bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-Effectiveness of Venetoclax and Rituximab Combination Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) in Argentina
Authors: Elgart Jorge Federico , Glancszpigel Mariana , Kanevsky Diego , Godar Maria , Touliet Valeria , Albaytero Natalia 
Published: November 2019

OBJETIVE: To estimate the cost- effectiveness of Venetoclax + Rituximab (VEN + R) versus ibrutinib in the treatment of Relapsed/Refractory (R/R) Chronic Lymphocytic Leukaemia (CLL), in Argentina from the Social Security perspective."
METHODS: A three-state partitioned survival model (including pre-progression, post-progression and death) developed in accordance with the NICE Guide to the Methods of Technology Appraisal and the ISPOR decision modelling guidelines was adapted to Argentina setting. Population inputs are derived from the MURANO trial. Efficacy and safety data for treatments in R/R CLL were obtained from the literature. The cost of medication was based on country level drug prices. Costs of resources used for routine medical attention and the management of adverse events were based on tariffs from social security system of Argentina. Costs were expressed in US dollars ($) (exchange rate 1$ = 37.10 AR$, November 2018). A 30-year time horizon and the Social Security's payer's perspective were assumed. Costs and health outcomes were discounted at 5%. Deterministic and probabilistic sensitivity analyses (PAS) were performed.
RESULTS: Over a 30-year time horizon, VEN + R regimen generates a significantly lower total treatment cost in comparison to Ibrutinib (- US dollars ($) 312.679,37). In QALYs the result is higher in VEN + R related to the comparator (5.83 vs. 4.18). These show that VEN + R is a dominant treatment strategy over Ibutrinib in patients with R/R CLL. The univariate sensitivity and scenario analysis confirm the robustness of this result. Likewise, the probabilistic sensitivity analysis shows that there is a 100% probability that VEN + R is a cost-effective strategy against Ibrutinib.
CONCLUSIONS: This study shows that in Argentina, VEN+R would be dominant treatment option (better results and lower costs) compared with ibrutinib in R/R CLL patients.

Disclosures
Elgart: 3eff: Consultancy. Glancszpigel:3eff: Employment. Kanevsky:Abbvie: Employment. Godar:Abbvie: Employment. Touliet:Abbvie: Employment. Albaytero:3eff: Employment.
Comparison of the DONOR Lymphocyte Infusion and Second Allogeneic STEM-CELL Transplantation in the Treatment of First Hematological Relapse after Allogeneic STEM-CELL Transplantation in Adults with ACUTE Leukemia
Authors: Demiroglu Haluk , Aladag Elifcan , Chao Nelson J. , Buyukasik Yahya , Goker Hakan 
Published: November 2019

Purpose: Relapse after allogeneic hematopoietic bone marrow transplantation (AHSCT) in acute leukemia is a poor prognosis indicator. Although there is no definite opinion about the optimal treatment chemotherapy, second allogeneic hematopoietic stem cell transplantation (AHSCT2) or donor lymphocyte infusion (DLI) are among the treatment options. Relapse after allogeneic transplantation remains unfortunately quite common and we frequently face difficult management decisions. The decision to offer either option is based on several factors, including donor availability, remission status, presence of disabling comorbidities, and center or physician preference. The aim of this study was to investigate the effect of AHBMT2 or DLI on survival in relapsed transplant patients suffers from acute leukemia. Method:We here in report a retrospective analysis of single-center experience with AHBMT2 and DLI to treat patients relapsing from acute leukemia after a first AHBMT from 2003 to 2018.We enrolled the study 20 patients who underwent DLI and 6 patients who underwent AHBMT2. Result:There was no significant difference in OS between the groups afterward intervention (p:0,9) The 2-year survival rate was 33% in the AHBMT2 group and 43% in the DLI group. After intervention, chronic GVHD was observed only in DLI group. Conclusion: DLI can be considered after relapse as a safer and less toxic method than AHBMT2.

Disclosures
No relevant conflicts of interest to declare.
Simultaneous Inhibition of Mcl-1 and Induction of DNA Damage Accumulation By Chidamide, a Novel Selective HDACi, Potentiates the Cytotoxicity of ABT-199 in Acute Myeloid Leukemia
Authors: Xu Bing , Chen Kai , Yang Qianying , Zha Jie , Zhao Haijun , Feng Liying , Chen Xiaolei , Fu Guo , Young Ken H. 
Published: November 2019

Acute myeloid leukemia is a heterogeneous hematopoietic neoplasia with a poor clinical outcome despite its treatment have made great progress in recent years. Strategies for targeting Bcl-2 using ABT-199 attract increasing attentions. however, most treatment failure strongly correlates with acquired up-regulation of MCL-1, which become the Achilles's heel of ABT-199 in clinical use. Here we describe low-cytotoxicity dosage of Chidamide (CS055), a novel selective HDACi designed in China, potentiated the cytotoxicity of ABT-199 towards diverse AML cell lines in vitro and primary samples obtained from patients with AML ex vivo, especially those carrying hyperleukocytosis, as well as highly active in vivo in a AML patient-derived xenograft murine model, while sparing normal peripheral blood mononuclear cells. Mechanistically, ABT-199/CS055-induced cytotoxicity was closely associated with inactivation of Mcl-1 and simultaneous induction of DNA damage accumulation. Of note, we also find a superior resensitization activity of CS055 in contrast with Romidepsin. In summary, our findings suggest that CS055 enhance the eliminating activity of ABT-199 towards AML cells, thus implying a highly promising and potent strategy for treatment of relapsed and refractory AML.

Disclosures
No relevant conflicts of interest to declare.
Outcome of Atypical Presentations of Hairy Cell Leukemia
Authors: Moustafa Afraa , Shwaylia Hawraa M , Aldapt Mahmood , Yassin Mohamed A 
Published: November 2019

Hairy cell leukemia (HCL) is a distinctchronic lymphoproliferative disorder that accounts for 2% of all adult leukemias. The median age at the time of diagnosis is 52 years with a male to female ratio of 4:1.
Hairy cell leukemia predominantlycharacterized by infiltration of peripheral blood, bone marrow, and spleen by malignant cells with prominent irregular cytoplasmic projections, namely, "hairy cells". HCL patients may be asymptomatic or develop symptoms of cytopenia, particularly infections .
The exact prevalence of atypical presentation of HCL is difficult to be determined because most cases were published as incidental reports.
The classical presentation of Hairy cell leukaemia includes splenomegaly (80-90%), pancytopenia (60-80%) and hepatomegaly (40-50%), however, the same may not be true in the clinical settings.
As hairy cell leukemia may present with a wide range of atypical organ involvements which could result in a diagnostic dilemma.
The aim of this literature review is to highlight non- classical presentations of HCL and the importance to have high index of suspicion to consider a diagnosis of HCL based on histomorphological features even in the absence of classical clinical features.
Method:
We searched the medline database (PubMed), GoogleScholar from1985 until 2018 with the following search terms: atypical presentation of hairy cell leukemia ,unusual cases of hairy cell leukemia,unique hairy cell leukemia presentation.
Result:
A total of 21 cases were found, with age range from (29-88),5 cases were female and the rest were males.
Skeletal involvement was the most common presentation with osteolytic bone lesion.
Majority of the patients were treated with Cladribine,13/21 showed complete remission.
Discussion:
HCL is an indolent disorder of B-cell origin that accounts for 2% of all forms of leukemia and 8% of lymphoproliferative diseases.
In our literature review we looked up the unique presentations, which
Most of the reported cases we found involved the skeleton in the form of pathological fracture and osteolytic lesion.
Serositis, in the form of massive ascites and pleural effusion has been reported. Additionally, Cases of central nervous system involvement and presentation at young age were observed.
Due to rarity of the disease and no established treatment modality for unusual organ involvement, standard treatment with Cladribine result in complete remission in 61% of the observed cases.
Conclusion:
While Classical presentation of hairy cell leukemia is well described in the literature.
atypical presentation is still rare but with diverse presentation.
most of the cases reviewed in the literature were middle age males, majority had good response to treatment, while the rest had disease progression .
rare pretension of Hairy cell leukemia despite being rare should always be considered ,particularly in cases of pathological fractures or unexplained serositis.
Table

Disclosures
No relevant conflicts of interest to declare.
Development of Exosome-Capturing Antibody-Conjugated Nucleic Acid Medicines Targeting Multiple Myeloma Cells
Authors: Soma Emi , Toda Yuki , Hosogi Shigekuni , Yamayoshi Asako , Ashihara Eishi 
Published: November 2019

Nucleic acid medicines including small interfering RNAs (siRNAs) are expected to be next-generation therapies. However, targeted delivery of siRNAs into cancer cells, especially hematological cancer cells, via systemic administration is limited by the lack of efficient and cell-specific delivery systems. We previously demonstrated that cancer cell-derived exosomes are preferentially transfer into their parental cancer cells. Based on this observation, we hypothesized that monoclonal antibody (mAb)-conjugated siRNAs that capture exosomes can efficiently deliver siRNAs into hematological cancer cells (Figure 1). To test this hypothesis, we developed a noncovalent Ab-conjugated siRNA system and confirmed the efficient delivery into multiple myeloma (MM) cells. We selected the surface antigen CD63 to capture MM cell-derived exosomes. An anti-CD63 mAb was thiolated using Traut's reagent and then modified with a linear (D-arginine (Arg))9 (9r) or branched (Arg)18 (9+9r) peptide (vehicle). The anti-CD63 mAb-Arg:siRNA complex was obtained by mixing anti-CD63 mAb-Arg and siRNA in phosphate-buffered saline and incubating the mixture.
A gel shift assay showed that the anti-CD63 mAb-linear Arg construct bound to siRNAs in a construct concentration-dependent manner and the optimal vehicle-to-siRNA ratio was 5:1. By contrast, the anti-CD63 mAb-branched Arg construct bound to siRNAs at lower concentrations, and the optimal vehicle-to-siRNA ratio was 1:1-2.5:1. We next examined uptake of fluorescence-labeled siRNAs by OPM-2 MM cells using a confocal microscope. A higher level of siRNAs was delivered using the anti-CD63 mAb-branched Arg construct than using the anti-CD63 mAb-linear Arg construct; therefore, we used the former construct for further experiments. We investigated the knockdown effects of the CD63 mAb-branched Arg construct conjugated with luc siRNA in luciferase-expressing OPM-2 cells (OPM-2-luc cells). Luciferase activity decreased to 55.9% in OPM-2-luc cells following uptake of this construct. We next examined the mRNA transcript levels of MYC and CTNNB1 (β-catenin) mRNA transcript levels by RT-PCR in OPM-2 cells treated with the anti-CD63 mAb-branched Arg construct conjugated with MYC and CTNNB1 siRNAs. Treatment with mAb-conjugated siRNAs at a vehicle-to-siRNA ratio of 1:1 decreased the mRNA transcript levels of MYC and CTNNB1 to 52.5% and 55.3%, respectively (Figure 2).
In conclusion, exosome-capturing antibody-conjugated siRNAs are effectively delivered into MM cells via uptake of exosomes by parental cells. We are currently investigating their delivery into other hematological cancer cells. This technology might lead to a breakthrough in drug delivery systems for hematological cancers.

Disclosures
No relevant conflicts of interest to declare.
The Impact of a Mandatory Prescription Drug Monitoring Program (PDMP) on Opioid Prescription Among Sickle Cell Disease Patients By Emergency Medicine Physicians in Community Teaching Hospitals in Philadelphia
Authors: Shikdar Sufana , Edlukudige Keshava Vinay Edlukudige , Lambert Peter , Gudipally Sindusha , Esposito Anthony , Bendesky Brad , Green Eric 
Published: November 2019

Introduction:
Although opioids are the recommended treatment for acute pain management in sickle cell disease (SCD) patients, the opioid epidemic may have negatively affected the care of these patients in the emergency care settings. Literature suggested that ED physicians routinely overestimate opioid misuse in patients with SCD. Pennsylvania mandated Prescription drug monitoring programs (PDMP) in August 2016 which may affect ED opioid prescription among SCD patients. We evaluated the impact of that PDMP on opioid prescription in the management of acute pain for patients with SCD.
Method:
The data collection took place in the two community hospitals (Mercy Fitzgerald and Mercy Philadelphia Hospital) in Philadelphia. Participants were adults (aged ≥18 years) diagnosed with SCD who triaged for pain in the ED was included in the study. We grouped the encounter by year of PDMP implementation: prior to September 2016 (January 2016-August 2016), and after September 2016 (January 2017-August 2017) to collect patient records of a 6-month period and analyzed the data on number of visits, treatment types, opioid dispensing and total morphine milligram equivalents (MMEs) drug prescriptions during the ED visit. Paired t-test and chi square test were used to compare pre- and post-intervention results. Repeat encounters within 7 days period were excluded in the study.
Result:
The study included 180 qualifying ED visits (92 pre-intervention; 88 post-intervention). PDMP intervention was not significantly associated with reductions in the with opioid prescribing or the amount of prescribed MMEs. The mean age is 32.7 and 58% were male; and all were of African American race/ethnicity. However, prescriptions for non-opioid analgesics increased significantly during the same periods (p<0.012).
Conclusion:
During January 2017-August 2017, PDMP implementation was not associated with a change in opioid prescription among SCD patients in our community teaching hospitals in Philadelphia. The use of the PDMP would be expected to increase narcotic use by correctly identifying SCD patients as not having opioid misuse. The failure to increase narcotics suggests that the use of PDMP data to adjust prescribing for SCD patients is not adequate. As PDMP is crucial for addressing the opioid crisis, clinicians should also use PDMP data for more tailored care in SCD patients. Integration of palliative care could be more pragmatic approach in balancing opioid abuse and access to opioids for pain management among SCD patients.

Disclosures
No relevant conflicts of interest to declare.
Observation on the Efficacy of Consolidation Chemotherapy Combined with Allogeneic Natural Killer Cell Infusion in the Treatment of Low and Moderate Risk AML
Authors: Jiang Hao , Huang Xiaojun , Wang Chunjian , Gong Lizhong , Jia Jinsong , Liu Xiaohong , Wang Yu , Yan Chenhua , Chang Yingjun , Zhao Xiaosu , Shi Hongxia 
Published: November 2019

Objective To evaluate the efficacy of consolidation chemotherapy combined with allogeneic natural killer (NK) cell infusion in the treatment of low or intermediate-risk(LIR) AML. Methods 23 cases of LIR AML patients with hematologic complete remission (CR) were enrolled from January 2014 to June 2019 and treated with mIL-21/4-1BBL actived NK cell transfusion combined with consolidation chemotherapy after 3 consolidation courses. Control group were concurrent patients from Department of Hematology and their gender, age, diagnosis, risk stratification of prognosis, CR and the number of courses of consolidate chemotherapy before NK cell transfusion were matched with LIR AML patients. Results A total of 45 times of NK cells were injected into 23 LIR AML patients during 4 to 7 courses of chemotherapy. The median NK cell infusion quantity was 7.5 (6.6~8.64) x 109/L, and the median survival rate of NK cells was 95.4 (93.9~96.9) %. Among them, the median CD3-CD56 + cell number is 5.0(1.4 ~ 6.4) × 109/L, which accounts for 76.8(30.8 ~ 82.9) %; The number of CD3+CD56+ cells was 0.55 (0.24~1.74) x 109/L, accounting for 8.8 (4.9~20.9) %. Before NK cell infusion, the number of patients with positive MRD in the treatment group was 9/23 (39.1%), and the control group was 19/46 (41.3%) (X2=0.03, P=0.862). After NK cell infusion, There was no significant difference in MRD that went from negative to positive between the treatment group and the control group(14.3%vs 22.2%, X2=0.037, P=0.847). In the treatment group, 66.7% (6/9) of the MRD were converted from positive to negative, which was significantly higher than that in the control group10.5% (2/19) (X2=6.811, P=0.009). Morphological recurrence occurred in 1 case of MRD negative in the treatment group and 2 cases of MRD positive in the control group. By the end of the follow-up, the median follow-up was 35 (10~59) months, the number of patients with morphological recurrence in the treatment group was 30.4% (7/23), which is significantly lower than that in the control group (50.2%, 24/46)(X2=2.929, P=0.087),although there was no statistically significant difference between the two groups. There was no significant difference on MRD-negative between the treatment group and the control group(43.5% vs 43.5%, X2=1.045, P=0.307).The 3-year leukemia -free survival were better in the treatment group(65.1±11.1)% than that in the control group (50.0±7.4)%(P=0.047). The 3year overall survival in the treatment and chemotherapy groups were(78.1±10.2)%and (65.8±8.0)%(P=0.212), respectively. Conclusion The consolidation of chemotherapy combined with allogeneic NK cell infusion contributes to the further remission of patients with LMR AML and the reduction of long-term recurrence.
Figure

Disclosures
No relevant conflicts of interest to declare.
Seven Cases of JAK2 Mutation Negative Chronic Polycythemia Patients with Elevated IGF-1R
Authors: Shi Guanfang , Morcus Rewais , Liaukovich Maksim , Wong Ching , Gotlieb Vladimir , Wang Jen-Chin 
Published: November 2019

We previously reported that assaying blood MNC (Mononuclear cells) IGF-1 levels by Flow cytometry, will be helpful in differentiating Polycythemia vera (PV) from secondarypolycythemia (1). Patients with chronic polycythemia who are negative for JAK2 V617F or exon 12 mutation and who lack the typical bone marrow findings of polycythemia vera will remain a diagnostic enigma. We collected 7 cases of patients who had persistent chronic erythrocytosis ranging from 1-15 years with negative driver mutations, lacking the typical PV bone marrow findings and absence of secondary causes such as smoking or malignancies. Blood mononuclear cells (MNC ) were collected as well as blood DNA extracted for 237 genes including EPO-R, PHD2, VHL or HIF-1-alpha (Familial erythrocytosis genes)with Next generation sequence, performed by Genoptyx lab (Carisbad, CA) and assayed for IGF-1R by flow cytometry as described previously (1). The results are shown in Table 1.
Conclusion. All these 7 patients with elevated IGF-1R who had no evidence of familial erythrocytosis gene mutation nor had any secondary cause for erythrocytosis, likely carried the diagnosis of PV. It was shown that EEC formation in PV is due to IGF-1 hypersensitivity (2), andsecondary polycythemia do not show significantly elevated IGF -1R (1). Hence the elevated IGF-1R in these 7 patients strongly suggests the diagnosis of PV, re-affirming our proposal that simple procedures to assay blood MNC cells for IGF-1R by flow cytometry will be helpful in the diagnosis of PV and to be added as one of the minor criteria in the diagnosis of PV.
References
1. Wang JC, et al . Quantification of IGF-1 Receptor May Be Useful in Diagnosing Polycythemia Vera-Suggestion to Be Added to Be One of the Minor Criterion.PLoS One. 2016 Nov 3;11(11):e0165299. doi: 10.1371/journal.pone.0165299.
2. Correa PN, Eskinazi, D and Axelrad AA .Circulating Erythroid Progenitors in Polycythemia Vera Are Hypersensitive to Insulin-like Growth Factor-l In Vitro: Studies in an Improved Serum-Free Medium Blood, Vol83, No 1 (January l), 1994: pp 99-1

Disclosures
Wang: Incyt: Research Funding.
Updated Meta-Analysis of Randomized Controlled Trials on Primary Ambulatory Thromboprophylaxis (PATP) in Patients with Locally Advanced or Metastatic Lung Cancer Receiving Chemotherapy
Authors: Thein Kyaw Zin , Tijani Lukman , Oo Thein H. 
Published: November 2019

Introduction: Lung cancer (LC) is the second most common cancer in both sexes and is the leading cause of cancer mortality in the United States. Thrombosis is the second leading cause of death in cancer patients and PATP in solid cancer patients were performed in research trials to decrease venous thromboembolism (VTE) rates with ultimate aim to improve survival. We undertook an updated meta- analysis of RCTs to determine the benefit and risk of PATP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOAC) in patients with locally advanced or metastatic LC receiving chemotherapy.
Methods: We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2019. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied.
Results: A total of 5,375 patients with LC from five RCTs and a subgroup of another four RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, certoparin, dalteparin, nadroparin, semuloparin and tinzaparin, intermediate dose of enoxaparin and prophylactic dose of rivaroxaban were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 114 (4.16%) in PATP group and 207 (7.85%) in control group with a RR of 0.53 (95% CI: 0.43 to 0.67, P < 0.001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.001) with an estimate of the number needed to treat (NNT) of 28 to prevent one VTE event. MB events were reported in 26 (1.37%) patients in PATP group compared to 15 (0.84%) in control group according to an analysis of 6 RCTs. The pooled relative risk for MB was statistically non-significant at 1.57 (95% CI: 0.85 to 2.88, P = 0.15).
Conclusions: Our analysis showed that the relative risk reduction is 46% with a NNT of 28 to prevent one VTE without increasing MB events in ambulatory patients with locally advanced or metastatic LC. Selection of appropriate patients who are high risk for VTE is crucial and further studies are required to define high risk subsets of LC patients receiving chemotherapy who may benefit from PATP.

Disclosures
Oo: Janssen and Janssen: Other: Research: site co-investigator ; Medical Education Speakers Network: Honoraria.