Hematology Commons^™

Tp53-Altered Chronic Lymphocytic Leukemia Treated With Firstline Bruton’S Tyrosine Kinase Inhibitor-Based Therapy: A Retrospective Analysis, Hua-Jay J Cherng, Raamis Khwaja, Rashmi Kanagal-Shamanna, Guilin Tang, Jan Burger, Philip Thompson, Alessandra Ferrajoli, Zeev Estrov, Koji Sasaki, Deepa Sampath, Xuemei Wang, Hagop Kantarjian, Michael Keating, William G Wierda, Nitin Jain

Faculty, Staff and Student Publications

Long-term follow up of prospective studies has shown that continuous Bruton's tyrosine kinase inhibitor (BTKi) therapy leads to durable remissions in previously untreated patients with TP53-altered chronic lymphocytic leukemia (CLL); however, it is unknown how variant allele frequency (VAF) of TP53 mutation (TP53-m) or percentage of cells with deletion of chromosome 17p [del(17p)] influences efficacy of firstline BTKi. We performed a retrospective analysis of 130 patients with CLL with baseline del(17p) and/or TP53-m treated with BTKi with or without the BCL2 inhibitor venetoclax (VEN) and with or without CD20 antibody in the firstline setting. A total of 104/130 (80%) patients …

Maternal Iron Deficiency Programs Rat Offspring Hypertension In Relation To Renin-Angiotensin System And Oxidative Stress, Ya-Hui Chang, Wan-Hsuan Chen, Chung-Hao Su, Hong-Ren Yu, You-Lin Tain, Li-Tung Huang, Jiunn-Ming Sheen

Faculty, Staff and Student Publications

Hypertension is an important public health challenge, affecting up to 30-50% of adults worldwide. Several epidemiological studies indicate that high blood pressure originates in fetal life-the so-called programming effect or developmental origin of hypertension. Iron-deficiency anemia has become one of the most prevalent nutritional problems globally. Previous animal experiments have shown that prenatal iron-deficiency anemia adversely affects offspring hypertension. However, the underlying mechanism remains unclear. We used a maternal low-iron diet Sprague Dawley rat model to study changes in blood pressure, the renal renin-angiotensin system, oxidative stress, inflammation, and sodium transporters in adult male offspring. Our study revealed that 16-week-old …

Predictive Factors And Outcomes For Ibrutinib In Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter Cohort Study, Narendranath Epperla, Qiuhong Zhao, Sayan Mullick Chowdhury, Lauren Shea, Tamara K Moyo, Nishitha Reddy, Julia Sheets, David M Weiner, Praveen Ramakrishnan Geethakumari, Malathi Kandarpa, Ximena Jordan Bruno, Colin Thomas, Michael C Churnetski, Andrew Hsu, Luke Zurbriggen, Cherie Tan, Kathryn Lindsey, Joseph Maakaron, Paolo F Caimi, Pallawi Torka, Celeste Bello, Sabarish Ayyappan, Reem Karmali, Seo-Hyun Kim, Anna Kress, Shalin Kothari, Yazeed Sawalha, Beth Christian, Kevin A David, Irl Brian Greenwell, Murali Janakiram, Vaishalee P Kenkre, Adam J Olszewski, Jonathon B Cohen, Neil D. Palmisiano, Elvira Umyarova, Ryan A Wilcox, Farrukh T Awan, Juan Pablo Alderuccio, Stefan K Barta, Natalie S Grover, Nilanjan Ghosh, Nancy L Bartlett, Alex F Herrera, Geoffrey Shouse

Department of Medicine Faculty Papers

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% …

Pneumonitis After Immune Checkpoint Inhibitor Therapies In Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study, Ajay Sheshadri, Alberto A Goizueta, Vickie R Shannon, David London, Guillermo Garcia-Manero, Hagop M Kantarjian, Farhad Ravandi-Kashani, Tapan M Kadia, Marina Y Konopleva, Courtney D Dinardo, Sherry Pierce, Abdulrazzak Zarifa, Aya A Albittar, Linda L Zhong, Fechukwu O Akhmedzhanov, Muhammad H Arain, Mansour Alfayez, Ahmad Alotaibi, Mehmet Altan, Aung Naing, Tito R Mendoza, Myrna C B Godoy, Girish Shroff, Sang T Kim, Saadia A Faiz, Dimitrios P Kontoyiannis, Fareed Khawaja, Kristofer Jennings, Naval G Daver

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality.

Methods: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were …

Antiphospholipid Antibodies And Vitamin D Deficiency In Covid-19 Infection With And Without Venous Or Arterial Thrombosis: A Pilot Case-Control Study, Ruchi Shah, Yaqub Nadeem Mohammed, Tracy J Koehler, Jasmeet Kaur, Margarita Toufeili, Priyanjali Pulipati, Ahmed Alqaysi, Ali Khan, Mahrukh Khalid, Yi Lee, Parveen Dhillon, Anna Thao Dan, Nicholas Kumar, Monica Bowen, Anupam A Sule, Geetha Krishnamoorthy

Faculty, Staff and Student Publications

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with thromboembolism. Antiphospholipid antibody (APLa) formation is one of the mechanisms. Vitamin D deficiency has been associated with thrombosis in antiphospholipid antibody syndrome.

OBJECTIVE: Measure APLa and vitamin D in hospitalized COVID-19 patients with and without thrombosis to evaluate if thromboembolism is associated with concomitant APLa and vitamin D deficiency.

METHODS: Case-control study. Hospitalized COVID-19 patients with a thromboembolic event (ischemic stroke, myocardial infarction, deep venous thrombosis/pulmonary embolism, Cases n = 20). Controls (n = 20): Age, sex-matched without thromboembolic events. Patients with autoimmune disorders, antiphospholipid antibody syndrome, thrombophilia, anticoagulation therapy, prior thromboembolism, chronic …

Antithrombin-Iii Mitigates Thrombin-Mediated Endothelial Cell Contraction And Sickle Red Blood Cell Adhesion In Microscale Flow, William J. Wulftange, Erdem Kucukal, Yuncheng Man, Ran An, Karamoja Monchamp, Charlotte D. Sevrain, Himanshu R. Dashora, Allison Bode, Jane A. Little, Umut A. Gurkan

Faculty Scholarship

Individuals with sickle cell disease (SCD) have persistently elevated thrombin generation that results in a state of systemic hypercoagulability. Antithrombin-III (ATIII), an endogenous serine protease inhibitor, inhibits several enzymes in the coagulation cascade, including thrombin. Here, we utilize a biomimetic microfluidic device to model the morphology and adhesive properties of endothelial cells (ECs) activated by thrombin and examine the efficacy of ATIII in mitigating the adhesion of SCD patient-derived red blood cells (RBCs) and EC retraction. Microfluidic devices were fabricated, seeded with ECs, and incubated under physiological shear stress. Cells were then activated with thrombin with or without an ATIII …

Immunophenotypic And Molecular Features Of Acute Myeloid Leukemia With Plasmacytoid Dendritic Cell Differentiation Are Distinct From Blastic Plasmacytoid Dendritic Cell Neoplasm, Wei Wang, Jie Xu, Joseph D Khoury, Naveen Pemmaraju, Hong Fang, Roberto N Miranda, C Cameron Yin, Siba El Hussein, Fuli Jia, Zhenya Tang, Shimin Hu, Marina Konopleva, L Jeffrey Medeiros, Sa A Wang

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number …

Recurrence Of Thrombotic Thrombocytopenic Purpura After Vaccination With Mrna-1273 Covid-19 Vaccine, Spyridon Ntelis, Kathryn Champ

Journal of Community Hospital Internal Medicine Perspectives

Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage. Several cases of TTP associated with administration of COVID-19 vaccines have been reported. We report a case of a 63-year-old woman with a past medical history of hypertension, diabetes mellitus, chronic kidney disease, HIV infection, and remote history of TTP who presented with several days of shortness of breath on exertion, chest tightness, low-grade fever, and bruising thirty-three days after receiving the second dose of the mRNA-1273 COVID-19 vaccine. Thrombocytopenia and hemolytic anemia with schistocytes were noted on testing, and ADAMTS13 activity …

Chemotherapy Port Induced Svc Thrombosis In A Patient With Non-Metastatic Breast Cancer, Brooke Kania, Erinie Mekheal, Moutaz Ghrewati, Nader Mekheal, Jalal Koj, Alisa Farokhian, Michael Maroules

Journal of Community Hospital Internal Medicine Perspectives

Cancer patients are at a higher risk of complications such as venous thromboembolism (VTE). This risk increases in patients who receive chemotherapy. Despite the increased risk, common locations for VTE are similar to those in patients without cancer. Chemotherapy-port-related thrombosis represents a rare complication due to the location and frequent use of access (with Heparin flushes) as part of the standard care. Attention should be made to this rare complication, which may progress to superior vena cava (SVC) syndrome. SVC syndrome typically presents in females around the age of 57 years old. Management of this syndrome can be difficult and …

Tp53 Copy Number And Protein Expression Inform Mutation Status Across Risk Categories In Acute Myeloid Leukemia, Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury

Faculty, Staff and Student Publications

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as …

Long-Term Follow-Up For The Development Of Subsequent Malignancies In Patients Treated With Genetically Modified Iecs, David H M Steffin, Ibrahim N Muhsen, Laquisa C Hill, Carlos A Ramos, Nabil Ahmed, Meenakshi Hegde, Tao Wang, Mengfen Wu, Stephen Gottschalk, Sarah B Whittle, Premal D Lulla, Maksim Mamonkin, Bilal Omer, Rayne H Rouce, Andras Heczey, Leonid S Metelitsa, Bambi J Grilley, Catherine Robertson, Virginia Torrano, Natalia Lapteva, Adrian P Gee, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop

Faculty, Staff and Students Publications

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, …

Global Think Tank On The Clinical Considerations And Management Of Lipoprotein(A): The Top Questions And Answers Regarding What Clinicians Need To Know, Salim S. Virani, Marlys L. Koschinsky, Lisa Maher, Anurag Mehta, Carl E. Orringer, Raul D. Santos, Michael D. Shapiro, Joseph J. Saseen

Office of the Provost

Evidence from Mendelian randomization studies suggest that lipoprotein(a) (Lp(a)) has a causal role in the development of atherosclerotic cardiovascular disease risk. However, guidelines and consensus statement recommendations vary regarding how clinicians should incorporate Lp(a) into patient care. To provide practical answers to key questions pertaining to Lp(a) that clinicians will find useful when assessing and treating patients, a global think tank was convened. Representatives from seven national and international stakeholder organizations answered questions that were focused on: Lp(a) measurement; ethnic, gender, and age considerations; factoring Lp(a) into risk assessment; and current and emerging treatment options for elevated Lp(a). This manuscript …

Characterization And Assessment Of Barriers And Facilitators To The Decision-Making Process For Blood And Blood Donor Safety In The United States: A Collective Case Study, Lauren A. Crowder

Doctor of Philosophy in Translational Health Sciences Dissertations

Background: Over 16 million blood components are transfused to patients in need every year in the United States (Jones et al., 2021). Because of the reliance on human blood donors, the donation and transfusion of blood will always be associated with some level of risk for both donors and recipients; the tolerability of these risks may vary from stakeholder to stakeholder. While the U.S. Food and Drug Administration (FDA) concedes that attaining a blood supply with zero risk for transmission of infectious diseases may be unattainable (U.S. Food and Drug Administration, 2019), they continue to strive for the lowest …

A Pilot Phase Ib/Ii Study Of Whole-Lung Low Dose Radiation Therapy (Ldrt) For The Treatment Of Severe Covid-19 Pneumonia: First Experience From Africa, Mansoor Saleh, Karishma Sharma, Jasmit Shah, Farrok Karsan, Angela Waweru, Martin Musumbi, Reena Shah, Shahin Sayed, Innocent Abayo, Noureen Karimi, Stacey Gondi, Sehrish Rupani, Grace Kirathe, Heldah Amariati

Internal Medicine, East Africa

Background: Low dose radiation therapy (LDRT) has been used for non-malignant conditions since early 1900s based on the ability of single fractions between 50–150 cGy to inhibit cellular proliferation. Given scarcity of resources, poor access to vaccines and medical therapies within low and middle income countries, there is an urgent need to identify other cost-effective alternatives in management of COVID-19 pneumonia. We conducted a pilot phase Ib/II investigator-initiated clinical trial to assess the safety, feasibility, and toxicity of LDRT in patients with severe COVID-19 pneumonia at the Aga Khan University Hospital in Nairobi, Kenya. Additionally, we also assessed clinical …

Urgent Cytoreduction For Newly Diagnosed Acute Myeloid Leukemia Patients Allows Acquisition Of Pretreatment Genomic Data And Enrollment On Investigational Clinical Trials, Kunhwa Kim, Marina Konopleva, Courtney D Dinardo, Gautam Borthakur, Sanam Loghavi, Guilin Tang, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Caitlin R Rausch, Musa Yilmaz, Koji Sasaki, Nicholas J Short, Nitin Jain, Mark Brandt, Sherry Pierce, Guillermo Garcia-Manero, Farhad Ravandi, Hagop Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did …

Prediction Of Survival With Intensive Chemotherapy In Acute Myeloid Leukemia, Koji Sasaki, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Nicholas Short, Nitin Jain, Naval Daver, Elias Jabbour, Guillermo Garcia-Manero, Joseph Khoury, Sergej Konoplev, Sanam Loghavi, Keyur Patel, Guillermo Montalban-Bravo, Lucia Masarova, Marina Konopleva, Hagop Kantarjian

Faculty, Staff and Student Publications

Progress with intensive chemotherapy and supportive care measures has improved survival in newly diagnosed acute myeloid leukemia (AML). Predicting outcome helps in treatment decision making. We analyzed survival as the treatment endpoint in 3728 patients with newly diagnosed AML treated with intensive chemotherapy from 1980 to 2021. We divided the total study group (3:1 basis) into a training (n = 2790) and a validation group (n = 938). The associations between survival and 27 characteristics were investigated. In the training cohort, the multivariate analysis identified 12 consistent adverse prognostic variables independently associated with worse survival: older age, therapy-related myeloid neoplasm, …

Treatment-Free Remission In Patients With Chronic Myeloid Leukemia Following The Discontinuation Of Tyrosine Kinase Inhibitors, Fadi G Haddad, Koji Sasaki, Ghayas C Issa, Guillermo Garcia-Manero, Farhad Ravandi, Tapan Kadia, Jorge Cortes, Marina Konopleva, Naveen Pemmaraju, Yesid Alvarado, Musa Yilmaz, Gautam Borthakur, Courtney Dinardo, Nitin Jain, Naval Daver, Nicholas J Short, Elias Jabbour, Hagop Kantarjian

Faculty, Staff and Student Publications

Tyrosine kinase inhibitors (TKIs) discontinuation in patients with Philadelphia-chromosome-positive chronic myeloid leukemia (Ph-positive CML) is increasingly considered. We aim to evaluate the outcome of patients with CML who discontinued TKIs, and determine the factors associated with differences in the success rates of treatment-free remission (TFR). Patients with Ph-positive CML treated between October 1999 and February 2017 who discontinued therapy were analyzed. A major molecular response (MMR) was defined as BCR-ABL1/ABL1 ratio on the International Scale ≤0.1%. TFR failure was defined as the loss of MMR on any single test. We analyzed TFR rates according to duration and depth of response, …

Bloodstream Infections In Hematologic Malignancy Patients With Fever And Neutropenia: Are Empirical Antibiotic Therapies In The United States Still Effective?, Andrea J Zimmer, Erica Stohs, Jane Meza, Christopher Arnold, John W Baddley, Pranatharthi Chandrasekar, Zeinab El Boghdadly, Carlos A Gomez, Eileen K Maziarz, Jose G Montoya, Steven Pergam, Kenneth V Rolston, Michael J Satlin, Gowri Satyanarayana, Shmuel Shoham, Lynne Strasfeld, Randy Taplitz, Thomas J Walsh, Jo-Anne H Young, Yuning Zhang, Alison G Freifeld

Faculty, Staff and Student Publications

Background: Rising antimicrobial resistance rates may impact the efficacy of empirical antibiotic treatment for febrile neutropenia in high-risk cancer patients. Lacking contemporary data about the epidemiology, antibiotic resistance patterns, and clinical outcomes from bloodstream infections (BSIs) in US cancer patients, it is unclear if current guidelines remain relevant.

Methods: In a cross-sectional study, 14 US cancer centers prospectively identified BSIs in high-risk febrile neutropenic (FN) patients, including those receiving chemotherapy for hematologic malignancies or hematopoietic stem cell transplantation.

Results: Among 389 organisms causing BSI in 343 patients, there was an equal distribution of gram-negative (GN) and gram-positive (GP) bacteria, with …

Platelet Function In Trauma: Is Current Technology In Function Testing Missing The Mark In Injured Patients?, Jacob B Schriner, Mitchell J George, Jessica C Cardenas, Scott D Olson, Kimberly A Mankiewicz, Charles S Cox, Brijesh S Gill, Charles E Wade

Faculty, Staff and Student Publications

Platelets are subcellular anucleate components of blood primarily responsible for initiating and maintaining hemostasis. Following injury to a blood vessel, platelets can be activated via several pathways, resulting in changed shape, adherence to the injury site, aggregation to form a plug, degranulation to initiate activation in other nearby platelets, and acceleration of thrombin formation to convert fibrinogen to fibrin before contracting to strengthen the clot. Platelet function assays use agonists to induce and measure 1 or more of these processes to identify alterations in platelet function that increase the likelihood of bleeding or thrombotic events. In severe trauma, these assays …

Pirtobrutinib Inhibits Wild-Type And Mutant Bruton’S Tyrosine Kinase-Mediated Signaling In Chronic Lymphocytic Leukemia, Sarah Tettamanti, Maria Caterina Rotiroti, Greta Maria Paola Giordano Attianese, Silvia Arcangeli, Ronghua Zhang, Priyanka Banerjee, Giovanni Galletti, Sheighlah Mcmanus, Massimiliano Mazza, Fabio Nicolini, Giovanni Martinelli, Cristina Ivan, Tania Veliz Rodriguez, Federica Barbaglio, Lydia Scarfò, Maurilio Ponzoni, William Wierda, Varsha Gandhi, Michael Keating, Andrea Biondi, Federico Caligaris-Cappio, Ettore Biagi, Paolo Ghia, Maria Teresa Sabrina Bertilaccio

Faculty, Staff and Student Publications

Chimeric antigen receptors (CAR)-modified T cells are an emerging therapeutic tool for chronic lymphocytic leukemia (CLL). However, in patients with CLL, well-known T-cell defects and the inhibitory properties of the tumor microenvironment (TME) hinder the efficacy of CAR T cells.

We explored a novel approach combining CARs with lenalidomide, an immunomodulatory drug that tempers the immunosuppressive activity of the CLL TME. T cells from patients with CLL were engineered to express a CAR specific for CD23, a promising target antigen. Lenalidomide preserves CD23.CAR T cells in vitro effector functions in terms of antigen-specific cytotoxicity, cytokine release and proliferation. Overall, lenalidomide …

Cardiovascular Events In Patients Treated With Chimeric Antigen Receptor T-Cell Therapy For Aggressive B-Cell Lymphoma, Raphael E Steiner, Jose Banchs, Efstratios Koutroumpakis, Melody Becnel, Cristina Gutierrez, Paolo Strati, Chelsea C Pinnix, Lei Feng, Gabriela Rondon, Catherine Claussen, Nicolas Palaskas, Kaveh Karimzad, Sairah Ahmed, Sattva S Neelapu, Elizabeth Shpall, Michael Wang, Francisco Vega, Jason Westin, Loretta J Nastoupil, Anita Deswal

Faculty, Staff and Student Publications

Standard of care (SOC) chimeric antigen receptor (CAR) T-cell therapies such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are associated with multisystem toxicities. There is limited information available about cardiovascular (CV) events associated with SOC axi-cel or tisa-cel. Patients with CV comorbidities, organ dysfunction, or lower performance status were often excluded in the clinical trials leading to their Food and Drug Adminsitration approval. An improved understanding of CV toxicities in the real-world setting will better inform therapy selection and management of patients receiving these cellular therapies. Here, we retrospectively reviewed the characteristics and outcomes of adult patients with relapsed/refractory large …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Myeloid And Histiocytic/Dendritic Neoplasms, Joseph D Khoury, Eric Solary, Oussama Abla, Yassmine Akkari, Rita Alaggio, Jane F Apperley, Rafael Bejar, Emilio Berti, Lambert Busque, John K C Chan, Weina Chen, Xueyan Chen, Wee-Joo Chng, John K Choi, Isabel Colmenero, Sarah E Coupland, Nicholas C P Cross, Daphne De Jong, M Tarek Elghetany, Emiko Takahashi, Jean-Francois Emile, Judith Ferry, Linda Fogelstrand, Michaela Fontenay, Ulrich Germing, Sumeet Gujral, Torsten Haferlach, Claire Harrison, Jennelle C Hodge, Shimin Hu, Joop H Jansen, Rashmi Kanagal-Shamanna, Hagop M Kantarjian, Christian P Kratz, Xiao-Qiu Li, Megan S Lim, Keith Loeb, Sanam Loghavi, Andrea Marcogliese, Soheil Meshinchi, Phillip Michaels, Kikkeri N Naresh, Yasodha Natkunam, Reza Nejati, German Ott, Eric Padron, Keyur P Patel, Nikhil Patkar, Jennifer Picarsic, Uwe Platzbecker, Irene Roberts, Anna Schuh, William Sewell, Reiner Siebert, Prashant Tembhare, Jeffrey Tyner, Srdan Verstovsek, Wei Wang, Brent Wood, Wenbin Xiao, Cecilia Yeung, Andreas Hochhaus

Faculty, Staff and Students Publications

The upcoming 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours is part of an effort to hierarchically catalogue human cancers arising in various organ systems within a single relational database. This paper summarizes the new WHO classification scheme for myeloid and histiocytic/dendritic neoplasms and provides an overview of the principles and rationale underpinning changes from the prior edition. The definition and diagnosis of disease types continues to be based on multiple clinicopathologic parameters, but with refinement of diagnostic criteria and emphasis on therapeutically and/or prognostically actionable biomarkers. While a genetic basis for defining diseases is sought …

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.

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 …

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.

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 …