Hematology Commons^™

Synergy Of Venetoclax And 8-Chloro-Adenosine In Aml: The Interplay Of Rrna Inhibition And Fatty Acid Metabolism, Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen

Faculty, Staff and Student Publications

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado …

The Correlation Of D-Dimer To Stroke Diagnosis Within 24 Hours: A Meta-Analysis, Adeel Ahmad, Zara Islam, Saad Manzoor Ahmad, Zouina Sarfraz, Azza Sarfraz, Miguel Felix, Ivan Cherrez-Ojeda

Department of Paediatrics and Child Health

Background: Diagnosing D-Dimer early is essential to optimize clinical treatment and quality of life and reduce mortality. This study aims to identify the difference of D-Dimer levels (ng/ml) in patients with stroke within the 6- and 24-h period compared to patients that mimic stroke.
Methods: An electronic database search across PubMed/MEDLINE, Cochrane, Web of Science, CINAHL, EMBASE, and Scopus was conducted until December 10, 2021. Studies were eligible if they included adult patients with stroke compared to stroke mimics or controls reporting D-Dimer values. Quality assessment was conducted using GRADE. The standardized mean difference and 95% confidence intervals were calculated …

Clonal Hematopoiesis Is Associated With Higher Risk Of Stroke, Romit Bhattacharya, Seyedeh M Zekavat, Jeffrey Haessler, Myriam Fornage, Laura Raffield, Md Mesbah Uddin, Alexander G Bick, Abhishek Niroula, Bing Yu, Christopher Gibson, Gabriel Griffin, Alanna C Morrison, Bruce M Psaty, William T Longstreth, Joshua C Bis, Stephen S Rich, Jerome I Rotter, Russell P Tracy, Adolfo Correa, Sudha Seshadri, Andrew Johnson, Jason M Collins, Kathleen M Hayden, Tracy E Madsen, Christie M Ballantyne, Siddhartha Jaiswal, Benjamin L Ebert, Charles Kooperberg, Joann E Manson, Eric A Whitsel, Nhlbi Trans-Omics For Precision Medicine Program, Pradeep Natarajan, Alexander P Reiner

Faculty, Staff and Student Publications

Background and purpose: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.

Methods: We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association …

Symptom Clusters, Physical Activity, And Quality Of Life: A Latent Class Analysis Of Children During Maintenance Therapy For Leukemia, Mary C Hooke, Michelle A Mathiason, Audrey Blommer, Jessica Hutter, Pauline Mitby, Olga Taylor, Michael E Scheurer, Alicia S Kunin-Batson, Wei Pan, Marilyn J Hockenberry

Faculty, Staff and Students Publications

BACKGROUND: Children undergoing treatment for acute lymphocytic leukemia (ALL) report co-occurring symptoms of fatigue, sleep disturbances, and depression as a symptom cluster. Physical activity (PA) may influence symptom severity and quality of life (QOL).

OBJECTIVES: This study examined changes in symptoms and QOL during ALL maintenance in children categorized by symptom cluster and explored the influence of PA and symptoms on QOL.

METHODS: Self-report of fatigue, sleep disturbance, and depression; QOL; and PA were measured at the beginning and end of maintenance in 42 children aged 3 to 18 years with ALL. Children were categorized into symptom cluster groups based …

The Impact Of Disruptive Physician Behavior On Support Staff And Patients: A Quantitative Secondary Analysis, Michael C. Marino

Electronic Theses and Dissertations

In this quantitative secondary analysis, the purpose was to examine the nature of disruptive physician behavior (DPB) from the support staff and patient perspectives. Healthcare staffing shortages existed prior to the global pandemic and have increased, creating importance for employee retention and recruitment. I wanted to understand the impact of physician behavior on staff turnover rates in a private oncology practice, its effect on patient satisfaction rates, and to compare these rates of physicians that display DPB with physicians that do not display this behavior in a private hematology oncology community outpatient setting in the Southwest United States. To answer …

Zanubrutinib For Treatment-Naïve And Relapsed/Refractory Chronic Lymphocytic Leukaemia: Long-Term Follow-Up Of The Phase I/Ii Au-003 Study, Gavin Cull, Jan A Burger, Stephen Opat, David Gottlieb, Emma Verner, Judith Trotman, Paula Marlton, Javier Munoz, Patrick Johnston, David Simpson, Jennifer C Stern, Radha Prathikanti, Kenneth Wu, William Novotny, Jane Huang, Constantine S Tam

Faculty, Staff and Student Publications

The phase I/II AU-003 study in patients with treatment-naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow-up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response …

Subtype-Specific And Co-Occurring Genetic Alterations In B-Cell Non-Hodgkin Lymphoma, Man Chun John Ma, Saber Tadros, Alyssa Bouska, Tayla Heavican, Haopeng Yang, Qing Deng, Dalia Moore, Ariz Akhter, Keenan Hartert, Neeraj Jain, Jordan Showell, Sreejoyee Ghosh, Lesley Street, Marta Davidson, Christopher Carey, Joshua Tobin, Deepak Perumal, Julie M Vose, Matthew A Lunning, Aliyah R Sohani, Benjamin J Chen, Shannon Buckley, Loretta J Nastoupil, R Eric Davis, Jason R Westin, Nathan H Fowler, Samir Parekh, Maher Gandhi, Sattva Neelapu, Douglas Stewart, Kapil Bhalla, Javeed Iqbal, Timothy Greiner, Scott J Rodig, Adnan Mansoor, Michael R Green

Faculty, Staff and Student Publications

B-cell non-Hodgkin lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL, such as diffuse large B-cell lymphoma, have been comprehensively interrogated at the genomic level, but rarer subtypes, such as mantle cell lymphoma, remain less extensively characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth, including diffuse large B-cell lymphoma, …

Safety And Activity Of Pembrolizumab In Combination With Rituximab In Relapsed Or Refractory Follicular Lymphoma, Loretta J Nastoupil, Collin K Chin, Jason R Westin, Nathan H Fowler, Felipe Samaniego, Xiaoyun Cheng, Man Chun John Ma, Zhiqiang Wang, Fuliang Chu, Ly Dsouza, Chizobam Obi, Jennifer Mims, Lei Feng, Shouhao Zhou, Michael Green, Richard Eric Davis, Sattva S Neelapu

Faculty, Staff and Student Publications

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were …

Activation Of Ras/Mapk Pathway Confers Mcl-1 Mediated Acquired Resistance To Bcl-2 Inhibitor Venetoclax In Acute Myeloid Leukemia, Qi Zhang, Bridget Riley-Gillis, Lina Han, Yannan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N Konoplev, Shannon R Sweeney, Jeremy A Ryan, Yulia Jitkova, Kenneth Dunner, Shaun E Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen Kurtz, Vivian R Ruvolo, Helen Ma, Connie C Weng, Cassandra L Ramage, Natalia Baran, Ce Shi, Tianyu Cai, Richard Eric Davis, Venkata L Battula, Yingchang Mi, Jing Wang, Courtney D Dinardo, Michael Andreeff, Jeffery W Tyner, Aaron Schimmer, Anthony Letai, Rose Ann Padua, Carlos E Bueso-Ramos, Stefano Tiziani, Joel Leverson, Relja Popovic, Marina Konopleva

Faculty, Staff and Student Publications

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance …

Combination Of Tipifarnib And Sunitinib Overcomes Renal Cell Carcinoma Resistance To Tyrosine Kinase Inhibitors Via Tumor-Derived Exosome And T Cell Modulation, Jacob W. Greenberg, Hogyoung Kim, Miae Ahn, Ahmed A. Moustafa, He Zhou, Pedro C. Barata, A. Hamid Boulares, Asim B. Abdel-Mageed, Louis S. Krane

School of Graduate Studies Faculty Publications

Background: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. Methods: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Ex-osomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. Results: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated …

Effective Therapy For Aml With Runx1 Mutation By Cotreatment With Inhibitors Of Protein Translation And Bcl2, Christopher P Mill, Warren Fiskus, Courtney D Dinardo, Christine Birdwell, John A Davis, Tapan M Kadia, Koichi Takahashi, Nicholas Short, Naval Daver, Maro Ohanian, Gautam Borthakur, Steven M Kornblau, Michael R Green, Yuan Qi, Xiaoping Su, Joseph D Khoury, Kapil N Bhalla

Faculty, Staff and Student Publications

The majority of RUNX1 mutations in acute myeloid leukemia (AML) are missense or deletion-truncation and behave as loss-of-function mutations. Following standard therapy, AML patients expressing mtRUNX1 exhibit inferior clinical outcome than those without mutant RUNX1. Studies presented here demonstrate that as compared with AML cells lacking mtRUNX1, their isogenic counterparts harboring mtRUNX1 display impaired ribosomal biogenesis and differentiation, as well as exhibit reduced levels of wild-type RUNX1, PU.1, and c-Myc. Compared with AML cells with only wild-type RUNX1, AML cells expressing mtRUNX1 were also more sensitive to the protein translation inhibitor homoharringtonine (omacetaxine) and BCL2 inhibitor venetoclax. Homoharringtonine treatment repressed …

Lymphoma With Tuberculous Granulomas, Jyoti Mohan Lal, Anila Rashid

Department of Pathology and Laboratory Medicine

Chronic granulomatous inflammation is a common finding in lymphoproliferative disorders (LPDs), but it is important to exclude coexisting mycobacterium tuberculosis (MTB) especially in patients from areas of high endemicity. This case emphasizes the relevance of performing MTB culture on bone marrow exhibiting LPD and concomitant granulomas

Randomized Phase Iii Bmt Ctn Trial Of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions In Myeloablative Hematopoietic Cell Transplantation For Hematologic Malignancies, Leo Luznik, Marcelo C Pasquini, Brent Logan, Robert J Soiffer, Juan Wu, Steven M Devine, Nancy Geller, Sergio Giralt, Helen E Heslop, Mary M Horowitz, Richard J Jones, Mark R Litzow, Adam Mendizabal, Lori Muffly, Eneida R Nemecek, Lynn O'Donnell, Richard J O'Reilly, Raquel Palencia, Johannes Schetelig, Leyla Shune, Scott R Solomon, Sumithira Vasu, Vincent T Ho, Miguel-Angel Perales

Faculty, Staff and Students Publications

PURPOSE: Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).

METHODS: This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or …

Impact Of Frontline Treatment Approach On Outcomes In Patients With Secondary Aml With Prior Hypomethylating Agent Exposure, Nicholas J Short, Sangeetha Venugopal, Wei Qiao, Tapan M Kadia, Farhad Ravandi, Walid Macaron, Courtney D Dinardo, Naval Daver, Marina Konopleva, Gautam Borthakur, Elizabeth J Shpall, Uday Popat, Richard E Champlin, Rohtesh Mehta, Gheath Al-Atrash, Betul Oran, Elias Jabbour, Guillermo Garcia-Manero, Ghayas C Issa, Guillermo Montalban-Bravo, Musa Yilmaz, Abhishek Maiti, Hagop Kantarjian

Faculty, Staff and Student Publications

BACKGROUND: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain.

METHODS: We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54).

RESULTS: Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted …

Utility Of Blood As The Clinical Specimen For The Diagnosis Of Ocular Toxoplasmosis Using Uracil Dna Glycosylase-Supplemented Loop-Mediated Isothermal Amplification And Real-Time Polymerase Chain Reaction Assays Based On Rep-529 Sequence And B1 Gene, Bahman Rahimi Esboei, Shirzad Fallahi, Mohammad Zarei, Bahram Kazemi, Mehdi Mohebali, Saeedeh Shojaee, Parisa Mousavi, Aref Teimouri, Raziyeh Mahmoudzadeh, Mirataollah Salabati, Hossein Keshavarz Valian

Wills Eye Hospital Papers

Background: Ocular infection with Toxoplasma gondii is a major preventable cause of blindness, especially in young people. The aim of the present study was to assess detection rate of T. gondii DNA in blood samples of clinically diagnosed of ocular toxoplasmosis using uracil DNA glycosylase-supplemented loop-mediated isothermal amplification (UDG-LAMP) and real-time quantitative PCR (qPCR) based on REP-529 and B1.

Methods: One hundred and seventeen patients with clinically diagnosed ocular toxoplasmosis (OT) were participated in the study as well as 200 control patients. Peripheral blood samples were assessed using UDG-LAMP and qPCR techniques targeting REP-529 and B1.

Results: Detection limits of …

Allogeneic Transplant And Car-T Therapy After Autologous Transplant Failure In Dlbcl: A Noncomparative Cohort Analysis, Mehdi Hamadani, Ajay K Gopal, Marcelo Pasquini, Soyoung Kim, Xianmiao Qiu, Sairah Ahmed, Aleksandr Lazaryan, Vijaya Raj Bhatt, Andrew Daly, Premal Lulla, Stefan Ciurea, Jordan Gauthier, Vaibhav Agrawal, Natalie S Grover, Lazaros Lekakis, Dipenkumar Modi, Parastoo B Dahi, Megan M Herr, P Connor Johnson, Hamza Hashmi, Peiman Hematti, Frederick L Locke

Faculty, Staff and Students Publications

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR)-T cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto)HCT. Although the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis, we report outcomes of patients with DLBCL (≥18 years) undergoing a reduced intensity alloHCT or CAR-T therapy with axicabtagene ciloleucel during 2012 to 2019 after a prior auto-HCT failure and apply the CIBMTR prognostic …

Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang

Faculty, Staff and Students Publications

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes …

Red Blood Cell Distribution Width In Hospitalized Covid-19 Patients., Preethi Ramachandran, Mahesh Gajendran, Abhilash Perisetti Md, Karim Osama Elkholy, Abhishek Chakraborti, Giuseppe Lippi, Hemant Goyal

Other Specialties

Introduction: Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is causing dramatic morbidity and mortality worldwide. The Red Blood Cell Distribution Width (RDW) has been strongly associated with increased morbidity and mortality in multiple diseases.

Objective: To assess if elevated RDW is associated with unfavorable outcomes in hospitalized COVID-19.

Methods: We retrospectively studied clinical outcomes of hospitalized COVID-19 patients for their RDW values. In-hospital mortality was defined as primary outcome, while septic shock, need for mechanical ventilation, and length of stay (LOS) were secondary outcomes.

Results: A total of 294 COVID-19 patients were finally studied. Overall prevalence …

The Efficacy And Safety Of Thrombopoietin Receptor Agonists In Patients With Chronic Liver Disease Undergoing Elective Procedures: A Systematic Review And Meta-Analysis, Ingrid Lindquist, Sven R Olson, Ang Li, Hanny Al-Samkari, Janice H Jou, Owen J T Mccarty, Joseph J Shatzel

Faculty, Staff and Students Publications

Thrombopoietin receptor agonists (TPO-RAs) can mitigate preprocedural thrombocytopenia in patients with chronic liver disease (CLD) however their effects on procedural outcomes is unclear. In this meta-analysis, we aimed to better define the efficacy, thrombotic risk and bleeding mitigation associated with the use of preoperative TPO-RAs in patients with CLD. We performed a systematic review and meta-analysis of randomized placebo-controlled clinical trials to assess the use of preprocedural TPO-RAs in patients with CLD, searching MEDLINE, EMBASE and the Cochrane library database. Six publications comprising eight randomized trials (1229 patients; 717 received TPO-RAs, 512 received placebo) and three unique TPO-RAs were retrieved. …

The Utility Of Fungal Blood Cultures: A Quality Improvement Study, Brigette Schuman, Elizabeth Savage, Vanessa Hoytfox

View All Washington/Montana GME

Presented at the 2022 Virtual Northwest Medical Research Symposium