bluuebunny/crossref_metadata_2025 huggingface dataset:
Poor Outcome of CRLF2 Rearranged Philadelphia Negative Acute Lymphoblastic Leukemia Adults Patients
Authors: Elnahass Yasser H , Fahmy Omar A , Samra Mohamed Abdel Mooti , Elrefaey Fatma A , Bokhary Mahmoud T , Elsherif Haitham , Afifi Hazem H , Elkomy Abdallah S , Hola Mona , Mahmoud Hossam K
Published: October 2019

BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph'-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1 positive ALL and a poor outcome. Rearrangements of cytokine receptor like factor 2 (CRLF2) are identified in approximately 50% of Ph'-like and 10% of B-other ALL patients.

AIM: To identify the incidence of CRLF2 rearrangements and the frequency of relapse in a cohort of B-other Precursor B-ALL adults Egyptian patients who were treated with conventional therapy at National Cancer Institute, Cairo University.

METHODS: The routine diagnostic work-up at diagnosis included Bone marrow aspiration, immunophenotyping, karyotyping, fluorescent in situ hybridization (FISH) for BCR-ABL1 and KMT2A (MLL) and CRLF2 rearrangements (IGH-CRLF2 or P2RY8-CRLF2), and molecular analyses of BCR-ABL1 translocations. Patients within the age group 18-25 years received Total XV protocol while patients >25 years received Hoelzer's protocol.

RESULTS: Forty patients were included (22 males, 18 females). Median age at diagnosis was 25 years (18 -65). Median TLC was 14.9 x109/L (1.1 - 201), median Hb was 9.9 gm/dl (5-12.9), median platelet count was 47 x 109/L (19-359) and median BM blasts count was 90% (30-100). CRLF2 rearrangement was detected in 4/40 (10%) patients. All CRLF2 positive patients (100%) relapsed at 6 months vs. 11/36 (30%) CRLF2 negative (p<0.001). At 6 months follow up, disease free survival (DFS) was 70% in CRLF2 negative patients vs. 0% in CRLF2 rearranged (p=0.04). At 1 year follow up, overall survival (OS) was 30 (75%) for CRLF2 negative vs. 0 (0%) for CRLF2 positive patients (p=0.01).

CONCLUSION: CRLF2 rearrangements constitute a high risk independent prognostic factor in adult precursor B-ALL patients denoting a poor outcome and should be studied in ALL Ph' negative patients. Additional TKI therapy should be included for this category of patients in our protocols to improve outcome.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Diagnostic Accuracy of Age-Adjusted D-Dimer Cutoff in Suspected Cases of Pulmonary Embolism
Authors: Dhakal Prajwal , Iftikhar Harris Mian , Wang Ling , Panthi Sagar , Shrotriya Shiva , Rayamajhi Supratik
Published: October 2019

Introduction

Current guidelines recommend use of clinical pretest probability scores, d-dimer assay, and imaging studies in the diagnosis of pulmonary embolism (PE). Studies have shown that normal d-dimer levels with low-intermediate probability in Wells score can safely exclude PE in most cases. Usually, d-dimer level of less than 500 µg/L is used to decide that no further imaging studies such as computed tomography pulmonary angiography (CTPA) or ventilation perfusion (V/Q) scan) are required. However, the conventional cutoff of 500 µg/L may not be as specific in all patients as d-dimer levels increase with age. Thus, use of age-adjusted d-dimer cutoff has been advocated which is defined as (age × 10) µg/L in patients 50 years or older.

Objective

To study if age-adjusted d-dimer is helpful in decreasing imaging studies without missing the diagnosis of PE in suspected cases.

Methods

We did an observational retrospective study of all consecutive adult patients who presented to the emergency department from January 2014 to December 2016. The patients who were clinically suspected with PE and underwent subsequent workup along with d-dimer assays were included for analysis. The number of imaging studies performed for PE diagnosis were recorded.

Results

We included 3,197 patients in the study. Median age was 55 years, and 67% were females (Table 1). Total 2,937 (92%) patients had elevated d-dimer levels based on conventional d-dimer cutoff compared to 2,526 (79%) patients based on age-adjusted d-dimer cutoff. The age-adjusted d-dimer cutoff was more specific (21% vs 8%, p-value<0.0001) but less sensitive (100% vs 95%, p-value= 0.15) than conventional cutoff (Table 2). The use of age-adjusted d-dimer cutoff would have avoided 409 (13% of total) imaging studies (Table 3). However, 2 cases (0.7% of total) with PE, which would have underwent imaging study with conventional cutoff, would have been missed with age-adjusted d-dimer cutoff. The Wells score was 3, intermediate pretest probability, for both cases of PE.

Conclusion

Age-adjusted d-dimer cutoff can significantly decrease the number of imaging studies performed in cases of suspected PE. However, as shown in our study, there is a chance of missing cases with actual PE. Thus, clinicians should always be aware of a rare probability of false negative result with age-adjusted d-dimer levels. Further stratification of the probability risk or the prompt use of imaging studies in cases with higher clinical suspicion can help in accurate diagnosis of PE.

Disclosures

No relevant conflicts of interest to declare.
Ultra-Deep Sequencing Leads to Earlier and More Sensitive Detection of Known or Novel Mutations of BCR-ABL1 in Chronic Myeloid Leukemia
Authors: Xiao Hongli , Wang Heng , Lou Jin , Chen Weihong , Zhang Qiaoxia , Du Xin
Published: October 2019

Detection of BCR-ABL1 mutations that inhibit tyrosine kinase inhibitors is important for the treatment of CML patients. Sanger sequencing (SS) technique is considered the gold standard for mutation detection in a clinical laboratory. We analyzed 40 clinical samples from 22 CML patients with TKI resistance by ultra-deep sequencing (UDS) and compared the results with classical SS-based tests. UDS facilitates the detection of low levels of mutations (<20% allele frequencies) that SS does not detect. In subgroups of cases with multiple mutations, UDS was also able to determine whether two mutations were on same BCR-ABL1 allele (compound) or not (polyclonal). We found a pair of compound mutations unreported: F359C/E450 which confer high-level resistance to first-generation TKI imatinib, second-generation TKIs dasatinib and nilotinib, third-generation TKI ponatinib and a new TKI GZD824. UDS provides a reliable method for identifying low levels of BCR-ABL1 mutations.

Disclosures

No relevant conflicts of interest to declare.
The Platelet Isoform of Phosphofructokinase in Acute Myeloid Leukemia: Clinical Relevance and Prognostic Implication
Authors: Luo Xiaodan , Zheng Dantian , Zheng Runhui , Wang Chunyan , Xu Lihua , Tan Huo
Published: October 2019

Background: Phosphofructokinase (PFK), a key enzyme of the glycolytic pathway, has L (liver), M (muscle), and P (platelet) isoforms with different tissue distributions. The Platelet Isoform of PFK (PFKP) plays an important role in regulating aerobic glycolysis and macromolecular biosynthesis to support cell growth. Up-regulation of PFKP is associated with progression and metastasis of varied kinds of solid organ tumor. However, less is known about the association between PFKP and hematology malignancy. Here, we investigated the role of PFKP in acute myeloid leukemia (AML).

Methods: To characterize PFKP mRNA expression in AML, we performed qRT-PCR on bone marrow cells (BMCs) from 55 newly diagnosed AML patients with the median age of 47 years (range 16-82 years). The FAB type is M0 (2/55), M1 (3/55), M2 (15/55), M3 (11/55), M4 (11/55) and M5 (11/55). Two patients were diagnosed with myelodysplastic syndromes related AML. We screened for mutations in a selected panel of genes (NPM1, CEPBA, FLT3, KIT, WT1 and TP53), based on which patients were further categorized into standard (19/55), intermediate (21/55) and poor (15/55) cytogenetic risk groups. Patients were categorized into PFKPhigh and PFKPlow groups according to the median mRNA expression of PFKP. Complete remission (CR) rate was compared between two groups after 1 cycle and 4 cycles of chemotherapy. One year-relapse rate, overall survival rate (OS) and disease free survival rate (DFS) was also compared between PFKPhigh and PFKPlow groups.

Results: PFKP mRNA expression of AML patients was significantly higher than that of the normal control (P<0.05). PFKP expression in different cytogenetic risk groups were evaluated and the result showed that the mRNA expression in poor risk group was much higher than that in standard or intermediate group (P<0.05). According to the median mRNA expression of PFKP, patients were categorized into PFKPhigh (28/55) and PFKPlow (27/55) groups. The CR rate after the first cycle of treatment was higher in PFKPlow group, but did not differ significantly after another 3 cycles of chemotherapy were finished. PFKP mRNA expression was decreased after patients received CR (P<0.05). In 32 out of 55 patients, autologous hematopoietic stem cell transplantation (HSCT) (N=20) or allogeneic HSCT (N=12) was performed after 4 cycles of chemotherapy. In 20 patients post auto-HSCT, 1 year-relapse rate was higher and OS and DFS was decreased significantly in PFKPhighgroup compared to PFKPlow group. However, results showed no difference between two groups for patients post allo-HSCT.

Conclusions: PFKP expressions were increased in AML especially patients in poor cytogenetic risk group. PFKP might be a prognostic factor of poor clinical outcome of AML.

Disclosures

No relevant conflicts of interest to declare.
Russian Experience of Bosutinib Use in Chronic Myeloid Leukemia Patients in Routine Clinical Practice
Authors: Shuvaev Vasily , Vinogradova Olga , Martynkevich Irina , Natalya Novitskaya , Fominykh Mikhail , Tsareva Svetlana , Shikhbabaeva Dzhariyat , Pankrashkina Maria , Chernikov Mikhail , Sharkunov Nikolay , Zotova Irina , Udaleva Vera , Motyko Ekaterina , Voloshin Sergei
Published: October 2019

Background. The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) have diminished death probability and have changed the disease course. Achievement of complete cytogenetic response (CCyR) and major molecular response (MMR) are serve as warranties for freedom of progression and death from CML. There are many of CML patients are needed to change of initial TKI therapy with choice of the most efficient and safe drug for continuous life-long therapy to reach the optimal results of CML treatment. The newest of registered TKI drug in Russia is Bosutinib which has dual BCR-ABL and SRC kinase inhibitory activity and had showed good tolerability and efficacy in case of other TKIs resistance or intolerance.

Aim. To analyze of own Bosutinib experience in patients with chronic myeloid leukemia with other TKIs resistance or intolerance and to make comparison with clinical trial results.

Materials and methods. Clinical trials results from peer-reviewed journals. Outpatients charts of 51 patients (25 male and 26 females) with CML. Disease phase at the moment of Bosutinib therapy initiation was as follows: chronic - 37; acceleration - 8, blastic - 6. Bosutinib was used in the next lines of TKI therapy: second - 10; third - 18; fourth - 23. The indications for Bosutinib therapy were: intolerance to previous TKI - 21; resistance to previous TKI - 30.

Results. Median of therapy duration was 6 months (1-50 months). The adverse events and tolerability of Bosutinib were similar with clinical trials data. The treatment was withdrawn by the adverse event only in 5 (10%) patients. The rates of the responses in the whole group of patients were as follows: CHR - 88%, stable in 76%; CCyR - 39%, stable in 37%, MMR - 31% and was 25% at the last follow-up. The Bosutinib efficacy in real life settings was slightly higher than clinical trials data. The factors influencing treatment responses were: disease phase, cause of switching to Bosutinib, line of therapy and presence and kind of BCR-ABL mutations, Therapy was continued in 22 (43%) patients, most them achieved stable optimal treatment response (CCyR and MMR).

Conclusions. Bosutinib is a real alternative to other tyrosine kinase inhibitors and has its own mechanism of action and adverse events profile. The use of Bosutinib in real life clinical practice settings showed its efficacy and tolerability and could serve as base for recommendation to apply Bosutinib in hematology practice in Russia.

Disclosures

No relevant conflicts of interest to declare.
Direct Oral Anticoagulants in Patients with Myeloproliferative Neoplasms: A Single Institution Retrospective Study
Authors: Deloughery Emma P. , McBane Robert D. , Ashrani Aneel A. , Tefferi Ayalew , Slusser Joshua P , Pruthi Rajiv K.
Published: October 2019

Introduction: Myeloproliferative neoplasms (MPN) are associated with an increased risk of venous (VTE) and arterial (ATE) thromboembolic events (TE). Anticoagulation needs to be balanced between the risk of incident and recurrent TE and risk of hemorrhage. While data on outcomes of anticoagulation with warfarin in patients with MPN are available, data on safety and efficacy of direct oral anticoagulants (DOACs) in this subgroup are not. Herein, we present outcomes of use of DOACs in patients with MPN at our institution.

Methods: In this retrospective cohort study, we searched the Mayo Clinic clinical databases for patients meeting the WHO criteria for MPN who had been prescribed a DOAC between 2011 and 2017. The MPN diagnosis had to have predated the DOAC prescription. Medical records of consenting patients meeting study criteria were reviewed and data on demographics, diagnosis of MPN, indication for DOAC prescription, and their efficacy (incident or recurrent TE) and safety (hemorrhagic events) were abstracted.

Results: Over the study period, 19 patients (female = 10) met inclusion criteria. The median age of patients at MPN diagnosis was 67 years (35-83), and 73 years (53-86) at initiation of DOAC. Prescribed DOACs included rivaroxaban (n=12), apixaban (n=6), and dabigatran (n=2) (one patient received rivaroxaban and was switched to apixaban). MPN diagnoses included polycythemia vera (PV) (n=9), essential thrombocythemia and chronic myeloproliferative neoplasm NOS (3 each), chronic myeloid leukemia and myelofibrosis (2 each). Indications for DOAC included thromboembolism (n=13; 68%) (arterial:2 and venous:11), and atrial fibrillation (afib) (n=6; 31%). The median duration of DOAC therapy was 241.5 days (range 13-1879). Five patients were switched from warfarin to rivaroxaban (n=4) and apixaban (n=1) at patient and/or provider preference; the rest were initiated on the DOAC de novo based on provider preference.

Of the 19 patients, one patient each experienced a major hemorrhagic and TE event. One patient with PV who was on rivaroxaban for afib required hospitalization for gastrointestinal hemorrhage due to gastritis; DOAC was discontinued following this episode. One other patient with PV had a non-ST elevation myocardial infarction while on rivaroxaban for afib and prior stroke; DOAC was continued. There were no deaths attributable to DOAC use.

Discussion: Our limited data suggests that use of DOACs in patients with MPN is feasible with an acceptable balance between risk of hemorrhage and recurrent thrombosis. Additional data on long term outcomes of DOACs in MPNs are needed.

Disclosures

No relevant conflicts of interest to declare.
Study on Use of CAR-T Cells in Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Liu Jun , Tan Xu , Ying-Ying Ma , Mai-Hong Wang , Liu Yao , Lei Gao , Peiyan Kong , Zhang Cheng , Zhang Xi , Zeng Defu
Published: October 2019

Background: The chimeric antigen receptor T (CAR-T) cells have showed strong anti-leukemia role, which can treat or prevent relapse by targeting minimal residual disease for patients undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). The infusion of allogeneic CAR-T cells may cause the graft-versus-host disease, which could limit its use during and after allo-HSCT. It is still unclear whether CAR-T cells can be used during and after allo-HSCT. In this study, the use of CAR-T cells in these situation was explored.

Methods: Two patients with relapsed/refractory acute lymphoblastic leukemia (ALL) received allo-HSCT, the CAR-T cells was used as a reduced-intensity conditioning regimen. Another three patients with high-risk ALL received preventive infusion of CAR-T cells on days +60 after allo-HSCT.

Results: For patients undergone allo-HSCT, the time of peak CAR-T cell proliferation was detected after the first infusion of CAR-T cells on day 7. The engraftment and full donor cell engraftment were established. The disease was in complete remission with negative minimal residual disease, which was undetectable by flow cytometry. No graft-versus-host disease and serious cytokine release syndrome was found. For patients received preventive infusion of CAR-T cells, the CAR-T cells continually survival. No graft-versus-host disease and serious cytokine release syndrome was found. The disease is complete remission for 1-6 months.

Conclusion: It is safety and effective for CAR-T cells used in allogeneic hematopoietic stem cell transplantation.

Disclosures

No relevant conflicts of interest to declare.
Primary Extranodal Diffuse Large B-Cell Lymphomas Are Enriched for Mutations in MYD88 and CD79B.
Authors: Weissinger Stephanie Ellen , Moeller Peter , Marienfeld Ralf , Bloehdorn Johannes , Viardot Andreas
Published: October 2019

Introduction: Diffuse large B-cell lymphomas (DLBCLs) with mutations in MYD88 and CD79B are a distinct molecular subentity according to recent analysis ("MCD-type" according to R. Schmitz et al., N Engl J Med 2018; and partially "cluster 5" according to B. Chapuy et al., Nature Medicine 2018). Both mutations were found particularly in specific anatomical localizations.

Methods: To evaluate the incidence of MYD88 and CD79B mutations in primary extranodal DLBCL, we analyzed 111 tumor specimens of 99 patients. We performed targeted resequencing analysis to detect MYD88, CD79B, CARD11 and BTK mutations.

Results: MYD88 mutations were frequently found in primary CNS lymphoma (67%), lymphoma of Waldeyer´s ring and paranasal sinuses (ENT) (44%), breast (75%), testicular (60%) and cutaneous (50%); the majority of mutations (89%) were located on L265P. CD79B mutations were frequent in CNS lymphoma (57%), lymphoma of ENT (52%) and breast lymphoma (50%). Both mutations occur simultaneously in CNS lymphoma (48%) and ENT lymphoma (33%). CARD11 mutations were frequently found in CNS lymphoma (33%) and in ENT lymphoma (26%). BTK mutations were found rarely, with the highest frequency (11%) in ENT lymphoma.

Conclusion: Both, mutations in CD79B and MYD88 are frequent in primary extranodal lymphoma particularly in CNS lymphoma, lymphoma of Waldeyer's ring and paranasal sinuses, testicular, cutaneous and breast lymphoma. These findings may contribute to establish targeted therapeutic intervention of B-cell signaling in this subentity.

Disclosures

Weissinger: Bristol-Myers Squibb: Research Funding. Viardot:BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria; Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.
Prognostic Impact of Deletion 17p Clone Size on Outcome in Chronic Lymphocytic Leukemia Patients (A Real Life Routine Practice Perspective in Brazil)
Authors: Bigni Ricardo , de Souza Fernandez Teresa , Rego Mayara , Luise Ingrid , Abdelhay Eliana , Fernandez Cecilia , Araujo Keyla
Published: October 2019

Objectives: Chronic lymphocytic leukemia (CLL) presents a heterogeneous clinical course. Treatment mainly aims to control clinical manifestations and improving survival. Some biological markers have significant prognostic value. Cytogenetic studies in CLL have central role to refine the follow-up of disease evolution, to guide treatment options and monitoring response. Due to low mitotic index in conventional cytogenetic studies, fluorescence in situ hybridization (FISH) became an indispensable tool. The main objective of this study was analyze the presence of del(17p13) using FISH and the percentage of positive cells that have impact on survival, along with clinical characteristics from CLL patients. Methods: Seventy-one CLL patients were studied from 2010 to 2017. Median age was 57 years old and male patients were 56,4%. FISH analysis was performed using peripheral blood samples from patients and TP53 spectrum srange/CEP 17 spectrum green probe (Vysis). Statistical analysis was performed with SPSS20.0 software. Results: Twenty-eight of 71 patients had positive FISH for del(17p13) and the evidence of more than 20% del(17p13) cells was related to a worse overall survival (p<0,05). No difference in survival was observed between negative FISH patients and those with less than 20% del(17p13) cells. Conclusions: Patients presenting del(17p13) in more than 20% of cells had worse prognosis with reduced survival. Our results suggest the prognostic relevance of deletion17p clone size detected by FISH in CLL patients.

Disclosures

Bigni: Janssen: Honoraria, Research Funding.
Akt-Mediated Platelet Apoptosis and Its Therapeutic Implications in Immune Thrombocytopenia
Authors: Yan Rong , Chen Mengxing , Dai Kesheng
Published: October 2019

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with anti-platelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIba autoantibodies. Consistent with these findings, anti-GPIba monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIba antibody binding activates Akt which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIba antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling, or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal new pathogenic mechanisms of ITP with anti-GPIba autoantibodies, more importantly, suggest novel therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.

Disclosures

No relevant conflicts of interest to declare.
Toward a Proteome-Complete Computational Model of the Human Red Blood Cell
Authors: Yurkovich James T , Yang Laurence , Palsson Bernhard O
Published: October 2019

The human red blood cell has served as a starting point for the application and development of systems biology approaches due to its simplicity, intrinsic experimental accessibility, and importance in human health applications. Here, we present a multi-scale computational model of the human red blood cell that accounts for metabolism and macromolecules. Proteomics data are used to place quantitative constraints on individual protein complexes that catalyze metabolic reactions, as well as a total proteome capacity constraint. We explicitly describe molecular mechanisms-such as hemoglobin binding and the formation and detoxification of reactive oxygen species-and account for sequence variations between individuals, allowing for personalized physiological predictions. This model allows for direct computation of the oxyhemoglobin curve as a function of model species and a more accurate computation of the flux state of the metabolic network. More broadly, this work represents another step toward building increasingly more complete systems biology whole-cell models.

Disclosures

No relevant conflicts of interest to declare.
Predictors of Mortality in Neutropenic Enterocolitis Among Children and Young Adults with Acute Myeloid Leukemia in Low Middle Income Countries
Authors: Khedr Reham , Abdel Waged Mohamed , Fathy Marwa , Zekri Wael
Published: October 2019

Background: Neutropenic enterocolitis (NEC) is a life-threatening disease with substantial morbidity and mortality, seen primarily in patients with hematologic malignancies. The frequency of NEC has increased with the widespread use of chemotherapeutic agents such as the taxanes, which cause severe gastrointestinal mucositis. Methods: This was a retrospective study at the National Cancer Institute, Cairo University. The computerized records were screened for ultrasound or computerized tomographic scan requests for abdominal pain for all Acute myeloid pediatrics inpatients (2012-2016). Retrospective case analysis was used to collect clinical data for patients with features of NEC. D 30 Mortality was reported. Results: The incidence of NEC among our inpatients was 24% (49/203). Forty-Three children had radiologically confirmed Typhlitis, and 6 had clinical features alone. Most (93%) patients were profoundly neutropenic (ANC less than 100). All of the patients received conservative management. All of them needed ICU admission. Eighteen children had a variable period of bowel rest, including 12 patients who were supported with total parenteral nutrition. Three patients had laparotomy that revealed extensive colonic bowel necrosis (1), perforated bowel loop (1), and a perforated appendix (1). Two out of three cases of Laparotomy were diagnosed with Mucormycosis. 30-Days mortality was 44.8% (22/49). Relapsing Typhlitis in subsequent courses was observed in 6/27 (22%) patients. Fulminant gram-negative sepsis without surgical intervention was the leading cause of death in this cohort. NEC related mortality was significantly higher among patients receiving high-risk protocol with more intensive chemotherapy and in patients with other Co-Morbidities [chest infections and/ or Cardiac affection] with a P-value of 0.005 and 0.037 respectively. Also, mortality was increased among patients with more than 2 presenting clinical symptoms with a P-value of 0.01. Conclusion: Although surgical intervention should be reserved for specific complications, its delay increases the incidence of NEC related mortality. Though rare, fungal infection should be suspected especially in cases with worsening signs of typhlitis despite broad antimicrobial coverage. Early management and better supportive care of underlying Co-morbid conditions can decrease NEC related mortality.

Disclosures

No relevant conflicts of interest to declare.
A U.S. Food and Drug Administration Age Based Pooled Analysis of Cytokine Release Syndrome and Neurotoxicity in Subjects with Relapsed/Refractory Lymphoma Treated with Chimeric Antigen Receptor (CAR) T Cell Therapy
Authors: Sharma Poornima , Singh Harpreet , Bouchkouj Najat , Krauss Aviva C. , George Bindu
Published: October 2019

Background: With recent FDA approvals of CAR T cell therapy for the treatment of relapsed/refractory aggressive B cell non-Hodgkin lymphoma, an increasing number of older adults will be treated with this therapy. An improved understanding of the safety of CAR T cell therapy in this population is important to inform clinical decision making for the treatment of older subjects.

Methods: Data from two prospective single arm studies (n=214) of two approved CART cell products for the treatment of relapsed/refractory lymphoma were pooled and analyzed. Rates of cytokine release syndrome (CRS), as well as severity and treatment modalities (oxygen, vasopressor support, tocilizumab and steroids) were pooled and analyzed by age. Selected neuropsychiatric events were pooled and analyzed by age.

Results: Age was balanced between the two studies. The median age of subjects was 58 years (range 22-76 years). Of the 214 total subjects, 24% were 65 years of age and older.

CRS and neurotoxicity were evaluated in the subjects who received treatment with CAR T cell therapy. (Table 1).

*Two studies employed different grading methods for CRS; Lee's criteria (Lee DW et al, Blood 2014) and U Penn criteria (Porter DL et al, Blood 2014)

Conclusions: This exploratory analysis suggests overall similar rates of CRS and grade 2 and higher CRS in subjects less than 65 years as compared to 65 years of age and older. There appears to be an overall higher rate of encephalopathy and grade 3 and higher delirium/encephalopathy in adults 65 years and older compared to less than 65 years of age. The inclusion of greater numbers of patients ≥ 65 years of age in clinical trials will further inform clinicians about the safety and efficacy of CAR T cell therapy in older adults.

Table 1: Adverse Events by Age in subjects treated with CART cell therapy

Disclosures

No relevant conflicts of interest to declare.
Quality Initiative in Clinical Practice: A Single Institution Appraisal of Quality Metrics in the Management of Newly Diagnosed Diffuse Large B-Cell Lymphoma Based on the American Society of Hematology Practice Improvement Module
Authors: Bischin Alina , Aboulafia David M. , Vishnu Prakash , Knopf Kevin , Chen Ruqin
Published: October 2019

ABSTRACT

Background: In 2014, the American Society of Hematology (ASH) established a practice improvement module (PIM) incorporating quality metrics for management of diffuse large B cell lymphoma (DLBCL). Such PIMs have allowed physicians to monitor the quality of care in their practice. We implemented a DLBCL quality improvement initiative (QII) at our institution in January, 2015. In an appraisal of this initiative, we reviewed the ASH PIM metrics and included several others to assess adherence to guidelines for treatment of DLBCL and to examine the need for institutional improvement.

Methods: Patients who were newly diagnosed with DLBCL and received treatment at our institution from January 2006 through December 2017 were identified. Electronic medical records were reviewed for documentation of ASH PIM quality measures (e.g., key pathologic features of DLBCL, lymphoma staging, screening for hepatitis B virus (HBV) infection in patients receiving rituximab-based chemotherapy, etc). We also reviewed the proportion of patients who had assessment of prognosis by revised International Prognostic Index (r-IPI) score, testing for hepatitis C (HCV), HIV viral infections, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL.

Results: Following implementation of the QII, our institution saw improvement in most quality metrics. Particularly significant were improvements in reporting of key molecular features (45.45% to 91.6%, P < 0.0001), screening for HBV (41.82% to 91.67%, P < 0.001) and HIV infections (33.94% to 87.5%, P < 0.0001). All patients post-QII had a PET-CT scan for staging of DLBCL and there was a significantly lower use of bone marrow biopsy (61.2% to 33.33%, P = 0.011).

Conclusion: Implementation of a quality initiative and employing standardized metrics can aid in improving institutional quality of care for patients with newly diagnosed DLBCL, and allows opportunity to build and ensure better adherence to evolving national and professional patient care guidelines.

Figure. Figure.

Disclosures

No relevant conflicts of interest to declare.
Human Treg Can Suppress Th17 Inflammatory Cytokine Secretion Independent of IL-2 Deprivation
Authors: Adair Patrick , Parvathaneni Kalpana , Kim Yong Chan , Scott David W.
Published: October 2019

Human Th17 cells are an inflammatory subset of CD4+ (CD4) T helper cells implicated in host of debilitating diseases and disorders such as multiple Sclerosis, rheumatoid arthritis, and psoriasis, as well as inhibitor formation in Hemophilia A. Although it is well established that regulatory CD4T cells (Tregs) can suppress other T helper (Th) effector cells (e.g. Th1, Th2, etc), their ability to suppress human Th17 cells is unresolved. This is attributed to several factors including plasticity between Treg and Th17 cells, the observation that Th17 cells express less IL-2 (and by extension are less dependent on IL-2) than other Th effector cells and consequently are less susceptible to Treg suppression via IL-2 deprivation. Using autologous naïve Tregs and effector memory CCR6+ CD4 T cells differentiated to Th17 cells from healthy human donor peripheral blood mononuclear cells, we performed a kinetic analysis of the IL-2 sensitivity via phosphorylated STAT5 expression. We show that Treg and Th17 cells have similar rates of pSTAT5 expression in vitro. We also show that both cell types have similar expression levels of the high affinity IL-2a receptor, CD25, following activation. Despite this, naïve Tregs successfully abrogated the secretion of IL17A by Th17 cells following 12hr co-culture. Furthermore, this abrogation is dependent on the strength of Treg activation and does not involve cytotoxic mechanisms, as viability of the Th17 cells remain high. These results suggest that human Tregs can suppress inflammatory IL-17A secretion from effector memory Th17 cells via mechanisms independent of IL-2 deprivation but dependent on strength of activation through Treg T-cell receptor. (Supported by NIH grant R01 HL126727)

Disclosures

No relevant conflicts of interest to declare.
The Comparison of Melphalan Administration on Day 3 with Administration on Day 1 on Neutrophil and Platelet Engraftment in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation
Authors: Unal Ali , Kaynar Leylagül , Yıldızhan Esra , Keni Nermin , Güven Zeynep , Eser Bulent , Cetin Mustafa
Published: October 2019

Objective: High dose chemotherapy followed by ASCT is the most important step of MM treatment. Melphalan, an alkylating agent, is the most preferable drug for conditioning regimens and dosage and timing is important with regards to side effects or engraftment timing. Engraftment time is determinative on infections and hospitalization duration.

Methods: We compared the neutrophil and thrombocyte engraftments retrospectively in patients with multiple myeloma who received melphalan 200 mg/m2 single dose on day -3 and day -1 as conditioning regimen. There were 29 patient receiving melphalan on day -1 and 42 patient on day -3.

Results: The mean neutrophil engraftment times for day -1 group and day -3 group were 12,8 ±2.4 days and 10,4±1.3 days, respectively (p < 0,001). The mean thrombocyte engraftment times for day -1 group and day -3 group were 13,48 ±3,7 days and 12,7±3,3 days, respectively (p :0,36). In day -3 group, there was no failure neither in neutrophil nor in thrombocyte engraftment but 1 patient could just get thrombocyte engraftment on day 33. In day -1 group, 2 patients could not get engraftment failure.

Conclusion: Administration of melphalan on day -3 is better than on day -1 in terms of neutrophil engraftment and hence in terms of hospitalisation duration.

Disclosures

No relevant conflicts of interest to declare.
Demographics and Survival in Primary Effusion Lymphoma: SEER Database Analysis
Authors: Khoury John , Willner Christopher Allen , Gbadamosi Bolanle , Gaikazian Susanna , Jaiyesimi Ishmael
Published: October 2019

Background: Primary effusion lymphoma (PEL) is one of the least common of the AIDS-related lymphomas, accounting for less than 4% of cases. The optimal treatment for primary effusion lymphoma (PEL) remains unclear and there is a paucity of data regarding this neoplasm, which carries a uniformly poor prognosis. Antiretroviral therapy in addition to chemotherapy has shown to improve survival in a few small retrospective studies.

Methods: Between 2002 and 2014, all cases of PEL were extracted from the population-based cancer registries of the Surveillance Epidemiology and End Results program (SEER). Instances of PEL were identified with the ICD-O-3 (9678) histological code. Frequency, demographics, and survival data were assessed using SPSS statistical software.

Results: A total of 117 cases of PEL were identified. PEL was significantly more prevalent in men (89.7%) and in Caucasians (77.8%) with median age at diagnosis of 49 years. Median overall survival in the entire cohort was 6 months; CI, 3.7 to 8.2 months. Of all PEL cases, 62.4% received chemotherapy and 37.6% did not. Those who received chemotherapy had a median overall survival of 10 months vs less than one month when compared to subjects who did not receive chemotherapy (p = 0.002). PEL was the cause of death in 40.2% of the cases. PEL-specific median overall survival was markedly higher (29.000 months) than that of the entire cohort. Multivariable analysis demonstrated that age and race were not associated with mortality. Chemotherapy was associated with decreased mortality risk (HR, 0.45; CI, 0.28 -0.74; p = 0.002)

Conclusions: In confirmation of previously published data, the highest incidence of PEL was found in Caucasian males. Subjects who received chemotherapy were found to have improved overall survival outcome. Other factors not related to PEL were associated with early mortality in this population.

Disclosures

No relevant conflicts of interest to declare.
Academic Centers Are Associated with Improved Survival Outcomes in High Risk Diffuse Large B-Cell Lymphoma Patients
Authors: Ermann Daniel A. , Noble Victoria Vardell , Kallam Avyakta , Armitage James O.
Published: October 2019

Background:

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, and is characterized as a heterogenous disease associated with varying outcomes. The International Prognostic Index (IPI) has been the standard for baseline prognostic assessment in these patients. In this study we aimed to determine the impact of treatment facility (academic versus non-academic centers) on overall survival outcomes in DLBCL patients stratified by IPI score risk groups, with a focus on high risk disease as this is associated with poorer outcomes.

Methods:

The 2018 National Cancer Database (NCDB) was utilized for patients diagnosed with DLBCL between 2004-2015. Patients were then stratified based on IPI risk score from low to high risk. Four risk groups were formed: low (0-1), low-intermediate (2), high-intermediate (3), and high (4-5). Overall survival was calculated using Kaplan-Meyer analysis with bivariate cox proportional hazard ratios to compare survival by facility type (academic or community centers) within these risk groups.

Results:

A total of 160,137 patients were identified. Of these cases 31.8% were classified as low risk, 21.9% were low-intermediate risk, 22.2% were high-intermediate risk, and 24% were high risk. 59.3% of patients were treated at a community center and 40.7% were treated at academic centers. Treatment at academic centers was associated with a significantly improved overall survival (OS) for each risk category. Median survival (in months) for high risk IPI score DLBCL was 47.9 months in community and 61.1 months in academic centers (p<.0001). Median survival for high-intermediate risk score was 48.3 months in community and 87.3 months in academic centers (p<.0001). Median survival for low-intermediate score was 90.3 months in community and 122.8 months in academic centers (p<.0001). Median survival for low risk score was 132 months in community and 148 months in academic centers (p<.0001). Hazard ratios for academic center versus community center for high risk, high-intermediate, low-intermediate and low risk are 0.768, 0.71, 0.848 and 0.818 respectively (p<.0001).

Conclusions:

Facility type is significantly associated with improved survival outcomes across all IPI based risk groups for DLBCL. This benefit is especially significant in higher risk disease where positive outcomes are less common, suggesting treatment at academic centers may be particularly beneficial in these patients. Some of the possible reasons for this difference may include provider experience, increased access to resources, and opportunity for clinical trials. Further investigations into the factors contributing to such disparities should be done to help standardize care and improve outcomes.

Disclosures

No relevant conflicts of interest to declare.
Efficacy and Safety of Hydroxyurea in the Treatment of Sickle Cell Anemia Children in Jos, North Central Nigeria
Authors: Ofakunrin Akinyemi Olugbenga David , Adekola Kehinde U. , Oguche Stephen , Okpe Edache Sylvanus , Sagay Atiene Solomon
Published: October 2019

Introduction: Sickle Cell Anaemia (SCA) is a genetic disorder with significant morbidity and mortality, and Nigeria accounts for the highest burden of the disease worldwide. Hydroxyurea has been shown to positively modify the disease pathogenesis, but its use is low among Nigerian SCA patients because of efficacy and safety concerns. Hence, this study evaluated the efficacy, tolerability and safety of hydroxyurea in Nigerian children with SCA.

Methods: A Quasi-experimental study with a before and after design using hydroxyurea as the intervention in 54 SCA children aged 4-17years, who have had at least two or more painful vaso-occlusive events requiring parenteral analgesia in the previous 12 months.

The number of Vaso-Occlusive Crisis (VOC), Acute Chest Syndrome (ACS), blood transfusions and hospitalisations in the previous 12 months obtained from the subjects' hospital records; and percentage fetal haemoglobin, Packed Cell Volume (PCV), White Blood Cell Counts (WBC) and Platelet Counts at baseline and after 12 months of hydroxyurea therapy were compared.The research participants were observed clinically for tolerability and adverse events of hydroxyurea while haematologic toxicity of hydroxyurea was monitored using complete blood count at specified intervals.

Wilcoxon Signed-Rank Test was used to compare the differences in the median values of the clinical and haematologic parameters at baseline and after 12 months of hydroxyurea therapy and a p-value of < 0.05 was considered statistically significant.

Results: The number of VOCs and hospitalisations reduced from the median baseline values of 3(2-3) and 2(2-3) respectively to 0(0), (p <0.0001). Blood transfusions as well as ACS declined from 48.1% and 11.2% at baseline to 5.6% and 0.0% respectively (p <0.05). The median PCV increased from 26.0(22.0-27.0) % to 28.0(25.8-30.2) % (p <0.0001) while the median WBC reduced from 11.1(7.3-14.6) x 109/L to 6.2(4.8-10.4) x 109/L (p < 0.0001) and the median platelet counts reduced from 411(264-496) x 109/L to 347(251-402) x 109/L (p= 0.009). A dose-dependent and reversible leucopenia was observed among six children (11.1%), otherwise, hydroxyurea was safe and well tolerated in the study population.

Conclusion: These findings suggest that hydroxyurea is efficacious, tolerable and safe in SCA children in Jos, Nigeria. The findings could serve as part of an educational template that could help improve the level of utilisation of hydroxyurea among sickle cell anaemia children in Jos, Nigeria.

Disclosures

No relevant conflicts of interest to declare.
Disparities in Foundation and Federal Support and Development of New Therapeutics for Sickle Cell Disease and Cystic Fibrosis
Authors: Farooq Faheem , Strouse John J
Published: October 2019

BACKGROUND: Sickle cell disease (SCD) and cystic fibrosis (CF) are rare inherited disorders of similar severity. Disparities in funding between these two diseases have been long recognized and likely contribute to limited access to care and treatments for sickle cell disease. Private investment in therapeutics for these and other orphan diseases has greatly increased in the past ten years. We hypothesized that these increased private expenditures may help correct disparities in research publications, clinical trials, and FDA approval of new therapies.

METHODS: We compared funding and research output for SCD and CF between 2008-2012 versus 2013-2017. We estimated disease-specific funding using NIH Research Portfolio Online Reporting Tools and the Form 990 financial reports for foundation expenditures of multiple organizations dedicated to each disease from 2008-2016. We developed a comprehensive search strategy to identify relevant publications in PubMed and new postings of US based interventional clinical trials by disease. In addition, we reviewed FDA drug approvals and new indications for each disease from 2008-2017.

RESULTS: Average annual NIH funding per affected individual was 3.4-fold greater for CF than SCD from 2008 to 2016. Between 2008-2012, private foundation funding was 161-fold greater for CF than SCD. Between 2013-2016, private funding was 971-fold greater for CF than SCD. There were 1.8 times as many PubMed publications for CF compared to SSD. There was no significant difference in PubMed publications between the two time periods. There was a significant increase in interventional clinical trials for SCD between 2013-2017, with the largest increase coming from university/philanthropic funded trials. However, CF has significantly increased FDA drug approvals of both novel compounds and novel indications.

CONCLUSIONS: Although the US prevalence of SCD is three times greater than CF, the amount of federal and private foundation research funding is magnitudes greater for CF. Foundation funding for CF benefited significantly from revenue based on the successful development of targeted therapies. However, despite the significant funding difference, the number of clinical trials for SSD are comparable to CF and have increased over the past few years. Research productivity as measured by articles indexed in PubMed, and new drug approvals remain substantially higher for cystic fibrosis despite greatly increased industry investment in orphan diseases.

Disclosures

Strouse: Global Blood Therapeutics: Consultancy.
Recombinant Activated Coagulation Factor VII (rFVIIa) for Treatment of the Tracheobronchial Bleeding in Mechanically Ventilated (MV) Thrombocytopenic Patients (pts)
Authors: Galstian Gennadii M. , Polevodova Olesya A. , Zorenko Vladimir Yu. , Savchenko Valeriy G.
Published: October 2019

Introduction and Objectives: MV in thrombocytopenic pts could be complicated by life threatening tracheobronchial bleeding. The systemic treatment with tranexamic acid or rFVIIa increases the risk of thromboembolic events. Presented in airspace tissue factor (TF) reacts as a cofactor in augmenting the activity of FVIIa 1000-fold. Topical treatment of the inhalation with rFVIIa has not been studied yet. The aim of the study was to evaluate hemostatic effect of rFVIIa inhalation for treatment of the tracheobronchial bleeding in MV thrombocytopenic pts.

Materials and Methods: The results of rFVIIa inhalation were investigated in 5 acute leukemia pts (2 males, 3 female). All pts were mechanically ventilated through tracheostomy tube and had life threatening tracheobronchial bleeding. Before intervention all pts had low platelet count 50-120х109/l (median 65 х109/l), lowered Quick prothrombin (55-64%, median 58%), prolonged APTT (55-57s).

Results. All pts received rFVIIa as an inhalation over five to ten minutes. For inhalation rFVIIa (Koagil VII, Generium, Russia, Vial of 2.4 mg) was diluted in 10 ml of isotonic saline. If, after 20 min, there is no response to rFVIIa second dose of rFVIIa (2.4 mg) as an inhalation was administrated. Bleeding was stopped in 3/5 pts, in 2 pts the intensity of bleeding decreased. There were no changes in APTT and Quick prothrombin registered. Median plasma FVII activity before inhalation was 82%, after inhalation - 73%. There were no changes on the TEG (figure 1). Thus, despite local hemostatic effect we did not registered systemic effects of rFIIa after inhalation

Conclusion. Topical treatment of the tracheobronchial bleeding with rFVIIa inhalation provided hemostatic effect. There were not be systemic adverse effects in as much as the alveolocapillary membrane does not allow the transmembranous passage of rFVIIa.

Disclosures

No relevant conflicts of interest to declare.