bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Bendamustine Pretreatment on Stem Cell Mobilization and Autologous Stem Cell Transplantation in Patients with Multiple Myeloma
Authors: Pönisch Wolfram , Wiesler Julia , Wagner Ina , Leiblein Sabine , Edel Elvira , Al-Ali Haifa K. , Vucinic Vladan , Hegenbart Ute , Heiß Christiane , Niederwieser Dietger , Goldschmidt Hartmut 
Published: October 2019

Abstract
Abstract 1933

Introduction:
Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. Treatment of patients with newly diagnosed multiple myeloma using Bendamustine and Prednisone in comparison to Melphalan and Prednisone results in superior complete response rate and prolonged time to treatment failure (Poenisch et al, Res Clin Oncol 132: 205–212;2006). So far, however, reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after Bendamustine therapy is missing.
Material and Methods: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 63 patients with multiple myeloma who had received Bendamustine pretreatment at the university Hospitals Leipzig and Heidelberg over a period of sixteen years. Patients had a median age of 59 (range, 31–72) years. The cumulative dosis of Bendamustine per patient ranged between 120 and 2400mg/qm and was administered during a median of three (range 1–10) cycles. The mobilization regimen consisted of Cyclophosphamide 4g/qm (n=41) or 7g/qm (n=4) and G-CSF (2×5ug/kg). Alternative regimens such as CAD, CED, TCED and others were also used in the remaining patients. Apheresis was started as soon as peripheral blood CD34+ counts exceeded 10×106/l with a harvest target of 4×106 CD34+/kg using 4 times the blood volume. The minimal accepted target was 2×106 CD34+/kg.

Results:
Stem cell mobilization and harvest was successful in 60 of the 63 patients (95 %). In 19 of 60 patients (32 %) a single apharesis was sufficient to reach the target. The median number of aphareses was two (range 1–7) and the median CD34+ cell-count/kg was 5.9 (range 1.7–20.4) x106. Information on autologous SCT is available from all 60 patients with successful harvest. Engraftment was successful in 59 of 60 patients. The median time to leucocytes count > l ×109/l was reached after 12 days and the time to untransfused platelet count of >50×109/l was 14 days. 54 patients (90%) responded after the autologous SCT with 6 CR, 4 nCR, 12 VGPR, and 32 PR. The event free survival at 36 months was 31 % and overall survival was 68 %.
In conclusion, the stem cell mobilization and autologous SCT is feasible in multiple myeloma patients who have received Bendamustine pretreatment.

Disclosures:
Pönisch: Mundipharma: Honoraria, Research Funding. Niederwieser:Mundipharma: Research Funding.
Cytomegalovirus (CMV) gB3 Genotype Is Associated with Acute Gvhd and CMV Disease in Allogeneic Hematopoietic Stem Cell Transplant Recipients (HSCT)
Authors: Dieamant Débora de Campos , Bonon Sandra Helena Alves , Aranha Francisco J P , Duarte Gislaine O. , Fernandes Virginio C.O. , Souza Carmino Antonio De , Costa Sandra Cecília Botelho , Vigorito Afonso Celso 
Published: October 2019

Abstract
Abstract 1958
Based on sequence variation in the UL55 gene that encodes glycoprotein B (gB), human cytomegalovirus (CMV) can be classified into four gB genotypes. Previous studies have suggested an association between CMV gB genotype and clinical outcome in patients who underwent an allogeneic hematopoietic stem cell transplant (HSCT). Objectives: The goals of this study were: identify patients with active infection caused by CMV in recipients of HSCT; determine the prevalence of CMV genotypes in the study group; correlate genotype with the CMV disease, acute GVHD and overall survival. Study design: The diagnosis of active CMV infection after allogeneic HSCT was detected by Antigenemia (AGM) and/or Nested-PCR (N-PCR). Positive samples from patients with active CMV infection were submitted to genotyping using the N-PCR to amplify a region of UL55, followed by restriction analysis based on HinfI and RsaI digestion. Real-time PCR (qPCR) was used to determine the viral load during active CMV infection and antiviral treatment. Results: Were evaluated 63 allogeneic HSCT recipients, 49/63 patients (78%) presented active CMV infection detected by AGM and/or N-PCR, in a median time of 38 days after the transplant. The distribution of CMV gB genotypes in these 49 patients with active CMV infection was as follow: gB1, 19/49 (38.8%); gB2, 17/49 (34.7%); gB3, 3/49 (6.1%); gB4, 7/49 (14.3%) and three patients (6.1%) had mixed infection with gB1+gB3, gB1+gB4 and gB2+gB4. Acute GVHD grade II-IV occurred in 17/49 (34.7%) patients: 8/19 (gB1-42%), 1/17 (gB2 - 5.9%), 4/4 (gB3 - 100%) and 4/9 (gB4 - 44.4%). The distribution of the frequency of acute GVHD grade II-IV between the genotypes was statistically different (p=0.008). CMV disease occurred in 3/49 (6.1%) patients, characterized for gastrointestinal disease and these three patients had infection with CMV gB3 genotype. This genotype of CMV was also associated with higher viral load during antiviral treatment and worse survival. Conclusions: This study demonstrated that the frequency of active CMV infection in HSCT population was high (78%). The most prevalent genotype in patients with active CMV infection was gB1 and gB3 genotype was associated with acute GVHD grade II-IV, CMV gastrointestinal disease, higher viral load during antiviral treatment and worse survival.

Disclosures:
No relevant conflicts of interest to declare.
Prophylaxis of Acute Gvhd Using Stromal Cell Therapy: Preliminary Results After Administration of Single or Multiple Doses of Multistem® in a Phase I Trial
Authors: Maziarz Richard T. , deVos Timothy , Bachier Carlos , Goldstein Steven C. , Leis Jose F. , Perry Robert , Deans Robert , Hof Wouter J Van't , Lazarus Hillard M. 
Published: October 2019

Abstract
Abstract 1987

Background.
MultiStem®, a multipotent adult progenitor cells (MAPC) collection, is an immune-modulatory, bone marrow-derived adult adherent allogeneic stromal cell product manufactured to large scale, assuring consistency of universal donor cell product during clinical evaluation. Pre-clinical studies showed safety of IV infusion and survival benefit in a haploidentical transplantation rat model of acute GVHD (Kovacsovics 2008, 2009).

Methods.
An open label Phase I clinical dose escalation study is being conducted with the primary goal to assess safety of MAPC as an adjunct treatment for human subjects undergoing myeloablative allogeneic HSCT for hematologic malignancies. Patients have been enrolled for MultiStem® administration as a single dose or in multiple weekly doses. Infusional toxicity and RRTs are assessed for 30 days following the last study drug dose administration. Secondary endpoints include incidence of acute GVHD, infection and survival through day 100. Dose escalation is guided by the Continual Reassessment Method (CRM).

Results.
In the single dose arm, 18 patients with AML (9), MDS (4), CML (3) and ALL (2) from 5 clinical centers were administered MultiStem® IV at 1, 5, or 10 million cells per kg at day 2 after allogeneic HSCT. There was no observed infusional toxicity. Two patients experienced Bearman RRTs (Gr 3 mucositis; Gr 3 renal & pulmonary failure) deemed unrelated to study product. Engraftment occurred in all 18 patients. The median time to neutrophil engraftment for related (n=7) and unrelated (n=11) HSCT was 15 days (range, 12–16 days) and 14 days (range, 11–25 days), respectively. The 100-day cumulative incidence of Grade II-IV and III-IV GVHD was 28% and 6% (n=18). In the highest MultiStem® dose group (n=9) there was no grade III-IV GVHD, and only one case of grade II GVHD, which subsequently resolved with treatment. 17/18 patients have been enrolled in the multidose arm. Results of safety endpoints and interim results of all secondary endpoints of repeated MultiStem® administrations following HSCT will be presented.

Conclusion.
Single dose administration of MultiStem® is well-tolerated, without observation of infusional toxicity or graft failure. Together with the observed low incidence of severe aGVHD, these findings are supportive of the concept that stromal stem cell therapy is safe and may be harnessed as an efficacious therapeutic option for acute GVHD prophylaxis following HSCT.

Disclosures:
Maziarz: Athersys, Inc: Patents & Royalties, Research Funding. Perry:Athersys, Inc.: Employment. Deans:Athersys, Inc: Employment. Van't Hof:Athersys, Inc.: Employment.
The Impact of Anti-HLA Antibodies on Allogeneic Hematopoietic Stem Cell Transplantation Outcomes After Reduced-Intensity Conditioning Regimens
Authors: Detrait Marie Y. , Dubois Valerie , Sobh Mohamad , Morisset Stephane , Tedone Nathalie , Nicolini Franck E. , Labussiere Helene , Gillis Lilia , Barraco Fiorenza , Cannas Giovanna , Ducastelle Sophie , Fattoum Jihane , Thomas Xavier , Chelghoum Youcef , Michallet Mauricette 
Published: October 2019

Abstract
Abstract 2038

Introduction:
Anti-HLA antibodies are associated with several complications in solid organ transplantations but their impact after allogeneic hematopoietic stem cell transplantation (HSCT) is not very well defined yet.

Patients and methods:
To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allogeneic HSCT after reduced-intensity conditioning (RIC) regimen between 2005 and 2010. Acute myeloid leukaemia (n=52,48.5%) and multiple myeloma (n=18,17%) were the most common diagnosis in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation.

Results:
We found in 24 patients (22%) the presence of anti-HLA antibodies. There was no association between the presence of anti-HLA antibodies and engraftment, incidence of relapse or acute GvHD. The presence of anti-HLA antibodies was associated with worse survival in univariate analysis (HR 2.04; [95%CI,1.21–3.44], p=0.0056) and in multivariate analysis (HR 2.63; [95%CI, 1.32–5.25], p=0.006). The 3-year probability of OS was 34% (95%CI, 24–49) without anti-HLA antibodies and 16% (95%CI, 6–41) in their presence (Figure 1). The other significant factors on survival were the disease status at transplantation, the age, minor and major ABO incompatibilities between donor and recipient, the sex-mismatching and the CMV status. Moreover, the positive anti-HLA antibodies group showed a trend of higher TRM in univariate analysis (p=0.07) and in multivariate analysis (HR= 1.9; [95%CI, 0.94 – 3.9], p=0.076). The TRM at 3 years after transplantation were 31% (95%CI, 26–37) without anti-HLA antibodies and 46% (95%CI, 36–57) in their presence (figure 2). The causes of the pejorative effect of the anti-HLA antibodies were not defined yet but we observed microangiopathy associated with vascular endothelium damage which could be related to the presence of anti-HLA antibodies.

Conclusion:
Our study suggests that anti-HLA antibodies should be tested and considered as an important prognostic factor for transplant outcomes after RIC HSCT.

Disclosures:
No relevant conflicts of interest to declare.
The Association of a Single Nucleotide Polymorphism in the Chemokine CXCL10 Gene with Transplant Outcomes After HLA-Matched Unrelated Bone Marrow Transplantation for Low Risk Hematologic Malignancies
Authors: Nakata Katsuya , Espinoza Luis J. , Onizuka Makoto , Fukuda Takahiro , Kawase Takakazu , Morishita Eriko , Kodera Yoshihisa , Morishima Yasuo , Ohtake Shigeki , Nakao Shinji , Takami Akiyoshi 
Published: October 2019

Abstract
Abstract 2048
CXCL10, also known as interferon gamma inducible protein 10, is a chemokine secreted by several cell types including monocytes, endothelial cells and fibroblasts that plays important roles in the stimulation and migration of natural killer cells and T cells. The single nucleotide polymorphism (SNP) rs3921 located in the 3'-untranslated region of the CXCL10 gene has been reportedly associated with acute GVHD and with invasive aspergillosis after allogenic stem-cell transplantation. In this study, we analyzed the impact of rs3921 polymorphism on transplant outcomes in patients undergoing unrelated HLA-matched myeloablative bone marrow transplantation (BMT) through the Japan Marrow Donation Program. The CXCL10 genotypes were retrospectively analyzed in a cohort of 652 pairs of patients with hematologic malignancies and their unrelated donors. The genotype frequencies of GG, CG and CC were 1%, 13% and 86% in recipients and 1%, 12% and 87% in donors (P=0.62). The recipient GG or CG genotype was associated with significantly better overall survival (OS; P=0.02; Fig1). No difference was noted in transplant-related mortality, disease relapse or graft-versus-host disease in relation to the recipients' polymorphism. The multivariate analysis showed that in patients with low risk disease, the recipient GG or GC genotype remained statistically significant for better OS (hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.30 to 1.01; P=0.05). The donor CXCL10 genotypes did not significantly influence the transplant outcomes. These results suggest an association of the recipient GG or GC genotypes with better transplant outcomes after unrelated HLA-matched BMT. These findings could therefore be useful in creating therapeutic strategies such as risk-adapted management of transplanted patients.

Disclosures:
No relevant conflicts of interest to declare.
Population-Based Health Care Cost Estimates Related to Non-Hodgkin Lymphoma (NHL)
Authors: Mittmann Nicole , Cheung Matthew , Isogai Pierre K , Saskin Refik , Liu Ning , Hoch Jeffrey S , Leighl Natasha , Trudeau Maureen E , Evans William K , Dainty Katie N , Earle Craig C. 
Published: October 2019

Abstract
Abstract 2068

Background:
There is limited information on the cost of non-Hodgkin lymphoma (NHL) management. This study provides population-based estimates of the costs for individuals with NHL from a Canadian perspective using provincial administrative databases.

Methods:
All individuals residing in Ontario with a diagnosis of first incident NHL from the Ontario Cancer Registry (2005–2009) were matched to non-NHL controls. Matching was based on age (same birth year), geography, income quintile, and resource utilization bands (2 years prior to cancer diagnosis). Each NHL case was matched to a maximum 5 controls. NHL cases from the Ontario Cancer registry were linked with their unique and encrypted health card number to provincial health claims databases (Ontario Ministry of Health and Long-Term Care and Cancer Care Ontario). Resources for this analysis included physician visits, hospitalizations, emergency room visits, medications, home care and same day surgeries. Unit costs (in 2009 Canadian dollars) were applied to resources. All costs were inflated to 2009. Costs were presented as the mean annual cost for all patients and by clinical stage.

Results:
There were 13,336 NHL cases matched to 65,668 controls. The NHL and control groups were demographically similar. For both groups, the median (25th and 75th percentile) age was 68 (56 to 77) years and 55% were male. Geographically, 86% of both groups were from urban areas. Total and disaggregated mean annual costs for NHL and controls are presented in the table. The mean cost difference between the NHL and control groups represents the mean cost attributable to NHL. Inpatient hospitalization and medication costs attributable to NHL represented 51% and 30% respectively, of the total mean annual cost attributable to NHL. Clinical stage at NHL diagnosis was available for a subset of the NHL cases (37%). Total mean annual cost by stage is also presented in the table. For the entire cohort, mean annual cost attributable to NHL was $16,778. In comparison, mean annual cost attributable to NHL by stage at diagnosis ranged from $9,575 (stage I) to $26,099 (stage IV).

Conclusion:
This study provides total and stage-specific cost estimates for NHL where attributable costs were 3 to 7 fold higher than those for non-NHL controls and increased by stage. Cost drivers included medications and inpatient care. Further work will focus on costing other resources including radiation, other chemotherapies and chronic care.

Disclosures:
No relevant conflicts of interest to declare.
Toll-Like Receptor 4 Mediates Heme Induced Acute Lung Injury: Preclinical Study of Resatorvid in Sickle Cell Disease
Authors: Ghosh Samit , Adisa Olufolake , Yang Yu , Tan Fang , Ofori-Acquah Solomon F 
Published: October 2019

Abstract
Abstract 2113
Sickle cell disease (SCD) is characterized by multiple exacerbating events that cause intravascular hemolysis. Heme released into the circulation is scavenged by multiple plasma proteins and delivered to the liver for degradation. Our recent data indicate that this process is impaired in SCD resulting in excess protein-free plasma heme (PFPH) that triggers a lethal form of acute lung injury (ALI) in mice. In this study, we tested the hypothesis that toll-like receptor 4 (TLR4) mediates heme-induced ALI. Wild-type and two TLR4 mutant strains (B6.B10ScN-Tlr4lps-del/JthJ and C3H/HeJ) were intravenously injected with a dose range of ferric heme (0–210 micromoles/kg) and respiratory function monitored using a pulse oximeter. Excess PFPH was associated with reductions in oxygen saturation (SpO2) and breath rate in the wild-type mice but not in the TLR4 variants. Lungs of heme-treated wild-type mice were congested, edematous, hemorrhagic, and had thickened alveolar walls, while no histological abnormalities were found in the TLR4 variants. All heme-treated wild-type mice succumbed within 2 hours, while all TLR4 variants survived. Transgenic mice expressing exclusively human sickle hemoglobin (SS) were intravenously injected with a small molecule TLR4 inhibitor (resatorvid/TAK-242), or a lipid vehicle prior to induction of lung injury with heme (35 micromoles/kg). TAK-242 preserved lung function in the majority of SS mice that failed to scavenge excess PFPH, while both SpO2 and breath rate deteriorated in vehicle treated mice. The unique response to heme by TAK-242 and vehicle-treated SS mice was supported by histological analysis and survival (TAK-242; 76.9% vehicle; 23.5%, n=13–17; log-rank survival test, p<0.01). We provide the first evidence that the interaction between heme and TLR4 can be pathological, specifically causing a lethal form of ALI. Our data on TAK-242, a phase II drug, offers an attractive option to explore TLR4 inhibition as a novel therapeutic strategy to limit progression of acute chest syndrome.

Disclosures:
Ofori-Acquah: Emory University: Patents & Royalties.
Heme Induced Organ Failure in Sickle Cell Disease Is Spatiotemporally Determined by the Amount of Heme Released Into the Bloodstream
Authors: Ghosh Samit , Adisa Olufolake , Aryee Doreen , Tan Fang , Ofori-Acquah Solomon F 
Published: October 2019

Abstract
Abstract 2135
Circulating heme is scavenged by multiple plasma proteins and delivered to the liver for degradation. We have recently demonstrated that heme scavenging is variably impaired in transgenic mice with sickle cell disease (SCD). In this study, we tested the hypothesis that excess protein-free plasma heme (PFPH) in the blood circulation, and excess scavenged protein-bound plasma heme (PBPH) destined for degradation cause different types of organ damage in SCD. Transgenic mice expressing exclusively human sickle hemoglobin (SS) were intravenously injected with a dose of heme (25 micromoles/kg) to elevate PBPH only, or with a dose (70 micromoles/kg) sufficient to raise PFPH. In agreement with our previous findings, PFPH was associated with severe lung injury and 100% lethality within 2 hours. This phenomenon occurred independent of any liver involvement. Modest elevation of circulating heme sufficient to raise PBPH only, increased alanine aminotransferase and aspartate aminotranferase 3- to 4-fold (P<0.001) within 12 hours, caused 55% lethality by 72 hours, with severe liver damage but no lung involvement. There was no effect on lung and liver function in control AA and AS mice administered the same doses of heme given to the SS mice. Recombinant human hemopexin rescued SS mice from heme induced lung damage and sudden death, however, the same group of mice developed severe liver damage and succumbed 24–48 hours later. Finally, in a cohort of 27 patients with SCD, a sudden drop in hemoglobin of 0.5 to 4.0 g/dl was associated with a marked increase in ALT 3–7 days later (p=0.027). Collectively, these results show for the first time that acute elevation of circulating heme causes two distinct organ pathologies with different mortality profiles in SCD. Therapeutic strategies based solely on enhanced scavenging of excess heme may provide short-term pulmonary benefits with deleterious long-term effects on liver function.

Disclosures:
Ofori-Acquah: Emory University: Patents & Royalties.
Quaternary Organization of GPIb-IX Complex and Insights Into Bernard-Soulier Syndrome Revealed by the Crystal Structures of GPIbβ Ectodomain and a GPIbβ/GPIX Chimera
Authors: McEwan Paul A. , Yang Wenjun , Carr Katherine H. , Mo Xi , Zheng Xiaofeng , Li Renhao , Emsley Jonas 
Published: October 2019

Abstract
Abstract 2195
Platelet glycoprotein (GP)Ib-IX receptor complex contains three subunits, GPIbα, GPIbβ and GPIX, which assemble with a ratio of 1:2:1. Dysfunction in surface expression of the complex leads to Bernard-Soulier syndrome (BSS). We have crystallized the GPIbβ ectodomain (GPIbβE) and determined the structure to reveal a single leucine-rich repeat with N- and C-terminal disulfide bonded capping regions. The central region of the structure can be divided into concave parallel β-sheet and convex loops. The crystal structure of a GPIbβE/GPIXE chimera that contains three non-continguous convex loops of GPIX and retains a GPIbβ-binding site of GPIX (Mo et al. J. Thromb. Haemost. 7:1533–40, 2009) was also determined. The chimera, but not GPIbβE, forms a homotetramer in the crystal, revealing a quaternary interface between GPIbβ and GPIX ectodomains. Central to this interface is residue Tyr106 from GPIbβ that inserts into a shallow and largely hydrophobic pocket generated by two convex loops from GPIX. Mutagenesis studies confirmed this interface as a valid representation of interactions between GPIbβ and GPIX in the full-length complex. Eight GPIbβ missense mutations identified from BSS patients were examined in transiently transfected Chinese hamster ovary cells for changes to the GPIb-IX complex surface expression. Six of the eight mutations lead to secretion defect and/or misfolding of GPIbβE. In contrast, the other two mutations, A108P and P74R, were found to maintain normal secretion and folding of GPIbβE but were unable to support GPIX surface expression. The close structural proximity of these mutations to Tyr106 and the GPIbβE interface with GPIX indicates that residues Ala108 and Pro74 in GPIbβ are located at the GPIbβE/GPIXE interfaces. Based on the tetrameric arrangement of the chimera structure, we propose a structural model for the GPIb-IX complex that embodies its organizing principles and helps to provide mechanistic insights on its assembly, function and regulation.

Disclosures:
No relevant conflicts of interest to declare.