bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variations in GRIA1 On Chromosome 5q33 Related to Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia (ALL).
Authors: Chen Shih-Hsiang , Pei Deqing , Yang Wenjian , Cheng Cheng , Jeha Sima , Evans William E. , Pui Ching-Hon , Relling Mary V. 
Published: October 2019

Abstract
Abstract 112

Asparaginase, an important antileukemic agent for ALL, is isolated from bacterial sources, and hence hypersensitivity reactions frequently occur; these reactions may attenuate its enzymatic activity and thus its antileukemic effect. Inherited genomic variations are known to affect the risk of hypersensitivity to some medications, but those that affect the risk of asparaginase allergy are not known. We interrogated 500,000 single nucleotide polymorphisms (SNPs) in 485 children with ALL treated on a single clinical trial to identify SNPs associated with allergy to native E. Coli (Elspar) asparaginase. A total of 204 (41%) patients developed an allergic reaction, most of which were NCI grade 2. We divided the patients into a discovery (n = 322) and a validation (n = 163) cohort, balancing for age, sex, treatment arm, race, and the occurrence of asparaginase allergy. Among the top 100 SNPs significantly associated with allergy in the discovery cohort, SNPs on chromosomes 5 and 19 were overrepresented, hosting 12 SNPs annotated to genes. Among these 12 SNPs, only one SNP (rs4958381 in GRIA1 on chromosome 5q33) replicated in the validation cohort (p = 2.8 ′ 10−5 and 2.0 ′ 10−3 in the discovery and validation cohorts, respectively). This locus has been associated with asthma or atopy. We further found that an additional 11 SNPs annotated to GRIA1 (a glutamate receptor gene) associated with asparaginase allergy at p < 0.05 in the discovery cohort, 4 of which replicated in the validation cohort (rs10070447, rs6890057, rs4958676, and rs6889909) at p < 0.05. Based on GRIA1 SNP rs4958381, the cumulative incidence of asparaginase allergy (Figure) was 74%, 44%, and 32% for those with the AA, AG, and GG genotypes, respectively (n = 485, p = 4.2 ′ 10−8). The 5q33 region hosts several cytokine and immunomodulatory genes, with multiple genome-wide studies implicating this locus in asthma and atopy. An agnostic genome-wide approach implicates genomic variations in GRIA1 on chromosome 5q33 as predisposing to the risk of asparaginase allergy.

Disclosures:
No relevant conflicts of interest to declare.
MICA-129 Genotype, Soluble MICA and Anti-MICA Antibodies as Biomarkers of Chronic Graft Versus Host Disease.
Authors: Boukouaci Wahid , Busson Marc , de Latour Regis Peffault , Rocha Vanderson , Toubert Antoine , Charron Dominique , Socie Gerard P , Tamouza Ryad 
Published: October 2019

Abstract
Abstract 1138
Poster Board I-160

Background
The MHC class I-related chain A (MICA) molecules is of particular in non T-cell receptor (TCR)-mediated immune function. MICA engages NKG2D, a C-type lectin expressed on effector cells including NK, and T cells. Such engagement triggers NK cells and co-simulates T lymphocytes to mount adequate immune response. Further, a soluble isoform of MICA (sMICA) has been implicated in the pathogenesis of a variety of cancers, auto-immune and other organ transplant-related disorders through NKG2D receptor down regulation. Functionally relevant polymorphism of the MICA gene may also contribute to inter-patients variability in allo-immune responses as observed in various clinical settings including organ-transplantation. A methionine (met) to valine (val) change at position 129 of the alpha 2-heavy chain domain categorized the MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor. Given the demonstrated importance of MICA in immune pathways, in this study, we explored the MICA-related parameters namely MICA-129 gene polymorphism, pre- and post-transplant serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) in a HLA-matched sibling HSCT setting.

Results
We evaluated whether MICA-129 gene polymorphism, pre- and post-HSCT sMICA and MICA Abs could influence the incidence of chronic graft-versus-host disease (c.GvHD) and relapse of their disease in 211 HLA-identical sibling pairs.
In multivariate analysis on chronic GvHD risk, 3 factors reached significance: recipient MICA-129 val/val genotype (HR = 1.52; 95% confidence interval [95%CI] = 1.02-2.24; P =.04), older recipient age (3 15 years) (HR = 3.36; 95%CI = 1.65-6.84; P =.001) and source of stem cells (PBSC vs BM) (HR = 1.67; 95%CI = 1.10-2.53; P =.017). Since acute GvHD (aGvHD) is a major risk factor of subsequent c.GvHD, we then introduced aGvHD as a time-dependant co-variate in the multivariate analysis model. This analysis confirmed that the risk conferred by the MICA-129 val/val genotype is independent from aGvHD. Elevated post-HSCT sMICA serum levels were also independently associated with c.GvHD (p =.0001) regardless of history of acute GvHD. On the contrary, the presence of pre-transplant MICA Abs confers protection against c.GvHD (p =.04). There was an inverse relationship between MICA Abs and sMICA suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse.

Conclusion
Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for c.GvHD monitoring.

Disclosures
No relevant conflicts of interest to declare.
Gene Expression Patterns Associated with Cytarabine Pharmacology and Outcome in Pediatric Acute Myeloid Leukemia.
Authors: Lamba Jatinder K. , Crews Kristine , Pounds Stanley , Cao Xueyuan , Gandhi Varsha , Plunkett William , Baker Sharyn D. , Pui Ching-Hon , Campana Dario , Downing James R. , Rubnitz Jeffrey , Ribeiro Raul C 
Published: October 2019

Abstract
Abstract 114
To identify genes that influence responses to cytarabine (ara-C) treatment, we explored the association of gene expression in leukemic cells at diagnosis with multiple pharmacological and clinical end-points in children with acute myeloid leukemia (AML) treated with ara-C on the St. Jude AML97 clinical trial. We applied a novel statistical procedure, PRojection Onto the Most Interesting Statistical Evidence (PROMISE; PR), to identify genes with expression levels associated with clinical and pharmacological endpoints. To do this, we first defined the following values of the clinical and pharmacological variables as “therapeutically beneficial” :higher leukemic cell ara-C triphosphate levels, lower DNA synthesis values on days 1 and 2 of treatment relative to baseline, decreases in leukocyte counts on day 2 of treatment, improved response and decreased risk of relapse, death, or second malignancy. We considered a gene to show a therapeutically beneficial pattern of association if its expression was positively correlated with ara-CTP levels, negatively correlated with DNA synthesis levels, negatively correlated with decrease in leukocyte counts on day 2, positively correlated with better treatment response, and negativelycorrelated with the risk of relapse or death. A gene showed a therapeutically detrimental pattern of association if its expression had the opposite correlations with the clinical and pharmacological variables. We performed five variable (PR5 using early pharmacologically interesting phenotype measures) or seven variable (PR7 all the above indicated phenotypes) PROMISE analyses. PR5 identified 275 beneficial probe sets and 69 detrimental probe sets (p ≤ 0.005). PR7 analysis identified 112 beneficial probe sets and 115 detrimental probe sets (p ≤ 0.005). To confirm these results, we performed a PROMISE for a cohort of patients treated with ara-C and other agents on the AML02 protocol. Gene expression in leukemic cells at diagnosis was analyzed for a beneficial or detrimental pattern of association with three phenotypes (PR-3); diagnostic blast ara-C cytotoxicity, minimal residual disease (MRD) and event-free survival (EFS). Eighty-one probe sets identified by PR5 or PR7 analyses in the initial cohort were confirmed in the PR-3 analysis of AML02 data. Genes identified in the present study may serve as predictive markers of response and candidates for future drug development.

Disclosures:
No relevant conflicts of interest to declare.
Influence of Genetic Variability of GSTM1 and GSTT1 Null Alleles Between Donor and Recipient in the Development of Acute Graft Versus Host Disease.
Authors: Contento-Gonzalo Alejandro , Alcala-Peña Magdalena , Barrios Manuel , Ortiz-Pareja Macarena , Jiménez-Velasco Antonio , Román-Gómez José , Gomez Antonio P. Torres , Heiniger Ana Isabel 
Published: October 2019

Abstract
Abstract 1154
Poster Board I-176

INTRODUCTION
Glutathione-S-transferase (GST) M1 and T1 are multifunctional enzymes involved in the metabolism of environmental carcinogens and chemotherapeutic drugs. The immunogenic activity of these enzymes and their association with graft rejection has been widely proved in solid organ transplantation. In this study we examined whether genetic variability (absence versus presence of the gene in donor/recipient pairs) could be related to acute graft versus host disease (aGvHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) from related donor (RD).

PATIENTS AND METHODS
We evaluated 64 patients with acute leukemia (34 AML and 30 ALL) undergoing alloSCT and receiving myeloablative conditioning (MAC), with a minimum follow-up of 100 days. Donors were HLA-identical siblings in all cases, except in 2 presenting only a single HLA disparity. As source of HSCs, bone marrow progenitors were used in 25 patients (40%) and peripheral blood progenitors in 39 (60%). Total body irradiation (TBI) was used for conditioning treatment in 18 cases (28%). GvHD prophylaxis consisted of a short-term combination of Cyclosporine and Methotrexate. Presence in homozygous or heterozygous (positivity) or absence (negativity) of GSTM1/T1 genes were determined by real-time PCR. A Chi-square test was used to evaluate qualitative variables and non-parametric tests for quantitative variables. The Cox proportional-hazard model was applied to multivariate analysis.

RESULTS
GSTT1 and GSTM1 positivity was observed in 73 and 47% of patients, respectively, and in 72 and 46% of donors, respectively. Nineteen of 64 patients (30%) presented grade II-IV aGvHD. The incidence of grade II-IV aGVHD in GSTM1-positive patients was 79% versus 21% in GSTM1-negative patients. In univariate analysis, only GSTM1 positive patients developed grade II-IV aGvHD (p=0.001). In multivariate analysis, GSTM1 positivity was the only variable significantly associated with the appearance of grade II-IV aGvHD (p=0.002). No significant association was detected between GSTT1 genetic variability and the incidence of aGvHD. We found no significant difference in patients overall survival in relation to GSTM1 and GSTT1 genetic variability.

CONCLUSIONS
GSTM1-positive recipients develop more likely grade II-IV aGvHD, independently of other known risk factors. GSTM1 gene determination (homozygous or heterozygous) could be used to assess the aGvHD risk in allogeneic hematopoietic stem cell transplantation.

Disclosures
No relevant conflicts of interest to declare.
Influenza A H1N1 Virus Infection in Two Hematopoietic Stem Cell Transplant Recipients.
Authors: Bastos Diogo Assed , Rodrigues Celso Arrais , Patah Poliana , Dias Beatriz Souza , Rocha Vanderson , Novis Yana 
Published: October 2019

Abstract
Abstract 1169
Poster Board I-191
In April 2009, a novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. Since then, several cases have been reported, with subsequent cases observed in many other countries. Clinical presentation may range from mild symptomatic patients to cases of severe clinical presentation and death due to pneumonia and respiratory failure. Definition of high risk groups are thought to be similar to those defined for seasonal influenza, including young children and elderly patients, pregnant women and patients with chronic medical conditions, especially immunocompromised hosts. Hematopoietic stem cell transplant (HSCT) recipients are at high risk for infectious complications, including severe viral infections. To our knowledge, there are no reported cases of S-OIV infection in HSCT recipients to date. The clinical features and the possible consequences of this novel influenza virus in this setting remain unknown. We describe two HSCT recipients with confirmed influenza H1N1 virus infection and a benign clinical course after oseltamivir treatment. The first case is a 12 year-old male patient with diagnosis of acute myelogenous leukemia in second complete remission who underwent an unrelated umbilical cord blood transplant with two 4/6 HLA-mismatched cord blood units. Graft-versus-host disease (GVHD) prophylaxis consisted of the association of cyclosporine and mycophenolate mofetil. Additionally, he was also being treated for an invasive aspergillosis with oral voriconazole. On day+3 after transplant, he developed fever, rhinorrhea, and dry cough. A nasal wash and a nasal swab were positive for influenza A by direct immune fluorescence and for influenza A H1N1 by real-time polymerase chain reaction (RT-PCR). Computed tomography of the nasal sinus and thorax were unremarkable. Oseltamivir therapy (75 mg po twice daily for 10 days) was initiated the same day with progressive improvement of symptoms. Oseltamivir was well tolerated and there was no interference with serum levels of cyclosporine. The second case is a 30 year-old female patient with gray zone non-Hodgkin lymphoma in relapse after autologous stem cell transplant that underwent an HLA-matched related HSCT in September 2008. She relapsed 6 months after the transplant. Cyclosporine was withdrawn. Ten days later, she developed fever rhinorrhea, and myalgia. Influenza A H1N1 was confirmed by RT-PCR of a nasal wash specimen. Treatment with a 5-day course of oseltamivir (75 mg po twice daily) was initiated and the patient had a favorable clinical course, with no complications. These two cases of confirmed influenza H1N1 virus infection in HSCT recipients with a benign clinical course highlight the need for a better understanding of the clinical course and management of this novel viral agent in severely immunocompromised hosts.

Disclosures:
No relevant conflicts of interest to declare.
Partially Matched Related Donor Transplantation Can Achieve Outcomes Comparable to Unrelated Donor Transplantation for Patients with Hematologic Malignancies.
Authors: Huang Xiao Jun , Xu Lan-Ping , Liu Kai yan , Liu Dai-Hong , Wang Yu , Chen Huan , Chen Yu-Hong , Han Wei , Wang Jing-Zhi , Chen Yao , Zhang Xiao-Hui , Shi Hongxia , Wang Feng-Rong , Tang Fei-Fei 
Published: October 2019

Abstract
Abstract 1197
Poster Board I-219
Abstract

Purpose:
To compare the outcomes of patients undergoing hematopoietic stem cell transplantation (HSCT) from partially matched related donors (PMRDs) or unrelated donors (URDs) for hematologic malignancies without the use of in vitro T cell depletion (TCD).

Experimental Design:
297 consecutive patients were performed HSCT from URDs (n = 78) or PMRDs (n = 219) during the same time period. Incidences of graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), overall survival (OS) and leukemia-free survival (LFS) are compared between the PMRD and URD groups.

Results:
All patients achieved full engraftment. The cumulative incidences of grades II to IV acute GVHD in the PMRD and URD cohorts were 47% (95% CI, 33%-62%) versus 31% (CI, 20%-42%, P = .033), with a relative risk (RR) = 1.72 (1.01-2.94), P = .046. The incidence of chronic GVHD did not differ significantly between the two cohorts (P = .17). Two-year incidences of NRM and relapse were 20% (CI, 15%-26%) versus 18% (CI, 10%-27%), with P = 0.98, and 12% (CI, 8%-16%) versus 18% (CI, 10%-27%), with P = .12, for the PMRD versus URD cohort respectively. Four-year OS and LFS were 74% (CI, 67%-80%) versus 74% (CI, 62%-85%), with P = .98, and 67% (CI, 59%-75%) versus 61% (CI, 47%-74%), with P = .74, respectively.

Conclusions:
Our comparisons demonstrate that every major end point, including relapse, NRM, OS and LFS, was comparable between the PMRD and URD groups.

Disclosures:
No relevant conflicts of interest to declare.
Variation of T-Reg and CD 200+ T- Lymphocytes After in Vitro Treatment with Active Drugs against CLL.
Authors: Parrinello Nunziatina , La Cava Piera , Tibullo Daniele , Giallongo Cesarina , Chiarenza Annalisa , Romano Alessandra , Cavalli Maide , Triolo Anna , Palumbo Giuseppe A , Di Raimondo Francesco 
Published: October 2019

Abstract
Abstract 1239
Poster Board I-261

Background
Purine analogues, in particular fludarabine, are considered the gold standard of treatment of CLL. However, fludarabine therapy is sometimes complicated by autoimmune haemolytic anemia (AHA). The mechanism of this side effect is not clear but it is conceivable that a fludarabine-induced suppression of some regulatory systems, including T-reg, is responsible for this phenomenon. In addition, we have observed that patients affected by autoimmune diseases such as AHA or PTI have a reduced number of T lymphocytes bearing the CD200 antigen that is considered a tolerogenic molecule. In this perspective, we evaluated the variation of T-reg and CD200+ T lymphocytes induced by incubating in vitro peripheral blood mononuclear cells (PBMC) of CLL patients and normal subjects with purine analogues and other drugs active against CLL.

Method
PBMC obtained from patients with chronic lymphocytic leukaemia (CLL) (n=9) and from normal adult (n=6) were isolated by density gradient and cultured in RPMI supplemented with 10% FBS and 1% of penicillin streptomicyn. Cells were then incubated for 24 hours with drugs at two concentrations: bendamustine (1 and 50 μg/ml) campath (1 and 5 μg/ml) prednisone ( 1 and 10 nM), fludarabine (0,25 and 10 μg/ml) pentostatin (3 and 60 μg/ml). The cytotoxicity was evalutated after 24 hours by trypan Blue and flow cytometry. T-reg cells were identified as CD4+/CD25+/FoxP3+ T cells and expressed as a percentage of the CD4+T-cell population.

Results
Although all of these drugs induced lymphocytes cytotoxicity, fludarabine, prednisone, and campath reduced also the percentage of T-reg and CD200+ T –lymphocytes, while bendamustin and especially pentostatin induced the same cytotoxicity but spared T-reg populations and CD200+ T-lymphocytes. Table I indicates results obtained with the highest concentration of drugs.
In conclusion, pentostatin and bendamustine seems to be active drugs against CLL and their usage shouldn't be complicated by autoimmune phenomena.

Disclosures
No relevant conflicts of interest to declare.
CKS1B Mediates SKP2/p27Kip1-Independent Myeloma Cell Survival and Disease Progression through Activation of MEK/ERK and JAK/STAT3 Signaling Pathways.
Authors: Zhan Fenghuang , Shi Lei , Wang Siqing , Xu Hongwei , Cao Thai M. , Xu Chunjiao , Wu Yong , Zangari Maurizio , Li Guiyuan , Tricot Guido J. 
Published: October 2019

Abstract
Abstract 126
We previously reported that CKS1B may influence myeloma (MM) cell growth and survival through SKP2/p27Kip1-dependent and -independent mechanisms. However, there is still no direct evidence to prove that CKS1B has a role in MM cell proliferation and disease progression. The present study was performed to establish its functional role and define CKS1B-mediated SKP2/p27Kip1-independent down-stream signaling pathways. CKS1B was over-expressed in OCI-MY5 and XG1 MM cell lines by lentivirus. Western blots confirmed CKS1B over-expression. Cells were cultured in medium containing 1% fetal bovine serum for 7 days. CKS1B-transfection resulted in increased cell proliferation compared to empty-vector (EV)-transfected controls. We also examined the role of CKS1B in myeloma resistance to the general used chemotherapeutic drugs, such as bortezomib (5nM), doxorubicin (100nM) and etoposide (100nM). Untreated cells and empty-vector (EV)-transfected cells with or without drug treatments served as controls. Significant less inhibition of cell growth and cell death was observed after drug treatment in CKS1B-transfected cells compared with controls (P < .05). To screen down-stream signaling pathways associated with cell growth and survival in OCI-MY5, MS28PE and XG-1 cells were transfected with specific CKS1B-shRNA, which resulted in decreased phosphorylation of MEK1/2, ERK1/2, STAT3, MCL1 and BCL2 compared to wild-type and control cells, transfected with scrambled CKS1B-shRNA. To confirm these results, we examined the alteration of STAT3, MEK/ERK and BCL2 signaling pathways in OCI-MY5 and XG1 cells after forced over-expression of CKS1B. Increased levels of p-MEK1/2, p-ERK1/2, p-STAT3, MCL1 and p-BCL2 were observed compared to the EV-transfected controls, confirming that CKS1B activates STAT3, MEK/ERK and BCL2 signaling pathways. In Contrast, SKP2 over-expression or p27Kip1 inhibition resulted in inhibition of STAT3 and MEK/ERK pathways with no remarkable changes inBCL2. Further investigation showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3, MEK/ERK and BCL2 signaling pathways only partially abrogated MM cell death and growth inhibition induced by CKS1B knockdown. Targeting either the STAT3, MEK/ERK or BCL2 signaling pathway with specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-over-expressing MM cells; their combination had a synergistic effect on cell death and growth inhibition. Our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in the therapy of aggressive CKS1B-overexpressing MM, which shows increased proliferation and drug-resistance

Disclosures:
No relevant conflicts of interest to declare.
A Stratified Metaanalysis of Desmopressin (DDAVP) for Minimising Perioperative Allogeneic Blood Transfusion.
Authors: Zotz Rainer B. 
Published: October 2019

Abstract
Abstract 1306
Poster Board I-328

Background
DDAVP has been evaluated in post-operative surgery patients without inherited bleeding disorders to determine whether it decreases blood loss and can minimise exposure to allogeneic transfusion. Previous reviews with overall negative results have not discriminated between prophylactic and therapeutic indications for DDAVP (Carless et al. 2006). The aim of this analysis was to create a systematic metaanalysis stratified for prophylactic administration of DDAVP to all patients as compared to a therapeutic indication, defined as blood loss >1l in the control group or prior aspirin medication.

Methods
Studies were evaluated in the metaanalysis when they were controlled trials in which adult patients, scheduled for non-urgent surgery, were randomised to DDAVP, or to a control group, who did not receive the intervention.

Results
Eighteen trials of DDAVP (n=1295) reported data on the number of patients transfused with allogeneic RBC transfusion. In subjects treated with DDAVP for therapeutic reasons, the pooled relative risk of exposure to perioperative allogeneic RBC transfusion was 0.36 (95%CI = 0.19 to 0.66). The use of DDAVP did significantly reduce blood loss; weighted mean difference (WMD) =-386 ml: 95% confidence interval (95%CI) =-542 to -231ml per patient) or the volume of RBC transfused (WMD = -340 ml: 95%CI = -547 to -134 ml per patient). In contrast, in subjects treated with DDAVP for prophylactic reasons, no significant benefit from using DDAVP was found.

Conclusions
Desmopressin administered for therapeutic indications significantly minimises perioperative allogeneic RBC transfusion in patients who do not have congenital bleeding disorders.

Disclosures
Zotz: CSL Behring: Research Funding. Off Label Use: DDAVP is a widely used drug for increasing coagulation factor VIII and von Willebrand Factor activities.