bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low Dose of Eltrombopag with Long-Term Response in Children with Severe Aplastic Anemia, Less Morbi-Mortality Better Quality of Life
Authors: Lopez-Santiago Norma C , Paredes Aguilera Rogelio a , Monsivais Orozco Angelica Cecilia , Gonzalez Pedroza Maria De Lourdes , Tavera Rodriguez Gabriela , Toscano Mara 
Published: November 2019

Refractory severe aplastic anemia (RSAA) has poor prognosis. Eltrombopag is a therapeutic option in patients that failed to ATG+CyA; in countries with poor outcomes their use is limited. Described experience with low doses of Eltrombopag 25mg/d.
CASE 1. Female 4 yo diagnosis SAA not responded after 2 cycles ATG, the first one with mesterolone for 6 months, continued pancytopenic with multiple transfusions (every 2/3 weeks) complicated by iron overload, and serious infections; presented CNS infection with secondary spastic paralysis, due chelation therapy development 2 cholestasis outbreak. Eltrombopag was started 25mg/d, after the first month, no more transfusion was needed with increase of neutrophils and platelet counts. After 7 months Eltrombopag for economic reasons was stopped with partial response. Hb >10g/dL, CAN >1000 m3 & platelets 99 X103. For 4 years; until now; she is doing well, no infections and no transfusions needed.
CASE 2. Male 2 yo, SAA not responded ATG course, he was inpatient during 8 months with multiple infections, bleeding complications and consequence transfusion was needed. Iron overload required iron chelation therapy, the medical orders and CyA was irregularly administrated, the parents not accept considered BMT, so Eltrombopag 25mg/d was started, 6 weeks later no more transfusion was required, the bleeding stopped and no mores infections were observed; after 7 months had a partial response Hb > 11g/dL CAN > 1000m3 & platelets 45 x103, and Eltrombopag was stopped.
This two patients use Eltrombopag as compassionate use, with good clinical results, in spite of low dose to get a partial hematological response.
Low dose of Eltrombopag is useful to induce partial response rapidily with an excellent clinical results even when it is discontinued.
Actually all patients with new SAA diagnostic are register in our Institution in a prospective protocol to receive ATG+CyA and start Eltrombopag 50mg/d with increase according to the response.
The low dose could be a good option for patients with refractory aplastic anemia to get a partial response in development countries with less morbidity-mortality and a better quality of life.

Disclosures
No relevant conflicts of interest to declare.
The Magnitude of Lactate Dehydrogenase Elevation As a Predictive Factor for Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma
Authors: Vieira Iolanda , Quintela Miguel , Moreira Cláudia , Chacim Sérgio , Domingues Nelson , Oliveira Isabel , Espirito Santo Ana , Moreira Maria Ilidia , Martins Ângelo , Viterbo Maria Luisa , Pereira Dulcineia , Mariz Jose Mario 
Published: November 2019

Introduction: The incidence of central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is approximately 5%. Although the introduction of rituximab for the treatment of DLBCL has reduced the risk of CNS relapse, the median overall survival of these patients remains only few months, emphasizing the need to accurately identify at-risk patients, screen for CNS disease, and develop effective therapeutic/prophylactic strategies.
Aim: To identify risk factors for CNS relapse in patients with DLBCL.
Methods: Retrospective analysis of patients with DLBCL diagnosed from January 2012 to December 2017 at a Cancer Institute. Patients with exclusive extranodal (EN) disease were excluded. Factors associated with CNS relapse were evaluated using Chi-square, Fisher's Exact Test, Mann-Withney U or T-Test, according to variable types and distributions. Survival was evaluated by Kaplan-Meier method and groups were compared by Log-rank test. Independent predictive factors were identified using Logistic Regression. A p value < 0.05 was considered statistically significant.
Results: Four hundred and seventy-nine patients were identified, 122 were excluded due to exclusive EN disease, and 357 patients were included in the study. With a median follow-up of 33 months, there were 10 (3%) CNS relapses. According to International Prognostic Index (IPI) factors in addition to involvement of kidneys and/or adrenal glands (CNS-IPI), 5 (50%) of these patients were classified as high risk, 4 (40%) intermediate risk and 1 (10%) low risk. Patients who development CNS involvement were significantly younger (57 vs. 65 years, p=0.036), presented higher levels of lactate dehydrogenase (LDH) (median 738 vs. 282 U/L, p<0.001) and lower levels of hemoglobin (median 10,3 vs. 12,1 g/dL, p=0.010) at diagnosis. No differences were found regarding to performance status, stage or number of EN areas. Two patients (18%) in the CNS relapse group had done CNS prophylaxis versus twenty two (6,3%) patients in the group without CNS relapse. In multivariate analysis, LDH >600 was the only independent predictive factor (HR 15.3, CI 95% 3.5 - 65.8, p<0.001). Overall survival in CNS relapse group was 22 months, versus not reached (p<0.001).
Conclusion: Although CNS-IPI is a robust model to estimate the risk of CNS relapse, it does not capture the full spectrum of those at high risk. Other clinical risk factors and biomarkers beyond this model might play an important role in this setting, such as the magnitude of LDH elevation

Disclosures
No relevant conflicts of interest to declare.
Managing Sickle Cell Disease Patients with Acute Pain Crisis in the Most Appropriate Setting
Authors: Gowhari Michel , Hughes-Dillard Tiesa , Ryan Catherine , Johnson Alexia 
Published: November 2019

Introduction: Pain is the top concern of individuals with sickle cell disease (SCD). Acute painful vaso-occlusive episodes in SCD are the leading cause of emergency department (ED) encounters and frequent hospital admissions. Well-documented disparities include significant delay and under treatment of SCD patients with acute pain crisis in the ED. An acute care observation unit (ACOU) staffed with SCD specialists can help to address these disparities. SCD patients treated in a dedicated ACOU have a 40% lower admission rate than patients treated in the ED. An expedited transfer and treatment program at our dedicated sickle ACOU at the University of Illinois Hospital (UIH) was implemented with the goal of improving overall care and decreasing the hospital admission rate for SCD patients.
Method: This is an outcome study of individuals with SCD >16 years of age who presented with an acute painful episode to UIH. A quality improvement project used the Plan-Do-Study-Act translation method. The following key areas were identified for intervention: 1) established criteria for direct ACOU admission, 2) expedited transfer to the ACOU from the ED, 3) addition of a third provider to expand hours, and 4) establishing a consistent but individualized pain treatment plan across the ED and ACOU. The number of admissions to hospital of patients with SCD was examined from September 2018 through August 2019. Applying the Donabedian triad of Structure, Process, and Outcomes, we demonstrated improved outcome and decrease hospitalization.
Results: There were 877 admissions to the ACOU from January to July of 2019, which is an increase of 37% compared to the same period in 2018. Of the 877 admissions, 793 were discharged home (90.4%) as compared to 88.6 % in 2018. The average time to first dose of opioids in the ACOU in 2019 was 55 minutes with and average decrease in the pain score of 2.62 during an average length of stay of 4:18 hours.
Conclusions: Expedited care and treatment with a focus on improving quality and improving access resulted in increased volume of patients treated and decreased rate of admission to the hospital. Allocating resources to a dedicated sickle acute care observation unit can significantly decrease inpatient hospitalizations.
Table.

Disclosures
No relevant conflicts of interest to declare.
Pretreatment Risk Factors Is a Strong Predictor of Outcome in Pediatric Hodgkin Lymphoma
Authors: Khedr Reham , Rashad Hanaa , Hamoda Asmaa Mohammed , Elwakeel Madeha , Khorshed Eman , Saad Mohamed , Mohamed Engy , Moussa Emad 
Published: November 2019

Background: During the last decades, the prognosis of Hodgkin lymphoma (HL) has been improved significantly with the introduction of effective chemotherapy and the implementation of risk-adapted treatment approaches. Identification of reliable risk factors is crucial to guide treatment throughout the disease. Objectives: We aimed to identify independent predictors of event-free survival (EFS) in pediatric/ adolescent HL using clinical data known at diagnosis and treated with the ABVD regimen at our hospital. Design/Method: This is a retrospective study done at Children's cancer hospital Egypt from July 2007 to December 2017. ALL Patients with Classical HL were enrolled in the analysis. The chemotherapy backbone was ABVD +/- RTH. Data analysis included all pretreatment Demographics, clinicopathological characteristics, and Laboratory findings. PET scan was performed at baseline and after two cycles of chemotherapy. Treatment was not changed according to the results of the interim scan. Results: A total of 737 patients were eligible for analysis.The Five-years OS 94.9% and the EFS 87.8% in these patients. Pretreatment Significant univariate predictive factors for the EFS were: Age<9.5 (HR 0.421; p = 0.002),, ESR (HR 0.421; p = 0.002), Hemoglobin <10.5 (HR 1.373; p = 0.014), TLC >11,000 (HR 0.368; p = 0.000), Stage IV( p = 0.000) and treatment groups (HR 0.180; p = 0.000). Although the pathological subtypes has a diverse EFS;NS: 86.6% MS: 92.9% Lymphocyte rich: 87.5% and Lymphocyte depleted: 41.7%, Histology has shown to be a powerful independent predictor of outcome ( p = 0.000).In the multiple regression model, NS Histology and stage remained strong predictive factors with a p-value of 0.011and 0.026 respectively, In addition to the significance of the Albumin level (HR 0.047, p= 0.011). The interim PET, as well as RTH, were highly significant on both univariate (p= 0.000 and 0.0002 respectively) as well as multivariate analysis (p= 0.001and 0.000 respectively). Conclusion: Age; stage IV disease; white blood cell count, and hemoglobin level are independent predictors of survival that can significantly impact survival. Optimizing initial therapy may improve overall EFS for these patients. Although CHL pathology is a significant independent predictor of EFS, its subtypes have different EFS and OS, which should be translated into changes in the treatment approach.

Disclosures
No relevant conflicts of interest to declare.
The Efficacy and Safety of Decitabine in Combination with ATRA, G-CSF and Low Dose Cytarabine(Dlaag Regimen)in Relapsed/Refractory Acute Myeloid Leukemia Not Suitable for Strong Chemotherapy : A Phase 2, Prospective, Single-Arm, Multicenter Study
Authors: Yang Li , Liu Ligen , Zhao Limin , Lu Yingting , Zhang Jing , Sun Lihua 
Published: November 2019

Background.
Patients with relapsed or refractory acute myeloid leukemia (R/R AML)who are intolerant of strong regimen chemotherapy have poor responsibility to chemotherapy and clinic remission is lower. The DNMT is depleted to reactivate the silencing tumor suppressor gene to exert anti-tumor effects. Vitro experiments confirmed that ATRA has an anti-leukemia effect on non-M3-AML cell lines. We perform the 2 phase, single-arm, multicenter study of Decitabine in Combination with ATRA, G-CSF and low dose cytarabine(DLAAG Regimen)in R/R AML not suitable for strong chemotherapy (NCT03356080).
Methods.
R/R AML patients aged more than 18 years not suitable for strong chemotherapy were eligible to enroll on this study. The objective was to assess the responses and safety of this therapy. All patients received subcutaneous decitabine injection 0.1-0.2mg/kg on days 1-3 ,8-10,15-17 .ATRA was taken orally at 45mg/m2 on day 4-6 and 15mg/m2on days 7-20. Subcutaneous injection cytarabine 15mg/m2 every 12 hours on days 1-10 and G-CSF 300ug/d on day 0 until disease remission or absolute neutrophils count ≥ 0.5×109/L were administered. The FLT3 inhibitor, arsenious acid, and the JAK-2 inhibitor, rotectinib, were allowed to be combined.All patients received one or two courses of induction treatments.
Results.
During the period from December 1, 2017 to July 2019, a total of 33 patients were recruited, including 17 women and 16 men. The median age is 64 years (range 46-82). In 33 patients, the overall response rate (ORR = CR + PR) was 36.3%, and the complete response rate (CRR = CR + CRi) was 33.3%. The early treatment-related mortality rate was 6.0%. One died of infection and one died of organ bleeding. Of the 26 patients with karyotype data, 11 received CR. Seven patients (63.6%) in CR showed normal karyotype, 2 patients (18.1%) in CR, and 1 patient (9.0%) in PR showed other moderate karyotypes. One case (9.0%) of the CR group had a poor karyotype. Statistical analysis showed that there was a statistically significant difference between the different karyotype groups (P < 0.05). Only 2 of the 10 FLT3 mutant patients achieved CR (20%). Two patients with abnormal MLL gene did not receive CR.
Conclusions
DLAAG regimen is effective and tolerated in patients with R/R AML who are not suitable for intensive therapy and could be as a bridging therapy regimen followed by HSCT.

Disclosures
No relevant conflicts of interest to declare.
Targeting Homologous Recombination in Lymphoid Malignancies: Evaluation of Four Small Molecule Inhibitors of RAD51
Authors: Day Melinda , Maclay Tyler , Cyr Amber , Hasham Muneer G , Chow Kin-hoe , Keniston ED , Mills Kevin 
Published: November 2019

Genomic instability is recognized as a driver of tumorigenesis and cancer progression. Loss of tumor suppressors or activation of oncogenes can induce DNA damage stress, promoting genomic instability and creating dependencies upon key DNA repair pathways. These dependencies can be targeted therapeutically to induce synthetic lethality. The homologous recombination (HR) repair pathway is an attractive target. HR deficient cancers are hypersensitive to numerous anticancer drugs, and tumors will often induce expression of HR genes to promote drug resistance. RAD51 is a key component of the HR pathway. RAD51 forms nucleoprotein filaments at sites of DNA damage and replication fork stalls, mediating homologous DNA strand exchange to promote recombinational repair of breaks and damaged replication forks. We utilized four small molecule inhibitors of RAD51-mediated HR for evaluation of RAD51 as a potential therapeutic target. Compounds CYT-0851, CYT-0853, CYT-1027, and CYT-1127 were evaluated for anti-cancer activity in vitro and in vivo. To determine the impact of the small molecules on RAD51 and HR, all four were tested for effects on RAD51 focus formation and sister chromatid exchange (SCE) activity. All the compounds showed a reduction in SCE activity, however only CYT-0851 and CYT-0853 produced a measurable reduction in RAD51 foci. We have previously shown that that RAD51 inhibition leads to accumulation of DNA breaks, and ultimately cell death, in cells expressing the DNA mutator protein Activation Induced Cytidine deaminase (AICDA/AID). Cytotoxicity assays were performed in an AID+ (Daudi, Burkitt's Lymphoma) and AID- (WI-38, fibroblast) cell lines. All four compounds were preferentially active in AID+ cells with little to no cytotoxicity observed in the AID-negative WI-38 cell line. CYT-0853 was the most potent in the Daudi cell line with an EC50 of 8nM. All four compounds were orally bioavailable in all preclinical species tested but showed differences in pharmacokinetics. Preclinical cell line derived xenograft models of AID-high Burkitt's lymphoma (Daudi) and B-cell acute lymphoblastic leukemia (CCRF-SB) were used to determine the in vivo anti-tumor activity of the compounds in lymphoid cancer models. CYT-0851 and CYT-0853 both showed significant anti-tumor activity with tumor growth inhibition of greater than 50% in both models. Further analysis showed drug exposure with CYT-0851 was more consistent in the CDX models than CYT-0853. Overall, these data indicate that RAD51 and HR are attractive therapeutic targets for the treatment of lymphoid malignancies and that CYT-0851 is a viable clinical development candidate.

Disclosures
Day: Cyteir Therapeutics: Employment. Maclay:Cyteir Therapeutics: Employment. Cyr:Cyteir Therapeutics: Employment. Mills:Cyteir Therapeutics: Employment, Equity Ownership.
Targeting AML: The Development of Two Functionally and Mechanistically Distinct Classes of Cereblon-Mediated Protein Homeostatic Modulators
Authors: Chourasia Aparajita Hoskote , Fung Leah , McElwee Brooke , Richard Normand , Lam Imelda , Torres Eduardo , Erdman Paul , Sullivan Robert , Hecht David , Chan Kyle WH , Mercurio Frank , Stirling David I 
Published: November 2019

Targeting disease-relevant proteins by exploiting the cells' very own protein homeostasis machinery is the next generation drug discovery platform that has come center stage for treatment of hematological malignancies. We present our novel and unique Protein Homeostatic Modulators (PHMsTM) - that promote ubiquitination and subsequent proteasomal degradation of known substrates as well as neosubstrates via Cereblon - as therapeutic candidates for acute myeloid leukemia (AML). Specifically, we report the discovery of two functionally and mechanistically distinct classes of Cereblon-mediated PHMsTM from phenotypic screens of our proprietary PHM®library. Unlike classical IMiDs, our oncology candidates, BTX508 and BTX1119 demonstrate significant cytotoxicity with IC50s in low-nanomolar range in a panel of AML cell lines. BTX508 is a purely cytotoxic compound that does not display immune modulatory activity. In contrast, BTX1119 is not only cytotoxic, but is also immunomodulatory in that it inhibits inflammatory cytokines such as IL-1β, IL-6 and TNF-α as well as induces IL-2, an indicator of T cell activation. BTX1119's immune modulatory activity is a 100-fold more potent when compared to Pomalidomide. The distinct functional activities exhibited by BTX508 and BTX1119 is a result of strategically engineered substrate degradation profiles. Importantly, BTX508 and BTX1119 exhibit a large safety window wherein the concentrations at which they target AML cells do not affect normal healthy cells such as liver epithelial cells or lung fibroblasts. To further establish BTX508 as a clinical candidate for AML, we performed in vivo efficacy studies in the MV-4-11 human AML xenograft model using athymic nude mice. A single daily dose of BTX508 results in a significant reduction in tumor volume. BTX508 exhibits significant oral bioavailability, thus making it a promising clinical candidate for treatment of AML as well as other potential hematological malignancies. With regard to BTX1119, we believe that incorporation of both the potent cytotoxic and immunomodulatory properties into a single molecule holds great therapeutic promise; however, to evaluate the synergistic potential of this combination will require use of a humanized mouse model - this work is ongoing.

Disclosures
No relevant conflicts of interest to declare.
Small Molecule Screening Identifies Rho-Associate Protein Kinase (ROCK) As a Regulator of NK Cell Cytotoxicity Against Cancer
Authors: Lee Grace , Karunanithi Sheela , Jackson Zachary , Wald David 
Published: November 2019

NK cells are a subset of lymphocytes that directly recognize and lyse tumor cells without the limitation of antigen specific receptor recognition. In addition to behaving as cytotoxic effector cells, NK cells unlike T cells are not thought to elicit graft versus host disease. The combination of these characteristics makes NK cells a powerful tool for adoptive cell therapy. Despite the promise of NK cell therapy, key hurdles in achieving significant clinical efficacy include both generating sufficient numbers of highly tumoricidal NK cells and maintaining the cytotoxic activity of these cells in vivo despite the immunosuppressive tumor microenvironment.
Our lab and others have developed several feeder cell line-based expansion modules that robustly stimulate the ex vivo proliferation of NK cells. However, strategies to enhance and sustain the activity of NK cells once administered in vivo are still limited. In order to identify strategies to enhance the cytotoxic activity of NK cells, we developed a high-throughput small molecule screen (Figure 1A) that involved a calcein-based cytotoxicity assay of ex vivo expanded and treated NK cells against ovarian cancer cells (OVCAR-3). 20,000 compounds were screened and the screen was found to be highly robust (Z'&gt;0.59). We identified 29 hits that led to at least a 25% increase in cytotoxicity as compared to DMSO control-treated NK cells. One of the most promising hits was the pan-ROCK inhibitor, Y-27632 that led to an 30% increase in NK killing of the OVCAR-3 cells. We validated that ROCK inhibition leads to enhanced NK cell cytotoxic activity using Y-27632 (Figure 1B) as well as other well-established ROCK inhibitors such as Fasudil using a flow cytometry based killing assay. Y-27632 increased NK cell cytotoxicity in a dose- and time- dependent manner. ROCK inhibition consistently led to ~10-25% increase in NK cell cytotoxic activity directed against a variety of ovarian (Figure 1C) and other solid tumor cell lines (Figure 1D). Interestingly, we found that the NK hyperactivation persists for up to 48hrs after washing off the drug that may enable ex vivo stimulation before NK cell infusion. Our preliminary results showed that ROCK inhibition activates PI3K-dependent Akt activation (Figure 1E). We hypothesize that ROCK inhibition restores Akt activation which may be critical for NK cell activating receptor pathways and our current investigations will test these hypotheses.
ROCK inhibitors, such as Y-27632 and Fasudil have been utilized in both preclinical and clinical studies for a variety of diseases such as atherosclerosis, neurodegenerative disorders, and ocular diseases. However, the consequences of ROCK inhibition in NK cells has not been thoroughly investigated. Our work shows a promising novel strategy to significantly enhance NK cell therapy against cancer that has high translational potential.

Disclosures
No relevant conflicts of interest to declare.