bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single Center Real-World Experience of Daratumumab and Extra-Medullary Myeloma
Authors: Bishnoi Rohit , Shah Chintan , Moreb Jan , Murthy Hemant S. 
Published: October 2019

Abstract
Background: Daratumumab (Dara) was recently FDA approved for the treatment of relapsed/refractory multiple myeloma (RRMM). We evaluated a real-world single-center experience of Dara salvage therapy for RRMM.
Methods: Patients treated at the University of Florida with Dara for RRMM between January 2016 and February 2018 were included. Data was collected by chart review and analyzed for patient demographics, disease characteristics, treatment, and outcomes.
Results: 25 patients (13 as monotherapy and 12 in combination) were included, with a median age of 63 (range, 42-86) years. Median time from MM diagnosis to Dara initiation was 51.3 (range, 8.4 -162.3) months. The median duration of Dara therapy was 72 days (range, 7 - 622). The median number of Dara doses was 7 (range, 2- 49). The best response to DARA was Very Good Partial Response (VGPR) in 1 (4%), Partial Response (PR) in 17 (68%), while 7 (28%) had Progressive Disease (PD). Overall Response Rate (ORR) to Dara was 72%. By the end of the study period, another 11 (44%) patients progressed while on DARA with a total of 18 (72%) patients having PD at the time of analysis. Estimated median progression free survival (PFS) after starting Dara was 155 days (95% CI: 21 - 289) and estimated median overall survival (OS) in the entire cohort was 11.7 months (95% CI: 4.2 - 19.2). Post DARA, 1 (4%) patient with VGPR underwent ASCT, while 9 (36%) went on to have other therapies which included HyperCVAD, Melphalan, and clinical trials, and 8 (32%) were treated with only best supportive care.
Of 18 patients who had PD, 10 (40%) patients had a progressive extramedullary disease (EMD), of whom 6 (24%) had EMD prior to starting Dara, while another 4 (16%) patients developed new EMD while on Dara. PFS in the EMD cohort was 63 days (95% CI: 23 - 103), which was shorter than patients with no EMD (333 days; 95% CI: 42 - 624) (P= 0.08). Estimated median OS in patients with EMD was 5.4 months while in patients with no EMD was 16.1 months (p =0.16).
Conclusions: DARA therapy does have good ORR (72%) in RRMM, however, there was an unusually high incidence of progressive or newly diagnosed EMD in RRMM patients treated with Dara/Dara-containing regimens, suggesting that Dara may not be effective in treating or preventing EMD. Moreover, we noticed patients who have EMD or develop new EMD tends to have worse outcomes. The underlying escape mechanism for EMD remains unknown and warrants further investigation.
Table. Table.

Disclosures
No relevant conflicts of interest to declare.
Validation of a Sensitive Flow Cytometry Assay to Assess Minimal Residual Disease of Multiple Myeloma Cells in Apheresis Product
Authors: Jones Nicholas , Ragheb Josette William , Ngo Brian , Uyeji David , Hii Anselm L. 
Published: October 2019

Abstract
For treatment of patients with multiple myeloma (MM), flow cytometry has become a widely used and valuable method for the evaluation of minimal residual disease (MRD) in bone marrow. Use of an optimized single-tube, 10-color flow cytometry panel for assessment of MM MRD has shown to be beneficial in patient monitoring and has shown correlation to the acknowledged EuroFlow 8-color, 2-tube method. In order to further correlate levels of MM and relapse in patients, validation of a sensitive MM MRD assay that can be applied to testing for residual disease in apheresis product prior to autologous stem cell transplant, a standard treatment for patients with multiple myeloma. This approach can exhibit great value in patient monitoring and treatment. As new combination therapies are developed for treatment of multiple myeloma in concert with autologous stem cell transplantation, evaluation of MRD in apheresis will likely continue to grow in importance. The purpose of this study is to show the validation and sensitivity of a flow cytometry assay designed to detect Multiple Myeloma (MM) cells in G-CSF and other mobilized apheresis samples from human Multiple Myeloma patients. Using GSM-mobilized apheresis product, spiked with different levels of patient de-identified MM plasma cells, validation of a 10-color MM MRD panel can be evaluated, intended to mimic patient apheresis at varying levels of residual disease post treatment. As with any minimal residual disease assessment, a high number of events are required to ensure sensitivity and precision. Typically, acquisition of 3-5 x 107 events is required to ensure precision of MM MRD levels to 0.001%.

Disclosures
No relevant conflicts of interest to declare.
Genomic Sequencing Reveals Complex and Actionable Molecular Profiles across Hematologic Malignancies
Authors: Galanina Natalie , Jamieson Catriona , Kurzrock Razelle 
Published: October 2019

Abstract
The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. We describe 235 such patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and their potential actionability. Overall, 227 patients (96.5%) had adequate tissue. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), acute myeloid leukemia (11%), myeloproliferative neoplasm (9.2%), acute lymphoblastic leukemia (8.8%) and multiple myeloma (7.5%). Most patients (N = 197/227 (87%)) harbored ≥1 genomic alteration(s); 170/227 (75%), ≥1 potentially actionable alteration(s) targetable by an FDA-approved (mostly off-label) or an investigational agent. (Table 1) Altogether, 551 distinct alterations were seen, most commonly involving TP53 (9.3% of patients), TET2 (4.2%), DNMT3A (3.3%), ASXL1 (2.5%), MLL (2.5%), and KRAS (2.2%). (Figure 1 and Figure 2) The median tumor mutational burden (TMB) was low (1.7 alterations/megabase); 12% of patients had intermediate or high TMB (higher TMB correlates with favorable response to anti-PD1/PDL1 inhibition in solid tumors). In conclusion, 96.5% of patients with hematologic malignancies have adequate tissue for comprehensive genomic profiling. Most patients had unique molecular signatures, and 75% had alterations that may be pharmacologically tractable with gene- or immune-targeted agents.

Disclosures
No relevant conflicts of interest to declare.
Survival Among Minority Populations with Chronic Myeloid Leukemia: A Surveillance Epidemiology and End Results Database Analysis
Authors: Agbedia Owhofasa , Ngwa Julius , Darbari Deepika S. , Oneal Patricia 
Published: October 2019

Abstract
Introduction: Cancer affects people of all races in the U.S.; however, the burden is greater for minority populations. This is influenced by factors such as demographics, behavioral factors, and access to medical services. The disparity is well documented in some solid tumors. However, little information exists on a racial disparity in survival among minority populations diagnosed with chronic myeloid leukemia (CML) especially in the era of targeted therapies. A better understanding of the population impact of CML will drive further research into approaches to improve overall outcomes.
Methods: All cases of CML diagnosed between 1973 and 2017 and with available follow-up data reported in the Surveillance, Epidemiology, and End Results database were reviewed. We performed a population-based study of CML to evaluate survival by race and calendar year of diagnosis: 1975-1989 (the era of cytotoxic therapy; busulfan and hydroxyurea), 1990-2000 (the era of Allogeneic hematopoietic stem cell transplantation or interferon-alfa ± cytarabine), and 2001-2015 (the era of targeted therapy; Tyrosine Kinase Inhibitors).
Results: A total of 14572 (56.4% were females) patients diagnosed with CML were included in our analysis. The racial distribution was 83.4% white, 10% black, 0.8% American Indian/Alaska Native and 5.9% Asian or Pacific Islander. 5314 (36.5%), 3725 (25.5%) and 5544 (38%) cases of CML were diagnosed during the 1975-1989, 1990-2000 and 2001-2015 eras respectively. The median 5-year survival improved by race with each era, with the greatest improvement observed among patients diagnosed during the 2001-2015 era. Although a trend of improvement in the median 5-year survival is seen across all age categories, patients 65 years and older continue to experience only a modest survival benefit in the era of targeted therapies (Table 1). No significant differences in survival by race was observed in the era of targeted therapies (Figure 1).
Conclusions: This survival analysis includes a longer follow-up duration (Diagnosis Years: 1973-2015) for patients with CML compared to prior studies. Although an overall improvement in median survival is seen across all age groups and by each era, survival benefits are lagging in certain populations (black and American Indian/ Alaska Native) older than 65. SEER database captures information from metropolitan counties in the United States and this may not truly reflect the health of the entire US population.

Disclosures
No relevant conflicts of interest to declare.
Pharmacologic Targeting of LIN28/Let-7 in Acute Myeloid Leukemia
Authors: Roos Martina M , Li Michelle , Amara Pang , Chute John P 
Published: October 2019

Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy with high relapse rates and mortality due to the outgrowth of chemotherapy-resistant leukemic stem cells (LSCs). Thus, the development of novel therapeutic strategies capable of eradicating human AML represents a major area of unmet medical need. The RNA binding protein, LIN28, is a known driver of many cancer stem cells, AML included, wherein overexpression of LIN28 correlates with reduced patient survival. LIN28 blocks the function of the let-7 microRNA family, which exert tumor suppressive effects by repressing oncogenes and cell cycle regulators including MYC, RAS and CyclinD. Thus, LIN28 is an attractive mechanistic target for the purpose of inhibiting AML LSCs. Using a targeted high-throughput screen, we identified a class of small molecules which selectively block the LIN28/let-7 interaction (Roos et al., ACS Chem Biol, 2016). Preliminary studies demonstrate that a lead small molecule markedly impairs the proliferation and clonogenic capacity of human AML cell lines and primary patient AML samples. In vivo, systemic administration of a lead small molecule LIN28/let-7 inhibitor decreases leukemic tumor burden, reduces LSC numbers and significantly improves animal survival. Mechanistic studies revealed that targeted inhibition of the LIN28/let-7 axis restores let-7 microRNA levels in AML LSCs and subsequently inhibits a panoply of key oncogenic driver genes, including the NF-ĸB pathway, a hallmark for LSC proliferation. Furthermore, AML cell lines and primary patient cells treated with the LIN28/let-7 small molecule inhibitor showed a block at the G1/S phase interface and significantly decreased cell cycle progression. Consequently, LIN28/let-7 inhibition leads to LSC differentiation and ultimately leukemic cell death. In summary, we demonstrate for the first time the drugability of the LIN28/let-7 axis in vivo and reveal a novel pharmacological means to suppress a multitude of oncogenic driver genes in human AML. These results suggest that small molecule inhibition of LIN28/let-7 has high therapeutic potential as a new class of targeted therapies for AML.

Disclosures
No relevant conflicts of interest to declare.
Engineering Precision Medicine to Increase Graft-Versus-Lymphoma Activity: Hematopoietic Stem Cells Modified with Chimeric Antigen Receptors
Authors: De Oliveira Satiro N. , Truscott Laurel C , Kao Roy L , Chiou Tzu-Ting 
Published: October 2019

Abstract
Background: Patients with refractory or recurrent B-lineage hematological malignancies have less than 50% of chance of cure. Trials using autologous T-cells engineered with anti-CD19 chimeric antigen receptors (CAR) have demonstrated complete remissions even in chemotherapy-resistant malignancies, but the persistence of the cells is transient, limiting efficacy. Our hypothesis is modification of hematopoietic stem cells (HSC) with CAR will lead to persistent production of target-specific immune cells in multiple lineages, enhancing graft-versus-tumor activity and development of immunological memory.
Design/Methods: Using CD19 as target, we generated second-generation CD28- and 4-1BB-costimulated CAR constructs for modification of human HSC for assessment in vitro and in vivo, using third-generation lentiviral vectors. Additionally, co-delivery of suicide gene systems was tested to allow ablation of gene-modified cells.
Results: Gene modification of HSC with anti-CD19 CAR using lentiviral vectors did not impair differentiation or proliferation, and led to functional CAR-expressing cell progeny, at 40-50% transduction efficiency and engineered antigen-dependent cytotoxicity in myeloid, NK and T-cells. In vivo studies using humanized NSG engrafted with CAR-modified HSC demonstrated similar levels of humanization to non-modified HSC, with multilineage CAR-expressing cells present in bone marrow, spleen, blood and thymus in stable levels up to 44 weeks of life. No animals engrafted with CAR-modified HSC presented autoimmunity or inflammation. Ex vivo cells presented antigen-dependent cytotoxicity against targets. Mice engrafted with CAR-modified HSC had decreased CD19+ populations and successfully presented tumor growth inhibition and survival advantage at tumor challenge (55-60%). CAR-modified HSC led to development of T-cell effector memory and T-cell central memory phenotypes, confirming the development of long-lasting phenotypes due to directed antigen specificity. Mice humanized with gene-modified HSC presented significant ablation of gene-modified cells after treatment (p=0.002). Remaining gene-modified cells were close to background on flow cytometry and within two logs of decrease of vector copy numbers by ddPCR in mouse tissues.
Conclusions: CAR modification of HSC for cancer immunotherapy is feasible. This approach can be applied to different cancers by adjusting target specificity and could be employed in the context of HSC transplantation to augment the anti-lymphoma activity. It also bears the possibility of decreased morbidity and mortality and offers alternative treatment for patients with no available sources for bone marrow transplantation, benefiting ethnic minorities. These results also give proof of principle for CAR-modified HSC regulated by suicide gene; further studies are needed to enable clinical translation.

Disclosures
No relevant conflicts of interest to declare.
Mitochondrial Regulation Is Essential for Erythroid Nuclear Clearance
Authors: Liang Raymond , Menon Vijay , Lin Miao , Nowak Roberta , Fowler Velia M. , Girnun Geoffrey , Ghaffari Saghi 
Published: October 2019

Abstract
The terminal steps of red blood cell (RBC) generation involve an extensive cellular remodeling. This encompasses alterations of cellular content through five erythroblast stages that result in the expulsion of the nucleus (enucleation) followed by loss of mitochondria and all other organelles, and a transition to anaerobic glycolysis. Whether there is any link between the erythroid removal of the nucleus and the function of any other organelle including mitochondria remains unknown. Here we show that mitochondria are essential for nuclear clearance. We first demonstrate through high-throughput single-cell imaging and confocal microscopy that as mouse bone marrow erythroblasts mature (Gate 3: TER119+,CD44low, FSClow), mitochondria migrate to one end of the cell, aggregate and trail behind the nucleus as it extrudes from the cell, a prerequisite for enucleation to complete. We further show that mitochondrial localization behind the nucleus has similar kinetics as nuclear polarization. This process is also conserved in mouse fetal liver erythroid cells as well as in primary human CD34+-derived erythroblasts in culture. Notably, kinesin inhibition disrupts mitochondrial motility and localization and reduces significantly erythroblast enucleation rate in the absence of any impact on dynein or tubulin. These results suggest that mitochondria function as necessary chaperones during erythroblast enucleation. Furthermore, mitochondrial activity distinguishes erythroblasts on the verge of enucleation from others at the same erythroblast stage (Gate 3). We show that active mitochondrial respiration facilitates nuclear condensation and is required for nuclear extrusion. To our surprise however, metabolite profiling revealed that late-stage erythroblasts sustain mitochondrial metabolism and subsequent enucleation primarily through extracellular pyruvate but independently of glucose oxidation or anapleorotic reactions of amino acids. 13C-labeled metabolite tracing also confirmed pyruvate incorporation into mitochondria while glycolysis was minimal in orthochromatic erythroblasts. Thus, we provide evidence for the first time of a link between erythroid enucleation and mitochondrial metabolism. The process described establishes a model of mitochondrial compartmentalization within the cell for providing essential metabolites in a precise spatial and temporal manner. These findings are likely to improve the in vitro production of RBC and might be relevant to anemias of congenital mitochondrial disorders and aging.

Disclosures
No relevant conflicts of interest to declare.
Therapeutic Effect of Platelet Transfusion in Patients with Acute Lymphocytes Treated with CART Therapy
Authors: Yan Liu , Jue Xie , Hu Yongxian , Huang He 
Published: October 2019

Abstract
Background: CART therapy is the most effective method for the treatment of acute lymphoblastic leukemia (ALL) right now, which accompanied with severe cytokine storms (CRS) during treatment, resulting in severe platelet destruction and reduction. So the treatment of platelet transfusion is particularly important to the CART therapy. However, there is no clinical consensus on when given platelet transfusion can patients obtain the maximum benefit.
Methods: In the study, 14 ALL patients were enrolled for the CART treatment. The patients with platelet transfusion refractoriness (PTR) were excluded for non-immune factors such as large spleen and high fever. Blood routine and cytokines such as IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-17A were monitored during treatment. Body temperature should be less than 38 degrees before transfusion of platelets. Analyze the efficacy of platelet transfusion in patients before the CART treatment, the time with CRS, and after the CRS. The platelet transfusion effect was determined by 24-hour corrected count increment (CCI) (greater than 7.5 considered as effective, otherwise as invalid).
Results: All the patients in the study were treated with platelet transfusion before CART treatment. There was a CSR-3 level in every patients during the treatment. Four of them didn't get platelet transfusion as the lowest platelet count is more than 10×109/L without bleeding tendency. Ten of them received platelet transfusion treatment during CRS and the average of the cytokine were higher than before (IL-2 (12.65±21.08 pg/ml), IL-6 (8540.57±6791.91 pg/ml), IL-10 (1547.46±2939.45 pg/ml), IFN-γ (2846.49±2480.88 pg/ml),P<0.01). The 24 hour CCI of the 10 patients before CART treatment were 10.91±3.27, during CRS were 4.18±4.28, and after CRS were 8.72±2.93 (P<0.01). During the CRS, 24 hour CCI is higher in patients with platelet count below 5×109/L than patients with platelet count between 5-10×109/L(P<0.01).
Conclusion : CRS during CART treatment accelerated platelet consumption, resulting PTR. Platelet transfusion could not be given to patients when they were experiencing the most serious CSR without bleeding tendency, but it can be considered when the platelet count is less than 5×109/L,
Key Words: acute lymphoblastic leukemia, severe cytokine storms, platelet transfusion.
Fig 1: the relationship between 24 hour CCI and the highest IL-6:
The IL-6 is so high that we reduced it by one thousand times in the figure. The 24 hour CCI is negatively correlated with IL - 6, P<0.01, R=-0.92.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Second Primary Malignancies in Peripheral T-Cell Lymphoma, Not Otherwise Specified; A SEER Database Analysis
Authors: Kunwor Ranju , Nepal Mahesh , Ho Dominic , Ghimire Krishna 
Published: October 2019

Abstract
Background: Development of second primary malignancies (SPM) in Peripheral T-cell lymphoma, not otherwise specified (PTCL- NOS) patients is not well studied. This study was conducted to evaluate SPM in PTCL- NOS patients using data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries.
Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER*Stat) 18 database. We compared secondary cancer rate among adult PTCL-NOS patients ≥ 20 years of age during the period of 2000 - 2015. We used SEER MP-SIR session and Graph pad scientific software to calculate p value and Observed/Expected (O/E) ratio and excess risk per 10,000 compared to general population.
Results: The total number of adult PTCL-NOS patients reported was 3,321. Among them 211 patients developed ≥1 SPM, 75% of SPM occurred ≤ 5 yrs from the diagnosis of PTCL-NOS. All site secondary cancer (n=224) incidence was significantly higher among PTCL-NOS patients compared to general population with O/E: 1.73, p value < 0.05 with excess risk of 93.94 per 10,000.
Most common SPMs were Non-Hodgkin's lymphoma (NHL) with O/E: 9.53, P-value <0.05, excess risk 46.28; all leukemia O/E: 5.0, P value <0.05, excess risk 14.31; melanoma O/E: 2.29, p value<0.05, excess risk 7.27. The risk of all SPMs was increased within 5 yrs from the diagnosis of PTCL-NOS. However, risk of NHL as SPM continues after 5 yrs of diagnosis of PTCL-NOS. Sub group analysis by age and sex showed the similar pattern in the incidence of SPM.
Conclusions: This study showed that overall risk of second malignancies among PTCL- NOS patients is higher compared to general population. The risk of leukemia, lymphoma and melanoma is significantly increased during the first five years of diagnosis of PTCL-NOS.

Disclosures
No relevant conflicts of interest to declare.