bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub
Authors: Wood William A. , Neuberg Donna S. , Thompson J. Colton , Tallman Martin S. , Sekeres Mikkael A. , Sehn Laurie H. , Anderson Kenneth C. , Goldberg Aaron D. , Pennell Nathan A. , Niemeyer Charlotte M. , Tucker Emily , Hewitt Kathleen , Plovnick Robert M. , Hicks Lisa K.
Published: December 2020

Coronavirus disease 2019 (COVID-19) is an illness resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019. Patients with cancer, and especially those with hematologic malignancies, may be at especially high risk of adverse outcomes, including mortality resulting from COVID-19 infection. The ASH Research Collaborative COVID-19 Registry for Hematology was developed to study features and outcomes of COVID-19 infection in patients with underlying blood disorders, such as hematologic malignancies. At the time of this report, data from 250 patients with blood cancers from 74 sites around the world had been entered into the registry. The most commonly represented malignancies were acute leukemia (33%), non-Hodgkin lymphoma (27%), and myeloma or amyloidosis (16%). Patients presented with a myriad of symptoms, most frequently fever (73%), cough (67%), dyspnea (50%), and fatigue (40%). Use of COVID-19–directed therapies, such as hydroxychloroquine (n = 76) or azithromycin (n = 59), was common. Overall mortality was 28%. Patients with a physician-estimated prognosis from the underlying hematologic malignancy of <12 months at the time of COVID-19 diagnosis and those with relapsed/refractory disease experienced a higher proportion of moderate/severe COVID-19 disease and death. In some instances, death occurred after a decision was made to forgo intensive care unit admission in favor of a palliative approach. Taken together, these data support the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection. Batch submissions from sites with high incidence of COVID-19 infection are planned to support future analyses.
Chemotherapy-free frontline therapy for CLL: is it worth it?
Authors: Rhodes Joanna M. , Barrientos Jacqueline C.
Published: December 2020

The treatment of chronic lymphocytic leukemia (CLL) embodies one of the great success stories in translational research, with the development of therapies aimed at disrupting crucial pathways that allow for the survival and proliferation of the malignant clone. The arrival of targeted agents into our armamentarium, along with the advent of novel monoclonal antibodies that can achieve deeper remissions, has steered the field to a new treatment paradigm. Given the panoply of therapeutic options available, the question arises whether chemotherapy still has a role in the management of CLL. The novel targeted agents, which include the Bruton’s tyrosine kinase inhibitors, ibrutinib and acalabrutinib, along with the B-cell lymphoma-2 inhibitor, venetoclax, are highly effective in achieving a response with improved remission duration and survival, particularly in high-risk patients. Despite this major progress, the new agents bring a unique set of toxicities unlike those associated with cytotoxic chemotherapy. There is a paucity of head-to-head comparisons among all of the novel agents, because their approval was based on randomization against traditional chemoimmunotherapeutic regimens. Parallel to the increase in the number of available targeted agents, there has been a significant improvement in quality of life and life expectancy of the patients with a CLL diagnosis over the last decade. Our review will examine whether “chemotherapy-free” frontline treatment approaches are worth the associated risks. Our goal is to help identify optimal treatment strategies tailored to the individual by reviewing available data on monotherapy vs combination strategies, depth of response, treatment duration, and potential toxicities.
Standard treatment approaches for relapsed/refractory chronic lymphocytic leukemia after frontline chemoimmunotherapy
Authors: Moreno Carol
Published: December 2020

Despite the effectiveness of chemoimmunotherapy (CIT), in most cases the clinical course of chronic lymphocytic leukemia (CLL) is characterized by consecutive episodes of disease progression and need for therapy. Treatment possibilities for patients with CLL in whom CIT fails whose disease progresses after initial CIT include pathway inhibitors (PIs) and, for selected patients, cellular therapy (ie, allogeneic stem cell transplant, chimeric antigen receptor T cells). PIs (ie, Bruton tyrosine kinase inhibitors, phosphatidylinositol 3-kinase inhibitors, and BCL2 inhibitors) are revolutionizing the treatment of CLL. PIs have proved to be more effective than CIT, both as upfront therapy and for relapsed/refractory disease, largely because they may overcome the negative impact of adverse biomarkers (eg, TP53 aberrations, unmutated IGHV) on outcomes and because of their acceptable toxicity. In this article, the management of patients with relapsed/refractory CLL is discussed, with a particular emphasis on the role of PIs.
How to approach shared decision making when determining consolidation, maintenance therapy, and transplantation in acute myeloid leukemia
Authors: Walker Alison R.
Published: December 2020

Until recently, treatment options for patients with acute myeloid leukemia (AML) were limited to cytotoxic chemotherapeutic agents that possessed little specificity for the cytogenetic and molecular mutations known to risk stratify patients with this disease. With the approval of multiple new therapies, not only have the agents that we treat patients with changed, but the way we talk about these options, decide on, and manage therapy has also been transformed. Given these complexities, it is important that we help patients make an informed decision by weighing the risk of relapse with patient wishes and desired quality of life. Shared decision making (SDM) is an approach to medical decision making for those situations in which most clinicians would agree that there is more than 1 correct choice for a patient. Here we review the principles of SDM and provide an overview of the 3-talk model and how it may be incorporated into the care of patients with AML.
Improving interpretation of genetic testing for hereditary hemorrhagic, thrombotic, and platelet disorders
Authors: Lambert Michele P
Published: December 2020

The last 10 years have seen an explosion in the amount of data available through next-generation sequencing. These data are advancing quickly, and this pace makes it difficult for most practitioners to easily keep up with all of the new information. Complicating this understanding is sometimes conflicting information about variant pathogenicity or even about the role of some genes in the pathogenesis of disease. The more widespread clinical use of sequencing has expanded phenotypes, including the identification of mild phenotypes associated with previously serious disease, such as with some variants in RUNX1, MYH9, ITG2A, and others. Several organizations have taken up the task of cataloging and systematically evaluating genes and variants using a standardized approach and making the data publicly available so that others can benefit from their gene/variant curation. The efforts in testing for hereditary hemorrhagic, thrombotic, and platelet disorders have been led by the International Society on Thrombosis and Haemostasis Scientific Standardization Committee on Genomics in Thrombosis and Hemostasis, the American Society of Hematology, and the National Institutes of Health National Human Genome Research Institute Clinical Genome Resource. This article outlines current efforts to improve the interpretation of genetic testing and the role of standardizing and disseminating information. By assessing the strength of gene–disease associations, standardizing variant curation guidelines, sharing genomic data among expert members, and incorporating data from existing disease databases, the number of variants of uncertain significance will decrease, thereby improving the value of genetic testing as a diagnostic tool.
Novel targets in aggressive lymphoma
Authors: Maddocks Kami
Published: December 2020

Targeting CD20 with the monoclonal antibody rituximab has improved survival in patients with aggressive B-cell lymphomas, the majority of which are cured with chemoimmunotherapy. Patients progressing through or relapsing after their treatment have a poor prognosis. Despite a number of promising novel agents with efficacy in relapsed disease, randomized trials building on the chemoimmunotherapy backbone have failed to show further survival benefit. Significant progress has been made in the last few years in relapsed or refractory disease with the emergence of therapies that harness the patient’s immune system to fight disease. The approval of 2 chimeric antigen receptor T-cell products has provided potential for curative therapy, although challenges remain with toxicities and access. The approval of the antibody drug conjugate polatuzumab in combination with chemoimmunotherapy has offered survival benefit to patients who are not candidates for more aggressive approaches and has the potential to change the standard of care for initial management. Several targeted agents have proven effective, but the majority do not produce durable responses, requiring development in combination with other targeted or conventional therapies. Herein, promising targets in aggressive lymphoma with the greatest potential for improving outcomes in these patients are discussed. Novel therapies, their toxicities, and their potential role in initial or subsequent treatment are highlighted.
Special pre- and posttransplant considerations in inherited bone marrow failure and hematopoietic malignancy predisposition syndromes
Authors: Bonfim Carmem
Published: December 2020

Advances in the diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have provided insight into the complexity of these diseases. The diseases are heterogeneous and characterized by developmental abnormalities, progressive marrow failure, and predisposition to cancer. A correct diagnosis allows for appropriate treatment, genetic counseling, and cancer surveillance. The common IBMFSs are Fanconi anemia, dyskeratosis congenita, and Diamond-Blackfan anemia. Hematopoietic cell transplantation (HCT) offers curative treatment of the hematologic complications of IBMFS. Because of the systemic nature of these diseases, transplant strategies are modified to decrease immediate and late toxicities. HCT from HLA-matched related or unrelated donors offers excellent survival for young patients in aplasia. Challenges include the treatment of adults with marrow aplasia, presentation with myeloid malignancy regardless of age, and early detection or treatment of cancer. In this article, I will describe our approach and evaluation of patients transplanted with IBMFS and review most frequent complications before and after transplant.
Optimizing management of acute leukemia in community centers and when to refer
Authors: Jillella Anand P. , Cortes Jorge E. , Kota Vamsi K.
Published: December 2020

Treatment of acute leukemia has been delivered predominantly in academic and larger leukemia treatment centers with the infrastructure and staff needed to manage patients receiving complex therapeutic regimens and supportive care. However, in recent years, several oral agents and less-myelosuppressive regimens were approved, making it possible for these patients to receive therapy in smaller community hospitals and oncology office practices. In this review, we discuss the optimum community setting, type of patient who can be treated, agents that can be applied, and an appropriate clinical circumstance in which a referral to a tertiary center should be made.
Practice patterns and outcomes for adults with acute myeloid leukemia receiving care in community vs academic settings
Authors: Halpern Anna B. , Walter Roland B.
Published: December 2020

Consistent with observations in other disease settings, retrospective studies have indicated that treatment outcomes for adults with acute myeloid leukemia (AML) are better in higher- vs lower-volume hospitals and academic vs nonacademic centers, with greatest benefits noted in acute promyelocytic leukemia. Younger age, more frequent receipt of chemotherapy and hematopoietic cell transplantation, and differences in comorbidities and socioeconomic factors may partially account for these differences. With new therapeutic options including oral small molecule inhibitors and parenteral drugs suitable for outpatient administration, there is increasing interest from patients and physicians in treating AML in the community setting and avoiding referral to academic centers. This may be particularly true for older adults, for whom treatment rates in the community have historically been low, and for those with comorbidities, because treatment benefits are estimated to be low, and thus travel to academic centers is perceived as especially burdensome. How the volume-outcome relationship is affected by the shift of the treatment landscape in AML over the last few years is unknown. Additionally, improvements in supportive care (transfusion support, broad-spectrum oral antimicrobials), resulting in gradually decreasing early death rates over time, and the growing focus on the impact of AML therapy on quality of life and treatment cost concerns further fuel the larger trend toward an increasing proportion of care delivered in the outpatient setting. Here, we examine whether the current shift of administering chemotherapy and supportive care to the outpatient setting can be translated to the community setting without compromising patient outcomes.
Approaches to aggressive B-cell lymphomas in less fit patients
Authors: Bartlett Nancy L.
Published: December 2020

Treating unfit patients with aggressive B-cell lymphoma poses the dilemma of balancing potential cure while minimizing toxicity because of frailty and comorbidities. Age greater than 80 years and common comorbidities such as cardiovascular disease and poorly controlled diabetes mellitus often preclude the use of full-dose anthracyclines and steroids, the backbones of standard regimens for aggressive B-cell lymphomas. Assessing patient fitness remains subjective, with no consensus on best practice or how to integrate assessment tools into decision making. Incorporation of prephase steroids for all unfit patients may markedly improve performance status with consideration of standard dose therapy, especially in patients less than age 80. Although randomized studies are lacking, current data suggest patients age ≥ 80 years are considered unfit a priori and should receive dose-reduced anthracycline regimens or anthracycline-free regimens. Severe toxicity is highest after the first cycle of chemotherapy. Dose reductions for cycle 1 in unfit patients with plans to escalate as tolerated is often an effective strategy. Unfit patients often benefit from comanagement with gerontologists, cardio-oncologists, and endocrinologists depending on age and the nature of comorbidities. Palliative therapy for patients with newly diagnosed aggressive B-cell lymphoma results in median survivals of less than 3 months, and in general, should only be considered in patients with untreatable comorbidities such as advanced dementia or refractory metastatic solid tumors. Incorporating new, potentially less toxic agents such as novel antibodies, antibody–drug conjugates, and bispecific antibodies into first-line therapy is an exciting future direction with potential for substantial benefit in less fit patients.
Strategies for aggressive T-cell lymphoma: divide and conquer
Authors: Pinter-Brown Lauren C.
Published: December 2020

The aggressive peripheral T-cell lymphomas (PTCLs) are a heterogenous group of uncommon lymphomas of mature T lymphocytes dominated by 3 subtypes: systemic anaplastic large-cell lymphoma, both anaplastic lymphoma kinase positive and negative; nodal PTCL with T-follicular helper phenotype; and PTCL, not otherwise specified. Although the accurate diagnosis of T-cell lymphoma and the subtyping of these lymphomas may be challenging, there is growing evidence that knowledge of the subtype of disease can aid in prognostication and in the selection of optimal treatments, in both the front-line and the relapsed or refractory setting. This report focuses on the 3 most common subtypes of aggressive PTCL, to learn how current knowledge may dictate choices of therapy and consultative referrals and inform rational targets and correlative studies in the development of future clinical trials. Finally, I note that clinical-pathologic correlation, especially in cases of T-cell lymphomas that may present with an extranodal component, is essential in the accurate diagnosis and subsequent treatment of our patients.
Outpatient transfusions for myelodysplastic syndromes
Authors: Wood Erica M. , McQuilten Zoe K.
Published: December 2020

Patients with myelodysplastic syndromes (MDS) often need extended periods of red blood cell or platelet transfusion support, with the goal to manage symptoms of anemia and thrombocytopenia, respectively, and improve quality of life. Many questions about the optimal approach to transfusion management in MDS, especially in the outpatient setting, remain unanswered, including hemoglobin and platelet thresholds for transfusion. Restrictive transfusion approaches are often practised, but whether these are appropriate for outpatients with MDS, who are often older and may be frail, is not known. Current schedules for transfusion-dependent patients are burdensome, necessitating frequent visits to hospitals for sample collection and blood administration. Questions of optimal schedule and dosage are being explored in clinical trials, including the recently completed REDDS study. Patient-reported outcomes and functional assessments are increasingly being incorporated into research in this area so that we can better understand and improve transfusion support for patients with MDS.
Informed consent for genetic testing in hematology
Authors: Marron Jonathan M.
Published: December 2020

Informed 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

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 >4 weeks (>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 <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

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

The 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

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

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

While 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

As 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

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

Chronic 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

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

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

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

Up to 10% of the >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

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

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.
Evidence-Based Minireview: Abnormal uterine bleeding in users of rivaroxaban and apixaban
Authors: Jacobson-Kelly Amanda E. , Samuelson Bannow Bethany T.
Published: December 2020

Up to two-thirds of menstruating women experience abnormal uterine bleeding (AUB) when treated with oral anticoagulants. However, the true prevalence of AUB for specific agents remains uncertain, as many of these episodes, while interfering significantly with quality of life and overall health, are not captured by definitions of major bleeding (MB) or clinically relevant nonmajor bleeding (CRNMB) used in clinical trials. A 2017 systematic review determined that women taking rivaroxaban, but not edoxaban or apixaban, had a twofold higher risk of AUB than women taking warfarin. Since then, new data have become available from extension trials, cancer-associated venous thromboembolism trials, pediatric trials, and a few observational studies specifically examining AUB as an outcome. Reported rates of uterine CRNMB were low (around 1%) and similar for rivaroxaban and apixaban in all these studies, and no episodes of uterine bleeding meeting MB criteria were reported. Rates of AUB not meeting MB or CRNMB criteria were much higher, affecting up to 50% of women on rivaroxaban. Only 1 such study included women on apixaban, and no AUB was reported. In pediatric trials, 19% of girls experienced menorrhagia when treated with rivaroxaban. In conclusion, rates of uterine MB and CRNMB were low in all studies, but rates of other types of AUB not meeting these criteria ranged from 15.8% to 50%. We conclude that AUB is underreported due to the limitations of MB/CRNMB criteria despite its substantial impact on quality of life. We urge future investigators to include broader definitions of AUB to better capture the impact of this outcome in menstruating women treated with oral anticoagulants.
Identifying potential germline variants from sequencing hematopoietic malignancies
Authors: Kraft Ira L. , Godley Lucy A.
Published: December 2020

Next-generation sequencing (NGS) of bone marrow and peripheral blood increasingly guides clinical care in hematological malignancies. NGS data may help to identify single nucleotide variants, insertions/deletions, copy number variations, and translocations at a single time point, and repeated NGS testing allows tracking of dynamic changes in variants during the course of a patient’s disease. Tumor cells used for NGS may contain germline, somatic, and clonal hematopoietic DNA alterations, and distinguishing the etiology of a variant may be challenging. We describe an approach using patient history, individual variant characteristics, and sequential NGS assays to identify potential germline variants. Our current criteria for identifying an individual likely to have a deleterious germline variant include a strong family history or multiple cancers in a single patient, diagnosis of a hematopoietic malignancy at a younger age than seen in the general population, variant allele frequency > 0.3 of a deleterious allele in a known germline predisposition gene, and variant persistence identified on clinical NGS panels, despite a change in disease state. Sequential molecular testing of hematopoietic specimens may provide insight into disease pathology, impact patient and family members’ care, and potentially identify new cancer-predisposing risk alleles. Ideally, individuals should give consent at the time of NGS testing to receive information about potential germline variants and to allow future contact as research advances.
How to manage CML patients with comorbidities
Authors: Cortes Jorge
Published: December 2020

Patients with chronic myeloid leukemia (CML) often have comorbidities, at an incidence that might be higher than in the general population. Because of the favorable outcome of most patients with CML treated with tyrosine kinase inhibitors (TKIs), a greater number of comorbidities might be the most significant adverse feature for long-term survival. The presence of comorbidities may also affect the risk of developing adverse events with TKIs. This effect is perhaps best exemplified by the risk of developing arterio-occlusive events, which is greatest for patients who have other risk factors for such events, with the risk increasing with higher numbers of comorbidities. The coexistence of comorbidities in patients with CML not only may affect TKI selection but also demands close monitoring of the overall health condition of the patient to optimize safety and provide the opportunity for an optimal outcome to such patients. With optimal, holistic management of leukemia and all other conditions afflicting them, patients with CML and comorbidities may aim for a near-normal life expectancy, just as the more select patients enrolled in clinical trials now enjoy.
Management of AL amyloidosis in 2020
Authors: Palladini Giovanni , Milani Paolo , Merlini Giampaolo
Published: December 2020

In amyloid light chain (AL) amyloidosis, a small B-cell clone, most commonly a plasma cell clone, produces monoclonal light chains that exert organ toxicity and deposit in tissue in the form of amyloid fibrils. Organ involvement determines the clinical manifestations, but symptoms are usually recognized late. Patients with disease diagnosed at advanced stages, particularly when heart involvement is present, are at high risk of death within a few months. However, symptoms are always preceded by a detectable monoclonal gammopathy and by elevated biomarkers of organ involvement, and hematologists can screen subjects who have known monoclonal gammopathy for amyloid organ dysfunction and damage, allowing for a presymptomatic diagnosis. Discriminating patients with other forms of amyloidosis is difficult but necessary, and tissue typing with adequate technology available at referral centers, is mandatory to confirm AL amyloidosis. Treatment targets the underlying clone and should be risk adapted to rapidly administer the most effective therapy patients can safely tolerate. In approximately one-fifth of patients, autologous stem cell transplantation can be considered up front or after bortezomib-based conditioning. Bortezomib can improve the depth of response after transplantation and is the backbone of treatment of patients who are not eligible for transplantation. The daratumumab+bortezomib combination is emerging as a novel standard of care in AL amyloidosis. Treatment should be aimed at achieving early and profound hematologic response and organ response in the long term. Close monitoring of hematologic response is vital to shifting nonresponders to rescue treatments. Patients with relapsed/refractory disease are generally treated with immune-modulatory drugs, but daratumumab is also an effective option.