bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors Predicting the Outcome of the Blood and Marrow Transplant Patients Admitted to Intensive Care Unit.
Authors: Pati Nalini K , George Biju , Kerridge Ian , Gilroy Nicole , Nayyar Vineet , Stachowski Eddie , McGurgan Mary , Huang Gillian , Bradstock Kenneth F , Gottlieb David J , Hertzberg Mark 
Published: October 2019

Abstract
Abstract 3340
Poster Board III-228

Aim:
To identify factors predicting outcome of patients admitted to intensive care (ICU) following allogeneic haematopoietic stem cell transplantation (allo-HSCT).

Methods:
Retrospective audit of all allo-HSCT patients requiring ICU admission.

Results:
Between 2000 and 2009, 392 patients underwent allo-HSCT. Of these, 106 (27%) had 129 ICU admissions. The median age was 47 (range 16-65) with myeloablative transplant in 89 and reduced intensity in 40 patients. Respiratory failure was the main reason for admission (54.6%) followed by sepsis (41.5%).
During the period of ICU admission, 29.2% demonstrated improvement in organ failures, 39.2% remained stable and 28.4% deteriorated. Sixty-seven patients (51.9%) were discharged from ICU but only 48 (37%) were subsequently discharged from the hospital (ICU). Univariate analysis identified ICU admission within 30 days post HSCT, number of organ failures at admission, progression of organ failure during ICU admission, APACHE II score at admission, steroid refractory GVHD, and requirement for inotropic support or dialysis as significant predictors for survival in ICU. Patients requiring intubation and mechanical ventilation had a poorer outcome than the group who did not (84.4% Vs 20.0%, p=0.001). Those who required only non-invasive ventilation generally had a good outcome with 84.4% surviving til ICU discharge. While bacterial infection prior to ICU admission did not alter the outcome (p=0.221), the onset of a new infection in ICU was associated with a poor outcome (p=0.0001). Logistic regression analysis identified steroid refractory GvHD (P=0.027; 95% CI of 1.17-14.8), APACHE II score > 30 (p=0.003; 95% CI 1.5-10.5), admission <30 days post HSCT (p = 0.015; 95% CI 0.12-0.8), requirement of invasive ventilatory support (p = 0.005, 95% CI 2.58 – 223.83) and dialysis (p = 0.011; 95%CI 1.401 – 13.20) as significant factors for a poor outcome.

Conclusion:
More than 50% of patients admitted to ICU following allogeneic HSCT survive. A high APACHE II score, steroid refractory GVHD, admission into ICU within 30 days of HSCT, multiorgan failure, progression of organ failure during ICU stay, and the need for ventilation or dialysis, carries a dismal prognosis. Identification of risk factors associated with a poor outcome will assist in clinical management and may ultimately improve the outcome of patients requiring ICU admission following allogeneic HSCT.

Disclosures:
No relevant conflicts of interest to declare.
Pretransplant Factors That Influence Intravenous Busulfan Kinetics in Adult Patients.
Authors: McBride Ali , Fancher Karen , Kim Jongphil , Davis Donn , Conwell Michelle , Field Teresa , Anasetti Claudio , Perkins Janelle 
Published: October 2019

Abstract
Abstract 3350
Poster Board III-238
We performed a retrospective review of intravenous busulfan (Bu) pharmacokinetic (PK) parameters and pretransplant characteristics on patient receiving Bu and fludarabine (40mg/m2/day x 4) (BuFlu) prior to allogeneic hematopoietic cell transplant (HCT) in order to determine the predictive value of pretransplant characteristics on Bu area under the concentration time curve (AUC). Included in this analysis are 265 pts transplanted between 7/04 and 12/08 who received 130 or 145mg/m2/day for 2 doses then had doses 3 and 4 adjusted based on first dose PK parameters (from 5 plasma concentrations) to achieve a target AUC of 5300 micromole*min/L. Pretransplant variables collected included: gender, age, ethnicity, height, actual body weight (ABW), body surface area (BSA), body mass index (BMI), underlying diseases states (hypertension, diabetes mellitus, coronary artery disease and liver disease), transplant diagnoses, prior chemotherapy, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), serum creatinine (SCr), measured creatinine clearance (CrCl) and concomitant medications administered up to 24 hours prior to first Bu dose. Median first dose AUC was 5252 micromole*min/L (2633-21400 micromole*min/L). Univariable and multivariable analyses were utilized to identify prognostic factors that may affect AUC levels based on first dose kinetics. In univariable analyses, BMI and CrCl were negatively correlated with Bu AUC while AST and SCr were positively correlated. In addition, the use of azole antifungals, metronidazole proton pump inhibitors, doxycycline, and choice of antiseizure prophylactic medication also had a significant effect on Bu AUC. Multivariable analysis demonstrated BMI and CrCl were negatively associated with AUC (p=0.008 and 0.005, respectively) while AST was positively associated (p=0.035). The use of fluconazole, metronidazole and doxycyline was associated with higher AUCs (p=0.011, 0.021, and 0.004, respectively) while concurrent use of voriconazole was associated with lower AUC (p=0.011). Based on these data, pts with large BMI, increased CrCl, or on concomitant voriconazole may require larger doses of busulfan to achieve a target AUC whereas pts with an elevated AST or taking fluconazole, metronidazole and doxycyline may require less. In order to validate these findings, we are developing a population based dosing model that will require testing in a prospective pt sample.

Disclosures:
Field: PDL BioPharma: Research Funding. Perkins:PDL BioPharma: Research Funding. Off Label Use: IV busulfan and fludarabine for pretransplant conditioning.
Inhibition of p38 MAPK Promotes Hematopoietic Stem Cells Self-Renewal and Ex Vivo Expansion.
Authors: Wang Yong , Kellner Joshua , Zhou Daohong 
Published: October 2019

Abstract
Abstract 34
Activation of the p38 mitogen-activated protein kinase (p38 MAPK) is implicated in the inhibitory effects of TNF-α, TGF-β, interferons and reactive oxygen species (ROS) on hematopoiesis and self-renewal of hematopoietic stem cells (HSCs). Clinically, overactivated p38 MAPK contributes to the pathogenesis of myelodysplastic syndromes (MDS) and Fanconi anemia. Inhibition of p38 MAPK with pharmacological agents improves hematopoietic progenitors' function in MDS. However, it has yet to be determined if p38 MAPK plays a role in regulation of normal HSC self-renewal and whether inhibition of p38 MAPK can improve HSC ex vivo expansion. In the present study, we found that sorted mouse bone marrow HSCs (Lin− Sca1+ c-kit+ cells or LSK+ cells) exhibited specific activation of p38 MAPK after seven days culture in serum-free medium supplemented with stem cell growth factors (SCF, Tpo and Flt3 ligand). The activation of p38 MAPK was associated with rapid differentiation of HSCs and induction of cellular senescence. Addition of SB203580 (SB, a specific p38 MAPK inhibitor) to the culture abrogated the activation of p38 MAPK, inhibited the induction of cellular senescence and increased the expression of several HSC self-renewing genes (such as CXCR4, HoxB4 and Gfi1). Moreover, HSCs cultured with SB resulted in a significantly greater HSC expansion than HSCs cultured without SB as assessed by flow cytometry and cobblestone area-forming cell (CAFC) assay. Finally, competitive repopulation assays revealed that HSCs expanded with SB produced a dramatic increase in donor-derived engraftments after transplantation to irradiated recipients. These findings suggest that p38 MAPK plays an important role in the regulation of HSC self-renewal and its inhibitors (e.g. SB203580) may be clinically useful in the ex vivo expansion of HSCs.

Disclosures:
No relevant conflicts of interest to declare.
Y90 Plus High Dose BEAM with Autologous Stem Cell Transplantation for Chemorefractory Non Hodgkin Lymphoma.
Authors: Krishnan Amrita , Raubitschek Andrew , Palmer Joycelynne , Nademanee Auayporn P. , Kogut N. , Yamauchi Dave , Popplewell Leslie , Federico Laura , Simpson Jennifer , Tsai Ni-Chun , Forman Stephen J 
Published: October 2019

Abstract
Abstract 3423
Poster Board III-311
Long term survival for patients with chemo-refractory non-Hodgkin lymphoma (NHL) is poor even with high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Strategies such as novel transplant conditioning regimens and post transplant maintenance therapy are being evaluated to improve outcomes. Herein we report on the results of a phase II study designed to assess the impact of a novel radioimmunotherapy (RIT) based conditioning regimen of Y90 ibritumomab tiuxetan in conjunction with high dose BEAM (BCNU, Etoposide, Ara–C, Melphalan) in patients with poor risk NHL. Between May 2002 and Jan 2009, 31 patients who were either primary induction failure (n=18) or in partial remission (n=13) underwent HDC with Y90 plus BEAM. Patients received an imaging dose of Indium 111 on day -21 followed by a treatment dose of Y90 (0.4mCi/kg) on day-14. HDC with BEAM was started on day -7. The median age at ASCT was 57 (range: 19–70). The majority of patients were male (n=23, 74%) and had advanced stage disease (III or IV) at the time of diagnosis, (n=23, 74%). The histologies included Follicular n=6, Diffuse Large B-cell n=13, Mantle cell n=8, and Transformed n=4. The median number of prior regimens was 2 (range: 1-5). All patients engrafted at a median of 11 days. At the time of analysis, 23 (74%) patients were alive, and eight had expired (seven due to relapse/progressive disease, one due to COPD). The non-relapse mortality was 3.2%. The median length of follow-up for surviving patients is 46.9 months (range: 3.3-75.0). The two-year overall survival and disease-free survival was 77.9% (95%CI: 62.7-87.6%) and 50.9% (95%CI: 40.5-60.3%) respectively for the entire cohort. However, the relapse rate in the subset of MCL pts was strikingly high and approached 80% at 4 yrs. The other subgroups had a stable DFS (figure 1). In conclusion in this poor risk group of patients Y90 plus high dose BEAM can induce responses and long term remissions, however, for patients with chemorefractory MCL other treatment approaches may be warranted.

Disclosures
Off Label Use: yttrium 90 in combination with high dose BEAM chemotherapy.
A Phase 1, Open-Label, Multi-Center, Multiple-Dose, Dose-Escalation Study of MDX-1342 in Patients with CD19-Positive Refractory/Relapsed Chronic Lymphocytic Leukemia.
Authors: Camacho Luis H , Joyce Robin , Brown Jennifer R , Chanan-Khan Asher , Amrein Philip C. , Assad Albert , Carrigan Marion 
Published: October 2019

Abstract
Abstract 3425
Poster Board III-313
MDX-1342 is a fully human monoclonal antibody (HuMAb) with enhanced antibody-dependent cellular cytotoxicity (ADCC) effector function, targeting CD19-membrane receptor which is highly expressed on malignant chronic lymphocytic leukemia (CLL) cells. An open-label, multi-center, multiple-dose, dose-escalating Phase 1 study is being conducted to determine the safety and tolerability profile of MDX-1342 in subjects with CD19-positive relapsed or refractory CLL. To date, MDX-1342 has been administered intravenously (iv) weekly for 4 weeks to 12 subjects (8 Male, 4 Female) - in cohorts of 3 subjects each - at doses of 0.7, 7, 40, and 200 mg/dose. Overall, MDX-1342 has been well tolerated. No drug-related serious adverse events have been reported among the 12 subjects treated. Grade 1 and 2 infusion reactions (including rigors, chills, and wheezing) have been observed in 9 subjects. This has been adequately managed with the use of antihistamines and corticosteroids. Dose escalation continues and a maximum tolerated dose has not yet been identified. Of the 9 currently evaluable subjects, 1 has experienced a partial response (40 mg/dose cohort), 6 have stable disease and 2 have discontinued due to progressive disease. Preliminary results indicate antileukemic signals with dose-correlative reductions in both white blood counts (WBC) and circulating CD20+ cells after one 4-week cycle of weekly i.v. infusions of MDX-1342. In the 40 mg/dose cohort, the median reduction in WBC was 62% and the median reduction in circulating CD20+ cells was 74%. Additional subjects are being accrued to higher dose cohorts to more accurately characterize the safety and clinical activity of MDX-1342 and to determine if there is a consistent cumulative drop in WBC and circulating CD20+ cells as the dose increases.

Disclosures
Assad: Medarex, Inc.: Employment. Carrigan:Medarex, Inc: Employment.
Cell of Origin Influences Leukemia Stem Cell Phenotype.
Authors: Krivtsov Andrei V. , Sinha Amit U. , Stubbs Matthew C. , Kung Andrew , Armstrong Scott 
Published: October 2019

Abstract
Abstract 3459
Poster Board III-347
MLL-fusion proteins can transform either hematopoietic stem cells (HSC) or granulocyte macrophage progenitors (GMP) into leukemia stem cells (LSC). However, the leukemogenic process in HSC may differ from that in GMP. We transduced HSC and GMP with MLL-AF9 or control retroviruses. Single-cell sorted MLL-AF9 expressing HSC or GMP could be serially replated for over 9 passages. Upon transplantation into syngeneic mice, 86.3% (n=22) of HSC:MLL-AF9 single cell derived clones (SCC) induced AML with a median latency of 61 days, while 33.3% of GMP:MLL-AF9 SCC induced AMLs with median latency of 100 days. Immunophenotype analysis of the resultant leukemias demonstrated that long-term repopulating HSC (LT-HSC) and GMP-derived leukemias were quite similar, with a GMP-like (LGMP) population enriched in LSC in both cases. Gene expression analysis demonstrated that globally the LGMP isolated from HSC derived AMLs (AML:HSC) and GMP derived AMLs (AML:GMP) were similar to each other but possessed specific genetic programs reminiscent of the cell of origin (HSC or GMP). For example Evi1, Jun, and Fos oncogenes were highly expressed in HSC and AML:HSC, but expressed at low level in GMP or AML:GMP. The genetic program that distinguished LGMP:HSC from LGMP:GMP was found to be enriched in hematopoietic stem cells compared to more differentiated myeloid progenitors and correlate with genetic programs in and human MLL-rearranged AML associated with a poor clinical outcome in two independent MLL-rearranged AML data sets. In order to directly assess differences in treatment response for leukemias derived from different cells of origin, we treated leukemic mice with a chemotherapeutic agent often used to treatment human AMLs. Treatment of leukemic mice with Etoposide reduced the spleen weights in mice transplanted with AML:HSC to a lesser extent (28%) than in mice transplanted with AML:GMP (88%). Altogether, these data indicate that cell of origin of AML can influence the genetic program of fully developed leukemia, and thus could account for some of the heterogeneity in human leukemias and perhaps outcome.

Disclosures
No relevant conflicts of interest to declare.
Hypermethylation of CD44 Is Characteristic of Specific Lymphoma Subtypes.
Authors: Röhrs Sonja , Romani Julia , Zaborski Margarete , Rosenwald Andreas , Drexler Hans G. , Quentmeier Hilmar 
Published: October 2019

Abstract
Abstract 3469
Poster Board III-357
Epigenetic inactivation of tumor suppressor genes (TSG) by promoter CpG island hypermethylation is a common hallmark of cancer. It is generally agreed, that CpG island hypermethylation profiles are specific for different tumor types [Costello et al., 2000, Nat Genet 25:132-138]. Using MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification), methylation of 24 different TSG was analyzed in 40 lymphoma cell lines representing Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). On average 8 ± 2.8 TSG out of the 24 analyzed were methylated per lymphoma cell line, whereas 0/24 TSG were methylated in healthy donor tonsils. Methylation frequencies decreased from HL, ALCL, BL, FL, DLBCL to MCL cell lines. The TSG methylation status of the most relevant genes was verified by methylation-specific PCR. Moreover, TSG hypermethylation correlated with transcriptional silencing as assessed by quantitative real time PCR. While our studies on the methylation status of TSG in lymphoma cell lines support previous methylation analyses performed on primary lymphoma patient material for many of the genes analyzed here, MS-MLPA screening also revealed a new interesting candidate: CD44. Hypermethylation of CD44 was characteristic of ALCL, BL, FL and DLBCL cell lines and allowed their discrimination from MCL and HL cell lines. In CD44 hypermethylated cell lines expression of CD44 was re-inducible at mRNA and protein levels by treatment with the demethylating agent 5-Aza-2'-deoxycytidine, confirming its epigenetic regulation. Furthermore, CD44 ligation with an anti-CD44 antibody induced apoptosis in CD44+ (CD44 unmethylated) lymphoma cell lines whereas CD44 hypermethylated cell lines showed no response. Thus, CD44 might be an interesting new epigenetic marker and a potential molecular target for the diagnosis and treatment of specific lymphoma subtypes.

Disclosures
No relevant conflicts of interest to declare.
Class I HLA-Specific Antibodies Can Cause “false-positive” Test Results in the Serotonin Release Assay for Heparin-Induced Thrombocytopenia (HIT).
Authors: Rocky Shiu-Ki Hui , Ellis Thomas M , Aster Richard H. , Curtis Brian R. 
Published: October 2019

Abstract
Abstract 3506
Poster Board III-443
A diagnosis of heparin-induced thrombocytopenia (HIT) is confirmed with support from the laboratory. Antibodies associated with HIT are specific for complexes made up of heparin and platelet factor 4 (PF4) and can be detected in a solid phase ELISA (PF4 ELISA). However, a functional test, the serotonin release assay (SRA) is regarded by many to be the “gold standard” for laboratory investigation of this disorder. In our facility, the SRA is performed by incubating serotonin-labeled platelets (pooled from three different group O donors) with test serum and low dose (0.1 units/ml) or high dose (100 units/ml) heparin and determining the percentage of total serotonin released. Release of serotonin (20-100%) with low dose heparin and inhibition of this release with high dose heparin is considered to be “positive” for platelet-activating HIT antibodies. Sera from some patients cause serotonin release with low dose heparin that is not inhibited with high dose heparin. The significance for these “indeterminate” reactions is unclear, but they are considered not to reflect the presence of “true” HIT antibodies.
We studied selected serum samples from 238 patients referred for HIT testing. Of these, 119 tested “true” positive and 117 produced “indeterminate” reactions in the SRA. The same samples were tested for the presence of antibodies reactive with beads coated with various Class I HLA antigens using a flow cytometric bead assay (Flow PRA, One Lambda). Sera producing at least 30% release in SRA and reactive with at least 20% of the bead panel were selected for analysis. As shown in Figure 1, there was a high correlation between the likelihood of an “indeterminate” SRA test result and the presence of Class I HLA antibodies (p &lt;&lt; 0.0001).
Figure 1 SRA Category No. with PRA &gt;/=20% No. with PRA &lt;20% Total Sample SRA “Indeterminate” (&gt;/=30% Release and Uninhibited by High Dose Heparin) 91 19 110 SRA “True Positive” (&gt;/=30% Release and Inhibited by High Dose Heparin) 36 72 108
As expected, there was a significant correlation between the strength of reactions produced by individual “true positive” sera in the SRA (% release) and in the PF4/heparin ELISA (O.D. value). However, in analyzing 38 sera with “true positive” test results in the SRA, we identified two that were negative in the PF4 ELISA and contained broad Class I HLA reactivity (reactive with 100% and 41% of the panel, respectively).
We conclude 1) Class I HLA antibodies are the major cause of “indeterminate” reactions in the serotonin release assay and 2) A subset of these antibodies can be inhibited by high dose heparin and therefore mimics the behavior of “true” HIT antibodies in the SRA. Unless the PF4 ELISA test is used together with the SRA, this type of reaction could lead to an erroneous diagnosis of HIT.

Disclosures:
No relevant conflicts of interest to declare.
Poster Board III-457 Surface Plasmon Resonance (SPR) Analysis Detects Clinically Significant Low Avidity HPA-1a Antibodies Not Identified by Conventional Serology.
Authors: Peterson Julie A. , Kanack Adam , Gitter Maria L. , Rathore Vipul , McFarland Janice , Curtis Brian R , Aster Richard H. 
Published: October 2019

Abstract
Abstract 3520
Poster Board III-457
Neonatal alloimmune thrombocytopenia (NATP) is caused by passively transmitted maternal antibodies specific for fetal platelet antigens inherited from the father. The diagnosis is made by demonstrating a maternal antibody specific for a paternal platelet alloantigen inherited by the affected infant. It is not unusual for mothers of suspected NATP cases to be antibody-negative using standard serologic methods. Assays routinely used to detect alloantibodies (flow cytometry, glycoprotein-specific solid phase assays) require repeated washing of the target cell or antigen to remove unbound antibody, followed by detection of bound antibody with a labeled secondary probe. Low avidity antibodies could dissociate from their targets during these washing steps and might, therefore, not be detected; however, the extent to which such antibodies cause human disease is controversial. Surface plasmon resonance (SPR) directly measures the accretion of ligand on an immobilized receptor in real time and could therefore lend itself to detection of low avidity, clinically significant human antibodies. In fact, Socher et al recently described use of SPR to detect maternal antibodies specific for the HPA-1a (PlA1) platelet antigen in two NATP cases not diagnosed by standard serology (Transf 49:943, 2009).
We have also studied the utility of SPR for detection of clinically important human antibodies. HPA-1a/a-positive and -negative GPIIb/IIIa was isolated from platelets and was immobilized in the lanes of a CM5 Biacore chip. IgG used for testing was doubly purified from serum to remove vitronectin and other proteins that might react with the target integrin through RGD binding sites, thereby masking antibody-specific signals. The range for binding of IgG from normal subjects to these targets was defined with IgG from 30 healthy donors.
In preliminary studies, we found that SPR analysis is about 5 times as sensitive as standard serology for detection of known HPA-1a-specific antibodies. We then studied maternal sera from 45 cases of suspected NATP in which the mother was HPA-1a-negative but no maternal antibody was detected. Seven of these sera were found to contain IgG that recognizes HPA-1a-positive, but not HPA-1a-negative GPIIb/IIIa. A comparison of the reaction kinetics of these antibodies with those of “conventional” HPA-1a-specific antibodies showed that the former have a significantly higher off rate, as would be expected of low avidity antibodies. We conclude that low avidity antibodies specific for HPA-1a are capable of causing NATP and may not be rare and that SPR may provide a unique tool for their detection. The extent to which SPR can be useful in studying other antibody-mediated human disorders deserves exploration.

Disclosures:
No relevant conflicts of interest to declare.