bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors Of Survival Outcomes In Phase I Relapsed Or Refractory Multiple Myeloma Patients
Authors: Harvey R. Donald , Barbee Meagan S. , Nooka Ajay K. , Kim Sungjin , Chen Zhengjia , Heffner Leonard T. , Kaufman Jonathan L. , Lonial Sagar 
Published: October 2019

Abstract

Objectives
Categorization of response criteria for multiple myeloma (MM) is based on magnitude of change in serum and urine paraprotein values and normalization of free light chain ratio (rFLC). However, the association between improvements in these surrogate markers and patient outcomes is not validated in the phase I setting. Early measures of response would be beneficial for patients and agents to identify those likely to have prolonged disease-free intervals and to validate agent activity for rapid movement to subsequent development.

Methods
We identified 31 trials that met enrollment criteria of phase I, relapsed or refractory disease, and non-transplant study population. Clinical and demographic data collected included age, sex, race, ECOG performance status (PS) at entry, myeloma subtype and isotype, prior therapy, cytogenetics at study entry, date of progression, and date of expiration. Patients with t(4;14), del13, del17p, t(14;16), or t(14;20) were considered to have non-standard risk cytogenetics. Evaluation of the relationship between progression free survival (PFS) and change in plasma cell activity by the rFLC and magnitude of response in serum/urine paraprotein per IMWG criteria was performed. Landmark analyses occurred at cycle 2 and 4, 8, and 12 months. Progression free survival (PFS) at 12 months was the primary outcome of interest.

Results
Among 87 patients; 47 (54%) were female; 56 (64%) white, 29 (33%) black; 27 (31%) non-standard risk cytogenetics; ECOG PS 1 in 73 (84%); and median prior lines 5 (1-11). Eighty were evaluable for paraprotein changes, 71 for rFLC. Normalization of rFLC at 4 months conferred a PFS advantage (11.3 v 2.8 months, p = 0.038) (Table 1). Normalization of rFLC by 12 months was found to predict PFS (6.1 vs. 2.8 months, p = 0.015) and a longer OS (45 vs. 17.4 months, p = 0.002). Magnitude of response in paraprotein was found to predict and correlate linearly with PFS at all time landmarks (r2 = 0.769 to 0.952). Analysis of PFS by IMWG criteria and by quartiles of 50% changes were both linear (p < 0.001) (Figure 1).

Conclusion
These findings suggest that normalization of the rFLC and magnitude of paraprotein response are viable surrogate disease endpoints in phase I clinical trials of novel agents and combinations. The use of current IMWG criteria in the phase I setting is valuable, but the addition of time of response and alterations of response boundaries should be further evaluated in the setting of improved treatments.

Disclosures:
Kaufman: Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.
Recovery Of Natural Killer Cells and Monocyte Subsets Following Autologous Peripheral Blood Stem Cell Transplantation Predicts Longer Progression Free Survival Among Multiple Myeloma Patients
Authors: Callander Natalie S , Rathouz Paul J , Asimakopoulos Fotis , Juckett Mark B , Coe Christopher L , Sheerar Dagna , Ersland Karen , Hematti Peiman , Costanzo Erin S 
Published: October 2019

Abstract
Prior research has shown that a timely immune recovery following peripheral blood stem cell transplantation (PBSCT) may improve progression free and overall survival for lymphoma and leukemia patients (pts). However, this has not been studied in multiple myeloma (MM) pts. We conducted an exploratory investigation of the extent to which the recovery of Natural Killer (NK) cell and monocyte (Mo) subsets predicted progression free survival (PFS) among MM pts following autologous PBSCT. Patients (N = 37) were treated with 200mg/m2 of melphalan, followed by infusion of >2 x106 CD34 cells/kg, and were followed prospectively for 3 to 36 months. Immunophenotyping and multicolor flow cytometry were used to identify NK and Mo subsets at Day 100 post-PBSCT. Disease progression or relapse was defined using IMWG criteria. Cox proportional hazard regression models were used to examine relationships between cell subpopulation counts and time from PBSCT to MM progression. All models were adjusted for ISS stage and risk (high, defined as plasma cell leukemia; loss of p53, myc rearrangement, t(14;16), t(14:20) by FISH; minus 13 by cytogenetics; versus standard) at diagnosis, and hazard ratios were standardized to correspond to a 2 standard deviation difference in the logarithm of NK or Mo cell counts. Compared to a healthy reference sample, MM patients showed good recovery of all Mo subsets with normal counts by Day 100, but CD56+CD3- NK cell numbers remained low, with the subset of NK cells expressing high CD16 particularly suppressed. During the follow-up period, 25 patients (67.6%) progressed or relapsed. Pts with higher Day 100 CD56+CD16hi NK cell counts had a longer PFS (hazard ratio = .351, p = .033). A similar effect was seen for CD56+CD16lo NK cells (hazard ratio = .321, p = .079). Higher CD14+ Mo counts were also associated with longer PFS (hazard ratio = .230, p = .007). An examination of Mo subpopulations showed that higher numbers of Mo expressing low or no CD16 predicted a longer time to disease progression (hazard ratio = .207, p = .011), but the inflammatory subsets with moderate or high CD16 expression were not significantly associated with PFS. Results suggest that MM patients who have lower NK cell and CD14+ Mo counts may be at risk for a poorer outcome following autologous PBSCT, with these subsets adding prognostic significance above and beyond cytogenetic risk and ISS stage. Subpopulations with greater regulatory and less inflammatory function had the most salient effects. These NK cell and Mo subsets may inhibit residual MM growth and progression and could serve as novel markers of the clinical outcome following PBSCT for MM.

Disclosures:
No relevant conflicts of interest to declare.
A Comparative Study Of The Outcome Of Isolated Chromosome 13q and Clonal Progression Detected By I-FISH Do Additional Cytogenetic Abnormalities Impact Survival In Multiple Myeloma
Authors: Peres Edward , Farhan Shatha , Kuriakose Philip , Michalowski Susan , Sitarik Alexandra , Janakiraman Suseela M , Jessica Sanchez , Janakiraman Nalini 
Published: October 2019

Abstract

Background
Chromosomal abnormalities detected by interphase fluorescence in situ hybridization (I-FISH) are an important prognostic marker in patients with multiple myeloma (MM). Isolated chromosome 13q has been considered standard risk when identified by I-FISH and high risk by conventional cytogenetics. The impact of additional cytogenetic abnormalities with chromosome 13q identified by I-FISH in regards to prognosis has not been fully defined. In this report, we describe the outcome of patient’s with multiple myeloma with isolated chromosome 13q and 13q+ (additional cytogenetic abnormalities) identified by I-FISH at our institution between January 2003 and January 2013 and had I-FISH analysis prior to treatment.

Methods
The primary objective was to compare patient’s outcomes in regards to response, time to progression, and overall survival between patients who had an isolated 13q and 13q+ identified by I-FISH in the bone marrow plasma cells. Kaplan & Meier curves were generated to calculate overall survival (OS) between the two groups.

Results
Between January 2003 and January 2013, we identified 76 patients by I-FISH who had either an isolated 13q or 13q+ in patients with multiple myeloma (Patient characteristics Table 1). Of the patients with an isolated 13q abnormality 33% received a bortezomib-based regimen and 38% in the 13q+ group. Of the patient’s with a isolated 13q 38% went onto receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) while 20% with a 13q+ received ASCT. African American patients with 13q consisted of 65% and 60% with 13q+ in our patient population. For the 13q or 13q+ who underwent high dose chemotherapy followed by autologous stem cell transplant OS was 85% compared to the non-transplant group 45% (p=0.01) (Figure 2). On follow up at a median of 2.5 years mortality occurred in 31% of the 13q patients compared to 62% in the 13q+ group. The overall survival at 5 years was 25% in the 13q+ group compared to 65% in the patient’s with an isolated 13q, With the 13q+ group having an overall poor OS (p=0.03)

Conclusion
Patients who harbor the 13q and additional cytogenetic abnormalities identified by I-FISH have a significant worse outcome compared to patients with an isolated 13q. These patients should be considered high risk and consideration for treatment with novel agents and autologous stem cell transplant followed by post-transplant maintenance therapy should be considered.

Disclosures:
No relevant conflicts of interest to declare.
Chromosome Instability Underlies Stem Cell Dysfunction and Neoplasia In Widespread Hematologic Disease Induced By Deregulated Cyclin E
Authors: Siu Ka Tat , Xu Yanfei , Bhattacharyya Mitra , Gurbuxani Sandeep , Hua Youjia , Minella Alexander C. 
Published: October 2019

Abstract
The Fbw7 ubiquitin ligase controls the expression of a number of oncoprotein substrates including cyclin E, Notch, c-Jun, and c-Myc. Using a knock-in mouse model (cyclin ET74AT393A), in which mutations were introduced into the cyclin E1 allele (Ccne1) to disrupt Fbw7-mediated ubiquitination specifically, we previously found that cyclin E dysregulation in vivo induces anemia with defects in erythroid differentiation and morphologic dysplasia of erythroid progenitors. We also found that cyclin ET74AT393A mice have fewer hematopoietic stem cells (HSCs) during steady-state hematopoiesis compared to wild-type counterparts. We performed serial transplantation experiments to assay comprehensively the self-renewal and multi-lineage reconstitution capacities of cyclin ET74AT393A HSCs. Contrary to our expectations, cyclin ET74AT393A HSC self-renewal appears normal after three rounds of serial transplantation; however, we identified defects in their multi-lineage reconstitution function. In cyclin ET74A T393A bone marrow erythroid cells, induction of a p53-dependent DNA damage response pathway appears to promote compensated erythropoiesis. In cyclin ET74A T393A HSCs, we similarly observed induced expression of canonical p53 target genes. We studied the effect of p53-loss on cyclin ET74A T393A HSCs and found that p53-null; cyclin ET74A T393A HSCs exhibit defects in both self-renewal and multi-lineage reconstitution. By enumerating chromosomes in metaphase spreads, we found p53-null; cyclin ET74A T393A hematopoietic stem and progenitor cells (HSPCs) demonstrate significant chromosomal instability (CIN). Importantly, we can recapitulate the self-renewal defects and CIN of cyclin ET74A T393A HSPCs with intact p53 by treating recipient animals with a single dose of 5-fluorouracil (5-FU). Thus, chromosomal stability is a key determinant for the maintenance of HSC self-renewal, and hematologic stress appears to unmask the potential for impaired Fbw7-dependent cyclin E ubiquitination to engender CIN in the presence of intact p53. Moreover, CIN is a characteristic feature of fatal T-cell malignancies that ultimately develop in recipients of cyclin ET74A T393A; p53-null HSCs. In pre-malignant thymocytes isolated from recipients of cyclin ET74A T393A; p53-null HSCs, aneuploidy is associated with the marked potentiation of cyclin E kinase activity in these cells by p53-loss. In malignant thymocytes, comparative genome hybridization analysis demonstrates clonal CIN associated with deregulated cyclin E expression combined with p53-loss. In toto, our data demonstrate the functional importance of cyclin E regulation by the Fbw7 ubiquitin ligase to the hematopoietic system and highlight CIN as a key mechanism underlying HSC dysfunction and malignancy induced by deregulated cyclin E in vivo.

Disclosures:
No relevant conflicts of interest to declare.
Hydroxyurea Therapy Reduces The Hypercoagulability State In a Sickle Cell Mouse Model
Authors: Colella Marina Pereira , Almeida Camila Bononi , Conran Nicola , Pallis Flavia Rubia , Franco-Penteado Carla Fernanda , Annichino-Bizzacchi Joyce Maria , Costa Fernando Ferreira , Vinicius de Paula Erich , Olalla-Saad Sara Terezinha , Traina Fabiola 
Published: October 2019

Abstract
Several lines of evidence show that sickle cell anemia (SCA) is characterized by a hypercoagulable state. SCA patients present an elevated rate of thrombotic complications and increased biological markers of coagulation activation. In a previous study we demonstrated that therapy with hydroxyurea (HU) in SCA patients was associated with reductions in hypercoagulability markers, in addition to reductions in hemolysis, inflammation and endothelial activation markers (Colella et al Journal of Thrombosis and Haemostasis 2012). In the present study, we attempted to further investigate whether the effect of HU on hemostatic activation is dependent on fetal haemoglobin (HbF) expression, hemolysis and/or inflammation. To do so, we used the BERK murine model of SCA, a homozygous model of SCA, incapable of expressing HbF. In this BERK model, treatment with HU results in no improvement in hemolysis, due to the lack of HbF induction (Lebensburger et al Haematologica 2010). The murine SCA model was generated by transplantation of nucleated bone marrow cells from BERK mice into lethally-irradiated C57BL6 mice. Only mice expressing > 97% of human hemoglobin S (HbS) at 10 weeks after transplantation were used in the study. HU therapy at the dose of 50mg/kg (HU group) or saline alone (control mice) was administered through intraperitoneal injections 5 times per week, initiated at 11 weeks after transplantation (approximate time of sickle marrow engraftment). After a treatment period of 16 weeks, blood samples drawn from the inferior cava vein were collected and submitted to evaluation of plasma levels of thrombin-antithrombin III (TAT), a final marker of thrombin generation, in both animal groups. We also evaluated plasma levels of the inflammation marker interleukin 6 (IL6), and the endothelial marker soluble vascular cell adhesion molecule-1 (sVCAM-1). TAT, IL6 and sVCAM-1 were all measured by commercially-available ELISA kits. Statistical analyses were performed using Mann-Whitney’s U test. Treatment with HU resulted in a significant reduction of TAT plasma levels (106.7 μg/L vs 138.5 μg/L; P = 0.05). Plasma levels of IL6 (7.1pg/mL vs 12.4pg/mL; P = 0.18) and sVCAM-1 (765.8 ng/mL vs 848.4 ng/mL; P= 0.43) presented non-significant reductions with HU treatment. Our results show that, in this murine SCA model, long-term HU treatment results in an improvement in the hypercoagulability state, even in the absence of HbF induction, or of a significant improvement of inflammation or endothelial activation. This indicates that HU may have a direct effect on inhibiting the activation of coagulation in SCA.

Disclosures:
No relevant conflicts of interest to declare.
Neurologic Complications In Pediatric Sickle Cell Patients Hospitalized For Priapism: An Analysis Of The Pediatric Health Information System (PHIS) Database
Authors: Jones Gary , Lee Brian R , Woods Gerald M , Dalal Jignesh , Kalpatthi Ram 
Published: October 2019

Abstract

Background
Priapism is a known complication of sickle cell disease (SCD). Though, blood transfusion is often used in the management of SCD-associated priapism (SAP), its safety and efficacy is not known. Transfusion has been associated with neurologic events including ASPEN syndrome (Association of Sickle cell disease, Priapism, Exchange transfusion, and Neurologic events) [Siegel et al. J Urol 1993]. A recent systematic review suggests that transfusion does not appear to be effective in SAP as determined by time to detumescense (Merritt et al. Can J Emerg Med 2006). Our objective is to examine the relationship between blood transfusions and neurologic complications (NCs) in the management of SAP.

Methods
We reviewed the data from 33 children’s hospitals within the Pediatric Health Information System (PHIS) database from 2000-2011. Patients ≤ 21 years of age with SCD were included for the analysis. SCD, priapism and all related conditions were identified by ICD-9 codes. We abstracted data on demographics, hospitalizations, transfusion, urologic procedures and neurologic changes (including stroke, seizure, headache, weakness, transient-ischemic attacks (TIAs), intracranial hemorrhage, and mental status changes). Fisher’s exact test was used to compare the prevalence of NCs. A p-value <.05 was considered statistically significant.

Results
From the year 2000 to 2011, a total of 7,929 unique male pediatric patients with SCD were identified. Among these 465 (5.9%) patients with 1,069 hospitalizations were identified as having SAP. The majority of these patients were HbSS (n=447; 96%). The frequency of SAP hospitalizations at various age groups were; 4.7% (0-2 years of age), 11.2% (3-5 years), 38% (6-12 years) and 46% (13-21 years). In the majority of SAP hospitalizations (63%, n=673) neither transfusions nor urologic procedures were performed, whereas blood transfusions, urologic procedures or both were performed in 25.2% (n=269), 6.6% (n=71) and 5.2% (n=56) of SAP hospitalizations respectively. There was no significant difference in the incidence of NCs between the patients who received transfusions and those who did not (4.1% vs. 4.7%, p = NS). Both bivariate (Table 1) and multivariate regression analysis (Table 2) revealed no statistically significant associations between NCs and blood transfusion, urologic procedure, age at hospitalization for priapism, or other SCD co-morbidities (VOC and ACS).

Conclusion
In our large pediatric sickle cell cohort, NCs associated with priapism were rare. Moreover, there was no significant association between the neurologic complications and blood transfusions or urologic procedures in SAP hospitalizations. Further studies are needed to understand the mechanism behind these neurologic complications and any associated risk factors.

Disclosures:
No relevant conflicts of interest to declare.
Aln-TMP: A Subcutaneously Administered RNAi Therapeutic Targeting Tmprss6 For The Treatment Of β-Thalassemia
Authors: Butler James , Fishman Shannon , Racie Tim , Hettinger Julia , Bettencourt Brian R , Charisse Klaus , Fitzgerald Kevin 
Published: October 2019

Abstract
The b-Thalassemias are a group of hereditary blood disorders resulting from insufficient beta globin production, ultimately giving rise to the signature clinical sequelae associated with β-Thalassemia which includes anemia, ineffective erythropoiesis, and secondary iron overload. Previously, we demonstrated that intravenous administration of an siRNA targeting hepatic Tmprss6 expression significantly ameliorated the disease phenotype in the Hbbth3/+ mouse model of Thalassemia Intermedia (Blood. 2013; 14;121(7):1200-8). The Tmprss6 gene encodes for the protein Matriptase-2 which negatively regulates Hepcidin gene expression by cleaving the Hepcidin regulatory protein Hemojuvelin; RNAi-mediated suppression of Tmprss6 removes this negative regulator, ultimately leading to an increase in Hepcidin expression. Increased Hepcidin expression leads to a significant decrease in serum iron concentration and Transferrin Saturation (TfSat), which in the β-Thalassemia disease setting, corrects ineffective erythropoiesis, ameliorates anemia, and mitigates secondary iron overload. The role of Tmprss6 in iron metabolism has been extensively characterized in animal and human studies and, together with the observation in the Hbbth3/+ mouse, represents an attractive therapeutic target for the treatment of β-Thalassemia.
To this end, we developed ALN-TMP, a subcutaneous RNAi therapeutic targeting hepatic Tmprss6 for the treatment of β-Thalassemia. ALN-TMP employs the GalNAc conjugate siRNA delivery platform that safely and effectively delivers siRNA to the liver for hepatic gene silencing. Preclinical animal data demonstrate ALN-TMP exhibits robust and durable dose-dependent gene suppression as single dose administration of ALN-TMP leads to > 80% Tmprss6 gene suppression for up to 3 weeks post-dose. This leads to concomitant increases in Hepcidin gene expression (>2x baseline levels) and subsequent decreases in total serum iron and TfSat (>50% decrease from baseline). The degree to which ALN-TMP modulates Hepcidin and serum iron mobilization is nearly identical to that observed in the previous Hbbth3/+ mouse studies and suggests ALN-TMP is a potent RNAi therapeutic with the potential of producing disease modifying effects in β-Thalassemia.

Disclosures:
Butler: Alnylam: Employment. Fishman:Alnylam: Employment. Racie:Alnylam Pharmaceutical, Inc: Employment. Hettinger:Alnylam Pharmaceuticals: Employment. Bettencourt:Alnylam Pharmaceuticals: Employment. Charisse:Alnylam Pharmaceuticals: Employment. Fitzgerald:Alnylam: Employment.
Acute Treatment Of Pulmonary Embolism With Rivaroxaban - Real Life Data From The Prospective Dresden Noac Registry (NCT01588119)
Authors: Köhler Christina , Werth Sebastian , Tittl Luise , Beyer-Westendorf Jan 
Published: October 2019

Abstract

Background and Objectives
In the EINSTEIN PE study rivaroxaban (RX) was found to be as effective as warfarin in the treatment of acute pulmonary embolism (PE) with superior safety. However, study results need to be confirmed in unselected PE patients in daily care.

Patients and Methods
Using prospectively collected data from a large regional registry of patients treated with novel direct oral anticoagulants (NOAC) in the district of Saxony, Germany, we evaluated the rate of recurrent VTE, other cardiovascular complications and bleeding events in patients receiving rivaroxaban for acute PE. In this ongoing registry, a network of 239 physicians enrols up to 2500 daily care NOAC patients who receive central prospective follow up (FU) by the registry office at day 30 day and quarterly thereafter to collect efficacy and safety data. All outcome events are centrally adjudicated using standard scientific definitions.

Results
Until July 31th 2013, 2249 patients were enrolled. Of these, 72 patients received RX for acute PE treatment (demographic data in table 1). Registry patients were older than the EINSTEIN PE population (67.3 vs. 55.8 years), 55.6% were female and 23.6% were treated for a recurrent VTE. During follow-up, unplanned rivaroxaban discontinuation rates were low (around 5%; table 1). So far, only one recurrent VTE event occurred (1.7 events per 100 patient years). One patient experienced non-fatal ischaemic stroke within 4 weeks after PE diagnosis (1.7 events per 100 patient years). Bleeding complications were frequent but only 2 major bleeding (non-fatal vaginal bleeds) occurred (3.3 events per 100 patient years). During follow-up three patients died of underlying diseases but none of these deaths were related to VTE or bleeding complications.

Conclusion
Acute PE treatment with rivaroxaban in daily care is effective, safe and well tolerated with low rates of unplanned treatment discontinuation. Thromboembolic and major bleeding complications are rare and seem to occur predominantly in the early phase of PE treatment.
At ASH, updated results from our registry will be presented

Disclosures:
Werth: Bayer Healthcare: Honoraria. Beyer-Westendorf:Pfizer: Research Funding, Speakers Bureau; Boehringer Ingelheim: Research Funding, Speakers Bureau; Bayer Healthcare: Research Funding, Speakers Bureau.