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

We are now a quarter of a century after the transformative impact of rituximab in improving overall survival for patients with follicular lymphoma. With a burgeoning array of effective immunochemotherapy approaches, we can now frame many patients' expectations of longevity and a "functional cure," with survival estimates for many newly diagnosed patients comparable to age- and gender-matched populations. We highlight not just heterogeneity in disease but also in patients, which influences therapeutic decision-making in an immunochemotherapy era where progression-free survival advances are associated with efficacy-toxicity trade-offs, and no clear overall survival advantage is associated with any specific regimen. We provide the metrics that assist, prognostication both at diagnosis and after initial therapy, but we also highlight the limited long-term follow-up in institutional, population, and clinical trial data sets to inform our survival estimates. Nonetheless, the data are sufficient to empower us to reframe more optimistic conversations with our patients and the lymphoma community, discussions that engender hope and planning for a life lived long, and well, after therapy for follicular lymphoma.

Besides transfusion therapy, ineffective erythropoiesis contributes to systemic iron overload in myelodysplastic syndromes with ring sideroblasts (MDS-RS) via erythroferrone-induced suppression of hepcidin synthesis in the liver, leading to increased intestinal iron absorption. The underlying pathophysiology of MDS-RS, characterized by disturbed heme synthesis and mitochondrial iron accumulation, is less well understood. Several lines of evidence indicate that the mitochondrial transporter ABCB7 is critically involved. ABCB7 is misspliced and underexpressed in MDS-RS, due to somatic mutations in the splicing factor SF3B1. The pathogenetic significance of ABCB7 seems related to its role in stabilizing ferrochelatase, the enzyme incorporating iron into protoporphyrin IX to make heme. Although iron-related oxidative stress is toxic, many patients with MDS do not live long enough to develop clinical complications of iron overload. Furthermore, it is difficult to determine the extent to which iron overload contributes to morbidity and mortality in older patients with MDS, because iron-related complications overlap with age-related medical problems. Nevertheless, high-quality registry studies showed that transfusion dependency is associated with the presence of toxic iron species and inferior survival and confirmed a significant survival benefit of iron chelation therapy. The most widely used iron chelator in patients with MDS is deferasirox, owing to its effectiveness and convenient oral administration. Luspatercept, which can reduce SMAD2/SMAD3-dependent signaling implicated in suppression of erythropoiesis, may obviate the need for red blood cell transfusion in MDS-RS for more than a year, thereby diminishing further iron loading. However, luspatercept cannot be expected to substantially reduce the existing iron overload.

Monoclonal gammopathy of undetermined significance (MGUS) is a highly prevalent disorder characterized by a small bone marrow plasma cell or lymphoplasmacytic clone (less than 10%) that produces a small amount of monoclonal paraprotein without associated organ damage. Most patients with MGUS display benign behavior indefinitely, but some progress to an overt malignancy, and others develop organ damage despite no increase in monoclonal protein, resulting in the so-called MG of clinical significance (MGCS). This concept includes different disorders depending on the organ involved, and among them, MG of neurological significance (MGNS) constitutes a real challenge from both a diagnostic and therapeutic point of view. Diagnosis is particularly difficult due to MGNS's heterogeneous clinical presentation and common lack of a diagnostic biopsy. On the other hand, the complexity of treatment lies in the lack of standardized regimens and the common irreversibility of neurological damage. Focusing on the neurological manifestations of MGUS affecting the peripheral nervous system, we describe 3 illustrative cases from daily practice and discuss different aspects of diagnosis to treatment, emphasizing the need for multidisciplinary management based on the close collaboration of neurologists and hematologists.

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain a challenging spectrum of clonal myeloid disease with poor prognosis. Recent studies have shown that in AML, MDS, and MDS/AML with biallelic TP53 loss, the TP53-mutated clone becomes dominant. These are highly aggressive diseases that are resistant to most chemotherapies. The latest 2022 International Consensus Classification categorizes these diseases under "myeloid disease with mutated TP53." All treatment approaches have not improved survival rates for this disease. Many newer therapies are on the horizon, including chimeric antigen receptor T/NK-cell therapies, mutated p53 reactivators, Fc fusion protein, and monoclonal antibodies targeting various myeloid antigens. This review summarizes the current approaches for myeloid disease with TP53 mutation and provides an overview of emerging nontransplant approaches.

Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that result from somatic mutations in hematopoietic stem cells, causing constitutive activation of JAK-STAT signaling pathways with consequent overproduction of 1 or more myeloid lineages. The initiating event in MPN pathogenesis is a genetic mutation, and consequently molecular profiling is central to the diagnosis, risk stratification, and, increasingly, monitoring of therapy response in persons with MPN. In this review we summarize current approaches to molecular profiling of classical MPNs (essential thrombocythemia, polycythemia vera, and myelofibrosis), using illustrative clinical case histories to demonstrate how genetic analysis is already fully integrated into MPN diagnostic classification and prognostic risk stratification. Molecular profiling can also be used in MPN to measure response to therapy both in clinical trials and increasingly in routine clinical practice. Taking a forward look, we discuss how molecular profiling in MPN might be used in the future to select specific molecularly targeted therapies and the role of additional genetic methodologies beyond mutation analysis.

The aging obstetric population, combined with more frequent myeloproliferative neoplasm (MPN) diagnoses in younger patients, will result in hematologic providers increasingly caring for MPN patients in pregnancy. There are special considerations that pertain to management of pregnancy in MPN patients. This includes increased risks of thrombosis and hemorrhage as well as pregnancy complications that are likely related to placental dysfunction associated with an MPN diagnosis, including preeclampsia, preterm delivery, and intrauterine growth restriction. Complicating these outcomes is the uncertainty of the safety of many commonly used drugs in MPNs in pregnancy and breastfeeding. Given the overall low incidence of pregnancy in MPNs, many guidelines are based on expert opinions and extrapolation from other high-risk pregnancy populations. In this case-based review, we summarize the literature on MPN pregnancy outcomes and synthesize recommendations to provide guidance on the antepartum and postpartum management of MPN patients. Special attention is also made to issues relevant to preconception, including fertility and the use of assisted reproductive technology.

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy typically characterized by anemia, thrombocytopenia, and end-organ injury. aHUS occurs due to endothelial injury resulting from overactivation of the alternative pathway of the complement system. The etiology of the dysregulated complement system is either a genetic mutation in 1 or more complement proteins or an acquired deficiency due to autoantibodies. Over the past decade, advancements in our understanding of the role of complement in the pathophysiology of aHUS as well as the availability of anticomplement drugs has been a game-changer for our patients. These drugs have revolutionized the clinical course, outcome, and prognosis of this disease. Therefore, all patients in whom aHUS is suspected should undergo testing for complement genetic variants and autoantibodies. In approximately 30% to 40% of patients, a genetic variant of uncertain significance (VUS) may be identified. Such patients should undergo further testing to define the significance of the VUS. A combination of antigenic, functional, and biomarker analyses can assist in establishing the significance of the variants and thereby define the etiology in most patients. These analyses will also help to determine the duration of treatment based on the individual's genetic alteration. This review aims to shed light on the diagnosis and management of aHUS and discusses how to stratify patients to determine who can safely discontinue anticomplement therapy.

Sickle cell disease (SCD) is a significant public health concern in sub-Saharan Africa, where it is the most prevalent genetic disorder, presenting numerous health care and sociocultural challenges. A case study of a young girl from Ghana's Ashanti region illustrates the stigma surrounding SCD, driven by traditional beliefs and misconceptions that perceive SCD as a spiritual affliction. This stigma results in social ostracism and discrimination, impacting affected individuals and their families. Despite the severe and unpredictable pain associated with SCD, effective management is often hampered by limited health care resources and infrastructure. In Ghana and other African countries, inadequate pain relief and a lack of specialized care worsen the suffering of people with SCD. Health care providers' responses vary from empathy to dismissal, reflecting broader systemic issues in care delivery. Stigma has extensive effects, including social exclusion, psychological distress, and educational setbacks. The case study underscores the vital role of community education and support networks, such as those provided by the Sickle Cell Foundation of Ghana and Sickle Cell Association of Ghana, in reducing humiliation and enhancing the lives of those affected by SCD. Addressing the complex challenges of SCD in Africa requires comprehensive strategies. Improving the health care infrastructure, promoting community education, and establishing robust support systems are crucial to alleviating the burden of SCD, with the involvement of both government and nongovernmental organizations. These measures help create a more inclusive and understanding environment for individuals living with this chronic condition, enhancing their quality of life and overall well-being.

The Affordable Care Act (ACA), fully implemented in 2014, introduced reforms to Medicaid and the Children's Health Insurance Program (CHIP), aiming to enhance health care access for vulnerable populations. Key provisions that can influence health outcomes in adolescents and young adults (AYAs) with blood cancers include Medicaid expansion, which covers adults with income less than or equal to 138% of the federal poverty level based on modified adjusted gross income (MAGI), streamlined eligibility and enrollment processes, CHIP and Medicaid integration, and dependent coverage reform. Non-MAGI eligibility pathways based on age, disability, or waiver programs provide alternative routes for Medicaid coverage. By improving insurance coverage, providing affordable care and financial protection, and addressing health-related social needs such as transportation to care, Medicaid expansion has the potential to mitigate outcome disparities along the continuum of AYA blood cancer care. However, challenges persist due to coverage gaps in nonexpansion states, complexities in administrative processes to maintain continuous coverage, and barriers to accessing specialists for complex, AYA-focused multidisciplinary cancer care. The ending of the COVID-19 public health emergency's Medicaid Continuous Enrollment Provision has disrupted coverage for many AYAs. Given limited research evaluating the impact of the ACA on AYA blood cancer outcomes, more evidence is needed to guide future policies tailored to this vulnerable population. Despite encouraging progress following the ACA, continued collaborative efforts between policymakers, health care providers, patient advocates, and researchers are essential for identifying targeted strategies to ensure continuous and affordable coverage, access to specialized and coordinated care, and fewer disparities in AYA blood cancer outcomes.