Hematology. American Society of Hematology. Education Program最新文献

Nearly 2 out of 3 patients with venous thromboembolism (VTE) and 1 out of 4 patients with atrial fibrillation (AF) will die within the year. Whether, when, and how to manage anticoagulation at the end of life requires many trade-offs. Patients and clinicians must balance symptom burden, greatly elevated bleeding and thrombosis risks, competing comorbidities and medications, and changing goals over time. This review uses cases of VTE and AF to present a framework for care that draws upon existing disease-specific data and cutting-edge palliative care science. It reviews strategies for the difficult task of estimating a patient's prognosis, characterizes the enormous public health burden of anticoagulation in serious illness, and analyzes the data on anticoagulation outcomes among those with limited life expectancy. Finally, an approach to individualized decision-making that is predicated on patients' priorities and evidence-based strategies for starting, continuing, or stopping anticoagulation at the end of life are presented.

Acute pain in sickle cell disease (SCD) involves multiple, complex downstream effects of vaso-occlusion, ischemia, and inflammation, ultimately resulting in severe and sudden pain. Historically, opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) have been the cornerstone of treatment for acute SCD pain. However, given the evolving understanding of the complexity of pain pathways in SCD and the desire to avoid NSAID and opioid-induced side effects, a multimodal approach is needed to effectively treat acute SCD pain. In this article we review recent research supporting the utilization of nonopioid pharmacologic interventions and nonpharmacologic interventions while also describing the research questions that remain surrounding their use and efficacy and effectiveness in the management of acute SCD pain. Furthermore, we review care delivery processes shown to improve acute SCD pain outcomes and highlight areas where more work is needed. Through this comprehensive approach, alternative mechanistic pathways may be addressed, leading to improved SCD pain outcomes.

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous category of disease entities occurring in the context of iatrogenic immune suppression. Epstein-Barr virus (EBV)-driven B-cell lymphoproliferation represents the prototype of quintessential PTLD, which includes a range of histologies named nondestructive, polymorphic, and monomorphic EBV+ diffuse large B-cell lymphoma (DLBCL) PTLD. While EBV is associated with the majority of PTLD cases, other drivers of lymphoid neoplasia and lymphoma transformation can occur-with or without EBV as a codriver-thus underlining its vast heterogeneity. In this review, we discuss the evolution in contemporary PTLD nomenclature and its emphasis on more precise subcategorization, with a focus on solid organ transplants in children, adolescents, and young adults. We highlight the fact that patients with quintessential EBV-associated PTLD-including those with monomorphic DLBCL-can be cured with low-intensity therapeutic approaches such as reduction in immune suppression, surgical resection, rituximab monotherapy, or rituximab plus low-dose chemotherapy. There is, though, a subset of patients (approximately 30%-40%) with quintessential PTLD that remains refractory to lower-intensity approaches, for whom intensive, lymphoma-specific chemotherapy regimens are required. Other forms of monomorphic PTLD, which are as diverse as the spectrum of defined lymphoma entities that also occur in immunocompetent patients, are rarely cured with lower-intensity therapies and appear to be better categorized as posttransplant lymphomas. These distinct scenarios represent the variations in lymphoid pathology that make up a conceptual framework for PTLD consisting of lymphoid hyperplasia, neoplasia, and malignancy. This framework serves as the basis to inform risk stratification and determination of evidence-based treatment strategies.

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions. However, ASCT is also hampered by acute and delayed toxicity. Thus, alternative first-line treatment strategies without ASCT but including novel agents are under investigation. With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care. Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined. In addition, it remains unclear how effective Bruton's tyrosine kinase inhibitor (BTKi) therapy will be in the relapsed setting for patients who received BTKi as part of first-line therapy. It also remains unclear whether the TRIANGLE data can be extrapolated to other BTKi, which is particularly relevant considering it is no longer FDA approved for MCL. Until then, individual patient characteristics and preferences, disease biology, and estimation of risk of toxicity needs to be taken into account when deciding about the addition of ASCT to an ibrutinib-containing induction therapy. For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.

Hormone-related venous thromboembolism (VTE) is common and entails scenarios in which VTE occurs during exposure to exogenous or endogenous female sex hormones, typically estrogen and progestogen. For the management of hormone-related VTE, it is important to realize that many patients use these hormones for a vital purpose often strongly related to the patient's well-being and quality of life. In this review we discuss clinical cases of VTE related to hormonal contraceptive use and pregnancy to illustrate key considerations for clinical practice. We cover practice points for primary VTE treatment and detail the evidence on the risk of recurrent VTE and bleeding in this population. The potential value of thrombophilia testing is described, including "who, why, when, what, and how." We also discuss key aspects of shared decision-making for anticoagulant duration, including a reduced-dose anticoagulant strategy in hormone-related VTE.

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic cell transplantation is characterized by microangiopathic hemolytic anemia (MAHA) with persistent schistocytosis, elevated markers of hemolysis, thrombocytopenia, and microvascular thrombosis leading to ischemic injuries in the kidneys and other organs. The initial evaluation of the disease requires confirmation of non-immune MAHA and careful examination of known secondary causes of TMA. Due to increased likelihood of long-term renal failure and overall mortality, a rapid diagnosis and treatment of the underlying trigger is needed. However, the diagnostic criteria proposed to define TA-TMA remain insufficient. sC5b9, the soluble form of the membrane attack complex of the terminal complement pathway, is the most studied prognostic biomarker for the disease, though its sensitivity and specificity remain suboptimal for clinical use. Current evidence does not support the cessation of calcineurin inhibitors without cause or the use of therapeutic plasma exchange. Many recent single-arm studies targeting the complement pathway inhibition have been reported, and larger randomized controlled trials are ongoing. This review aims to provide an evidence-based discussion from both adult and pediatric perspectives on the advances and conundrums in TA-TMA diagnosis and treatment.

Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or natural killer lymphocytes. Neutropenia-related infections and anemia represent the main manifestations. LGL leukemia is frequently associated with autoimmune disorders such as rheumatoid arthritis, Sjögren's syndrome, autoimmune endocrinopathies, vasculitis, or autoimmune cytopenia. Recent advances in the phenotypic and molecular characterization of LGL clones have underscored the pivotal role of a chronic antigenic stimulation and a dysregulation of the Jak/STAT signaling pathway in the pathophysiology linking leukemic-cell expansion and autoimmunity. In more than half of patients, there is a somatic STAT3 mutation. The disease is characterized by an indolent course, but approximately half of all patients will eventually require therapy. The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.

Acute myeloid leukemia (AML) is classified by risk groups according to a number of genetic mutations, which may occur alone or in combination with other mutations and chromosomal abnormalities. Prognosis and appropriate therapy can vary significantly based on a patient's genetic risk group, making mutation-informed decisions crucial to successful management. However, the presence of measurable residual disease (MRD) after induction and consolidation therapy, before hematopoietic cell transplant, and during posttransplant monitoring can be even more significant to patient prognosis than their genetic subtype. Clinicians must select MRD-monitoring methods most appropriate for a patient's genetic profile and a treatment regimen that considers both a patient's primary genetic subgroup and other risk factors, including MRD information. Recent clinical trial data and drug approvals, together with advances in the validation of MRD using next-generation sequencing, require a deeper understanding of the complex AML mutation and MRD matrix, enabling more insightful monitoring and treatment decisions for intensively treated AML patients. Here, we provide an overview on methods and clinical consequences of MRD monitoring in genetic subgroups of patients with AML. As treatment options become more personalized, on-treatment MRD monitoring will become even more important to effective AML care.

The ongoing development of molecularly targeted therapies in addition to the new standard of care combination of azacitidine and venetoclax (AZA-VEN) has transformed the prognostic outlook for older, transplant-ineligible patients with acute myeloid leukemia (AML). While conventional treatments, such as standard anthracycline and cytarabine- based chemotherapy or hypomethylating agent (HMA) monotherapy, are associated with a generally poor prognosis in this patient population, the use of these novel regimens can result in long-lasting, durable remissions in select patient subgroups. Furthermore, the simultaneous discovery of resistance mechanisms to targeted therapies and AZA-VEN has enabled the identification of patient subgroups with inferior outcomes, leading to the development, of new risk-stratification models and clinical investigations incorporating targeted therapies using an HMA-VEN-based platform. Treatments inclusive of IDH1, IDH2, FLT3, and menin inhibitors combined with HMA-VEN have additionally demonstrated safety and high rates of efficacy in early-phase clinical trials, suggesting these regimens may further improve outcomes within select subgroups of patients with AML in the near future. Additional studies defining the prognostic role of measurable residual disease following VEN-based treatment have further advanced prognostication capabilities and increased the ability for close disease monitoring and early targeted intervention prior to morphologic relapse. This review summarizes these recent developments and their impact on the treatment and survival of transplant-ineligible patients living with AML.

Anemia is a hallmark of chronic kidney disease (CKD), worsens with disease progression, and profoundly affects a patient's well-being. Major pathogenic factors are inadequate kidney erythropoietin (EPO) production and absolute and functional iron deficiency. The 2 mainstays of current anemia treatment are a) replacement therapy with recombinant EPO or 1 of its glycosylated derivatives, administered subcutaneously or intravenously, and b) intravenous (IV) iron injections. Over the past 5 years, hypoxia-inducible factor (HIF)-prolyl hydroxylase inhibitors (HIF-PHIs) have been approved in many countries for the management of anemia in both nondialysis and dialysis-dependent patients with CKD. Due to cardiovascular safety concerns, only 2 HIF-PHIs, daprodustat and vadadustat, have been approved for marketing in the United States, and only for patients on maintenance dialysis. HIF-PHIs are oral agents that are effective at improving and maintaining hemoglobin levels by activating HIF signaling in anemic patients with CKD. They stimulate the production of endogenous EPO, increase total iron-binding capacity through their direct effects on transferrin gene transcription, lower plasma hepcidin indirectly, and have beneficial effects on red blood cell parameters. Here, we discuss the mechanisms of action and pharmacologic properties of different HIF-PHIs. We discuss unwanted on-target and off-target effects, review cardiovascular and other safety concerns, and provide a benefit/risk-based perspective on how this new class of oral drugs might impact current anemia management in CKD. A clinical case is presented that highlights the clinical complexities and therapeutic challenges in managing anemia in CKD.