Hematology Commons^™

Emicizumab-Kxwh: A Critical Review, Kiera O'Leary

International Undergraduate Journal of Health Sciences

The first descriptions of haemophilia A were reported in the second century AD, with the first modern description by John Conrad Otto in 1803. Historically, the natural history of haemophilia A was associated with very high rates morbidity and mortality, often following trivial accidents. Although treatment options for haemophilia A have been revolutionised in recent decades, haemophilia A remains a hereditary disease of concern and factor replacement products remain the mainstay of treatment.

As such, patients with haemophilia can carry huge burdens, particularly when a complication such as a FVIII inhibitor is present. A recently approved novel therapeutic, Emicizumab-kxwh, has …

Hematologic Complications Of Immune Checkpoint Inhibitors, Michael H Kroll, Cristhiam Rojas-Hernandez, Cassian Yee

Faculty, Staff and Student Publications

Immune checkpoint inhibitors are a class of antineoplastic therapies that unleash immune cells to kill malignant cells. There are currently 7 medications that have been approved by the US Food and Drug Administration for the treatment of 14 solid tumors and 2 hematologic malignancies. These medications commonly cause immune-related adverse effects as a result of overactive T lymphocytes, autoantibody production, and/or cytokine dysregulation. Hematologic toxicities are rare and of uncertain mechanism, and therefore management is often based on experiences with familiar conditions involving these perturbed immune responses, such as autoimmune hemolytic anemia, immune thrombocytopenia, and idiopathic aplastic anemia. Management is …

Resistance To Targeted Therapies: Delving Into Flt3 And Idh, Sai Prasad Desikan, Naval Daver, Courtney Dinardo, Tapan Kadia, Marina Konopleva, Farhad Ravandi

Faculty, Staff and Student Publications

Recent advances in FLT3 and IDH targeted inhibition have improved response rates and overall survival in patients with mutations affecting these respective proteins. Despite this success, resistance mechanisms have arisen including mutations that disrupt inhibitor-target interaction, mutations impacting alternate pathways, and changes in the microenvironment. Here we review the role of these proteins in leukemogenesis, their respective inhibitors, mechanisms of resistance, and briefly ongoing studies aimed at overcoming resistance.

Regional Anesthesia For Sickle Cell Disease Vaso-Occlusive Crisis: A Single-Center Case Series, Cecile Karsenty, Venée N Tubman, Chyong-Jy Joyce Liu, Titilope Fasipe, Karla E K Wyatt

Faculty, Staff and Students Publications

Pain management is challenging for patients with sickle cell disease (SCD) who present in vaso-occlusive crisis (VOC). Opioid therapy is highly effective, nevertheless undesirable side effects can hinder their effectiveness. Regional anesthesia with deposition of perineural anesthetic offers nociceptive blockade, local vasodilatation, and reduces the inflammatory response. Among pediatric patients, continuous peripheral nerve block (CPNB) for perioperative adjunctive analgesia is safe. Herein, we describe the trajectory of a cohort of pediatric SCD patients with opioid-refractory upper-extremity VOC following placement of CPNBs for analgesia; highlighting reduced opioid consumption, improved pain scores, and decreased length of hospitalization.

Multi-Phenotype Analyses Of Hemostatic Traits With Cardiovascular Events Reveal Novel Genetic Associations, Gerard Temprano-Sagrera, Colleen M Sitlani, William P Bone, Miguel Martin-Bornez, Benjamin F Voight, Alanna C Morrison, Scott M Damrauer, Paul S De Vries, Nicholas L Smith, Maria Sabater-Lleal

Faculty, Staff and Student Publications

BACKGROUND: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.

OBJECTIVES: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.

METHODS: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen …

Axl/Mertk Inhibitor Ono-7475 Potently Synergizes With Venetoclax And Overcomes Venetoclax Resistance To Kill F Lt 3-Itd Acute Myeloid Leukemia, Sean M Post, Huaxian Ma, Prerna Malaney, Xiaorui Zhang, Marisa J L Aitken, Po Yee Mak, Vivian R Ruvolo, Tomoko Yasuhiro, Ryohei Kozaki, Lauren E Chan, Lauren B Ostermann, Marina Konopleva, Bing Z Carter, Courtney Dinardo, Michael D Andreeff, Joseph D Khoury, Peter P Ruvolo

Faculty, Staff and Student Publications

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that …

A Phase 1 Trial Of 8-Chloro-Adenosine In Relapsed/Refractory Acute Myeloid Leukemia: An Evaluation Of Safety And Pharmacokinetics, Rong Chen, Yuling Chen, Ping Xiong, Daniella Zheleva, David Blake, Michael J Keating, William G Wierda, William Plunkett

Faculty, Staff and Student Publications

Fadraciclib (CYC065) is a second-generation aminopurine CDK2/9 inhibitor with increased potency and selectivity toward CDK2 and CDK9 compared to seliciclib (R-roscovitine). In chronic lymphocytic leukemia (CLL), a disease that depends on the over-expression of anti-apoptotic proteins for its survival, inhibition of CDK9 by fadraciclib reduced phosphorylation of the C-terminal domain of RNA polymerase II and blocked transcription in vitro; these actions depleted the intrinsically short-lived anti-apoptotic protein Mcl-1 and induced apoptosis. While the simulated bone marrow and lymph node microenvironments induced Mcl-1 expression and protected CLL cells from apoptosis, these conditions did not prolong the turnover rate of Mcl-1, and …

Pirtobrutinib Inhibits Wild-Type And Mutant Bruton’S Tyrosine Kinase-Mediated Signaling In Chronic Lymphocytic Leukemia, Burcu Aslan, Gorkem Kismali, Lakesla R Iles, Ganiraju C Manyam, Mary L Ayres, Lisa S Chen, Mihai Gagea, Maria Teresa Sabrina Bertilaccio, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well …

Inhibition Of Mitochondrial Complex I Reverses Notch1-Driven Metabolic Reprogramming In T-Cell Acute Lymphoblastic Leukemia, Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva

Faculty, Staff and Student Publications

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with …

Igm Multiple Myeloma: A Rare Clinical Entity And Diagnostic Dilemma, Keerthy Joseph, Alison Greidinger, Marjan Koch, Eric Behling, Tulin Budak-Alpdogan

Cooper Rowan Medical Journal

IgM multiple myeloma is a rare disease that shares many common features with Waldenström macroglobulinemia and lymphoplasmacytic lymphoma. It has been described in the literature as having unique diagnostic findings that separate it from the more common IgG and IgA myelomas. It is important for physicians to be able to differentiate between IgM multiple myeloma, Waldenström macroglobulinemia and lymphoplasmacytic lymphoma as their treatments vastly differ. This case report describes the clinical presentation of a patient with IgM lambda multiple myeloma and highlights the pathologic and clinical findings that are specific to this rare entity. We aim to provide further evidence …

Acute Kidney Injury: Evaluating Risk Factors In Hematopoietic Stem Cell Transplant Patients, Jennifer Tenley, Pamela Millin, Austyn Franklin

Nursing Masters Papers

Hematopoietic stem cell transplant (HSCT) patients are at risk to develop acute kidney injury during the transplant process. Acute kidney injury (AKI) can occur due to a multitude of insults related to nephrotoxic medications, hypoperfusion, and dehydration. Additionally, patients who present for HSCT may have risk factors that could pose an increased risk of developing AKI which include chronic kidney disease, hematologic disease, type of transplant, conditioning chemotherapy, and poor pretransplant renal testing. The purpose of this secondary analysis was to identify the contributing factors that may influence the development of AKI, understand the relationships between the variables, and identify …

Hepatoid Adenocarcinoma Of Lung: A Rare And Challenging Tumor, Bipin Ghimire, Ashbina Pokharel, Samiksha Pandey, Ujjwal Jung Karki, Can Wang, Michael Stender

Conference Presentation Abstracts

Hepatoid adenocarcinoma (HAC) is an extremely rare extra-hepatic malignant tumor having hepatic features on pathology. Stomach is the most common site, and hepatoid adenocarcinoma of lung (HAL) accounts for 2.3 – 5% of all HACs. Less than 100 cases of HAL have been reported worldwide since its concept was put forward in 1990. A 63-year-old female presented to the ED with back pain. Initial evaluation revealed anemia (hemoglobin 6.7), hypercalcemia (12.1 mg/dl), GFR 54 mL/min. X-ray thoracic spine and chest showed two vertebral compression deformities and lytic lesions on multiple ribs. Initially, multiple myeloma was considered likely but further evaluation …

Merkle Cell Carcinoma While On Rituximab - Is It A Coincidence?, Bana Antonios, Emma Herrman, Mohammad Muhsin Chisti

Conference Presentation Abstracts

A 79-year old woman with history of relapsed Stage II, grade III follicular lymphoma was treated with four cycles of rituximab and bendamustine with an excellent response. She was subsequently placed on maintenance rituximab infusions every eight weeks. Six months later, she presented to the dermatology clinic with a newly raised erythematous papule on her left cheek. Excisional biopsy confirmed a diagnosis of Merkel cell carcinoma which was resected with wide margins. Merkel cell carcinoma (MCC) is a rare aggressive skin malignancy, with a dramatic increase in incidence in the past few decades. It grows and metastasizes rapidly and diagnosis …

Case Series: Bone Marrow Failure In Teen Siblings With Unique Rps19 Variant, Alexandra Prosser

Research Days

Background: Upon diagnosis of aplastic anemia, inherited bone marrow failure syndromes and acquired etiologies must be considered. Investigating causality is particularly important when multiple family members are affected. It is also essential to identify novel causative genetic variants of bone marrow failure to direct treatment in these patients.

Objectives: To describe the diagnosis and management of siblings who presented two weeks apart with severe pancytopenia and were diagnosed with severe aplastic anemia.

Methods: The first patient is a 13-year-old non-binary female who presented with severe pancytopenia on routine labs. Bone marrow biopsy revealed marked hypocellularity (0-10%) with hypoplasia. The second …

Stroke In Hfref Without Atrial Fibrillation And Concurrent Protein S Deficiency: What Is The Best Treatment?, Rohan Umrani, Trinava Roy, Bhavana Kadiyala, Yvette Wang

Rowan-Virtua Research Day

Hypercoagulable disorders are often the culprit for repeated strokes in young patients, with or without other comorbidities

Medications typically used for stroke prophylaxis:

• Warfarin
• Aspirin
• Direct Oral Anticoagulants (DOACs)

Warfarin is the preferred method of anticoagulation for stroke prophylaxis in patients with hypercoagulable disorders

A deficiency of protein S increases the risk of pro coagulation due to a relative deficiency of anticoagulants.

Patients with protein S deficiency tend to have recurrent venous thromboses and pulmonary emboli

Evidence Supporting A Role For The Immune Checkpoint Protein B7-H3 In Nk Cell-Mediated Cytotoxicity Against Aml, Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans-Jörg Bühring, V Lokesh Battula

Faculty, Staff and Student Publications

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop …

A Novel Approach To Triosephosphate Isomerase Deficiency, Kyra Mccarty

Research Days

Background: Triosephosphate isomerase deficiency (TPID) is a glycolytic pathway enzymopathy causing hemolytic anemia and neurologic dysfunction. TPID is caused by mutations in the TPI1 gene. These patients experience severe hemolytic anemia in infancy followed by progressive neurodegeneration. Diagnosis of TPID is made by measuring decreased TPI enzyme activity elevated dihydroxyacetone phosphate (DHAP) levels in the blood. The diagnosis is confirmed by molecular genetic testing. Neurological involvement typically manifests between 6 and 24 months of age, causing progressive motor dysfunction. Chronic axonal neuropathy is often present on nerve biopsy, and peripheral neuropathy is evident on electrophysiologic studies. Splenectomy and blood transfusions …

Primary Venous Thromboprophylaxis In Pediatric Oncology Patients, Kyra Mccarty

Research Days

Background: The Virchow’s Triad principles of venous stasis, endothelial damage, and hypercoagulability are all features of malignancy and contribute to the increased risk venous thromboembolism (VTE) seen in oncology patients. Additionally, certain chemotherapy treatments, presence of a central venous catheter and immobility are also intrinsically associated with malignancy diagnoses and exacerbate this risk. However, much debate exists over the use of thromboprophylaxis in the pediatric population, primarily due to lack of evidence regarding safety and efficacy, primarily the risk of major bleeding. Multiple retrospective studies have attempted to identify the primary risk factors for VTE in this pediatric oncology patient …

Dietary Supplement Use Among Brca1/2 Mutation Carriers, Ryan Rogers, Tara Ramgarajan, Virginia Uhley, Kristina Ivan, Dana Zakalik

Posters

INTRODUCTION
Women who carry BRCA1/2 mutations are at significantly increased risk of breast, ovarian, pancreatic and other cancer. Little is known regarding the use of dietary supplements among women harboring BRCA1/2 mutations. This study aims to characterize the utilization of and attitudes toward dietary supplement use in women who carry BRCA1/2 mutations.

Developing And Optimizing A Computable Phenotype For Incident Venous Thromboembolism In A Longitudinal Cohort Of Patients With Cancer, Ang Li, Wilson L Da Costa, Danielle Guffey, Emily M Milner, Anthony K Allam, Karen M Kurian, Francisco J Novoa, Marguerite D Poche, Raka Bandyo, Carolina Granada, Courtney D Wallace, Neil A Zakai, Christopher I Amos

Faculty, Staff and Students Publications

BACKGROUND: Research on venous thromboembolism (VTE) that relies only on the International Classification of Diseases (ICD) can misclassify outcomes. Our study aims to discover and validate an improved VTE computable phenotype for people with cancer.

METHODS: We used a cancer registry electronic health record (EHR)-linked longitudinal database. We derived three algorithms that were ICD/medication based, natural language processing (NLP) based, or all combined. We then randomly sampled 400 patients from patients with VTE codes (n = 1111) and 400 from those without VTE codes (n = 7396). Weighted sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were …