bluuebunny/crossref_metadata_2025_split huggingface dataset:
Informed consent for genetic testing in hematology
Authors: Marron Jonathan M. 
Published: December 2020

AbstractInformed consent is a fundamental component of modern health care. All competent adult patients have the legal and ethical authority to accept (consent) or refuse (dissent) recommended health-related interventions. Various models of informed consent have been described, and herein I introduce a model that divides informed consent into 7 distinct elements: competence, voluntariness, disclosure, recommendation, understanding, decision, and authorization. Genetic testing, which is rapidly becoming a common feature of both clinical care and research in hematology, adds additional layers of complexity to each of these consent elements. Using the example case of Mr. Smith, a man with newly diagnosed acute myeloid leukemia whose clinicians offer him genetic testing of the leukemia through a clinical trial, I highlight the challenges and controversies of informed consent for genetic testing, focusing on each consent element as it pertains to genetic testing in such a setting. Ultimately, given the growing importance of genetic testing for hematologic disorders, clinicians, and researchers in hematology should be facile at participating in all aspects of informed consent for genetic testing.
Practical approach to monitoring and prevention of infectious complications associated with systemic corticosteroids, antimetabolites, cyclosporine, and cyclophosphamide in nonmalignant hematologic diseases
Authors: Malpica Luis , Moll Stephan 
Published: December 2020

Abstract
Corticosteroids constitute a first-line therapy for adults and children suffering from nonmalignant immune-mediated hematologic diseases. However, high disease relapse rates during the tapering period or upon drug discontinuation result in long-term corticosteroid use that increases the risk of infection. This same concept applies to other immunosuppressive agents, such as antimetabolites, calcineurin inhibitors, and cyclophosphamide. Corticosteroids are associated with a length-of-treatment and dose-dependent risk for infection. Screening and antimicrobial prophylaxis against tuberculosis, hepatitis B, Strongyloides stercoralis, and Pneumocystis jirovecii pneumonia (PJP) might be indicated in patients who are scheduled to be on high-dose corticosteroids for &gt;4 weeks (&gt;30 mg of prednisone-equivalent dose [PEQ]) or in patients chronically treated (≥8 weeks of continuous or intermittent corticosteroid use) with moderate doses (≥15 to &lt;30 mg PEQ). Antimetabolites (azathioprine, mycophenolate) increase the risk of progressive multifocal leukoencephalopathy (PML); however, other opportunistic infections and viral reactivation have also been reported. In case of new onset of neurological symptoms, PML needs to be considered, and an urgent neurology consultation should be obtained. Cyclophosphamide-induced myelosuppression can lead to serious infections related to neutropenia. PJP prophylaxis should be considered with combination therapy of cyclophosphamide and corticosteroids until a PEQ dose ≤ 5 mg/d is reached. Data on infectious risk when cyclosporine is used in patients with nonmalignant hematologic diseases are lacking. Discontinuation of any immunosuppressive agent during an episode of infection is recommended. In all patients, adherence to an age-based immunization schedule is appropriate.
Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors
Authors: Hanlon Ashley , Brander Danielle M. 
Published: December 2020

Abstract
Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted.
Management of Waldenström macroglobulinemia in 2020
Authors: Castillo Jorge J. , Treon Steven P. 
Published: December 2020

AbstractThe management of Waldenström macroglobulinemia (WM) has evolved tremendously with recent genomic discoveries that correlate with clinical presentation and could help to tailor treatment approaches. The current diagnosis of WM requires clinicopathological criteria, including bone marrow involvement by lymphoplasmacytic lymphoma cells, a serum immunoglobulin M (IgM) monoclonal paraprotein, and presence of the MYD88 L265P mutation. Once the diagnosis is established, the relationship between the patient’s symptoms and WM should be carefully investigated, because therapy should be reserved for symptomatic patients. Bone marrow involvement and serum levels of IgM, albumin, and β2-microglobulin can be used to estimate the time until treatment initiation. The treatment of WM patients should be highly personalized, and the patient’s clinical presentation, comorbidities, genomic profile, and preferences, as well as toxicity of the treatment regimens, should be taken into account. Alkylating agents (bendamustine, cyclophosphamide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), anti-CD20 monoclonal antibodies (rituximab, ofatumumab), and Bruton tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib, zanubrutinib) are safe and highly effective treatment options in patients with WM. Because novel covalent and noncovalent BTK inhibitors (tirabrutinib, vecabrutinib, LOXO-305, ARQ-531), BCL2 antagonists (venetoclax), and CXCR4-targeting agents (ulocuplumab, mavorixafor) are undergoing clinical development in WM, the future of WM therapy certainly appears bright and hopeful.
Updates on the diagnosis and management of the most common hereditary porphyrias: AIP and EPP
Authors: Linenberger Michael , Fertrin Kleber Y. 
Published: December 2020

Abstract
The porphyrias are a family of metabolic disorders caused by defects in the activity of one of the enzymes in the heme biosynthetic pathway. Acute intermittent porphyria (AIP), caused by autosomal dominant mutations in the gene encoding hydroxymethylbilane synthase, can lead to hepatocyte overaccumulation and systemic distribution of the proximal porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). ALA and PBG are toxic to neurons and extrahepatic tissue and cause the neurovisceral clinical manifestations of AIP. Management of AIP includes awareness and avoidance of triggering factors, infusions of hemin for severe acute attacks, and, if indicated for chronic suppressive therapy, maintenance treatment with hemin or givosiran, a small interfering RNA molecule that antagonizes ALA synthase 1 transcripts. Erythropoietic protoporphyria (EPP) is most commonly caused by autosomal recessive mutations in the gene encoding ferrochelatase (FECH), the heme pathway terminal enzyme. FECH deficiency leads to erythrocyte overaccumulation and high plasma levels of lipophilic protoporphyrins that photoactivate in the skin, causing burning pain and erythema. Protoporphyrins excreted in the bile can cause gallstones, cholestasis, fibrosis, and ultimately liver failure. Management of EPP includes skin protection and afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin pigment and reduces photoactivation. Liver transplantation may be necessary for severe EPP-induced liver complications. Because AIP and EPP arise from defects in the heme biosynthetic pathway, hematologists are often consulted to evaluate and manage suspected or proven porphyrias. A working knowledge of these disorders increases our confidence and effectiveness as consultants and medical providers.
Therapy for lower-risk MDS
Authors: Carraway Hetty E. , Saygin Caner 
Published: December 2020

Abstract
Lower-risk myelodysplastic syndromes (MDS) are characterized by the presence of dysplasia, low bone marrow blast percentage, low number and depth of cytopenia(s), and relatively good-risk karyotpic and molecular abnormalities. A score of ≤3.5 on the Revised International Prognostic Scoring System classifies patients as lower-risk MDS. Information from a mutational profile of the MDS at time of diagnosis (and over serial time points) can be reassuring for predicted behavior of lower-risk MDS compared with one expected to progress more rapidly (higher-risk MDS). Supportive care continues to be the crux of treatment, although the options to reduce transfusion needs have improved in 2020. Erythropoiesis stimulating agents, lenalidomide, and luspatercept address the most frequent (and symptomatic) cytopenia (anemia) and are started only when patients are transfusion dependent. Patients can derive long-term benefits (years) from these approaches but will often progress to higher-risk MDS. Interestingly, some patients with lower-risk MDS can present with an isolated thrombocytopenia for which thrombopoietin receptor analogs such as romiplostim and eltrombopag are options (as long as blast counts are low). The presence of pancytopenia and or intensifying and unremitting clinical symptoms are often treated with hypomethylating agents or (anti–thymocyte globulin if hypocellular MDS is of concern). Targeted therapies are emerging for small subsets of MDS patients with specific somatic mutations (ie, TP53, IDH1/2, FLT3), although currently, there are no approved, mutation-directed medications to treat MDS.
Diagnosis and management of iron deficiency in chronic inflammatory conditions (CIC): is too little iron making your patient sick?
Authors: Fertrin Kleber Yotsumoto 
Published: December 2020

AbstractWhile iron deficiency remains the most common cause of anemia worldwide, low iron stores are associated with symptoms regardless of the presence of typical microcytic, hypochromic anemia and may be hard to recognize in patients with concurrent inflammation. Diagnosing and treating iron deficiency become more of a challenge because markers of iron status are influenced by low-grade inflammation present in common conditions, such as chronic kidney disease, cirrhosis, or heart failure. Here I present a pragmatic way of interpreting diagnostic lab tests to help clinicians recognize patients who are most likely to benefit from iron supplementation, choose between oral and parenteral administration, and make personalized decisions when patients do not fit usual guidelines.
CAR T cells for other pediatric non–B-cell hematologic malignancies
Authors: Lamble Adam J. , Gardner Rebecca 
Published: December 2020

AbstractAs CAR T-cell therapy has advanced in B-cell acute lymphoblastic leukemia, research is now underway to develop similar therapies for other lymphoid and myeloid malignancies for pediatric patients. Barriers, including antigen selection and on-target/off-tumor toxicity, have prevented the rapid development of immune-based therapies for T-lineage and myeloid malignancies. More recently, unique strategies have been developed to overcome these barriers, with several products advancing to clinical trials. For T-lineage diseases, targets have focused on CD5, CD7, and CD38, whereas myeloid disease targets have predominately focused on CD123, CD33, and, more recently, CLL-1. This review provides a comprehensive overview of these targets and approaches to overcoming safety concerns in the development of CAR T-cell therapies for pediatric patients with T-lineage and myeloid malignancies.
Management of heavy menstrual bleeding on anticoagulation
Authors: Samuelson Bannow Bethany 
Published: December 2020

Abstract
Heavy menstrual bleeding (HMB) is a common complication of anticoagulation, affecting ∼70% of menstruating women receiving oral anticoagulants. The risk of HMB is lower with apixaban and/or dabigatran than with rivaroxaban. HMB can result in iron deficiency with or without anemia, increased need for medical interventions, decreased quality of life, and missed school/work. Mainstays of treatment include hormone therapies such as the levonorgestrel intrauterine system, subdermal implant, and other progesterone-based therapies, which can result in decreased blood loss and, in some cases, amenorrhea. Combined hormone therapies can be used while patients continue receiving anticoagulation and are also highly effective for decreasing menstrual blood loss. Rarely, procedure-based interventions such as endometrial ablation may be required. Patients should be evaluated for iron deficiency and anemia and offered supportive therapies as needed. Abbreviating the course of anticoagulation or skipping doses can increase the risk of recurrent venous thromboembolism by as much as fivefold, but switching oral anticoagulants may be considered. Awareness of HMB and careful history taking at each visit are crucial to avoid a missed diagnosis.
Optimizing the management of chronic pain in sickle cell disease
Authors: Osunkwo Ifeyinwa , O'Connor Hazel F. , Saah Elna 
Published: December 2020

AbstractChronic pain in sickle cell disease (SCD) refers to pain present on most days lasting over six months. It can start during childhood and the prevalence increases with age. By adulthood, over 55% of patients experience pain on over 50% of days; 29% reporting pain on 95% of days. The true prevalence of chronic pain in SCD is likely underappreciated as it is mostly managed at home. Patients with chronic pain and SCD frequently seek acute care for exacerbation of underlying chronic pain difficult to distinguish from their usual acute vaso-occlusive crises. When treating chronic pain in SCD, the challenge is distinguishing between non-SCD related etiologies versus chronic pain resulting from SCD pathophysiological processes. This distinction is important to delineate as it will drive appropriate management strategies. Chronic pain in SCD has profound consequences for the patient; is often associated with comorbid psychiatric illnesses (depression and anxiety), not dissimilar from other chronic pain syndromes. They may also experience challenges with sleep hygiene, various somatic symptoms, and chronic fatigue that impair quality of life. How best to treat chronic pain in SCD is not definitively established. Both acute and chronic pain in SCD is typically treated with opioids. Emerging data suggests that chronic opioid therapy (COT) is a suboptimal treatment strategy for chronic pain. This review will discuss the complexity of managing chronic pain in SCD; pain that may be dependent or independent of the underlying SCD diagnosis. We will also describe alternative treatment approaches to high-dose COT.
Practical aspects of building a new immunotherapy program: the future of cell therapy
Authors: Berdeja Jesús G. 
Published: December 2020

Abstract
Cellular-redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, are rapidly changing the treatment landscape of hematologic malignancies and solid tumor malignancies. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the disease specialist, and the immune effector cell provider will be needed to provide optimal care longitudinally for any patient. I will discuss practical ways for any program to deliver these therapies and how future advances may widen availability beyond just a few centers.
Thrombolytic therapy in acute venous thromboembolism
Authors: Chiasakul Thita , Bauer Kenneth A. 
Published: December 2020

Abstract
Although anticoagulation remains the mainstay of treatment of acute venous thromboembolism (VTE), the use of thrombolytic agents or thrombectomy is required to immediately restore blood flow to thrombosed vessels. Nevertheless, systemic thrombolysis has not clearly been shown to improve outcomes in patients with large clot burdens in the lung or legs as compared with anticoagulation alone; this is in part due to the occurrence of intracranial hemorrhage in a small percentage of patients to whom therapeutic doses of a thrombolytic drug are administered. Algorithms have been developed to identify patients at high risk for poor outcomes resulting from large clot burdens and at low risk for major bleeding in an effort to improve outcomes in those receiving thrombolytic therapy. In acute pulmonary embolism (PE), hemodynamic instability is the key determinant of short-term survival and should prompt consideration of immediate thrombolysis. In hemodynamically stable PE, systemic thrombolysis is not recommended and should be used as rescue therapy if clinical deterioration occurs. Evidence is accumulating regarding the efficacy of administering reduced doses of thrombolytic agents systemically or via catheters directly into thrombi in an effort to lower bleed rates. In acute deep venous thrombosis, catheter-directed thrombolysis with thrombectomy can be used in severe or limb-threatening thrombosis but has not been shown to prevent postthrombotic syndrome. Because the management of acute VTE can be complex, having a rapid-response team (ie, PE response team) composed of physicians from different specialties may aid in the management of severely affected patients.
Does aspirin prevent venous thromboembolism?
Authors: Diep Robert , Garcia David 
Published: December 2020

Abstract
Venous thromboembolism (VTE; deep vein thrombosis and/or pulmonary embolism) is a well-established cause of morbidity and mortality in the medical and surgical patient populations. Clinical research in the prevention and treatment of VTE has been a dynamic field of study, with investigations into various treatment modalities ranging from mechanical prophylaxis to the direct oral anticoagulants. Aspirin has long been an inexpensive cornerstone of arterial vascular disease therapy, but its role in the primary or secondary prophylaxis of VTE has been debated. Risk-benefit tradeoffs between aspirin and anticoagulants have changed, in part due to advances in surgical technique and postoperative care, and in part due to the development of safe, easy-to-use oral anticoagulants. We review the proposed mechanisms in which aspirin may act on venous thrombosis, the evidence for aspirin use in the primary and secondary prophylaxis of VTE, and the risk of bleeding with aspirin as compared with anticoagulation.
Combining antiplatelet and anticoagulant therapy in cardiovascular disease
Authors: Barnes Geoffrey D. 
Published: December 2020

Abstract
Up to 10% of the &gt;3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.
Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency
Authors: Morris Emma C. 
Published: December 2020

Abstract
With recent advances in genetic sequencing and its widespread adoption for clinical diagnostics, the identification of a primary immunodeficiency (PID) as the underlying cause of diseases presenting to hematologists including refractory autoimmunity, cytopenias, immune dysregulation, and hematologic malignancy, is increasing, particularly in the adult population. Where the pathogenic genetic variants are restricted to the hematopoietic system, selected patients may benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although it is generally accepted that early allo-HSCT (ie, in infancy or childhood) for PID is preferable, this is not always possible. The clinical phenotype of non–severe combined immune deficiency forms of PID can be very heterogeneous, in part because of the high number of genetic and functional defects affecting T, B, and natural killer cells, neutrophils, and/or antigen presentation. As a result, some patients have less severe disease manifestations in childhood and/or a later de novo presentation. For others, a delayed diagnosis, lack of a genetic diagnosis, or a previous lack of a suitable donor has precluded prior allo-HSCT. Specific issues which make transplantation for adult PID patients particularly challenging are discussed, including understanding the natural history of rare diseases and predicting outcome with conservative management alone; indications for and optimal timing of transplant; donor selection; conditioning regimens; and PID-specific transplant management. The role of gene therapy approaches as an alternative to allo-HSCT in high-risk monogenic PID is also discussed.
Therapeutic development and current uses of BCL-2 inhibition
Authors: Roberts Andrew W. 
Published: December 2020

Abstract
B-cell lymphoma 2 (BCL2) is a key protein regulator of apoptosis. It is variably highly expressed in many hematological malignancies, providing protection from cell death induced by oncogenic and external stresses. Venetoclax is the first selective BCL2 inhibitor, and the first of a new class of anticancer drug (BH3-mimetics) to be approved for routine clinical practice, currently in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). To help understand the potential and limitations of this therapy, this brief review will touch on the history of development of venetoclax, dissect its mechanism of action, and summarize critical evidence for its approved use in the management of patients with CLL and AML. It will also consider recent data on mechanisms of resistance and explore concepts pertinent to its future development based on key lessons learned to date.