bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytarabine Either with Induction or Conditioning May Improve Outcomes Among Those Undergoing Autologous Transplantation in First or Second Remission for Mantle Cell Lymphoma
Authors: Shah Bijal D. , Little Bryan J , Cultrera Jennifer , Bello Celeste M. , Sokol Lubomir , Sotomayor Eduardo M. , Tomblyn Marcie , Ayala Ernesto 
Published: October 2019

Abstract
Abstract 4546

Introduction:
Consolidation with autologous transplantation (AutoSCT) may extend progression free survival when administered following initial induction. Published data suggest intensive cytarabine containing induction may improve outcome when administered prior to autologous transplantation.

Methods:
We retrospectively evaluated all patients with MCL transplanted at our institution before 2010. We identified 57 patients, among whom 52 were transplanted in first or second remission.

Results:
21 patients had received a cytarabine containing induction (most commonly R-HyperCVAD), among whom 14 also received cytarabine as a component of conditioning (BEAM+/−R). The most common induction in the remaining patients was R-CHOP. Among the 31 who did not receive a cytarabine based induction, 23 received cytarabine as a component of the pre-transplant conditioning regimen (BEAM+/−R).
The median PFS for those getting cytarbine with induction and conditioning was approximately 28 months (at which time 51% of patients continued without progression). The median PFS for those getting cytarabine with conditioning only was approximately 38 months (at which time 47% continued without progression). Logrank analysis shows no statistically significant difference between these groups (p one-sided = 0.29). Alternatively, those who did not receive any cytarabine had a median PFS of 20 months, with no survival beyond 33 months. Logrank analysis shows this to be inferior to those receiving cytarabine with induction/conditioning (p one-sided = 0.049), as well as among those who received cytarabine with conditioning only (p one-sided = 0.001).

Conclusions:
In the absence of randomized comparisons it is difficult to draw firm conclusions on the role of induction. These analyses would suggest that among those with chemosensitive disease able to proceed to transplant, more modern conditioning with cytarabine containing regimens may make up for lack of exposure to this agent during induction.

Disclosures:
Sokol: Celgene: Honoraria, Speakers Bureau.
An Observation On Clinical Outcomes of HLA-Haplotype Hematopoietic Stem Cell Transplantation with High-Dose and Post-Transplantation Cyclophosphamide for Children Malignancies Hematopathy
Authors: Li Chunfu , He Yuelin , Wu Xuedong , Peng Zhiyong , Feng Xiaoqin , Liu Qifa 
Published: October 2019

Abstract
Abstract 4547
We retrospectively analyzed early clinical outcomes of HLA-haploidentical HSCT with high-dose post-transplantation cyclophosphamide (Cy). Between June 2009 and June 2012, 20 patients with high-risk acute lymphoblastic leukemias (ALL, n = 10, CR1=5, CR>1=2, NR=3), acute myeloid leukemia (AML, n=7, CR1=3, CR>1=1£¬NR=3), chronic myeloid leukemia (CML) (n=1, CR), and lymphoma (n=2, CR) received HLA-haploidentical HSCT. All patients were HLA-mismatched equal to and more than HLA (at antigen level). All patients received conditioning therapy consisted of Busulfan, Cytarabine, Cy, VP-16 (or CCNU, or TT), and/or TBI. GVHD prophylaxis consisted of Cy 50mg/kg (for first 10 cases) or 40mg/kg (for second10 cases) on day 3 and 4, FK506 and MMF. The median follow-up time was 507 days. Donor chimerism was ¡Ý80% on day +60 but there were one patient with bone marrow failure (BMF) and two without platelet engraftment after day 60. The median time to neutrophil and platelet engraftment were 23 days and 25 days respectively, and no significant deference was found out between first 10 cases and second 10 cases. No II-IV acute GVHD was observed. However, the cumulative incidences of grade I and above GVHD were 60% (garde 1–2 acute GVHD was 40%; garde 3–4 acute GVHD was 15%), and chronic GVHD was 20% after DLI because of relapse. The cumulative incidences of relapse and non-relapse mortality (NRM) were 30% and 40% respectively. Cytopenia occurred in most patients within 6 months after transplant. Three-year overall survival and event-free survival are 35% and 30% respectively. Thirteen patients have died. The causes of death included relapse (n=5), infection (n=3), cGVHD (n=1), BMF (n=1), hemorrhagic cystitis (n=1).

Conclusions:
HLA-haploidentical HSCT with high-dose, post-transplantation Cy for malignancies hematopathy is selection of treatment, with less aGVHD or cGVHD, but also with high relapse and NRM.

Disclosures:
No relevant conflicts of interest to declare.
Tyro3, Axl Ve Mer (TAM) Receptors On Surfaces of Mononuclear Cells in Patients with B-Cell Chronic Lymphocytic Leukemia
Authors: Guney Dilvin , Tulunay Aysin , Pepedil Funda , Kaygusuz Isik , Adiguzel Cafer , Tuglular Tülin , Demir Muzaffer , Eksioglu-Demiralp Emel , Uras Fikriye 
Published: October 2019

Abstract
Abstract 4588

Background:
Tyro 3 (Sky), Axl, and Mer receptors are members of the family of tyrosine kinases and Gas6 is their ligand molecule. In some types of cancer, upregulation of Axl/Gas6 indicated a worse prognosis, but an opposite situation was observed in renal “cell” carcinoma. This contradiction may suggest that Axl/Gas6 pathway varies depending on the type of cancer. The objective of this study is to investigate TAM receptors on surfaces of mononuclear cells in patients with B-Cell chronic lymphocytic leukemia (B-Cell-CLL).

Material & Methods:
B-Cell-CLL patients (grade 0–1, according to the classification of RAI), who were not on a drug treatment, were recruited in this study (n= 20; 9 female, 11 male). Their ages were 44 to 74 (mean: 63), and the control group consisted of 13 healthy volunteers (5 female, 8 male), whose age range is 20–89 (mean: 36). Mononuclear cells were isolated by density gradient centrifugation, and then surface TAM receptors were detected by flow cytometry. Mononuclear cell were stained with the primary antibodies against Tyro3, Axl and Mer.

Results:
The percentage of the surface TAM receptors on mononuclear cells from the patient group (25–75% interquartile range): Tyro 3= 25.50 (4.2– 45.62); Axl= 17/55 (5.57– 36.32), and Mer= 19.90 (1.92– 37.55). In the control group the following values were obtained: Tyro 3= 2.60 (1.35–3.25); Axl= 0.9 (0.4–2.6), and Mer= 2.50 (0.35–3.65). The percentage of three of them was significantly higher in the B-Cell-CLL group than those in the control group (P<0.01).

Conclusion:
In conclusion, this preliminary study showed that TAM receptors on surfaces of mononuclear cells are higher in patients with B-Cell-CLL patients than the control group. Gas6/TAM signaling may play a potential role in the pathogenesis of B Cell-CLL. Further studies are required to elucidate the actual role of Gas6/TAM signaling in B-Cell-CLL. Gas6/TAM signaling might be a new strategic goal for the treatment of B-Cell-CLL.

Disclosures:
No relevant conflicts of interest to declare.
GM-CSF and IL-4 Derived Fusion Cytokine Reprograms Leukemic B-Cells to Anti-CLL Effectors
Authors: Deng Jiusheng , Pennati Andrea , Li Pingxin , Yuan Shala , Murphy Jordan , Ng Spencer , Sinha Rajni , Flowers Christopher R. , Galipeau Jacques 
Published: October 2019

Abstract
Abstract 4606
Fusion cytokines derived from GM-CSF and common γ-chain interleukins have potent gain-of-function properties to alter host immune response. Considering leukemic B cells from chronic lymphocytic leukemia (CLL) patients broadly express the IL-4 receptor, we generated a human GM-CSF and IL-4 derived fusokine GIFT4 to test its immune function on CLL-B cells. Unexpectedly, GIFT4 protein reprograms leukemic B cells into anti-CLL effectors with T-helper features. We show that GIFT4 recombinant protein led to IL4R-dependent hyper-phosphorylation of STAT5 in primary human CLL cells. GIFT4 treated CLL B-cells also up-regulated the expression of co-stimulatory molecules CD40, CD80 and CD86. These cells also secreted IL-1b, IL-6, ICAM1 and substantial IL-2. GIFT4-CLL B cells further propelled the expansion of IFN-g-producing CD314+ autologous cytotoxic NK and T cells in vitro. Administration of GIFT4 protein in NSG immune deficient mice decreased the survival of primary CLL cells from patients in murine circulation. Altogether, our data demonstrate that GIFT4 has potent anti-CLL immune function by reprograming leukemic B cells into anti-CLL helper cells. We propose that the newly bio-engineered fusokine GIFT4 could serve as a potential immunotherapeutic for CLL treatment.

Disclosures:
Flowers: Genentech: Membership on an entity's Board of Directors or advisory committees.
First-Line Prescribing Preferences of American Hematology-Oncology Physicians for Patients with CLL: Impact of Age, Co-Morbidities, and Tempo of Disease
Authors: Green Mark R. , Williams Michael E. , Willey Joanne , Scharf Mitchell , Neely Douglas , Heckman Michael G. , Foran James M. 
Published: October 2019

Abstract
Abstract 4608

Background:
FCR has been a preferred 1st line therapy approach in CLL for the past decade. However it is associated with substantial toxicity and not recommended in NCCN guidelines for patients over age 70. We studied the impact of age, co-morbidities, and tempo of disease on 1st line therapy prescribing preferences of American hematology-oncology physicians (AHOP) for patients with CLL.

Methods:
During Feb-March 2012, prescribing preferences of 325 individual AHOP were assessed using a proprietary, live, case-based market research tool (Challenging Cases™). A core case scenario was constructed with variations based on altered age, co-morbidities, and tempo of disease progression prior to initial therapy. Preference data were acquired using blinded audience response technology. Responses for each scenario were obtained prior to any display of participant selections. All sources of research support were blinded. Core scenario: 67y male; CD 38+, ZAP 70+, del 13q and del 11q CLL, adenopathy, lymphocytosis, splenomegaly, anemia (Hgb 9.5 gm) but no thrombocytopenia. Co-morbidities: medication-controlled hypertension, moderate restrictive airways disease, and type 2 diabetes managed with metformin. Modified scenario: same clinical presentation except the patient is 72 years of age. Slower tempo of disease scenario: age 68y, time frame of observation without treatment 3 years from diagnosis, now with disease progression, anemia 10.9 gms, FISH only del 13q.

Results:
A progressive decrease in preference for FCR and commensurate rise in preference for BR as first line therapy occurs as age increases and co-morbidities are present (p<0.001). See table 1

Conclusion:
As age crosses the 70 year threshold and as co-morbidities complicate therapy, there is a statistically significant increase in preference among AHOPs for prescribing bendamustine-rituximab as initial management for patients with RAI stage III CLL.

Disclosures:
Green: Xcenda: Employment; Teva: Consultancy, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors Other. Williams:Xcenda: Honoraria. Willey:Xcenda: Employment. Scharf:Xcenda: Employment. Neely:xcenda: Employment. Foran:Xcenda: Honoraria.
Autophagy Regulation and Dysfunction in Bone Marrow Malignancies
Authors: Pericole Fernando V , Lazarini Mariana , Duarte Adriana S. S. , Machado-Neto João , Olalla Saad Sara T. 
Published: October 2019

Abstract
Abstract 4623

Introduction:
Autophagy is a catabolic pathway by which cytoplasmic materials are degraded into the lysosome and it is also a quality control system for proteins and organelles. Autophagy plays an important role in cell adaptation to starvation, hypoxia, cell survival and cancer. Its core molecular machinery is tightly linked to metabolic pathways, such as LKB1/AMPK and mTORC1. Autophagy has been shown to play several important roles in cancer. Indeed, multiple autophagy genes have been characterized as tumor suppressor genes. In hematopoietic system, autophagy is required during myeloid and lymphoid differentiation, terminal erythroid mitochondrial clearance, production of proplatelets and also differentiation of monocytes into macrophages. Interestingly, autophagy seems disturbed in most bone marrow malignancies. Evidence in mice suggests that autophagy suppression (ATG7 or ATG5 knockdown models) in hematopoietic stem cells may be implicated in Acute Myeloid Leukemia (AML) pathogenesis. In Multiple Myeloma (MM), in vitro studies using cell lines showed autophagy activation and lysosome inhibitors (such as chloroquine) are currently been used in various combination treatments in clinical trials.

Aim:
The aim was to characterize the expression of autophagy machinery key genes (BECN1, MAP1LC3A, SQSTM1), as well as hypoxia master regulator (HIF1A) in total bone marrow cells from bone marrow malignancies: myelodysplasia (MDS), MM and AML patients, excluding acute promyelocytic leukemia.

Methods:
BECN1, MAP1LC3A, SQSTM1 and HIF1A levels were verified, by q-PCR, in diagnostic (or without any treatment) BM aspirates from 22 normal donors, 30 MDS (17 low-risk and 13 high-risk, according 2008 WHO classification), 43 AML and 11 MM patients.

Results:
BECN1 gene expression was increased in MM, compared with control group. All other groups did not differ from the control group. Comparing diseases amongst each other, AML had a lower BECN1 expression, compared with low-risk MDS and with MM (Figure 1A).

Disclosures:
No relevant conflicts of interest to declare.
A Novel Hybrid CFH/CFHR1–3 Gene in Atypical Hemolytic Uremic Syndrome
Authors: Hepgur Mehmet F. , Chaudhary Preeti , Sarkissian Sarmen , Smith Richard J. H. , Liebman Howard , Weitz Ilene C 
Published: October 2019

Abstract
Abstract 4644

Background:
Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia (MAHA), thrombocytopenia and renal failure in the absence of Shiga toxin exposure. Dysregulation of the alternative pathway by mutations in complement regulatory proteins or antibodies to these proteins have been implicated in the pathogenesis of the disorder.

Aims:
We report the late onset of aHUS in association with heterozygous deletion of two genes, CFHR1 and CFHR3, and a mutation in CFH, c.497G>T, p.Arg166Leu. The latter mutation has not previously been reported with aHUS.

Methods:
A 20-year-old female whose past history was unremarkable with the exception of a spontaneous abortion 3 months earlier, presented to an emergency room with abdominal pain and bloody diarrhea three days after eating raw fish. Within 4 days of hospitalization she developed MAHA, thrombocytopenia and renal failure. Studies were negative for Shiga toxin and showed an ADAMTS13 level of 40%. A diagnosis of aHUS was made. Treatment was initiated with daily plasma exchange (PE) which was increased to twice daily for 6 weeks. Response was poor. After discontinuing PE, the patient was treated on an IRB-approved compassionate-use protocol with eculizumab 900 mg weekly for four weeks followed by 1200 mg every two weeks.

Results:
The patient responded slowly to eculizumab. PK values of eculizumab were sub-therapeutic at week 4. On week 5, she was switched to the maintenance dose of 1200 mg every two weeks, which resulted in a rapid normalization of her platelet count and LDH, with further improvement of her renal function and normalization of her mental status. The patient is doing well on continued eculizumab treatment. Genetic testing revealed a known copy-number variation (CNV), hemizygosity for CFHR1 and CFHR3, and a mutation in short consensus repeat (SCR) 3 of CFH, p.Arg166Leu.

Summary/Conclusions:
This patient presented with aHUS unresponsive to PE, but responsive to eculizumab treatment. Genetic testing of complement regulatory genes identified a known CNV and a mutation in CFH, p.Arg166Leu. This mutation lies in SCR3 of CFH, a region of the protein important for fluid-phase regulation of the C3 convertase. Although it has been seen in a rare case of dense deposit disease, it has not has not been reported with aHUS. This patient's poor response to PE suggests that additional genetic factors may be present in this patient that affected the course of disorder. Her slow response to eculizumab may have been due to third spacing of the drug secondary to hypoalbuminemia with anasarca as documented sub-therapeutic levels were present on week 4. When the dose was increased to 1200 mg every two weeks, the patient rapidly improved with resolution of the aHUS.

Disclosures:
No relevant conflicts of interest to declare.
Switching From Romiplostim to Eltrombopag or Vice Versa for Immune Thrombocytopenia: Efficacy and Safety in 46 Patients
Authors: Khellaf Mehdi , Viallard Jean-François , Hamidou Mohamed , Cheze Stephane , Lefrere Francois , Fain Olivier , Audia Sylvain , Jardin Fabrice , Gyan Emmanuel , Durand jean Marc , Haioun Corinne , Bierling Philippe , Michel Marc , Godeau Bertrand 
Published: October 2019

Abstract
Abstract 4651
Romiplostim and eltrombopag, the first thrombopoietic receptor-agonists (TPO-RAs) with demonstrated efficacy against immune thrombocytopenia (ITP) in prospective controlled studies, were recently authorized in Europe for adults with chronic ITP. Their efficacies and safety profiles were evaluated in 46 ITP patients who sequentially received both drugs. Thirty-five patients first received romiplostim (romiplostim group), whereas eltrombopag (eltrombopag group) was the first TPO-RA for 11 patients. All but 2 patients had previously received corticosteroids and IVIg, and 70% had been given rituximab without responding. The splenectomy rate was 50% (23/46). Patients were switching from one to the other for the following reasons: lack of efficacy for half of them, platelet-count fluctuations for 11, side effects for 4 and 8 patients' preferences. For 50% to 80% of the patients, switching from 1 TPO-RA to the other effectively impacted the platelet count, with the disappearance of its fluctuations in 54%, and side effects resolved in 100%. In 80% of the patients, the 2 TPO-RAs achieved similar response patterns. Our results confirmed that switching from 1 TPO-RA to the other could be beneficial in clinical practice for patients with severe chronic ITP who failed to respond or experienced adverse events(s) to the first.

Disclosures:
Khellaf: AMgen: Honoraria; Glaxo Smith Kline: Honoraria. Viallard:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells
Authors: Xia Chang-Qing , Chernatynskaya Anna , Wasserfall Clive , Looney Benjamin , Wan Suigui , Clare-Salzler Michael , Atkinson Mark 
Published: October 2019

Abstract
Abstract 4670
Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders.

Disclosures:
No relevant conflicts of interest to declare.
Does Vitamin D Deficiency Play a Role in Sickle Cell Nephropathy?
Authors: Hamideh Dima A , Raj Vimal , Zilleruelo Gaston , Alvarez Ofelia A. 
Published: October 2019

Abstract
Abstract 4755

Background:
Although improvements in the management of sickle cell disease (SCD) have increased patient survival into adulthood, morbidity and mortality from end-organ damage remain major concerns. One of the most serious complications of SCD is renal failure, affecting about 20% of patients. Secondary prevention of the progression of SCD nephropathy is hindered by a lack of easily modifiable risk factors. Based on animal and observational human studies, vitamin D deficiency is potentially a novel, modifiable risk factor that may interrupt or delay the progression of kidney disease by suppressing renin gene expression and inflammation. Studies have reported varying prevalence rates of vitamin D deficiency in patients with SCD patients but their clinical significance is uncertain. The purpose of this exploratory study was to determine the association of vitamin D insufficiency with albuminuria among a cohort of patients with SCD.

Methods:
This cross-sectional study was performed using a cohort of patients with SCD. Serum creatinine, serum cystatin C, spot urine for albumin/creatinine ratio, 25-hydroxyvitamin D [25(OH) D] levels, measures of hemolysis, inflammation and other laboratory studies were obtained. Vitamin D insufficiency was defined as 25(OH) D levels ?30 ng/ml.

Results:
27 patients with SS disease were evaluated. The mean age was 18 +/− 4.9 years; 40% were males and 60 % females. Mean GFR by serum creatinine was 167 +/− 40 ml/min/1.73 m2 and by cystatin C was 150 +/− 29.4 ml/min/1.73 m2. Increased protein/creatinine ratio (ratio ? 0.2) occurred in 29 % of patients (n= 9). Increased albumin/creatinine ratio (ACR ?30 mg/g of creatinine, mean 216 mg/g of creatinine) occurred in 37% of patients (n= 10). 88% of subjects showed vitamin D insufficiency [n=24, mean 17+/− 7 ng/ml]. Mean 25 OH vitamin D level was 14.8 +/− 8.9 ng/ml (5–28) and 18.2 +/− 5 ng/ml (12–30) in subjects with and without albuminuria, respectively. Urinary ACR inversely correlated with 25(OH) D levels (r=-.4, P=.02). No correlations were observed between urinary ACR and other clinical or laboratory parameters (age, hemoglobin levels, percentage of reticulocytes and lactate dehydrogenase levels). Proteinuria correlated with age (r=-.4, P=.02) and reticulocyte counts (r=-.4, P=.02) in SS disease but not with other parameters.

Conclusion:
In conclusion, vitamin D insufficiency was common and significantly associated with albuminuria among patients with SCD. Additional studies are needed to clarify the causal relationship of vitamin D insufficiency with albuminuria and to determine the role of vitamin D supplementation to attenuate the development of SCD nephropathy.

Disclosures:
No relevant conflicts of interest to declare.