bluuebunny/crossref_metadata_2025 huggingface dataset:
Middle East Respiratory Syndrome (MERS) Infection in Hematological and Oncological Patients: A Case Series from a Tertiary Care Center in Saudi Arabia
Authors: Alaskar Ahmed , Bosaeed Mohammed , Rehan Hina , Mendoza May Anne , Alahmari Bader , Othman Adel , Alhejazi Ayman , Abuelgasim Khadega , Damlaj Moussab , Alzahrani Mohsen , Gmati Giamal , Salama Hind , Abolfotouh Mostafah , Shaheen Naila
Published: November 2019

We present the largest to date of a case series of nine patients with hematological and oncological malignancies who were infected with Middle East Respiratory Syndrome Coronavirus (MERS-CoV). MERS-CoV is a novel beta-coronavirus with a high fatality rate in comorbid patients. The majority of MERS cases globally were reported from Saudi Arabia (1983 cases, including 745 related deaths with a case-fatality rate of 37.5%) according to the WHO update of February 2019. All were clinically stable before acquiring the virus.

Most of the cases had an active disease as relapse or refractory with three cases being neutropenic. The clinical presentation and radiological features of the patients were variable and inconsistent (Table 1). Diagnosis was confirmed with RT-PCR assays targeting upstream of the E gene and the open-reading frame gene 1a which had to be done repeatedly and required an average of 3 (with max. of 7) samples for a test to be positive (Table 2). All the patients developed respiratory failure, were admitted to the critical care unit (ICU) and required mechanical ventilation. The length of hospital stay ranged from 15 - 48, with an average of 24 days. Unfortunately, all nine patients died within days after admission to the ICU. In addition, the time from diagnosis to death has an average of 9 days ranging from 2-24 days, respectively.

In conclusion, MERS CoV infection in hematology/oncology patients has a very poor prognosis regardless of the status of the underlying disease. The clinical presentation is not distinctive and confirming the diagnosis requires numerous respiratory samples. Measures to prevent nosocomial outbreaks should include proper compliance with personal protection equipment by health-care workers when managing patients with suspected and confirmed MERS-CoV infection and prompt isolation of infected patients. Future research is required to enhance our understanding of the disease and to evaluate superior diagnostic and therapeutic options.

Disclosures

No relevant conflicts of interest to declare.
Lymphatic Control of the Tumor Immune Microenvironment
Authors: Swartz Melody A.
Published: November 2019

Tumor engagement or activation of surrounding lymphatic vessels is well-known to correlate with tumor progression and metastasis in melanoma and many other cancers. We and others have identified several mechanisms by which the lymphatic growth factor VEGF-C and lymphangiogenesis can promote metastasis, including (i) increasing immune suppressive cell types and factors in the tumor microenvironment both directly and indirectly, (ii) inhibiting maturation of antigen-presenting cells and T cell activation, and (iii) driving changes in the stromal microenvironment that promote both cancer invasion and immune suppression. However, lymphatic activation also enhances communication with cells in the draining lymph node by antigen and cell transport, which may trigger the initiation of adaptive immune responses against the tumor. Under normal conditions, the potential anti-tumor effects are rendered 'dormant' by the pro-tumor immune suppression, and the tumor progresses. However, we are now observing that lymphangiogenic tumors are exceptionally responsive to immunotherapy, implying that the anti-tumor aspects can be unleashed when the overall balance of pro- and anti-tumor immune aspects is tipped enough towards the latter (e.g., upon tumor cell killing). On the mechanistic side, we are finding that 'lymphangiogenic potentiation' depends on tumor cell infiltration of both CD103+ dendritic cells and naïve T cells, driving local T cell education post-immunotherapy and antigen spreading. On the translational side, we are developing novel strategies to exploit lymphangiogenesis for cancer immunotherapy. Understanding the yin and yang of lymphatic activation in the tumor microenvironment and how it affects immunity may lead to exciting new translational strategies for cancer immunotherapy.

Disclosures

No relevant conflicts of interest to declare.
Synergistic Activity of Belantamab Mafodotin (anti-BCMA immuno-conjugate) with PF-03084014 (gamma-secretase inhibitor) in Bcma-Expressing Cancer Cell Lines
Authors: Eastman Stephen , Shelton Christopher , Gupta Ira , Krueger Julie , Blackwell Christina , Bojczuk Paul M
Published: November 2019

Multiple myeloma (MM) is a plasma cell malignancy characterized by clonal proliferation of plasma cells within the bone marrow. B cell maturation antigen (BCMA) is a cell-surface receptor required for the survival of plasma cells and is also ubiquitously expressed on MM cells. Belantamab Mafodotin (GSK2857916) is a humanised monoclonal anti-BCMA antibody, which is afucosylated and conjugated to the microtubule-disrupting agent monomethyl auristatin-F (MMAF). Upon binding to BCMA on the cell surface, belatamab mafodotin is rapidly internalised and the cytotoxic moiety (cys-mcMMAF) is released, leading to direct cell death.

BCMA is directly shed from the plasma membrane by gamma-secretase, a type-I sheddase. In order to further enhance belantamab mafodotin activity, we sought to increase cell surface levels of BCMA by blocking shedding of BCMA with a gamma-secretase inhibitor (GSI). We then determined the effect on the activity of belantamab mafodotin by combining belantamab mafodotin with PF-03084014, a highly-selective GSI. In order to understand combination effects against immuno-conjugate activity, a 3-day proliferation assay on a panel of multiple myeloma and lymphoma cell lines with varying levels of BCMA expression was conducted. The assay showed a 50 to 3,000-fold EC50 shift in cell lines sensitive to belantamab mafodotin across multiple lymphoma cell types.

Antibody-dependent cellular cytotoxicity (ADCC) activity of belantamab mafodotin in combination with PF-03084014 was also examined. In a 24-hour ADCC Jurkat reporter assay, an EC50 shift across multiple BCMA-expressing cell lines was observed. Even cell lines with very low BCMA expression, such as Raji, showed a synergistic increase in ADCC activity in combination with PF-03084014. Cell lines that were non-responsive in the cell proliferation assay, showed activity in the ADCC assay, indicating low-expressing BCMA cell lines remain sensitive to belantamab mafodotin, alone and in combination with PF-03084014.

Synergistic effect from this preclinical work provided rationale to support clinical evaluation of belantamab mafodotin in combination with PF-03084014 in a planned clinical trial (DREAMM-5).

Disclosures

Eastman: GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Krueger:GlaxoSmithKline: Employment, Equity Ownership. Blackwell:GlaxoSmithKline: Employment, Equity Ownership. Bojczuk:GlaxoSmithKline: Employment, Equity Ownership.
Low-Dose Triptolide Enhances Bromodomain Inhibitor JQ1-Induced Apoptosis of Acute Myeloid Leukemia Cells Via Down-Regulation of c-Myc Following RAS/MEK/ERK Inhibition
Authors: Xu Bing , Shi Yuanfei , Zhao Haijun , Qiu Yi
Published: November 2019

The current therapy for acute myeloid leukemia (AML) remains greatly challengeable because most patients ultimately relapse due to resistant to current chemotherapies. Therefore, development of novel therapies using a variety of agents targeting varying pathways is needed to further improve patients' survival. Here we report that low dose triptolide (TPL), a natural product derived from plant Tripterygium wilfordii, could enhance bromodomain inhibitor JQ1-induced apoptosis of AML cell lines as well as primary cells from patients with de novo and relapsed or refractory (R/R) AML, while sparing their normal counterparts. Moreover, combination of TPL and JQ1 showed a more powerful activity to suppress AML cell growth in a xenograft model than single agent. Mechanistically, the synergetic effects of TPL and JQ1 were associated with impaired mitochondrial membrane potential, increased reactive oxygen species (ROS) production and imbalance of the Bcl2 family of pro-apoptotic and anti-apoptotic proteins, leading to caspase-dependent apoptosis. Meanwhile, RNAseq analysis revealed that ERK/MAPK signaling cascades are responsible for the enhanced activity of TPL in combination with JQ1 against AML. In summary, this study demonstrates that low-dose TPL synergizes with JQ1 to target AML through inhibiting ERK/MAPK signaling and mitochondrial apoptosis pathway, supporting a potential option of combination of TPL and JQ1 for AML treatment.

Disclosures

No relevant conflicts of interest to declare.
Noninvasive Microscopic Imaging Reveals Increased Leukocyte Adhesion and Rolling in Skin of Acute Graft-Versus-Host Disease Patients Compared to Post-Transplant Controls
Authors: Saknite Inga , Byrne Michael T , Jagasia Madan , Tkaczyk Eric R.
Published: November 2019

BACKGROUND. The nature and kinetics of leukocyte migration are intimately connected to the pathophysiology of acute graft-versus-host disease (aGVHD). Real-time visualization of leukocyte-endothelial interactions in patients post hematopoietic transplantation (HCT) may augment clinical diagnosis and patient management. In this cross-sectional pilot study, we aimed to test the feasibility of parameters characteristic of leukocyte motion in skin capillaries as potential imaging biomarkers to detect aGVHD.

STUDY POPULATION. We enrolled 16 post-HCT patients: 8 patients with any organ aGVHD and 8 patients with no organ aGVHD on the day of the imaging. Diagnoses were retrospectively confirmed on day 100 by a transplant physician (MB), who was blinded to the results of the confocal imaging. 7 out of 8 aGVHD patients had only skin involvement: stage 1 (N=2 patients), stage 2 (N=2), and stage 3 (N=3) cutaneous aGVHD, whereas one patient had stage 1 gut aGVHD with no skin involvement. 6 out of 8 aGVHD group patients required systemic therapy with steroids.

METHODS. To noninvasively visualize leukocyte motion in the topmost capillaries of post-HCT patients' skin, we used a clinical reflectance confocal microscope (Vivascope 1500, Caliber I.D.). It enables real-time en face view of individual cells at 9 frames per second. We took twenty 30-second videos of different capillaries in the left volar forearm and left upper chest. We counted the number of adherent and rolling leukocytes per 10 minutes of videos per patient.

RESULTS. We found increased leukocyte rolling in the aGVHD group (average of 3 rolling leukocytes per patient), compared to post-HCT controls (average of 1 rolling leukocyte). Highest leukocyte rolling (>8 rolling leukocytes) was associated with increased all-cause mortality, but not predictive of transplant-related mortality (TRM). Similarly, we found increased leukocyte adhesion in the aGVHD group (average of 3 adherent leukocytes per patient), compared to post-HCT controls (average of 1 adherent leukocyte). Interestingly, we observed 7 adherent leukocytes in one patient who had isolated gut aGVHD and no skin involvement.

DISCUSSION. Our preliminary results show altered leukocyte-endothelial interactions in the skin capillaries of aGVHD patients, suggesting that confocal microscopy may be an important tool in augmenting the clinical diagnosis and managing post-HCT patients. Future studies should test whether there is a difference in the pattern of change in parameter values between patients who did and who did not develop aGVHD.

ACKNOWLEDGEMENT. This work was supported in part by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service.

Disclosures

Byrne: Karyopharm: Research Funding. Jagasia:Janssen: Research Funding; Kadmon: Consultancy; Incyte: Consultancy. Tkaczyk:Incyte: Consultancy.
Monitoring of Recombinant Activated Coagulation Factor VII (rFVIIa) Therapy in Patients (pts) with Inherited Factor VII (FVII) Deficiency
Authors: Galstian Gennadii M. , Polevodova Olesya A. , Yakovleva Elena , Shchekina Antonina , Davydkin Igor , Kudlay Dmitriy
Published: November 2019

Introduction and Objectives: Inherited FVII deficiency is a rare hemorrhagic disorder.Clinical bleeding does not correlate with the level of FVII plasma activity. FVII involves in the extrinsic coagulation pathway. ROTEM is point of care method. EXTEM is one of ROTEM screening tests. EXTEM analyses the extrinsic pathway of coagulation. Aim of the study was to evaluate hemostatic effect and safety of rFVIIa treatment in pts with inherited FVII deficiency.

Materials and Methods: The results of rFVIIa treatment were investigated in 4 pts (1 male, 3 females) with inherited FVII deficiency. Pts were treated with rFVIIa before gynecological (2), abdominal (1) and orthopedic surgery (1). Pts received 30 mcg/kg of rFVIIa (Koagil VII, Generium, Russia) before surgery. Plasma FVII activity, fibrinogen, INR, APTT, ROTEM and thromboelastography (TEG) parameters were investigated before rFVIIa administration, then in 15 minutes, in 2 hours, in 6 hours and in 12 hours.

Results: Before rFVIIa administration median plasma FVII activity was low, CT EXTEM was long and INR was greater than 3. TEG, APTT and fibrinogen were in normal ranges (table 1, fig. 1). Fifteen minutes after rFVIIa administration FVII:C activity increased, INR and CT EXTEM decreased. Hemostatic effect of rFVIIa remained during 12 hours. During this period CT EXTEM correlated with INR (r = 0.97, p<0.001). Other parameters did not change significantly. None patients had hemorrhagic complications.

Conclusion: CT EXTEM allowed to evaluate hemostatic effect of rFVIIa in operating room and good correlated with INR in pts with inherited FVII deficiency.

Disclosures

No relevant conflicts of interest to declare.
The Frequency of Calr and MPL Gene Mutations in Jak2 V617F - Positive Chronic Myeloproliferative Neoplasms in Russia
Authors: Makarik Tatiana V , Abdullaev Adhamjon O , Kulikov Sergei M. , Nikulina Elena E , Treglazova Svetlana A , Subortseva Irina N , Kovrigina Alla M. , Melikyan Anait L. , Sudarikov Andrey B , Savchenko Valery G.
Published: November 2019

Background. Ph-negative chronic myeloproliferative neoplasms (MPNs) are characterized by proliferation of one or more myeloid cell lineages and include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Somatic Jak2, MPL and CALR gene mutations are responsible for more than 90% of NPM cases. These mutations affect sequential stages of prolipherative signal transduction and therefore after the emergence of one type of mutation another types basically should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases.

Aim. To evaluate frequencies of MPL and CALR mutations in Jak2 positive MPN cases for Russian cohort of patients.

Methods. Archival DNA samples from MPN patients followed up at the National Research Center for Hematology between 2014 and 2019 included into retrospective study. DNAs and RNAs were extracted from blood using reagent kit from Interlabservice (Russia). Jak2 V617F mutation was quantified by real-time PCR kit from Syntol (Russia) according to manufacturers instructions. CALR exon 9 deletions/insertions were analyzed by fragment analysis (sensitivity >= 3%). MPL W515L/K mutations were assessed by in-house allele specific PCR. All cases were tested for phi-negativity using BCR-ABl p210 PCR kit from Interlabservice (Russia).

Results. At least one of the mutations was found in 3863 cases. Jak2 V617F mutation - 3385 cases (87.6%); CALR insertion or deletion - 471 case (12.2%); MPLW515L/K mutation - 31 case (0.8%). We have found 28 cases (0.7%) with Jak2 and CALR mutations combined and 3 cases (0.1%) with Jak2 and MPL mutations in the cohort studied. Matched measures were obtained at least twice at different time points during the course of disease for these cases. No cases with simultaneous CALR and MPL mutations were detected. In 23 from 31 (74%) cases with combined mutations Jak2 V617F allele burden was lower than 3%. Among cases with combined mutations 5 were diagnosed with PV, 8 - with ET, 8 - with PMF and 10 with unclassified MPN. No correlations between diagnosis, mutation combination or allele burden were found.

Conclusions. Based on the data, obtained on retrospective DNA samples we cannot state whether combined mutations are present in different clones of myeloid cells or in one. Indirectly, the fact that more often mutations in CALR and MPL genes were found in the cases with a low Jak2 V617F allele burden may indicate that additional mutations occur in the "competing" cell clone. Further prospective studies with mutation monitoring over the therapy are required to assess the value of combined mutations for MPN pathogenesis.

Disclosures

No relevant conflicts of interest to declare.
Determining Postoperative Thrombocyte Reduction Cut Off to Predict 30-Day Mortality in Patients Undergo Coronary Artery Bypass Graft Surgery
Authors: Rinaldi Ikhwan , Mansjoer Arif
Published: November 2019

Background

There are many factors associated with early mortality after CABG, including postoperative thrombocytopenia (Kertai, 2016). Many factors during CABG surgery, such as administration of heparin or cardio pulmonary bypass during surgery are related to thrombocyte count reduction (Hamid, Akhtar, Naqvi, & Ahsan, 2017; Arepally, 2017). However, it is possible for a post-CABG patient to suffer a significant thrombocyte reduction without reaching the thrombocytopenic state (thrombocyte count <150000/µL). Up to this time, there is still lack of study about association between thrombocyte reduction after surgery and 30-day mortality in patients undergo CABG. This study aim to determine cut off point for postoperative thrombocyte reduction as a predictor of 30-day mortality after CABG surgery.

Method

This is a retrospective cohort study using medical record of 263 adult patients who underwent CABG surgery in dr. Ciptomangunkusumo National Hospital on 2012-2015. Thrombocyte reduction was determined by substracting preoperative thrombocyte count from postoperative thrombocyte count. Receiver operating curve (ROC) analysis between percentage of thrombocyte reduction and 30-day mortality after surgery was done to obtain the sensitivity and specificity value of a particular degree of thrombocyte reduction. Cut off point was obtained from intersection between sensitivity and specificity value.

Result

Thirty-day mortality rate after CABG surgery in this study was 11.9%. Cut off point obtained from ROC analysis was 30% with area under the curve (AUC) 0.671. The sensitivity of this cut off point to predict early mortality after CABG surgery was 64.5%, while the specificity was 64.7%

Conclusion

Thrombocyte reduction more than or equal to 30% can be used as a predictor of 30-day mortality after CABG surgery.

Figure

Disclosures

No relevant conflicts of interest to declare.
The Novel Role That Nrf2 Plays in Erythropoiesis during Aging
Authors: Mbiandjeu Serge Cedrick Toya , Mattè Alessandro , Federti Enrica , Perduca Massimiliano , Andolfo Immacolata , Iolascon Achille , Valenti Maria Teresa , Pisani Arianna , Dalle Carbonare Luca , Pucci Pietro , Amoresano Angela , Narla Mohandas , De Franceschi Lucia
Published: November 2019

Erythropoiesis is a dynamic and multistep process, resulting in generation of red cells from hematopoietic stem cells. Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nrf2 is a key transcription factor that participates in acute response to oxidative stress and controls the expression of anti-oxidant and cytoprotective systems. We previously documented activation of Nrf2 during β-thalassemic erythropoiesis. In addition, a previous study reported a mild chronic hemolytic anemia as a result of increased erythrophagocytosis in mice genetically lacking Nrf2 (PNAS, 2004). Here, we show an age-dependent worsening of anemia in Nrf2-/- mice characterized by accelerated senescence of circulating erythrocytes in association with reticulocytopenia, suggesting a perturbation of erythroblast maturation. Indeed, we found ineffective erythropoiesis in 12 months-old Nrf2-/- mice with extramedullary erythropoiesis, increased ROS levels, reduction in the expression of Nrf2 related anti-oxidant proteins and apoptosis of erythroid precursor cells. In agreement, we observed an age dependent sensitivity of Nrf2-/- mice to stress erythropoiesis induced by either phenyhydrazine (PHZ) or doxorubicine. In 12-month-old mice we observed (i) activation of the unfoldeld protein response system (UPR) due to endosomal reticulum stress and (ii) impaired autophagy. The cytoprotective processes were unable to fully counteract oxidation re-directing cells towards apoptosis as supported by the increased activity of caspase-3. To understand the impact of oxidation in this model of accelerated senescence, we treated Nrf2-/- mice with astaxanthin, a powerful anti-oxidant but with low oral bioavailability, by administrating it in the form of PLGA loaded nanoparticles (ATS-NP). Treatment of Nrf2-/- mice with ATS-NP ameliorated the age-dependent anemia and decreased ineffective erythropoiesis through (i) inactivation of UPR system; (ii) improvement of autophagy and (iii) reduction in caspase-3 activity. In future studies, we plan to evaluate the impact of ATS-NP administration in other models of pathologic erythropoiesis. In summary, we propose that Nrf2, a key transcriptional factor plays a key protective role in regulating aged related oxidation and ensures normal erythroid maturation and growth.

Disclosures

No relevant conflicts of interest to declare.
Blockade of Lipid Receptor GPR31 Suppresses Platelet Reactivity and Thrombosis with Minimal Effect on Hemostasis
Authors: Van Doren Layla , Nguyen Nga , Garzia Chris , Fletcher Elizabeth , Stevenson Ryan , Jaramillo David , Kuliopulos Athan , Covic Lidija
Published: November 2019

Objective: Platelet agonist-activated 12-lipoxygenase (12-LOX)/12-Hydroxyeicosatetraenoic acid (12-HETE)/G protein-coupled receptor 31 (GPR31) signaling has been proposed to regulate platelet reactivity. While inhibition or genetic ablation of 12-LOX supports an important role of 12-HETE in response to platelet agonists thrombin and collagen, the participation of GPR31 in platelet lipid signaling has not been examined. We developed a potent pepducin inhibitor, GPR-310, to test the downstream involvement of GPR31 in thrombin and collagen mediated platelet activation and thrombosis.

Approach and Results: Treatment of mice with GPR-310 reversibly inhibited ex vivo platelet aggregation in response to thrombin and the PAR4 agonist, AYPGKF. There was significant protection (P<0.002) against FeCl3-induced carotid artery injury in mice by extending occlusion time from 100% occlusion at 27 min in the vehicle cohort to 20% occluded at 45 min in the GPR-310 cohort. GPR-310 treatment did not affect tail bleeding time. In human platelets, GPR-310 significantly (P<0.001) inhibited PAR4 agonist and collagen-mediated platelet aggregation and PAR4 calcium release. GPR-310 inhibited 12(S)-HETE- and PAR4-mediated RAP1 activation, with no effect on the PAR1-RAP1 signal. Accordingly, PAR1-mediated aggregation of human platelets was not affected by either GPR-310 or the 12-LOX inhibitor, ML355. GPR-310 caused a 5-fold shift in thrombin-mediated human platelet aggregation, comparable to a direct P2Y12 inhibitor, AZD1283. Dual GPR31 and P2Y12 inhibition showed synergy and protected against thrombin-mediated human platelet aggregation with a 19-fold shift. Blockade of GPR31 was more effective than the P2Y12 inhibitor in a thrombin-mediated clot retraction assay. Co-immunoprecipitation studies revealed that GPR31 and PAR4 form a heterodimeric complex in recombinant systems.

Conclusions: GPR31 may serve as a new therapeutic target in platelet-dependent arterial thrombosis and aggregation in humans.

Disclosures

No relevant conflicts of interest to declare.
Outcomes of Isolated Neutropenia Referred to Pediatric Hematology Oncology Clinic
Authors: Nagalapuram Vishnu , McCall David , Palabindela Prasannalaxmi , Bemrich Stolz Christina , Howard Thomas H. , Lebensburger Jeffrey D. , Hilliard Lee
Published: November 2019

Introduction: Patients with absolute neutrophil count (ANC) <1500 x10^9/L are frequently referred to Pediatric Hematology Oncology. Scant literature exists on outcomes and interventions for isolated neutropenia. We hypothesize that most patients will have resolved neutropenia without the need for an intervention from Pediatric Hematology Oncology.

Methods: We performed a five-year IRB-approved, retrospective chart review of patients referred to a Pediatric Hematology-Oncology clinic for isolated neutropenia. Patients were excluded if they also had anemia or thrombocytopenia at the time of the referral. Degree of neutropenia was categorized: 1) at the time of referral, 2) at the lowest value, and 3) at the current ANC as Mild: 1.001-1.500 x109/L, Moderate: 0.501-1.000 x109/L, Severe: 0.201-0.5 x109/L, or Very Severe ≤0.2 x109/L. Descriptive statistics and odds ratios were performed.

Results: Among 154 patients referred with isolated neutropenia over five years, 45 (29%) had mild neutropenia, 65 (42%) had moderate neutropenia, 29 (19%) had severe neutropenia, and 15 (10%) had very severe neutropenia. Only 29 (19%) patients progressed to a lower ANC category than their referral ANC category. At a median follow-up of 12 months, 101 (66%) patients had resolved neutropenia, 40 (26%) patients had mild, ten (6%) patients had moderate, three patients had severe, and one patient had very severe neutropenia. Most patients (54%) were not identified with a specific diagnosis. The most common diagnoses included viral suppression (16%), autoimmune neutropenia (14%) and drug induced neutropenia (8%). The most common medications reported as responsible for neutropenia were either anti-epileptic medications or immunosuppressant medications. No patients were diagnosed with a malignancy. Black patients had a 3.5 times higher odds of having persistent, mild, undiagnosed neutropenia which, for some patients, may be benign ethnic neutropenia. Seven (4.5%) patients received G-CSF therapy. Five patients were either managed by a Rheumatologist or an Immunologist. Finally, there were 16 hospitalizations that occurred in 10 patients for a prevalence of one admission for every 21 patient years. The most common admission diagnosis was febrile neutropenia without subsequent bacteremia (n=13).

Conclusion: Most pediatric patients referred for isolated neutropenia do not progress, develop leukemia, or require sub-specialty interventions. Hospitalization of patients referred for isolated neutropenia is rare as is bacteremia. This study provides important outcome data that can improve our counseling of pediatric patients identified with isolated neutropenia.

Disclosures

Howard: Novartis: Consultancy. Lebensburger:Novartis: Consultancy; Pfizer: Research Funding.
Ruxolitinib Is an Effective Salvage Treatment for Multidrug-Resistant Graft-Versus-Host Disease after Allogeneic Hematopoietic Transplantation
Authors: Liu Sining , Zhao Jiaoyu , Xu Lanping , Zhang Xiaohui , Wang Yu , Chen Yuhong , Liu Kaiyan , Huang Xiaojun , Mo Xiaodong
Published: November 2019

Aim:

Graft-versus-host disease (GVHD), particularly the multidrug-resistant (MDR) GVHD, is one of the most important complications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. The purpose of our study is to identify the efficacy of ruxolitinib in allo-HSCT recipients with MDR-GVHD.

Methods:

A total of 44 patients who received ruxolitinib treatment for MDR-GVHD after allo-HSCT between 2017 and 2019 were enrolled in this study (HLA-identical sibling donors: n=10; HLA-haploidentical related donors: n=34). MDR-GVHD was defined as GVHD showing no improvement after at least 3 types of treatments. Patients were treated with ruxolitinib as an add-on immunosuppression therapy at a dose of 5 mg orally twice daily, and it could be increased to 10mg twice daily if hematologic parameters were stable and no treatment-related toxicities were observed after the first 7 days of treatment. This work was supported by the Capital's Funds for Health Improvement and Research (grant number 2018-4-4089).

Results:

The median number of previous GVHD-therapies was 4 for both MDR-aGVHD and MDR-cGVHD. For MDR-aGVHD (n=16), the median time to response was 10 days (range, 2 to 65), and the overall response rate (ORR) was 62.5% (10/16) in, including 37.5% (6/16) complete response (CR) and 25.0% (4/16) partial response (PR). Patients with 3 organs involvement had a lower ORR compared to that of those with 1-2 organs involvements (88.9% vs 28.6%, P=0.035). The 1-year probability of overall survival after ruxolitinib was 62.1%. The rates of hematologic and infectious toxicities were 75.0% and 50.0% after ruxolitinib treatment.

For MDR-cGVHD (n=28), the median time to response was 30 days (range, 6 to 270), and the ORR was 78.6% (22/28), including 28.6% (8/28) CR and 50% (14/28) PR. The 1-year probability of overall survival after ruxolitinib was 90.0%. The rates of hematologic and infectious toxicities were 46.4% and 42.9% after ruxolitinib treatment.

Conclusions:

Ruxolitinib is an effective and safe salvage treatment for both MDR-aGVHD and MDR-cGVHD in allo-HSCT recipients.

Disclosures

No relevant conflicts of interest to declare.
Safety Analysis of Two Randomized Controlled Studies of Venetoclax in Patients with Chronic Lymphocytic Leukemia
Authors: Al Hadidi Samer , Kamble Rammurti , Miller-Chism Courtney Nicole , Mims Martha P.
Published: November 2019

ABSTRACT

BACKGROUND

Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to cell death of Chronic Lymphocytic Leukemia (CLL) cells. Multiple studies have demonstrated the efficacy and safety of venetoclax for treatment of relapsed/refractory or treatment naïve CLL.

METHODS

We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with venetoclax versus comparators. Data were pooled from 2 completed phase III randomized controlled studies that had included 406 venetoclax -treated and 402 comparator-treated patients with CLL as a first line in treatment naïve patients and for relapsed/refractory disease (Table.1). Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.

RESULTS

The median follow up duration is 25.95months (range: 23.8-28.1 months) for both venetoclax-treated and comparator-treated patients. Discontinuation because of AEs occurred at the same rate in both groups. When adjusted to exposure, hyperglycemia and diarrhea were the only common grade 3 AEs more often reported with venetoclax than with the comparators. The prevalence of common grade 3/4 AEs with venetoclax were <10% apart from neutropenia (55.2%) and infections/infestations (17.5%) though with adjustment to exposure time both of these side effects were more common in comparator arms (Table.2). Grade 3/4 venetoclax associated tumor lysis syndrome happened in 1.7%.

CONCLUSIONS

These results from an integrated analysis support a favorable benefit/risk profile of venetoclax in patients with CLL.

Disclosures

No relevant conflicts of interest to declare.
The Influence of FLT3-ITD Mutation on Baseline Levels of Selected Cytokines and Soluble Adhesion Molecules in Acute Myeloid Leukemia with Mutated NPM-1
Authors: Kupsa Tomas , Horacek Jan M , Jebavy Ladislav , Zak Pavel
Published: November 2019

Introduction: Cytokines and adhesion molecules have been studied as markers of immune system activation in various diseases including AML/MDS. These factors form a dynamic network which affects AML cell susceptibility to chemotherapy. We analyzed whether these factors may be associated with mutations specific for AML. The aim of our study was to evaluate hypothesis that baseline serum levels of these factors may be associated with mutation profile on the model of AML with mutation in NPM-1 and FLT3-ITD.

Methods: A total of 42 de novo AML patients (age 55.9 ± 11.5, median 60 years; 16 males, 26 females; all Caucasian) were analyzed. All patients had normal karyotype and mutation in NPM-1, 25 patients had mutation in FLT3-ITD. The subgroups have not differed in age. We evaluated baseline circulating levels of the following factors: interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10), epidermal growth factor (EGF), interferon-gamma (IFN-γ), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF), E-selectin (E-SEL), P-selectin (P-SEL), L-selectin (L-SEL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). All biomarkers were measured by biochip array technology on Evidence Investigator analyzer (Randox). Probability values (P) < 0.05 were considered statistically significant.

Results: The cases with FLT3-ITD mutation had higher levels of E-SEL (51.90 ± 19.90 mcg/L vs. 23.85 ± 14.07 mcg/L; p = 0.002), P-SEL (192.01 ± 77.29 mcg/L vs. 127.89 ± 48.47 mcg/L; p = 0.035) and lower levels of EGF (7.01 ± 7.08 ng/L vs. 20.64 ± 16.73 ng/L; p = 0.019) and TNF-α (3.55 ± 1.89 ng/L vs. 5.69 ± 3.55 ng/L; p = 0.049). The levels of L-SEL were higher in FLT3-ITD mutated AML, which was not statistically significant, possibly due to exceeding the upper limit or array sensitivity in majority of cases. The differences in baseline levels of other evaluated markers were not statistically significant.

Conclusions: Cytokines are an important part of cancer environment. In patients with normal karyotype and mutation in NPM-1, the presence of FLT3-ITD influenced levels of EGF, TNF-α, E-SEL, P-SEL and possibly L-SEL. Whether these findings are associated with adverse biology of FLT3-ITD positive leukemia is not known at the moment and requires further elucidation.

Disclosures

No relevant conflicts of interest to declare.
Value of Pre-Procedural Lymphocyte-to-Monocyte Ratio for Predicting New Cerebral Ischemic and Haemorrhagic Lesions Observed after Transcatheter Aortic Valve Implantation: A Pilot Study
Authors: Denimal Tom , Lassalle Fanny , Debry Nicolas , Rauch Antoine , Vincent Flavien , Staels Bart , Vincentelli André , Susen Sophie , Van Belle Eric , Dupont Annabelle
Published: November 2019

Introduction: TAVI (Transcatheter Aortic Valve Implantation) represents the gold standard technique for the treatment of symptomatic severe aortic stenosis in patients at elevated surgical risk. This intervention is consistently associated with ischemic and haemorrhagic complications. In almost 60 % of the procedure, new cerebral ischemic lesions are observed on systematic magnetic resonance imaging (MRI) and it could speed up cognitive impairment. The lymphocyte-to-monocyte ratio (LMR), a new inflammatory marker, has been recently associated with ischemic burden in cardiovascular diseases.

Objective: To study LMR changes before and after TAVI and investigate if LMR could be a predictive factor of new ischemic and haemorrhagic cerebral lesions after TAVI.

Methods: Patients admitted for TAVI who accepted to be included in the METHYSTROKE study (NCT02972008) undergo cerebral MRI the day before the intervention and a second one 3 days after the procedure in order to observe the occurrence of ischemic and haemorrhagic cerebral lesions. LMR was gathered the day before (D0) and the day after TAVI (D1) from complete blood cell count.

Results: A total of 124 patients were included in the present study (mean age was 82 ± 5.2 (SEM) years and 46% were male). Between D0 and D1, we observed a decrease in lymphocytes rate (mean (SD) : 1.25 (0.58) vs 1.14 (0.52) G/L, p=0.02) whereas the rate of monocytes raises (0.51 (0.27) vs 0.85 (0.42) G/L, p<0.0001). Between D0 and D1, the LMR significantly falls (3.1 (0.24) vs 1.51 (0.75), p<0.0001). New ischemic lesions occurred in 80 patients among the 124 (64.5%); LMR is significantly lower at D0 in patients who developed new cerebral ischemic lesions (2.30 (0.8) versus 2.97 (1.2), p=0.03). Each raise of pre-procedure LMR of a range of 0.1 increases the risk of post-operative cerebral ischemic lesions of 5.5 % (OR= 0.46, IC 95% 0.22-0.97, p=0.04). On the other side, 31 patients developed new haemorrhagic lesions on post-operative cerebral MRI (25%). Pre-procedure LMR was not significantly different among patients with and without haemorrhagic post-procedural cerebral complications (2.38 (0.93) vs 2.42 (1.1)).

Conclusion: This study demonstrated that LMR decreases during TAVI and that pre-procedure LMR, a simple, readily available and low-cost biomarker, could be a predictive factor of post-TAVI new cerebral ischemic lesions.

Disclosures

No relevant conflicts of interest to declare.
Favorable Outcome of Allogenic Stem Cell Transplant in Patients with Acute Myeloid Leukemia Carrying t(6;9)(p22;q34) / DEK-NUP214 Rearrangement
Authors: Li Yan , Wang Jianxiang , Wei Hui , Mi Yingchang , Wang Ying
Published: November 2019

Acute myeloid leukemia (AML) with t(6;9)(p22;q34) is listed as a distinct entity in the 2016 WHO Classification of Tumors of Heamatopoetic and Lymphoid Tissues, but the clinical features and prognostic impact are still not well established. We retrospectively reviewed 1620 AML patients diagnosed from the year 2013 to 2019 and 15 patients with t(6;9)(p22;q34) were identified. Their morphology, immunophenotype, cytogenetics, molecular findings, treatment and prognosis were analyzed. The incidence of AML with t(6;9)(p22;q34) is 0.9% (15/1620). There was 10 women and 5 men (ratio, 2:1) with a median age of 39 years (range:16-64). The median WBC count at diagnosis was 9.72×109/L(range: 1.78-45.4). According to French-American- British classification, 10 (66.7%) were M5 and 5 were M4. At cytogenetic level, t(6;9)(p22;q34) was the sole cytogenetic abnormality in 12 patients (80%) while 2 had one additional aberration and 1 presented with a complex karyotype. Molecular studies using next generation sequencing showed a unique mutation profile characterized by a high frequency of FLT3 mutations (10/13, 77%) including 9 cases with ITD and 1 case with TKD. Other mutations included RAS (3 NRAS and 2 KRAS) (5/13), FAT1 (4/13), NOTCH1 and PRDM1 (2/13 respectively). However, the common mutations of AML, such DNMT3A and NPM1, were rare in this subtype. The median number of mutated genes was 3 (range:1-6). Among the 9 patients with FLT3-ITD, FLT3-ITD ratio was measured in 5 patients and all showed a high ratio (median: 0.62, range: 0.59-1.11). All patients received induction chemotherapy; 12 (80%) patients achieved complete remission (CR) after one or two cycles of induction. Among these 15 patients, 7 underwent allogenic stem cell transplant (SCT) and all were alive in CR status at the last follow-up (median OS: 32.9 mon). In contrast, among the 8 patients who did not receive SCT, 5 died of disease relapse and the remaining 3 patients were newly diagnosed with a relatively short follow-up time (median OS: 10.4mon). In conclusion, t(6;9)/DEK-NUP214 AML represents a unique subtype of AML, with unique gene expression profiling (a high frequency of FLT3-ITD). Most patients can achieve CR after chemotherapy, allo-SCT can improve long term survival.

Figure

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Generic Imatinib in Chronic Phase of Chronic Myeloid Leukemia (CP-CML): Experience from a Multi-Center in China
Authors: Zhou Li , Liu Bingcheng , Hu Jianda , Qu Jianhua , Hou Ming , Sun Hui , Jin Jie , Shen Zhixiang
Published: November 2019

Background: Imatinib is the first TKI that was officially approved by the Food and Drug Administration (FDA) for the treatment of patients (pts) with CP-CML and it is the most commonly used treatment in CML pts on the international scene. Generic imatinib was offered and accessible as frontline treatment of CML in china in June 2013, which predictably lowered the cost of CML therapy. However the statistics regarding their effectiveness and tolerability in greater proportion of the population of CML pts are not available. (ClinicalTrials. gov number, NCT02317159.)

Aim: To evaluate the efficacy and safety of generic imatinib in the treatment of pts that were newly diagnosed with CP-CML.

Methods: In this multi-center, prospective open-label study, 75 pts with CP-CML were enrolled to receive generic imatinib mesylate capsules at a dose of 400 mg once daily. The primary end point was major molecular response (MMR) by 12 months. Imatinib plasma level and adverse events (AEs) were assessed.

Results: The Median age at diagnosis was 46 years (range 19-75 years), and 50 pts (66.7%) were male. The median follow-up was 22.1 (range0.5-24) months. 35 pts (44%), 26 pts (34.7%) and 12 pts (16%) were in low, intermediate and high risk group, respectively, according to Sokal prognostic score (Not available in 2 pts). By 12 months, the cumulative rate of MMR (BCR-ABL1IS ≤0.1%) was 42.7% (32/75), and the cumulative rate of complete cytogenic response (CCyR) was74.7% (56/75). Complete hematologic response (CHR), CCyR, MMR rate at 3 months,6 months and 12 months were shown in Table 1. For pts who presented with BCR-ABL1 IS≤ 10% at 3 months, had better response as compared with those with BCR/ABL1IS> 10% (Table 2). The estimated progression-free survival at 12 months was 94.7%. Imatinib plasma levels at 29 days on imatinib were variable in individual, with 1522.9±775.3 ng/mL for median level (rang 394.4 to3891 ng/mL). Although those numerical values showed difference, no statistically significant correlations were found between imatinib plasma level and CCyR or MMR(P=0.902;P=0.349). The incidents and profile of AEs were similar to those reported previously.

Conclusion: This study confirmed that generic imatinib produced in China is effective and well-tolerated in Chinese CP-CML pts. The outcome of generic imatinib in the treatment of CP-CML is similar to brand imatinib reported in the literatures. The introduction of generic imatinib at a reduced and affordable cost may strikingly impact the cost of care for CML and improve the clinical outcomes of CML in China.

Disclosures

No relevant conflicts of interest to declare.
Prothrombin Complex Concentrate in the Management of Major Bleeding Induced By Oral Anticoagulant Therapy: Experience of a Tertiary Care Center
Authors: Alsheef Mohammed Abdullah , Zaidi Abdul Rehman Z. , Kullab Ghaydaa Juma
Published: November 2019

Background

In patients taking oral anticoagulants and presenting with major bleeding, a rapid, effective, and safe reversal agent is urgently required. There are limited data of 4-factor prothrombin complex concentrate (4F-PCC) in the management of oral anticoagulant associated major bleeding.

Aims

The purpose of this study is to provide clinical experience regarding the effectiveness of 4F-PCC in the management of major bleeding induced by warfarin, dabigatran, and rivaroxaban.

Methods

A retrospective study of 43 patients who were admitted to our tertiary care center with major bleeding induced by oral anticoagulants and received 4F-PCC. The effectiveness of PCCs was assessed by using the International Society of Thrombosis and Hemostasis criteria. Descriptive statistics were utilized for analysis.

Results

Forty-three patients were screened for inclusion into the study; notably, 21% of patients were excluded from further analysis. Of those included in this analysis (n=22), gastrointestinal bleeding accounted for (45.5%), followed by musculoskeletal bleeding (18.2%). The indication for anticoagulation was stroke prevention atrial fibrillation and VTE in the majority of the patients (45.5%), (45.5%) respectively. Patients received a mean of 2085.2 IU of PCC. Before and after 24 hours of PCC administration, the median INR resulted in a significant reduction (P;<0.001), with median aPTT (P;0.018). After final adjudication, the hemostatic effectiveness of PCC was assessed as effective in 19 patients (86.4%) and ineffective in three patients (13.6%). No major complications occurred during treatment or any serious adverse events.

Conclusions

PPC immediately and effectively reversed the effect of warfarin and rivaroxaban in patients with major bleeding and partial effect on the reversal of dabigatran.

Figure

Disclosures

No relevant conflicts of interest to declare.
Characteristics and Trends of Sickle Cell Disease Patients Once Presented to the Emergency Department, Reflecting on a Possible Burden: United States (2010-2015)
Authors: Haykal Tarek , Al-Dulaimi Ragheed , Kerbage Josiane , Samji Varun , Goranta Sowmya , Deliwala Smit , Bachuwa Ghassan
Published: November 2019

Background: Sickle cell disease (SCD) is an autosomal recessive, multisystem disorder, characterized by chronic hemolytic anemia, painful episodes of vaso-occlusion, progressive organ failure and a reduced life expectancy. SCD is the most common monogenetic disease, with millions affected worldwide. It is estimated that there are 100,000 people living with SCD in the United States (US). Patients with SCD often use emergency department (ED) services to obtain medical care. Limited nationwide information in the recent years is available about ED use among patients with SCD.

Methods: Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) for the years 2010-2015 were analyzed, to examine the prevalence and care of SCD patients in the EDs across the US. The NHAMCS is a survey of hospital ED and outpatient visits. Cases were identified using ICD 9 codes and all analyses accounted for complex survey structure of the data.

Results: On average, approximately 1.4 million ED visits were estimated to have occurred between the years 2010 and 2015 with SCD as one of the diagnoses listed, where 860,000 were attributed to sickle cell crises. 37.29% were of female sex while 62.71% were males. 11.62% were under 15 years of age, 28.22% were between 15 and 24 years of age, 51.15% were between the ages of 25 and 44 years and 9.02% were older than 45 years. The chief complaint for the majority of cases was pain. The expected source of payment were Medicare and Medicaid at 30.45% and 41.98% respectively, while private insurance coverage and self-pay were only at 11.71% and 5.81% respectively. Of all SCD ED visits, 68.5% were considered as initial presentations and up to 23.37% were considered as follow-up. 33.31% of the visits ended up needing a hospital admission while 66.69% got discharged from the ED.In 43.39% of the visits, a form of imaging was ordered, compared to 56.61% where it was not. Upon getting triaged in the ED, 67.62% of all SCD visits needed either emergent or urgent medical attention, while the rest were either none-urgent, or a regular check-up.

Conclusion: In well-resourced countries, like the US, comprehensive care programs have increased life expectancy of sickle cell disease patients, with almost all infants surviving into adulthood. However unfortunately with poor control of the disease due to limited therapeutic options and with growing morbidity for the aging SCD patients, the burden on the medical system becomes extremely high. Our study highlights the significant burden SCD creates in the EDs across the US based on data collected from a national database.

Disclosures

No relevant conflicts of interest to declare.