bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Contribution of Proteasome Subunits to Myeloma Cell Viability and Proteasome Inhibitor Sensitivity
Authors: Shi Chang-Xin , Zhu Yuan Xiao , Bruins Laura Ann , Bonolo De Campos Cecilia , Stewart William , Braggio Esteban , Stewart A Keith 
Published: November 2019

Background
Bortezomib (BTZ) is highly effective in the treatment of multiple myeloma; however, emergent drug resistance is common. The underlying mechanisms of such proteasome inhibitor resistance are still incompletely understood.
Methods
To further understand its resistant mechanism, we generated eight multiple myeloma (MM) cell lines resistant to bortezomib (BTZ) by exposure to increasing drug concentration: five of them acquired novel PSMB5 mutations. Given the rarity of similar mutations in over 1,500 analyzed MM patients, we explored in depth the role of the proteasome on MM cell viability and BTZ sensitivity by systematically deleting the major proteasome targets of BTZ by CRISPR.
Results
We demonstrated that MM cell lines without PSMB5 were surprisingly viable (mutation corresponding yeast gene pre2 is lethal). PSMB5 mutated, BTZ resistant, MM cell lines were re-sensitized to BTZ when PSMB5 was experimentally deleted, implying that this mutation is activating in its drug resistance function. In contrast PSMB6 knockout was lethal to MM cell lines, which were efficiently rescued by re-introduction of wild type PSMB6. Interestingly, reduction in PSMB6 levels also prevented the splicing of the major catalytic subunits PSMB5, PSMB7, PSMB8 and PSMB10. PSMB6 engineered with no splicing function or catalytic activity, also restored viability, inferring that the contribution of PSMB6 to proteasome structure is more important than functional activity. Supporting this observation, BTZ sensitivity was restored in resistant MM cells line by introducing low level expression of mutated PSMB6 lacking splicing function. As with PSMB6, PSMB7 knockout was lethal to MM cell lines. In contrast, loss of immunoproteasome subunits PSMB8 and PSMB9 was neither lethal nor restored sensitivity to BTZ. Our results demonstrate that expression of the three constitutive proteasome subunits PSMB5, PSMB6 and PSMB7 is highly co-dependent. This dependence is relying on the structure, but not the function, of PSMB5 and PSMB6.
Conclusions
In summary, PSMB5 and PSMB6, but not PSMB8 and PSMB9, are highly relevant for BTZ sensitivity in MM. Absence of PSMB6 or PSMB7, but not PSMB5, was lethal in MM cell lines. Expression of PSMB5, PSMB6 and PSMB7 was highly co-dependent. Together these findings suggest that the modulation of expression rather than function of PSMB5, PSMB6 or PSMB7 may be a new therapeutic strategy.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of CAR-T Therapy with Safety Switch Targeting Bcma for Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Clinical Study
Authors: Fu Weijun , Du Juan , Jiang Hua , CHENG Zhi , Wei Runhong , Yu Kang , Jiang Songfu , He Feng , Fang Hongliang , Liu Yarong , Wang Pin 
Published: November 2019

Background: Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated T cells to express a second-generation CAR with the 4-1BB costimulatory domain along with a truncated epidermal growth factor receptor (tEGFR) as a safety switch. The preclinical study confirmed its high reactivity against MM cells. Methods: A phase 1 clinical trial (NCT03093168) has been launched to evaluate the safety and feasibility of this BCMA CAR-T cell product for treating RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have over 5% BCMA expression on plasma cells (Nine patient with extramedullary plasmacytoma does not express BCMA). Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m2, d-5 to d-3) and Flu daily for 3 days (25 mg/m2, d-5 to d-3) prior to the CAR-T infusion (d0) at a dose of 9×106CAR+ cells/kg. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity is graded by CTCAE 4.03. Results: As of March 1th, 2019, 46 patients had been infused with this intended dose of the autologous BCMA CAR-T cells, and 44 patients had reached at least 1 month of follow-up. As of this data cut-off, the overall response rate (ORR) for the 44 evaluable patients was 79.6%, including 2sCRs, 16CRs, 8VGPRs and 8PRs, and 16 patients reached MRD-negative response. The CAR-T cell expansion and persistence were consistently observed throughout these patients. The medianPFS is 15mon, and the median OS result has not been reached (49.16% progression-free survival, and 53.95% overall survival at 24 months). Among the 44 infused patients, 22.7% had grade 1-2 Cytokine release syndrome (CRS ) and 6.8% (3 patients) had grade 3 CRS. No grade 4 CRS reactions developed and all toxicities were fully reversible. Conclusions: Our result demonstrates the high potential of this single CAR-T infusion therapy for RRMM, including 2sCRs, 16CRs and ongoing clinical responses for more than 26 months, with manageable CRS to date. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy.

Disclosures
No relevant conflicts of interest to declare.
Safety and Anti-Tumor Activity Study of Loncastuximab Tesirine and Durvalumab in Diffuse Large B-Cell, Mantle Cell, or Follicular Lymphoma
Authors: Moskowitz Craig H. , Bastos-Oreiro Mariana , Ungar David , Dautaj Ilva , Kalac Matko 
Published: November 2019

Introduction:
Loncastuximab tesirine (Lonca) is an antibody-drug conjugate (ADC) comprising a humanized anti-CD19 antibody (Ab) conjugated to a pyrrolobenzodiazepine dimer toxin. In a Phase 1, first-in-human ADCT-402-101 clinical study, Lonca demonstrated single-agent anti-tumor activity with manageable toxicity in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). Durvalumab is a human monoclonal Ab of the immunoglobulin G-1 kappa subclass that blocks the interaction of programmed death-ligand 1 (PD-L1) with PD-1 on T-cells and with CD80 (B7.1) on other immune cells. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, including those that may result in tumor elimination. Preclinical data, as well as early results from clinical trials combining ADCs and checkpoint inhibitors, show potentially increased effectiveness of these therapeutics when used in combination and provide the rationale for the current trial.
Study Design and Methods:
This is a Phase 1b, open-label, dose escalation (Part 1) and expansion (Part 2) trial of Lonca combined with durvalumab in patients with R/R DLBCL, MCL, or FL (NCT03685344). The key inclusion and exclusion criteria for the ADCT-402-104 study are reported in Table 1, and the dosing schema is presented in Figure 1. This trial will evaluate the safety and tolerability, preliminary anti-tumor activity, pharmacokinetics, pharmacodynamics, and immunogenicity of Lonca combined with durvalumab. Patients will receive Lonca once every 3 weeks for 2 doses in total, and durvalumab every 4 weeks for up to 1 year. Patients with only partial response or stable disease at the second disease evaluation may receive 2 additional doses of Lonca given once every 3 weeks. During Part 1, the dose of Lonca will be escalated using a classic 3+3 design with a fixed dose of durvalumab. Part 2 will consist of up to 3 expansion cohorts, one for each of the DLBCL, MCL, and FL populations. All patients in Part 2 will receive the dose of Lonca determined in Part 1, with a fixed dose of durvalumab. The trial opened in February 2019 and recruitment is ongoing.
Study sponsored by ADC Therapeutics SA with the support of MedImmune Limited, a wholly-owned subsidiary of AstraZeneca Pharmaceuticals PLC, which supplies durvalumab (http://clinicaltrials.gov/show/NCT03685344).

Disclosures
Moskowitz: ADC Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Celgene: Consultancy; Pharmacyclics: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. Dautaj:ADC Therapeutics: Employment, Other: Stock options.
ABO Blood Groups and the Risk of Venous Thromboembolism (VTE) Among Saudi Patients at a Tertiary Care Hospital in Riyadh
Authors: Kullab Ghaydaa Juma , Zaidi Abdul Rehman Z. , Albaqmi Sultan , Alajlan Haya , Alsheef Mohammed Abdullah 
Published: November 2019

Background:
ABO blood types are scientifically proved to be associated with the risk of venous thromboembolism (VTE), but data is lacking in the Saudi population.
Aims:
We aimed to investigate the association between ABO blood types and VTE, to explore potential interactions between ABO blood type with sex and obesity status.
Methods:
This was a retrospective study with a total of 998 patients, who were admitted with venous thromboembolism at our tertiary care hospital, between January 2010 and January 2018. Demographic and clinical data were collected. We used chi-square tests to assess the association between ABO blood group and the development of VTE. It was decided that the test will be considered significant if the p-value is <0.05.
Results:
Out of 998 VTE patients, 506 of patients were excluded, because their ABO blood group was not tested. Therefore, 492 patients were qualified as study subjects, of whom 66% of patients had DVT, 23% of patients had pulmonary embolism. Most of them had provoked VTE. Female patients constituted the majority of the study subjects (82.5%). Sample distribution appeared that O blood group was present in 34.1% of all VTE patients, while non-O-blood groups were present in 66% of them. Overall, there was a non-significant difference between VTE in patients with non-O blood type compared to O blood type (p=0.268).
Conclusions:
Non-O-blood groups (A, B, AB) are the most common blood types in Saudi patients with VTE. There is no statistically significant association between ABO blood groups, gender, and obesity status.

Disclosures
No relevant conflicts of interest to declare.
TP53 Abnormality in Myelodysplastic Syndrome
Authors: Huang Fei , Chen Yu , Zhu Yuxing , Qiao Chun , Qian Sixuan , Li Jianyong , Shen Wenyi 
Published: November 2019

TP53 (tumor suppressor gene P53), one of the most important tumor suppressor genes, plays an important role in cell cycle arrest, cell senescence, apoptosis, differentiation and metabolism. The TP53 gene is located on 17p13.1, its encoded product is the transcription factor P53 protein, which is known as the "the guardian of the genome". Alterations of TP53 include mutations and deletions and are generally associated with advanced stages of disease, insufficient therapy-response and poor prognosis.
The main purpose of our study was to comprehensively analyze the TP53 mutation and 17p deletion in MDS in our single center. To better understand the relationship between TP53 abnormality and clinical phenotype, prognosis, leukemia transformation, therapeutic response of MDS. Next generation sequencing (NGS) method combining with cytogenetics analysis were used, 36 common related AML/MDS/MPN related genes such as TP53, TET2, WT1, ASXL1, U2AF1, RUNX1, etc were covered. According to the 2016 WHO classification and prognosis score system and from June 2011 to June 2017, 88 newly diagnosed MDS patients including 17 MDS-SLD, 32 MDS-MLD,6 MDS-RS,19 MDS-EB-1,11 MDS-EB-2 and 2 MDS-U, 1 5q- syndrome were enrolled. TP53 mutation/deletions were found in twenty-two (25%) of the 88 newly diagnosed MDS patients, among them,7 MDS-SLD, 4 MDS-MLD, 2 MDS-RS, 1 5q-, 6 MDS-EB-1 and 6 MDS-EB-2. TP53 mutation/deletions cases had a higher proportion of bone marrow blasts compared with TP53 negative cases (P=0.009), At the same time, TP53 positive were highly correlated with MDS-EB-2 subtype (P=0.025), complex karyotype (P<0.001). Based on a median follow-up time of 21(1-267) months in all pts, 13 patients (14.8%) progressed to AML and pts with TP53 mutation/deletions tended to progress to AML (P=0.056) with a shorter OS (P=0.005) and PFS (P=0.001). NGS data of accompanying mutation in other classical leukemia genes shown that compound TP53 and U2AF1 mutations were significantly associated with disease progression. For TP53 mutation/deletion group (n=22), we further sequenced the TP53 status at multiple time point of pre and after DAC treatment, results shown that all patients had persistent TP53 positive status before and after treatment.
In conclusion, our results indicate that in MDS TP53 mutation/deletions is highly correlated with MDS-EB-2 subtype, IPSS high-risk group, and complex karyotype. TP53 mutations that occur in the early stages of MDS may contribute to disease progression and leukemia transformation in conjunction with other molecular abnormalities. DAC improves outcomes in patients with TP53 mutation/deletion but may not clear TP53 mutations.

Disclosures
No relevant conflicts of interest to declare.
Dual Epigenetic Agents Plus Rituximab-Gemcitabine-Oxaliplatin As a Salvage Treatment in Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients
Authors: Qu Changju , Ping Nana , Kong Danqing , Xia Fan , Wu Depei , Jin Zhengming 
Published: November 2019

Background: Chemo-resistance is a core challenge in successful treatment of diffuse large B cell lymphoma (DLBCL). It has been previously reported that DNA hypermethylation and histone deacetylation are two major epigenetic modifications contributing to chemo-resistance in multiple tumors. Moreover, combination of histone deacetylase inhibitors (HDI) and DNA methyltransferase inhibitors (DNMTI) resulted in synergistic anti-lymphoma effect toward refractory and/or relapsed (R/R) DLBCL cells in vitro and in vivo xenografts. R-GemOx (rituximab, gemcitabine, and oxaliplatin), as a first-line chemotherapy regimen for elderly primary DLBCL patients or a salvage chemotherapy regimen for R/R DLBCL patients not candidates for high-dose therapy, has shown high activity with a relative low toxicity profile. Herein, we therefore aimed to assess the efficacy, safety, and feasibility of the dual epigenetic agents plus R-GemOx regimen (CD-R-GemOx) as a salvage treatment in R/R DLBCL patients.
Methods: 13 R/R DLBCL patients including 8 males and 5 females, diagnosed with R/R DLBCL on the basis of the 2008 World Health Organization guidelines, who had failed from previous salvage treatment were exposed to dual epigenetic agents (Chidamide 30mg biw and Decitabine 10mg/m2 qd d1-d5) and sequential R-GemOx(rituximab 375 mg/m² qd d6; gemcitabine 1 g/m² d7,d14; and oxaliplatin 100 mg/m² d8) for salvage chemotherapy. Median age of these patients was 56 (35-67) years old. Most (10/13) patients have advanced Ann Arbor stages. The cycle was repeated every 4 weeks. Clinical efficacy were assessed after two cycles.
Results: All thirteen (100%) patients achieved disease control response. Ten (76.9%) patients achieved an overall response at the end of the treatment, with three (23.1%) achieving a complete response. Common grade 3-4 adverse events were haematological toxicities (thrombocytopenia in ten [76.9%] patients, anaemia in six [46.2%], and neutropenia in twelve [92.3%]) and gastrointestinal complications (nausea in four [30.8%] patients, vomiting in one [7.7%], diarrhoea in six [46.2%] and mucositis in six [46.2%]). Besides, 6/13 (46.2%) cases manifested with pyrexia; 3/13(23.8%) cases manifested with increase of ALT and hyperbilirubinemia. All above toxicities were reversible and recovered within 1 month after chemotherapy. No neurological toxicities and treatment-related deaths were observed.
Conclusions: Our study indicates that combination of dual epigenetic agents and R-GemOx is a safe and promising salvage approach to managing R/R DLBCL patients and may serve as an optimal salvage treatment for bridging autologous transplantation.

Disclosures
No relevant conflicts of interest to declare.
Impact of Comorbidities on Survival of Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors
Authors: Engelbrecht Fernanda F , Miranda Eliana C , Delamain Marcia Torresan , Duarte Gislaine Borba , Souza Carmino Antonio , De Paula Erich V , Pagnano Katia B 
Published: November 2019

Tyrosine kinase inhibitors treatment changed dramatically the survival of CML patients, approaching to the survival of the normal population. Comorbidities may also impact treatment results.
Aim: to investigate the impact of comorbidities in the survival of CML patients treated with TKI
Methods: We collected clinical and laboratory data from CML patients treated in a single center from medical records from January 2001 to December 2018. Comorbidities were collected at diagnosis before treatment and Charlson comorbidity index (CCI) was calculated. Because of CML diagnosis, the lowest possible score was 2. Patients were treated with imatinib 400-600 mg and one was treated with dasatinib in first line. Management followed the European Leukemia Net recommendations. OS probabilities were calculated using Kaplan-Meier method. OS was defined as the time between diagnosis and death of any cause, independent of treatment. Cox models were estimated for the multivariate analysis. All calculations were performed with version 24.0 SPSS software.
Results: We included 273/310 patients in this analysis; 37 pts were excluded because of previous treated in other centers. Patients characteristics: 57.3% males, median age at diagnosis was 49 (14-86); 263 (96%) chronic phase and 11 (4%) accelerated phase; Sokal low risk 36.8%, intermediate 31.8% high risk 31.4%; EUTOS low risk (81.7%) and high risk (18.3%); median follow-up time was 92 months (1-223). Most frequent comorbidities: hypertension (27.2%); diabetes (7.5%). Smoking at diagnosis (15.3%). CCI group categories were: 2 (n=131), 3 (n=52), 4 (n=46), 5 or more (n=45). Probabilities of OS at 10 years for patients with CCI 2, 3 to 4 and ≥ 5 to were 81%, (95% confidence interval [CI]: 73-89%), 77% (95%CI: 63-100%), 69% (95%CI:53-85%), and 62% (95% CI: 38-86%), respectively. Probabilities of OS according to Sokal score was 86% (low risk) vs. 73% (intermediate) vs. 68% (high risk), P=0.002 and for EUTOS score 79% (low risk) vs. 61% (low risk), P=0.004. OS was lower in patients with hypertension (63% vs. 80%), P=0.018. In a multivariate analysis including CCI Sokal and EUTOS Score, smoking, diabetes, hypertension, the most powerful predictive factors for death were high and intermediate Sokal score and hypertension ((Wald test, P =0.003 and 0.049, respectively). There were 58 deaths, 22 not related to CML and 2 causes unknown.
Conclusions: Comorbidities represents an important cause for mortality in CML patients treated in real life, besides known disease risk factors as Sokal and EUTOS scores. CCI high scores and hypertension were related to a lower OS.
Figure 1

Disclosures
Delamain: Novartis: Honoraria. Pagnano:Abbvie: Consultancy; Sandoz: Consultancy; Pint Pharma: Consultancy.
Predictors of Heparin-Induced Thrombocytopenia in Adult Cardiac Surgery Patients
Authors: Allan Kari , Crow Jessica , Chasler Jessica , Athale Janhavi , Lindsley John , Streiff Michael B. , Dane Kathryn 
Published: November 2019

Background: The 4Ts, HIT-Expert Probability (HEP), and Post-Cardiopulmonary Bypass (CPB) screening tools for heparin-induced thrombocytopenia (HIT) have not been validated in cardiac surgery patients. Evidence remains unclear regarding which screening tool most accurately predicts HIT in this population.
Methods: HIT-positive and HIT-negative patients who underwent on-pump cardiac surgery within a six-year period were matched 1:2 in a case-control design. Each patient was scored with the 4Ts, HEP, and CPB tools. Sensitivities and specificities of each tool were calculated using standard cut-offs. The Youden method was utilized to determine optimal cut-offs in receiver operating characteristic (ROC) curves of each score, then sensitivities and specificities were recalculated. A multivariable logistic regression was performed to determine the association of scoring tool components and relevant clinical characteristics with HIT.
Results: Using standard cut-offs for the scoring tools, sensitivities for the CPB, HEP, and 4Ts tools were 100%, 93.9%, and 69.4%, respectively. Specificities were 51%, 49%, and 71.4%, respectively. Using the Youden method-derived optimal cut-offs, sensitivity of the CPB score remained 100% with improved specificity to 88.9%. Sensitivity of the 4Ts score declined to 51% and specificity improved to 93.9%. Pattern of platelet decline, absence of clinically significant bleed, body mass index, coronary artery bypass graft surgery, and postoperative heparin duration were significantly associated with HIT.
Conclusions: The 4Ts score has limited utility in cardiac surgery patients, whereas the CPB and HEP scores with standard cut-offs demonstrated high sensitivity but low specificity. A cut-off of 3 points or higher on the CPB score could increase specificity while preserving high sensitivity.

Disclosures
Crow: Research Point Global: Other: Clinical and coding data review services. Streiff:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Roche: Research Funding; Portola: Consultancy, Honoraria; Bayer: Consultancy, Honoraria.