bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Index for Predicting Overall Survival and Event-Free Survival In Total Therapy 3 Patients
Authors: Hoering Antje , Mitchell Alan , Sexton Rachael , Crowley John , Barlogie Bart 
Published: October 2019

Abstract
Abstract 1342

Background:
Today's front-line treatment of Multiple Myeloma is frequently based on the MIRT experience with Total Therapy 3 (TT3). We developed prognostic models and a web tool based on those models to predict survival and progression free survival.

Patients and methods:
Data from 303 patients enrolled on UARK 2003-33 and 177 patients treated on UARK 2006-66 was examined. Multivariate Cox regression analysis was used to determine the best prognostic model for overall survival (OS) and event-free survival (EFS) both in the presence and absence of baseline GEP-based risk information.

Results:
Variable selection resulted in consistent models; both OS and EFS models contained similar elements when the selection process terminated. When GEP-defined 70-gene risk information was available, variable selection for OS resulted in a model containing GEP-risk, β2M, cytogenetic abnormalities and LDH. All variables were chosen to be dichotomous. When GEP-defined 70-gene risk information was not available, we obtained two competing models for both OS and EFS. The variables significant for those models were β2M, cytogenetic abnormalities and LDH. In addition to those variables, albumin entered the competing model. Cumulative R squared, measuring the amount of statistical variability accounted for in a statistical model, was comparable in both. We therefore chose the model that is complementary to the model derived when GEP- based risk information was available. All statistical models used for predicting survival and event-free survival have a cumulative R squared of at least 30. The parameter estimates determined in those models were used to evaluate the predicted OS and EFS for a patient with specific baseline features. Two examples for a predicted OS curve with available GEP data are shown below. Figure 1 shows predicted overall survival with 95% confidence interval for a patient with low risk GEP, no cytogenetic abnormalities, β2M ≤ 5.5 mg/L and LDH < 190 U/L. Figure 2 displays the predicted overall survival with 95% confidence interval for a patient with high-risk GEP, cytogenetic abnormalities, β2M > 5.5 mg/L and LDH ≥ 190 U/L.

Conclusion:
A web tool was developed with radio-buttons that enable selection of variables based on observed baseline features of a specific patient. The tool then evaluates and displays the predicted OS and EFS curves with 95% confidence intervals based on the parameter estimates of the underlying multivariate model described above.

Disclosures:
No relevant conflicts of interest to declare.
High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis
Authors: Parmar Simrit , Khan Mubeen , Rondon Gabriela , Shah Nina , Bashir Qaiser , Tung Shawndeep , Shah Jatin J , Weber Donna , Orlowski Robert Z. , Giralt Sergio , Champlin Richard E. , Qazilbash Muzaffar H. 
Published: October 2019

Abstract
Abstract 1350

Background:
Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival.

Methods:
In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria.

Results:
The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS.

Conclusion:
In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival.

Disclosures:
No relevant conflicts of interest to declare.
TP53 Positively Regulates Cell Death through TRAILR2 (DR5) but Negatively through TRAILR1 (DR4) In Myeloma Cells
Authors: Surget Sylvanie , Gomez-Bougie Patricia , Chiron David , Humphreys Robin , Moreau Philippe , Le Gouill Steven , Harousseau Jean-Luc , Bataille Regis , Amiot Martine , Pellat-Deceunynck Catherine 
Published: October 2019

Abstract
Abstract 136
Mapatumumab and lexatumumab are human antibodies that bind and activate death receptors TRAILR1/TNFSF10A/DR4 and TRAILR2/TNFSF10B/DR5, respectively. Treatment of primary myeloma cells and myeloma cell lines with these mAbs induced cell death. Mapatumumab induced cell death more effectively than lexatumumab in a panel of 30 human myeloma cell lines (HMCLs). Interestingly, sensitivity to mapatumumab and lexatumumab was mutually exclusive and related to TP53 status (p=0.006). Indeed, wildtype TP53 HMCLs (n=9) were sensitive to lexatumumab (mean of death 40%) but resistant to mapatumumab (mean of death 7%). In contrast, abnormal (n=21) TP53 HMCLs were resistant to lexatumumab (mean of death 7%) but sensitive to mapatumumab (mean of death 44%). Of note, killing by lexatumumab was correlated to TRAILR2 expression while no correlation was found for TRAILR1 expression and lapatumumab killing. Transcriptomic analysis of 30 HMCLs revealed that HMCLs with abnormal TP53 status underexpressed 4 well-known p53 target genes, MDM2, CDKN1A, Bax and TRAILR2 (p<0.01). To activate p53 pathway in myeloma cells, we used melphalan at low doses. Melphalan treatment of wildtype HMCLs, but not of TP53 abnormal HMCLs, increased TRAILR2 expression and cell death mediated by lexatumumab. In contrast, melphalan did not alter TRAILR1 expression or mapatumumab-induced killing, suggesting that TRAILR2 but not TRAILR1 is a p53 target in myeloma cells. Silencing TP53 significantly increased mapatumumab apoptosis (>50% p<0.01). In good agreement with Bax underexpression in TP53 abnormal HMCLs, extensive silencing of key molecules of both extrinsic (caspase 8, caspase 3) and intrinsic pathways of apoptosis (caspase 9, Bid, Bim, Bax) showed that mapatumumab killing was dependent on the extrinsic pathway of apoptosis only: only silencing of caspase 8 or caspase 3 inhibited mapatumumab killing. Altogether, these data show that killing through TRAIL receptors is differentially regulated by p53 in myeloma cells, positively for TRAILR2 but negatively for TRAILR1. Interestingly, myeloma cells with an abnormal p53 that are more resistant to all drugs are more sensitive than wt ones to killing through TRAILR1 making this pathway very attractive for p53 deficient myeloma cells.

Disclosures:
No relevant conflicts of interest to declare.
Molecular Determinants of Lymph Node Microenvironment Induced Host Immune Tolerance In CLL: Role for CAV1, PTPN6, and PKCβ In the Process
Authors: Gilling Christine , Mittal Amit , Nganga Vincent , Palmer Vicky , Weisenburger Dennis D. , Bierman Philip , Bociek R. Gregory , Swanson Patrick , Joshi Shantaram 
Published: October 2019

Abstract
Abstract 1367
Previously, we have shown that gene expression profiles (GEP) of CLL cells from lymph nodes (LN), bone marrow (BM), and peripheral blood (PB) are significantly different from each other. Among the major pathways associated with differential gene expression, a “tolerogenic signature” involved in host immune tolerance is significant in regulating CLL progression. The genes associated with the tolerogenic signature are significantly differentially expressed in patient LN-CLL compared to BM-CLL and PB-CLL, suggesting that LN-CLL cells induce this immune tolerance. From 83 differentially expressed genes identified by GEP that are associated with immune dysregulation, we selected eleven genes (CAV1, PTPN6, PKCb, ZWINT, IL2Ra, CBLC, CDC42, ZNF175, ZNF264, IL10, and HLA-G) for validation studies to determine whether these genes are also dysregulated in the Emu-TCL1 mouse model of CLL. The results demonstrate a trend of upregulation of these genes as determined by qRT-PCR in the LN-tumor microenvironment. To further evaluate the kinetics of selected gene expression during tumor progression, we determined the expression levels of Cav1, Ptpn6, and Pkcb at 12, 24, and 36 weeks of CLL development in the Em-TCL1 mouse model. We found that the expression of all three genes increased as a function of age, indicating a correlation of gene expression with disease progression. In addition, as CLL progressed in these mice there was a marked decrease in CD4+ and CD8+ T cells. The murine data were further validated using CLL cells from the same patients with indolent versus aggressive disease indicating a similar trend in expression as CLL progressed (n=4). Furthermore, patient data analyzed by Kaplan Meier analyses of the expression levels of the selected genes indicated a significant association between down-regulation of PTPN6 (p=0.031) and up-regulation of ZWINT (p<0.001) with clinical outcome as determined by a shorter time to treatment (p<0.05). Functional analysis by knockdown of CAV1 and PKCb in primary patient CLL cells determined by MTT assay showed a decrease in proliferation following knockdown of these genes (p<0.005). Protein-interaction modeling revealed regulation of CAV1 and PTPN6 by one another. Additionally, the PTPN6 protein regulates B cell receptor (BCR) signaling and subsequently the BCR regulates PKCb. Therefore, these data from both mice and humans with CLL, argue that an aggressive disease phenotype is paralleled by expression of genes associated with immune suppression. In particular, evidence presented here suggests, dysregulation of CAV1, PTPN6, ZWINT, and PKCb expression promotes CLL progression.

Disclosures:
No relevant conflicts of interest to declare.
The Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Possess Strong Inhibitory Effect on Tumor Growth In a CLL-Like Xenograft Mouse Model
Authors: Paesler Julian , Gehrke Iris , Razavi Regina , Poll-Wolbeck Simon Jonas , Hallek Michael , Kreuzer Karl-Anton 
Published: October 2019

Abstract
Abstract 1393
As chronic lymphocytic leukemia (CLL) is still mainly treated using unspecific chemotherapy, new targeted therapies are highly desirable. Vatalanib and Pazopanib are potent orally available receptor tyrosine kinase inhibitors with high selectivity towards the vascular endothelial growth factor (VEGF)-receptor. VEGF-signaling is critically involved in the microenvironment-mediated prolonged survival of CLL cells. We investigated the efficacy and selectivity of both compounds in CLL cells and tested their effect on CLL like tumor xenografts in nude mice. Primary CLL cells (n=20) and healthy B-cells (n=5) were treated with Vatalanib and Pazopanib ranging from 1 to 200 μM. Both substances were tested for their apoptosis-inducing efficiency in a CLL cell coculture with the bone marrow-derived stromal cell line HS5 (n=4), which provides a strong survival support for CLL cells and mimick the in vivo situation. Apoptosis induction was monitored flow cytometrically by Annexin V-FITC/PI staining and by immunoblotting of caspases and PARP. Further, both compounds were administered daily via oral gavage at 100 mg/kg bodyweight to nude mice engrafted with CLL-like JVM3 cells for 21 days (n=10/group). Both substances effectively induced apoptosis in primary CLL cells with lethal concentration (LC) 50 of 48.4 μM and 32.7 μM for Vatalanib and Pazopanib, respectively. Healthy B-cells were largely unaffected. Furthermore, both substances showed similar apoptosis-inducing capacity when CLL cells were maintained on a survival-supporting HS5 feederlayer. In a CLL-like xenograft mouse model tumor growth was significantly inhibited by 76% and 77% after a treatment period of 21 days for Vatalanib and Pazopanib, respectively. In two mice complete tumor eradication could be observed after treatment with Vatalanib. No adverse side effects were observed during the treatment period. We conclude that the receptor tyrosine kinase inhibitors Vatalanib and Pazopanib have strong and selective anti-neoplastic activity towards CLL cells. As they are orally available and in general well tolerated they deserve further evaluation as a potential new therapeutic option for treatment of CLL.

Disclosures:
No relevant conflicts of interest to declare.
A Novel Factor XII Mutation, FXII Tokyo (R84P), Causing Factor XII Deficiency In a Patient with Hereditary Spastic Paraplegia
Authors: Matsuki Eri , Miyakawa Yoshitaka , Okamoto Shinichiro 
Published: October 2019

Abstract
Abstract 1404
Hereditary factor XII (FXII) deficiency is a clinically asymptomatic, autosomal recessive disorder. We have experienced a rare case of FXII deficiency in a patient with hereditary spastic paraplegia (HSP). This is the first report in the literature of the coexistence of these two disorders together with the analysis of their genetic cause.
The patient, who had no major bleeding episodes, presented with a prolonged APTT of 104.9 seconds. Further evaluation revealed decreased FXII activity of less than 10% and FXII antigen level of 17% with negative results on mixing study. Based upon these findings, she was diagnosed as having hereditary FXII deficiency. Her family history was positive for HSP on her mother's side, the genetic diagnosis of which had been confirmed in her younger daughter. Pedigree analysis showed that her two daughter's coagulation profiles were all within normal limit.
Sequencing of the 14 exons and intron/exon boundaries of the FXII gene revealed a novel missense mutation at exon 4 that substitutes arginine 84 to proline (R84P), which we named FXII Tokyo. The mutation status was also confirmed by restriction fragment length polymorphism using restriction enzyme BtgZI. To elucidate the molecular mechanism of FXII deficiency, wild type and R84P mutant FXII cDNA were transiently expressed in CHO cells. We performed Western blot analysis, and found that secretion but not synthesis of R84P mutant protein was markedly reduced compared to wild type.
Altogether, these results indicated that R84P mutation might impair the intracellular transport or secretion of FXII protein of the cells and could be a useful tool for the analysis of structure-function relationship and intracellular protein transport of FXII protein in future.

Disclosures:
No relevant conflicts of interest to declare.
Inhibitor Development In Patients with Mild and Moderate Hemophilia A: Results From a Single Centre.
Authors: Repesse Yohann , Gautier Philippe , Borel-Derlon Annie 
Published: October 2019

Abstract
Abstract 1407

The development of factor VIII (FVIII) inhibitors is usually considered uncommon among patients with mild and moderate hemophilia A (HA) and less frequent than in patients with severe HA. We report here the prevalence of FVIII inhibitors and their caracteristics in 167 patients with mild and moderate HA followed in Caen Hemophilia Treatment Centre (Table). FVIII molecular defects were identified by direct sequencing in 167 patients including 30 and 137 with mild and moderate HA, respectively. Following FVIII concentrates infusions, FVIII inhibitors occured in 7.8% of patients (13/167). Fifteen percent (2/13) were low-responding inhibitors. The risk of inhibitor development appeared to be associated with high-risk FVIII genotypes clustered in the A2 and C2 domains, especially p.Arg2150His (50%) and p.Arg593Cys mutations. Interestingly, we described inhibitor development associated with novel missense-mutations (p.Tyr1786Ser, p.Asp115Tyr and -219C>T substitutions in FVIII gene promoter). In addition, high regimen infusion of FVIII concentrates appeared as risk factor for FVIII inhibitors development. Indeed, 60% (8/13) developped FVIII inhibitors following massive infusion of FVIII concentrates associated with FVIII:C levels above 1.2 UI/dL. Inhibitors in mild HA usually cross-react with endogenous factor VIII reducing the circulating basal FVIII:C level and are associated with more bleeding events. Similarly, we observed the evolution of bleeding patterns in our cohort to severe phenotypes. Bleedings were treated with FVIII concentrates and bypassing therapies (activated FVII and activated-prothrombin complex). About 25% (3/13) of these inhibitors disappeared spontaneously. Induction of Immune Tolerance (ITI) protocoles with high doses of FVIII were initiated for 7 high-responding patients with a success rate of 85 % (6/7). However, inhibitors persisted long-term and remained troublesome in 1 of these patients despite of ITI protocole. For two patients, immunosuppressive treatment with corticosteroids was started. Inhibitors disappeared and the levels of FVIII:C became detectable within 6 months. Development of FVIII inhibitors, their disappearance and the efficacy of ITI regimen seem to be different from our experience between patients with mild or moderate HA and severe HA.

Disclosures:
No relevant conflicts of interest to declare.
Use of a Population Pharmacokinetic Model of ADVATE In Pediatric and Adult Patients with Hemophilia A Permits Limited Blood Sampling for Individual Dose Tailoring.
Authors: Oh MyungShin , Björkman Sven , Schroth Phillip , Fritsch Sandor , Collins Peter W , Fischer Kathelijn , Blanchette Victor S. , Casey Kathleen M. , Spotts Gerald , Ewenstein Bruce M. 
Published: October 2019

Abstract
Abstract 1416

Introduction:
A population pharmacokinetic (PK) model of a recombinant FVIII (rFVIII) was established on ADVATE® (Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method) studies in pediatric and adult patients with hemophilia A. The objective of this analysis was to evaluate the effect of reduced PK sampling time points on the estimated PK parameters in the population PK model.

Patients and Methods:
Plasma FVIII activity PK data were collected for 3 ADVATE® clinical trials in previously treated patients: 184 full PK data sets (11 time points) for 100 adults/adolescents, aged 10 to 65 years, and from 52 reduced sample PK data sets (5 time points) for 52 children, aged 1 to 6 years. A population PK analysis was conducted on a two-compartment structure model and the covariate effect of age and weight was explored.
Four reduced sampling scenarios from the full 10 post-infusion sampling time points, were investigated: 1) Reduced to 4 (1 hr, 9 hr, 24 hr, and 48 hr), 2) Reduced to 3 (6 hr, 24 hr, and 48 hr), 3) Reduced to 2 (6 hr and 24 hr), and 4) Reduced to 1 sampling time points (24 hr post-infusion). After applying the reduced sampling on a random 10% of sampling set at a time in the population PK model, the differences in model estimates and individual PK estimates between full and reduced sampling, were evaluated.

Results:
The two-compartment population PK model adequately described the data. Clearance (CL) was significantly correlated with age and body weight and central volume of distribution was also related with body weight.
Absolute deviations (%) from the estimates using full PK sampling in the Individual PK estimates (CL, Vss, and Half-life) using each of the reduced sampling time points were showed in the below table.

Conclusions:
It appears that PK parameters estimated using population PK model are robust to reduced sampling time points. Accurate measurement of PK on reduced samples gives patients and clinicians the opportunity to design treatment regimens that are better tailored to individuals.

Disclosures:
Oh: Baxter: Employment. Björkman:Baxter: Consultancy; Octapharma: Consultancy. Schroth:Baxter: Employment. Fritsch:Baxter: Employment. Collins:NovoNordisk: Consultancy, Honoraria, The EACH2 registry was funded by Novonordisk; Baxter Healthcare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fischer:Baxter: Consultancy; NovoNordisk: Consultancy. Blanchette:Bayer: Consultancy; Baxter: Research Support. Casey:Baxter: Employment. Spotts:Baxter: Employment. Ewenstein:Baxter Bioscience: Employment.