bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic BH3 Profiling As Pharmacodynamic Biomarker for the Activity of BH3 Mimetics
Authors: Pan Rongqing , Wang Youzhen , Qiu Shumei , Ryan Jeremy , Halilovic Ensar 
Published: November 2020

Pharmacodynamic (PD) biomarkers provide information about the pharmacologic effects of a drug on its target, i.e. to assess whether a given agent is engaging its target in the expected manner. There is currently no convenient PD marker for BH3 mimetics. BH3 profiling (BP) is a functional assay developed to measure cells susceptibility to apoptosis and cell's dependence on certain Bcl-2 anti-apoptotic proteins for survival. Dynamic BH3 profiling (DBP) measures the changes of BP signals after drug perturbations. In this study, we studied whether DBP with lymphoid cells can serve as a PD biomarker for the activity of BH3 mimetics.
Using DBP and cell lines with defined dependency, we first showed that BH3 mimetics BCL201 (S55746) and S63845 are highly selective for Bcl-2 or Mcl-1, respectively. Next, we treated primary human lymphoid cells with BCL201 and then conducted DBP. We asked if pretreatment with BCL201 altered mitochondrial sensitivity to different BH3 peptides. After treatment with 1 μM BCL201, an amount consistent with achievable levels in vivo, T cell sensitivity to the Mcl-1 selective MS1 peptide, but not Bad peptide or Bfl-1 selective FS1 peptide, increased significantly, from 20% to 51%. These results suggest that BCL201 treatment increases T cell dependency on Mcl-1 and that DBP of T cells with MS1 peptide may serve as a PD marker for BCL201 activity. Similar results were also observed in B cells.
Next, we conducted DBP on healthy T cells treated with S63845. T cell mitochondrial sensitivity to MS1 peptide or Bcl-xL selective HRK peptide did not change. However, the treatment increased mitochondrial sensitivity to the Bad and FS1 peptides significantly, boosting the signal from 10.2% to 57.2% and 46.8% respectively, suggesting DBP of T cells with Bad or FS1 peptides can be robust PD markers for S63845 activity. This results also indicate that S63845 treatment augmented T cell dependency on Bcl-2 and Bfl-1 for survival.
Currently, we are investigating whether DBP can be used as a PD biomarker for in vivo studies. Our preliminary data suggest that DBP works well across different species (rat, mouse, and human). More importantly, DBP can detect changes in mitochondrial apoptotic signaling of ex vivo rat cells after in vivo treatment with BH3 mimetics.
Conclusions: Exposure to BH3 mimetics causes changes in mitochondrial apoptotic signaling of T/B cells which are readily detectable by DBP. DBP with lymphoid cells may provide a robust PD biomarker for clinical trials testing BH3 mimetics, either as monotherapy or in combination with other agents.

Disclosures
Wang: Novartis Institutes for Biomedical Research: Current Employment. Qiu:Novartis Institutes for Biomedical Research: Current Employment. Halilovic:Novartis Institutes for Biomedical Research: Current Employment, Current equity holder in publicly-traded company.
Levels of N-Terminal Pro-B-Type Natriuretic Peptide Relate to Risk of Infection in Multiple Myeloma Patients
Authors: Huang Weimin , Wei Xiaolei , Wei Qi , Wei Yongqiang , Feng Ru 
Published: November 2020

Background
Infections are a major complication in multiple myeloma (MM) patients and are associated with inferior outcomes. Thus there is a pressing need to predict risk of infection in MM patients.
Methods
Data from 110 MM patients were retrospectively analyzed. Patients were divided into high and low N-amino terminal fragment of the N-terminal pro-B-type natriuretic peptide (NT-proBNP) groups using the cut-off value 300ng/L at diagnosis.
Results
This study showed patients with high NT-proBNP had significantly higher beta-2-micorglobin (B2M), creatinine, lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG-PS) score, international staging system (ISS) score and lower estimated glomerular filtration rate (eGFR), hemoglobin, albumin than patients with low NT-proBNP. During the follow-up period, 46% presented at least one grade ≥3 infection. Patients with high NT-proBNP had high cumulative incidences of infections at the first 4 months and at the end of follow-up. Multivariate Cox regression analysis proved NT-proBNP to be an independent significant prognostic factor for grade ≥3 infections (relative ratio [RR] 2.190, 95% confidence interval [CI]: 1.126-4.261, P = 0.021).
Conclusions
This study revealed the potential of NT-proBNP for predicting risk of infection in MM patients. NT-proBNP may be applied as a criterion to identify patients with high risk of infection, who can benefit from prophylactic measures.

Disclosures
No relevant conflicts of interest to declare.
The Prognostic Significance of Minimal Residual Disease in Multiple Myeloma in the Molecular Genetic Groups Msmart 3.0
Authors: Garifullin Andrey , Voloshin Sergei , Linnikov Sergey , Martynkevich Irina , Kuvshinov Alexey , Kuzyaeva Anastasiya , Chubukina Zhanna , Shuvaev Vasily , Kleina Elizaveta , Bakai Marina , Sсhmidt Alexander 
Published: November 2020

Assessment of the role of genetic abnormalities and minimal residual disease (MRD) is an active developing area in hematology. The use of genetic methods makes it possible to predict the course of the disease and apply an individualized approach to antimyeloma therapy. At the same time, the identification of MRD after therapy determines possibility of relapse.
Aim. To identify the prognostic potential of MRD in patients in the standard and high molecular risk groups.
Materials and methods. We analyzed 72 patients with MM (median age was 59 years (range 37-80), male/female - 1.3:1). All patients received initial therapy with proteasome inhibitors and / or immunomodulators. High dose therapy (MEL200) and autologous stem cell transplantation (ASCT) was carried out 50 (69%) patients. Standard cytogenetic and FISH methods were used to stratify patients in risk groups of mSMART 3.0. The standard risk (SR) was established in 52 (72%) patients, the high risk (HR) - in 20 (28%) patients. The MFC MRD status of bone marrow was evaluated after 4-6 cycles of induction therapy or after ASCT with use of 5-colors flow cytometry. MRD-negative status (MRD-) was based on level of clonal plasma cells &lt;10-4 in bone marrow sample.
Results. The MRD- was reached in 36% (26/72) patients. The median of OS in MRD+ group was 104 months, in MRD- was 146 months (p=.01). The median of PFS in MRD+ group was 26 months, in MRD- was 70 months (p=.00021). 2-years PFS in MRD+ group was 56%, in MRD- group was 100% (p=.00021). We divided patients into the following groups for evaluation the effect of MRD on survival in risk groups: SR МRD+ 34/72 (47%), SR МRD- 18/72 (25%), HR МRD+ 12/72 (17%) and HR MFC МRD- 8/72 (11%). The median of OS in HR MRD+ group was 72 months, in SR MRD+ - 104 months, in HR MRD- - 146 months, in SR MRD- was not achieved (p=.02). The median of PFS in HR MRD+ group was 24 months, in SR MRD+ - 26 months, in HR MRD- - 68 months, in SR MRD- - 70 months (p=.003). The 2-years PFS in HR MRD+ group was 44%, in SR MRD+ group was 50% and in SR MRD- and HR MRD- groups were 100% (p=.003).
Conclusion. The absence of MRD is the most important prognostic factor. The leveling of negative effect of genetic abnormalities become possible when the MRD-negative response status is achieved. Presumably, this is due to the elimination of clonal plasma cells owing to the use of optimal antimyeloma therapy which is based on the risk stratification.

Disclosures
Martynkevich: Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Shuvaev:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau.
Factors Associated with Survival and Severe Cytokine Release Syndrome of Patients with Relapsed/Refractory B-ALL Receiving CD19 CAR-T Cell Therapy
Authors: Li Xi , Luo Chengxin , Xu Shuangnian , Ma Yanni , Chen Jieping 
Published: November 2020

Background : Chimeric antigen receptor-modified T (CAR-T) cells against CD19 have achieved great therapeutic effect in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, factors associated with the duration of survival and the occurrence of severe cytokine release syndrome (CRS) after CD19 CAR-T cell therapy have not been fully defined.
Patients and Methods: We analyzed 24 patients with relapsed/refractory B-ALL who received CD19 CAR-T cell therapy in a phase Ⅰ/Ⅱ clinical trial (ClinicalTrials.gov, NCT02349698). Infused CAR-T cell characteristics, its expansion kinetics in vivo, patient characteristics and laboratory parameters were analyzed for their correlation with overall survival (OS), progression-free survival (PFS), and the incidence of severe CRS.
Results: Sixteen patients achieved complete remission (CR), among which 13 achieved minimal residual disease-negative CR. Patients achieved CR had significantly prolonged OS and PFS compared with those who did not. Multivariable cox regression showed that lower peak of CAR-T cell expansion and the occurrence of severe CRS were significantly associated with both inferior OS and inferior PFS, and higher proportion of effector memory T cells in the infused cells was only significantly associated with inferior PFS. Nineteen patients developed CRS, among which 6 developed severe CRS. Compared patients with mild CRS, patients with severe CRS experienced worse vital sign instability and pancytopenia, higher incidences of coagulation and organ dysfunctions, and higher concentrations of procalcitonin and cytokines. Multivariable logistic regression showed that higher pretreatment disease burden was independent predictor of severe CRS.
Conclusions: Clinical and biological factors correlated with survival and severe CRS of refractory/relapsed B-ALL patients receiving CD19 CAR-T cell therapy were identified. These data may be helpful for improving the efficacy of CAR-T cell therapy, facilitating the recognition and early intervention of severe CRS.

Disclosures
No relevant conflicts of interest to declare.
Clinical Analysis of Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Shen Biao , Pang Aiming , Jiang Erlie , Feng Sizhou , Han Ming-Zhe 
Published: November 2020

Objective: To analyze the risk factors and survival of the patients with hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT).Methods: Propensity score Matching was conducted for HC patients among 523 patients who received HSCT in Hematopoietic Stem Cell Transplantation Center, Institute of Hematology & Blood Disease Hospital, Chinese Academy of Medical Sciences from August 2016 to August 2019. Non-HC patients were selected with a ratio of 1:2 (HC: non-HC) and then statistically analyzed with SPSS 22.0. Results:130 HC patients and 233 non-HC patients were included in the study. There were HC of grade I-II in 114/130 cases(87.69%) and of grade III-IV in 16/130 (12.31%), The median time of onset was 33 days after HSCT(range 3-339 days).Univariate analysis indicated that HC occurrence were associated with the source of stem cells, infusion CD34+ cells count, morphologic remission before transplantation, HLA matching, urinary BK virus load and the drug of Bu in conditioning regimens. Multiple regression analysis showed that morphologic remission before transplantation, HLA matching and infusion CD34+ cells count were associated with HC. K-M survival analysis showed that the 1-year survival rate of HC and non-HC was 91.8% vs 86.3%, and the 2-year survival rate was 52.5% vs 50.6%, respectively, showing no statistical difference. ROC curve showed that when the level of BKV is higher than 5×108 copies /ml, the risk of HC would increase.
Conclusion: HC was associated with morphologic remission before transplantation, HLA matching and infusion CD34+ cells count. There was no significant difference in survival between HC and Non-HC groups. the level of urinary BKV load higher than 5×108 copies /ml may cause hemorrhagic cystitis symptoms.
Key words: hemorrhagic cystitis; Allogeneic hematopoietic stem cell transplantation; Risk factors; Prognosis

Disclosures
No relevant conflicts of interest to declare.
Outcomes of Red Cell Exchange in Pregnant Patients with Sickle Cell Disease: A Case Series
Authors: Khan Suheb Mahammed , Abughanimeh Omar , Ebers Steven , Eclov Julie , Bobr Aleh , Koepsell Scott A , Nester Alex , Harper James , Gundabolu Krishna , Buddharaju Laxmi Narayana 
Published: November 2020

Background:
Pregnant patients with sickle cell disease (SCD) have higher morbidity compared to patients without SCD. SCD during pregnancy can increase the risk of fetal and obstetrical complications including preterm birth, preeclampsia, and others. Moreover, during pregnancy SCD can become more severe resulting in more sickle cell vasoocclusive crisis. Prophylactic transfusion during pregnancy has been used in practice to reduce sickle cell pain crisis since hydroxyurea is contraindicated during pregnancy. However, using prophylactic red blood cell exchange (RBCX) has been a controversial topic. In this study, we aim to evaluate the outcomes of red blood cell exchange in pregnant patients with SCD
Methods:
This is a retrospective study. We evaluated the charts of three pregnant patients who were enrolled in the chronic RBCX program at the University of Nebraska Medical Center at the time of their pregnancy. Data was collected to assess the sickle cell disease related complications during pregnancy, outcomes of pregnancy, and safety of the red blood cell exchange.
Results:
A total of 19 exchange procedures were performed for three pregnant patients while being enrolled in the chronic red blood cell exchange program. Patients demographic is summarized in table 1. The indication for enrollment in the red cell exchange program were recurrent vasooclussive crisis in patient 1 and 3, avascular necrosis in patient 2. The pregnancies were uncomplicated except for preeclampsia in the third patient resulting on early delivery. Overall, the three patients had less frequent visits to the emergency room for sickle cell related complications after starting apheresis and during pregnancy (Figure 1). We believe that the modest improvement that was noticed for the third patient was due to late enrollment in the exchange transfusion program and her older age compared to the two other patients
Conclusion:
Our study shows that red blood cell exchange for SCD patients during pregnancy can be safe, feasible, and can reduce the visits to the emergency room due to SCD related complication. Further larger studies are warranted to confirm this.

Disclosures
Gundabolu: BioMarin:Consultancy;Bristol Myers Squibb pharmaceuticals:Consultancy.
Association of Pulmonary MALT Lymphoma and Sarcoidosis
Authors: Baig Nabil , Rao Ravi Dama , Daniel Vijai , Kandaswamy Chitra , Vedire Apurva 
Published: November 2020

Introduction
Sarcoidosis is a systemic granulomatous disease of unknown etiology characterized by the chronic inflammation. Mucosa associated lymphoid tissue (MALT) lymphoma is a low-grade marginal zone B-cell lymphoma of MALT often etiologically associated with chronic inflammation in the underlying organ. A rare association between sarcoidosis and MALT lymphoma has been reported.
Case Description
We present the case of a 75-year-old woman who presented with chronic cough and dyspnea of several years' duration. She was found to have fluctuating lung infiltrates on serial imaging studies. A bronchial biopsy revealed chronic inflammation, and no evidence of infection. She was then treated with oral steroids with a transient benefit. However, the infiltrate and symptoms recurred, therefore 8 months later, she underwent repeat imaging. This showed a relapse of the infiltrate and enlarged mediastinal lymphadenopathy. The lung infiltrate was biopsied (percutaneously). This demonstrated a MALT lymphoma. Imaging studies done for staging showed a large retroperitoneal lymph node. A biopsy of this node revealed non-caseating granulomas, consistent with sarcoidosis. Chemotherapy with bendamustine and rituximab was initiated for therapy of the MALT lymphoma.
Discussion
A rare association between pulmonary MALT lymphoma and underlying inflammation caused by sarcoidosis has been previously described. In our patient, sarcoidosis was diagnosed in a biopsy of a retroperitoneal lymph node, but we suspect that there is likely involvement of the mediastinal nodes.

Disclosures
Rao: Bayer & Daiichi Sankyo:Consultancy.Daniel:GSK:Other: Paid speaker for COPD medications.
T(4; 14) Is Not a Poor Prognostic Factor for Newly Diagnosed Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation in New Drug Era
Authors: Geng Chuanying , Yang Guangzhong , Gao Wen , Wang Huijuan , Li Yanchen , WU Yin , Zhou Huixing , Zhang Zhiyao , Jian Yuan , Chen Wenming 
Published: November 2020

Background
The prognostic value of t(4;14) in newly diagnosed multiple myeloma (MM) patients undergoing autologous stem cell transplantation (ASCT) remains controversial. We aimed to evaluate the prognostic value of t(4; 14) for newly diagnosed MM patients undergoing ASCT in new drug era.
Methods
We retrospectively analyzed 419 newly diagnosed MM patients under 66 years of age in Beijing Chaoyang hospital, Capital Medical University. The propensity score matching technique was used to reduce the bias between groups.
Results
Among 419 patients, 243 (58.0%) patients received ASCT after induction therapy including new drugs with 12 months. Patients with ASCT had significantly longer median overall survival (OS) (69.8 vs. 59.3 months, p=0.034) and progression-free survival (PFS) (35.0 vs. 23.9 months, p=0.001) than non-ASCT patients. Univariate Cox proportional hazards regression analyses showed that ASCT was correlated with longer OS (HR=0.720, 95%CI: 0.531-0.977, p=0.035) and PFS (HR=0.618, 95%CI: 0.470-0.814, p=0.001). The favorable effect of ASCT on PFS was confirmed in multivariate (HR=0.376, 95%CI: 0.195-0.723, p=0.003), but it had no impact on OS in multivariate analysis (p=0.289). In the propensity score matching analysis, 116 patients, 58 in each group, were identified. Among 116 matched patients, patients with ASCT had longer PFS (52.1 vs.23.3 months, p=0.002) and OS (89.2 vs.50.2 months, p=0.010). Among 121 patients received ASCT and t(4; 14) measurement by fluorescence in situ hybridization, 30 (24.8%) patients presented translocation t(4; 14). Univariate Cox analyses showed that t(4; 14) was not correlated with PFS (p=0.347) and OS (p=0.454). Multivariate Cox analyses also showed that t(4; 14) was not correlated with PFS (p=0.466) and OS (p=0.349). There was no significant difference in PFS (36.5 vs.37.0 months, p=0.344) or OS (54.0 vs.81.7 months, p=0.452) in ASCT patients with or without t(4;14).
Conclusion
These results demonstrated that ASCT was a favorable prognostic factor for newly diagnosed MM patients under 66 years of age, however, t(4; 14) had no prognostic value for newly diagnosed MM patients received ASCT in new drug era.

Disclosures
No relevant conflicts of interest to declare.
Coagulation Dysfunction and Hematological Changes in 633 Patients with COVID-19
Authors: Yang Mo , Deng Huixia , Yang Liuming , Li Liang , Ye Jieyu , Cheng Yucai , Tan Yafang , Chong Beng H , Li Qiang 
Published: November 2020

Background: A previously unknown beta-coronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. The virus was named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the international committee for the classification of viruses (ICTV). The disease caused by this virus was named as coronavirus disease 2019 (COVID-19). In addition to pulmonary manifestations, hematological changes such as lymphocytopenia, thrombocytopenia, and coagulation dysfunction can also be found in COVID-19 patients, and the mechanism is still unclear.
Case data and methods: A total of 633 COVID-19 patients from Wuhan hospital of China were retrospectively analyzed. Clinical case data of all patients were collected, including gender, age, chronic underlying diseases, outcome, and blood laboratory test results. The hematological features of COVID-19 patients and the factors affecting their outcome were analyzed.
Results: Of 633 patients with COVID-19, the median age was 62 years (interquartile range, IQR, 51.0-70.0) and 330 (52%) were men. Lymphocytopenia (lymphocyte count, 1.0 ×109 / L [IQR, 0.7-1.4]) occurred in 317/607 patients (52%), thrombocytopenia (platelet count &lt;100 × 109/ L) occurred in 14/62 death patients (23%), prolonged prothrombin time (13.8 seconds [IQR, 13.1-15.1]) in 289/486 patients (59%), increased D-Dimer level (0.7 mg/L[IQR, 0.2-2.9]) in 230/411 patients (57%) and increased C-reactive protein levels (10.7 mg/L [IQR, 2.2-49.7]) in 217/426 patients (51%) . Compared with the survival patients, death patients have higher white blood cell count (11.7 × 109/L [IQR, 8.4 to 15.6]), neutrophil count (10.8 × 109/L [IQR, 7.8 to 13.9]), neutrophil count/lymphocyte count (20.5 [IQR, 12.4-34.2]), activated partial thromboplastin time (36.8 seconds [IQR, 31.3-42.3]), prothrombin time (17.1 seconds [IQR, 14.7 to 19.7]), D-Dimer level (4.6 mg/L [IQR, 1.0 to 7.8]), C-reactive protein level (111.8 mg/L (IQR, 53.1 to 196.6), and low lymphocyte count (0.5 × 109/L [IQR, 0.3 to 0.7]). The results of logistic multivariate regression analysis showed that age, neutrophil count, prothrombin time, and C-reactive protein were risk factors for patients with COVID-19.
Conclusion: Hematological changes are common in patients with COVID-19. The early stage of the disease is mainly characterized by lymphocytopenia, thrombocytopenia, and the late stage may be characterized by more severe lymphocytopenia, even neutrophils elevation, elevated C-reactive protein, and severe coagulation disorder. The pathogenesis may be mediated by a direct viral infection and/or indirect immunopathology.

Disclosures
No relevant conflicts of interest to declare.