bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute GVHD in AML and MDS Patients Receiving Matched Related Donor (MRD) Reduced-Intensity Conditioning Allogeneic Hematopoietic Progenitor Cell Transplant (RIC-AHPCT) Correlates with Major Histocompatibility Complex Class I-Related Molecule A (MICA) Gene Polymorphisms,
Authors: Sobecks Ronald , Zhang Aiwen , Rybicki Lisa , Thomas Dawn , Kawczak Paul , Kalaycio Matt , Andresen Steven , Pohlman Brad , Dean Robert , Copelan Edward A. , Hanna Rabi , Duong Hien , Maciejewski Jaroslaw P. , Bolwell Brian J. , Askar Medhat 
Published: October 2019

Abstract
Abstract 4072
Donor immune effector cells including T and NK cells have been implicated in the development of GVHD after AHPCT. MICA is a ligand recognized by the activating receptor NKG2D that is expressed on the surface of NK, NKT, CD8+ and TCRγδ+ T cells. Allelic variants of MICA due to a single amino acid substitution at position 129 in the alpha2 domain have been reported to result in large differences in NKG2D binding. MICA alleles with a methionine (M) or valine (V) have been classified as having strong or weak binding affinity for NKG2D, respectively. It has been suggested that these variable affinities affect thresholds of NK cell triggering and T cell modulation. Homozygosity of V alleles (VV) has been associated with chronic GVHD (Boukouaci et al. Blood 2009;114:5216–5224). However, the effect of such polymorphisms on outcomes after RIC-AHPCT is not clear. We studied 31 patients (20 AML and 11 MDS) who had MRD RIC-AHPCT with fludarabine/low-dose TBI conditioning. All patients received peripheral blood stem cells and GVHD prophylaxis consisted of a calcineurin inhibitor and mycophenolate. Genotyping was performed retrospectively on patients' DNA samples by rSSOP to determine MICA 129 dimorphisms and they were then categorized as having VV (n=12), MV (n=17) or MM (n=2) dimorphisms. Post-transplant outcomes were compared between patients with VV (weak) vs. VM/MM (mixed/strong binding affinities). Outcomes were estimated using the cumulative incidence method and compared between groups with the Pepe-Mori test. Patients in the VV group had significantly less grade 3–4 acute GVHD (0 vs. 26%, respectively, p=0.022) and a trend to less chronic GVHD (8 vs. 37%, respectively, p=0.07) than the VM/MM group (see Figures).
There were no differences between these groups regarding pre-transplant patient characteristics, CD34+/TNC doses, neutrophil or platelet engraftment, CMV/other infections, relapse, relapse mortality, non-relapse mortality, relapse-free or overall survival. We conclude that assessment of MICA gene polymorphisms in MRD RIC-AHPCT patients may have important implications for predicting GVHD. Those with a MICA dimorphism indicating weak binding affinity (VV) for the NKG2D activating receptor may have less alloreactive recipient immune effector cells that decrease the risk of developing GVHD. Further investigation of this observation with larger study populations is warranted.

Disclosures:
No relevant conflicts of interest to declare.
NADPH Oxidase Regulates Cytarabine-Induced Apoptotic Death in Acute Myeloid Leukemia Cells
Authors: Khan Nazmul H , Sexton Kevin J , Grimm Melissa J , Segal Brahm H , Vigil Carlos E 
Published: October 2019

Abstract
Abstract 4258

Background:
Cellular metabolism and oxidative stress are important in the biology and pathophysiology of malignancies. Both increased reactive oxygen species [ROS] levels and induction of anti-oxidative pathways have been described in several malignancies, and may be modulate tumor biology and susceptibility to chemotherapy. Limited studies point to metabolic pathways, including ROS production, influencing pathogenesis and chemo-sensitivity of leukemia. NADPH oxidase is a critical enzyme in antimicrobial host defense and its activation results in ROS generation in myeloid leukemia cells. Our prior studies show that NADPH oxidase can activate Nrf2, a transcriptional factor that induces anti-oxidant and cytoprotective pathways. However the role of NADPH oxidase in chemotherapy-mediated apoptosis induction in leukemic cells is not well-known.

Hypothesis:
NADPH oxidase-derived ROS will increase sensitivity of AML cells to chemotherapy, whereas Nrf2 will be associated with chemotherapy resistance

Methods:
We evaluated the role of NADPH oxidase and Nrf2 in regulating cytarabine-induced cell death in wild-type [WT] and engineered PLB-985 cells, a human acute myelomonocytic leukemia cell line derivative. NADPH oxidase-deficient PLB-985 cells were generated by recombination with mutant gp91phox, a necessary component of NADPH oxidase. Nrf2-deficient cells were generated by shRNA (Nrf2shRNA) and depletion (>70%) of Nrf2 mRNA was confirmed by quantitative-PCR. WT and engineered PLB-985 cells were treated with cytarabine (12.5 to 750ng/ml for 24 – 48 hours) and cell death was determined by trypan blue exclusion and Annexin V/7-AAD staining.

Results:
NADPH oxidase-deficient PLB-985 cells were significantly more resistant to cytarabine compared to WT cells. Cytarabine (500 ng/ml for 48h) induced apoptotic cell death in 25% of NADPH oxidase-deficient vs. 53% of WT PLB-985 cells. Additional dose-response studies confirmed a significant effect of NADPH oxidase in potentiating cytarabine-induced cell death. Nrf2shRNA PLB-985 cells had either similar or modestly increased susceptibility to cytarabine-induced cell death compared to WT PLB-985 cells with empty vectors. NADPH-deficient/Nrf2shRNA PLB-985 cells had similar susceptibility to cytarabine as NADPH-deficient cells with empty vector.

Conclusions:
Our results show that NADPH oxidase potentiates apoptotic cell death by cytarabine in a myelomonocytic leukemia cell line. However, we did not observe a consistent effect of Nrf2 depletion on apoptotic cell death by cytarabine. These studies suggest that modulation of redox-stress may be a potential therapeutic approach in AML that merits further study.

Disclosures:
No relevant conflicts of interest to declare.
An Evaluation of Septicemia During Outpatient Consolidation Chemotherapy for Acute Myeloid Leukemia
Authors: Saini Lalit , Minden Mark D. , Schuh Andre , Yee Karen , Schimmer Aaron D , Gupta Vikas , Murray Cindy Susan , Brandwein Joseph 
Published: October 2019

Abstract
Abstract 4268

Introduction:
Ambulatory chemotherapy for acute myeloid leukemia (AML) is believed to reduce exposure to nosocomial multi-drug resistant organisms and the incidence of septicemia.

Materials and Methods:
In this retrospective analysis we assessed the frequency of septicemia in patients receiving consolidation therapy: 256 patients received the first consolidation cycle (C1) and 217 the second consolidation cycle (C2). Patients received consolidation as inpatients or on an ambulatory basis. All ambulatory patients received infection prophylaxis with ciprofloxacin, amoxicillin and fluconazole.

Results:
71 cycles of IP and 402 cycles of ambulatory consolidation chemotherapy were administered. Rates of bacteremia were higher in the IP cohort compared to the ambulatory patients (39.4% vs. 26.6%, p=0.028). IP in C1 but not C2 had significantly more septicemia then the ambulatory cohort within that cycle. Relative to C1, C2 was associated with significantly more bacteremia (p=0.03) and more Escherichia coli isolates (p=0.023) but there was no significant difference in the rates of total Gram-positive organisms (79.2% vs. 70.4%, p=0.32), total Gram-negative organisms (20.7% vs. 28.1%, p=0.32) or Streptococcus isolates (17% vs. 23.9%, p=0.34). All Streptococcus isolates in C2 were sensitive to penicillin despite amoxicillin prophylaxis whereas all E. coli strains in C2 were resistant to ciprofloxacin.

Conclusions:
Ambulatory consolidation chemotherapy for AML is associated with a reduced incidence of septicemia. The second consolidation cycle is associated with a higher incidence of bacteremia accounted for by increased rates of ciprofloxacin resistant E. coli and penicillin-sensitive Streptococcus.

Disclosures:
No relevant conflicts of interest to declare.
Individual T-Cell Receptors of γ9δ2T-Cells Mediate Differential Anti-Tumor-reactivity
Authors: Grunder Cordula , te oome Liane CJ , Kuball Jurgen HE 
Published: October 2019

Abstract
Abstract 4312
Immunotherapy with innate immune cells has recently evoked a broad interest as a novel treatment option for cancer patients. γ9δ2T-cells are an emerging innate cell population with strong anti-tumor-reactivity and a promising candidate for immune interventions. However, the molecular basis of recognition remains unclear as well as whether individual γ9δ2 clones have an advantage as compared to the bulk population in terms of anti-tumor-reactivity. Therefore, bulk γ9δ2T-cells were cloned and tested for reactivity against a broad panel of tumor cells. Between different clones a high variability in recognition pattern was observed in terms of specificity and functional avidity. A number of clones were more potent in tumor recognition while others were weaker than the original bulk population. Thus, we intent to elucidate the molecular basis of observed differences among anti-tumor-reactive clones. The contribution of NK-receptors to γδT-cell activation was verified but could not fully explain their reactive abilities. Therefore, we hypothesized that the diversity within the γ9δ2T-cell receptor (TCR) itself contributes to the differential activity of examined γ9δ2T-cell clones. Hence, clone derived γ9δ2TCRs were expressed in Jurkat- and peripheral blood T cells and indeed: individual γ9δ2TCRs mediated a distinct specificity and functional avidity. By exchanging δ-chains among TCR-transduced T-cell clones with constant γ-chain we demonstrate that distinct δ-chains mediate different functional avidity. Sequence alignments revealed that this phenomenon is selectively caused by differences in the δCDR3 region. Accordingly, alanine-scanning-mutations within δCDR3 were performed. Structurally important residues were identified as well as residues involved in regulating functional avidity, suggesting their importance in antigen-recognition.

Disclosures:
No relevant conflicts of interest to declare.
Preclinical Safety Pharmacology of Baxter’s Longer Acting rFVIII (BAX 855)
Authors: Dietrich Barbara , Kubik Susan , Ehrlich Hartmut J. , Scheiflinger Friedrich , Schwarz Hans Peter , Muchitsch Eva-Maria 
Published: October 2019

Abstract
Abstract 4357
Baxter has developed a PEGylated recombinant human factor VIII conjugate by modifying the FVIII molecule with polyethylene glycol (PEGylation). The product is derived from a CHO cell line using a plasma-protein-free method and a virus inactivation step. The objective of this preclinical study-program was to evaluate the safety of Baxter’s longer acting rFVIII in different species. The thrombogenic potential of Baxter’s longer acting rFVIII was evaluated in the rabbit stasis model developed by Wessler. Two lots of Baxter’s longer acting rFVIII were used to demonstrate consistent safety between different batches. Advate served as the control item. Baxter’s longer acting rFVIII was not thrombogenic in this preclinical model at a dose of 900 U/kg. There was no evidence of thrombogenic potential after intravenous treatment with either the test item or Advate, the active reference item. The effects of Baxter’s longer acting rFVIII on body temperature, heart rate, blood pressure, respiratory variables or QT, QTcf, PR and/or QRS intervals and respiratory system (intra-thoracic pressure) was evaluated in eight male, conscious telemetered cynomolgus monkeys. Baxter’s longer acting rFVIII was given at 150 and 600 U/kg/day to male monkeys by intravenous administration. Baxter’s longer acting rFVIII did not cause any adverse clinical, respiratory or cardiovascular effects and was very well tolerated at all dose levels tested. In conclusion, Baxter’s longer acting rFVIII did not cause any thrombocenic events or adverse clinical, respiratory or cardiovascular effects and was very well tolerated at all dose levels.

Disclosures:
Dietrich: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.
Black Cohosh Induced Pancytopenia: Case Report
Authors: El Amil Zeina G , Butera James N 
Published: October 2019

Abstract
Abstract 4383

Introduction:
Black cohosh (known as both Actaea racemosa and Cimicifuga racemosa), a member of the buttercup family is a perrenial plant that is native of North America. It has been widely used to relieve premenstrual problems, menstrual cramps and to control hot flushes and other menopausal symptoms. The mechanism of action of the black cohosh is not fully understood. Here, we report the case of a patient with pancytopenia related to the use of the black cohosh.

Case Report:
A 58 year old female patient with past medical history of dyslipidemia, presented with bruising after several months of taking black cohosh. Her complete blood count revealed a white blood cell count of 3.1×109/L (normal 3.5–11 ×109/l), hemoglobin of 10.6 g/dl (normal 11–15 g/dl), hematocrit of 31 % (normal 32–45%), mean corpuscular volume of 109 fL (normal 80–98 fl), platelets count of 37 000/μL (normal 150000–400000/μL). Her medications included lipitor, black cohosh and vitamin D. Her physical exam was remarkable only for bruising. Serum protein electrophoresis did not show any evidence of a monoclonal spike and a coomb’s test was negative. She had normal immunoglobulins level, haptogloin, LDH, liver function tests, iron studies, vitamin B12 and folate. Her prothrombin and activated partial thromboplastin times were within reference range. Her peripheral smear showed macrocytic red blood cells and decreased platelets. Her bone marrow biopsy and aspirate showed a hypocellular bone marrow (cellularity of 25–30%), with a predominance of erythroid precursors that exhibit shift toward immaturity and mild to moderate megaloblastoid changes, moderately decreased myeloid precursors, slightly decreased megakaryocytes, and normal iron stores, there was no increase in the bone marrow blasts (0.6%). She also had a flow sent for paroxysmal nocturnal hemoglobinuria, which showed normal levels of expression of CD55 and CD59 of the neutrophils and the red cells. Upon presentation, the black cohosh was stopped. Following this, her white count, hemoglobin and platelets improved slowly (figures 1,2,3,) without any further interventions, but it took over 2 years for her counts to normalize.

Conclusion:
Black cohosh is an over the counter herbal medicine that has been widely used by women to control premenstrual symptoms, menstrual cramping and menopausal symptoms. Many side effects have been described in the past but its effect on the bone marrow has never been studied. In our patient, Black cohosh caused pancytopenia that was reversible; however the recovery was very slow.

Disclosures:
No relevant conflicts of interest to declare.
Imatinib (IM) Treatment In Chronic Myeloid Leukemia (CML). Clinical Practice Limitations
Authors: Enrico Alicia Inés , Bendek Georgina , Prates Maria Virginia , Guerrero Virginia , Napal Juan Jose , Riscala Carlos , Lopez Ileana , Milone Santiago , Milone Jorge 
Published: October 2019

Abstract
Abstract 4454

Introduction:
CML represents 15% all of oncohematologic diseases in adults. IM changed the history of the disease. At one year of treatment, the emblematic IRIS study showed Major Cytogenetic Responses (MCyR) of approximately 87% and Complete Cytogenetic Responses (CCyR) of around 76%, with PFS to accelerated phase or blast crisis of 97.7% and 91.5%, respectively.

Objective:
To assess treatment characteristics and responses in a group of patients treated with IM in clinical practice.

Materials and Method:
113 medical records of patients with CML diagnosed between 1998–2011 from two institutions in the Argentine Republic were retrospectively analyzed.

Result:
Mean population age was 46 years old (r 18–73) 65 male, 48 female. 97% in chronic phase, the rest in accelerated phase. 31% presented comorbidities at diagnosis. Cytogenetic abnormalities at diagnosis, in addition to the classic t(9:22), included: trisomy 8 and double Philadelphia chromosome in 4 tests. Only 7 patients had qualitative BCR/ABL determined at diagnosis. 25% had received interferon, patients received IM 400 mg and only 2% received 300 or 600 mg doses. 2.6% of patients did not achieve CHR. Cytogenetic responses assessed at any time of treatment were: Major: 12%, Minor 20%, Complete 51%, None 3%, 14% were not assessed. With a mean follow-up time of 46 months, the overall survival was 75%. 10% of patients progressed to BC/AP, 11 % of patients died due to disease-related causes or comorbidities.

Conclusions:
With a mean follow-up time of 46 months for chronic phase CML, treatment with IM achieved complete cytogenetic responses in 51% of patients, and progression occurred in 10% of patients.

Disclosures:
No relevant conflicts of interest to declare.
Cytogenetic Risk Groups and Minimal Residual Disease Are Strong Prognostic Factors for Post-Transplant Outcome in Patients with Acute Myeloid Leukaemia and Myelodysplastic Syndrome
Authors: Blau Olga , Graul Katja , Sindram Annette , Thiel Eckhard , Blau Igor Wolfgang 
Published: October 2019

Abstract
Abstract 4482
Allogeneic stem cell transplantation (alloSCT) is a curative treatment option for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Relapse after alloSCT is still a major cause for the treatment failure. Molecular genetic (FLT3, NPM1 mutations) and cytogenetic risk-categories have an important impact on the prognosis of patients undergoing alloSCT. However, it has been shown that there is a closely relationship between the level of minimal residual disease (MRD) and relapse after alloSCT in leukemia patients.
We analyzed 140 AML/MDS patients transplanted at our institution. We examined the contribution of cytogenetic aberrations and molecular genetic markers detected prior alloSCT to survival, relapse, and mortality after transplantation. Furthermore, we analyzed MRD status after consolidation therapy and in post-transplant period. We classified molecular genetic/cytogenetic status before alloSCT into 2 groups: low-risk: good and intermediate-risk karyotype, FLT3-wt, NPM1-mutated cases and high-risk: adverse-risk cytogenetic, FLT3-ITD mutated cases. A good risk karyotype was present in 8 patients; an intermediate risk in 56 patients, whereas 76 patients had a poor cytogenetic risk. 51 patients were treated with standard myeloablative conditioning regiments prior to alloSCT, 73 patients received reduced intensity conditioning and 16 non-myeloablative conditioning. 40 patients had a matched-related donor and 100 patients had a matched-unrelated donor. Overall survival (OS) in the group of patients with low cytogenetic risk was 839 days as compared with 613 days in high-risk group. The low risk cohort also showed a lower relapse (33% vs. 51%, p<0,03) and mortality rate (20% vs. 71%, p<0,003). We analyzed MRD status in all patients after consolidation therapy. MRD negative patients are characterized by favorable prognosis as compared with MRD positive patients, OS 87% vs. 53%, p<0,001. We conclude that risk-stratification combining molecular genetics and cytogenetics aberrations at the time of diagnosis with post-consolidation MRD status improve identification of high-risk category of patients. New treatment strategies are needed to overcome poor outcome of high risk AML patients, for instance, immunotherapy options like prophylactic DLI, shorter and modified immunosuppression, specific reduced intensity conditioning or new drugs like tyrosine kinase inhibitors.

Disclosures:
No relevant conflicts of interest to declare.
Sirolimus Combined with Dexamethasone for the Treatment of a Patient with Interferon Resistant Hydroa Vacciniform-Like Lymphoma
Authors: Liu Zhigang , Jia Yongqian , Gong Yuping , Guo Yong , Liu Jiazhuo , Liu Ting 
Published: October 2019

Abstract
Abstract 4992
Hydroa vacciniform-like lymphoma is an unusual pediatric cutaneous T-cell lymphoma, which rarely involved with adults. Chemotherapy and/or radiotherapy had little or no benefit. Patients may have a response to α-interferon. We report here an adult case with interferon resistant hydroa vacciniform-like lymphoma that has been successfully treated with sirolimus, an mTOR pathway inhibitor.
The patient is a thirty-five year old women,she begun with recurrent cutanous rash and small vesicule around her mouth and nose 3 years ago. One year before, the symptoms were exacerbated with obvious vesiculopapular eruption, edematous, blisters, ulcers, scarring and crusts in her face. Scattered vesiculopapular could be seen in her upper chest and extremities accompanied with fever and submandibular lymphadenopathy. Facial skin biopsy showed angiocentric infiltrates from the epidermis to the subjacent dermis. The infiltrate cells showed a cytotoxic T-cell phenotype, with positive TCR gene rearrangement and EBER expression in situ hybridization. EBV serum test showed EBV-IgA and IgG positive, but serum EBV-DNA was negative. Patient was given α-interferon 300 million units, intramuscularlly, two times a week, plus prednisone 30mg per day, orally. Patients' skin lesions were improved, but present recurrent episodes of papulovesicular eruptions. For the past 3 month patient had a recurrent high fever and exacerbated vesiculopapular eruptions and blisters. Laboratory test showed anemia and neutropenia, serum biochemistry and marrow examination confirmed that a lymphoma associated hematophagocytosis was complicated. Sirolimus was started at an initial dose of 1.5mg, orally, every 12 hours, combined with dexamethasone 10mg/day, intravenously. Three days later the fever begun to resolved and the skin lesion gradually subsided. Two weeks later the skin lesions disappeared and the dose of sirolinmus begun to tapered to 1.0mg, orally, every 12 hours, with prednisone 30mg/day, orally. By three month of follow-up the patient still on stable and be observed.

Disclosures:
No relevant conflicts of interest to declare.
MicroRNAs Alterations in Chronic Myelomonocytic Leukemia Are Independent of Loci of Genomic Imbalance As Detected by Oligonucleotide Array CGH (oaCGH)
Authors: Nassiri Mehdi , Czader Magdalena 
Published: October 2019

Abstract
Abstract 5022

Background:
Chronic myelomonocytic leukemia (CMML) remains a heterogeneous group of diseases with variable patient outcomes and no well-defined targeted therapy. We studied microRNA (miRNA) expression profiles and their relation to the diagnostic and clinical parameters in CMML, and compared it their genomic DNA alteration with oligonucleotide array CGH (oaCGH).

Design:
Bone marrow samples from 22 patients with CMML were studied. Seventeen patients presented with CMML-1 and 5 with CMML-2. Nine cases had total WBC count of less than 13×109/L. All cases were negative for BCR-ABL1 translocation. Microarray studies were performed using Agilent human miRNA microarrays (version 1.0) containing probes for 470 human and 64 human viral miRNAs cataloged in the Sanger database v9.1. Selected miRNA were validated using Quantitative real-time PCR using ABI TaqMan microRNA assay. Agilent human oaCGH microarrays (105k) containing probes for more than 99000 sequences were used to study genomic DNA.

Results:
None of the microRNAs that were significantly altered or were associated with predictive power in select CMML subtypes were mapped to loss or gain loci by oaCGH. Although few were mapped close to a specific amplified or deleted region.

Conclusions:
Significantly over- or under-expressed miRNAs are found in subtypes of CMML, that do not correlate with genomic gain and loss regions as detected by high density oaCGH. Our finding might imply that multiple underlying mechanisms at level of DNA/RNA and microRNA are responsible for heterogeneity of CMMLs.

Disclosures:
No relevant conflicts of interest to declare.