more aggressive lymphomas, other cancers, and infections that complicate the course of CLL.

Disclosures:
Off Label Use: Phase I study using PGG beta glucan in CLL. Zent:Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding.
The Myeloma Genome in Drug Refractory Extra-Medullary Disease Identifies Mutations in Proteasome, Cereblon and Glucocorticoid Pathways
Authors: Egan Jan , Kortuem Klaus Martin , Shi Chang-Xin , Schmidt Jessica , Craig David , Carpten John , Stewart Keith 
Published: October 2019

Abstract
Abstract 3968
To better understand the genetic events associated with extra-medullary multiple myeloma (MM) we completed whole exome, long-insert whole genome and RNA sequencing on a patient with t(14;16) and neck adenopathy, as well as whole genome sequencing on two additional patients with respectively: t(4;14) and plasma cell leukemia, and del 17 with chest wall mass. All patients had multi-drug resistant disease and del 13. The frequency of somatic non-synonymous single nucleotide variants (SNV) ranged from 119 to 498, including an average of 15 truncating SNV, as well an average of 75 structural variants (range 2–147). Importantly, in one patient a truncating mutation, Q99*, on one allele and minor clone point mutation, R283K, on the second allele was observed in CRBN, a gene whose expression is required for effective lenalidomide and pomalidomide anti-myeloma activity. In the same patient a non-synonymous mutation, E171K, was also observed in PSMG2, a proteasome assembly protein, and a non-synonymous mutation, G369A, in NR3C1, a glucocorticoid receptor. Subsequently we have sequenced CRBN in 27 patients and 7 cell lines and have found no further examples of mutation in CRBN but have previously reported a bi-alleleic focal deletion in the MM.1Sres cell line. Mutations in NR3C1 have not previously been described in other MM genomes. Other, potentially clinically relevant mutations in the three patients were observed in FGFR3, PRDM1, STAT5B, NRAS, KRAS, PIK3CA, NF1, ATM, NFKB2, CKS1B and ERBB4. Although the three patients did not share a unifying event, a number of mutated genes observed were shared with other published myeloma genomes including RB1, TP53, MLL3, JAG2, VAV3 and SETD2. We also looked at pathway activation across the three genomes with the most statistically mutated pathways including VEGF signaling and activation, cell adhesion and chemokines, cytoskeleton remodeling, integrins in carcinoma progression, TP53 signaling and NOTCH signaling. In conclusion, we have identified, for the first time, the presence of a mutation in CRBN in a myeloma patient as well as mutations in PSMG2 and NR3C1, likely associated with drug resistance.

Disclosures:
Schmidt: Karyopharm: Research Funding. Carpten:Life Technologies: Research Funding. Stewart:Millenium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.