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

Arterial and venous thromboses differ in pathophysiology but share overlapping risk factors such as obesity, metabolic syndrome, and aging. Patients with established arterial disease, such as coronary artery disease, stroke, and peripheral artery disease, may develop venous thromboembolism (VTE) during the acute or chronic phase of their illness. This creates therapeutic tension when anticoagulation for VTE overlaps with antiplatelet therapy. We propose a stepwise clinical approach that first identifies precipitating factors for VTE, then modifies antiplatelet therapy according to the chronicity of the arterial condition and finally estimates thrombosis against bleeding risk aided by scoring systems, available evidence for combination treatment, and interdisciplinary collaboration. Two clinical cases exemplify this stepwise approach.

The role of minimal residual disease (MRD) testing is well defined in curable hematological malignancies like acute lymphoblastic leukemia. However, in chronic lymphocytic leukemia (CLL), which is an incurable low-grade lymphoma, MRD is mostly investigational, especially in the relapsed setting. Newer techniques are trying to get to even deeper levels than before-for instance, 10-6 with sequencing. Here we describe the current techniques of MRD testing in CLL and explore the applications of these modalities in relapsed/refractory CLL in novel targeted therapies, cellular therapy, and other immunotherapies that can lead to deep and durable remissions, especially when used in combinations. More and more prospective interventional trials are now using MRD testing to inform decisions, and the data from these trials will further elucidate the best use of MRD testing in CLL patients. For now, MRD testing is not used for treatment decisions in the real world, although it can be done for monitoring in patients with high-risk genetics.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with disparate outcomes. While about two-thirds of patients have historically been cured with standard frontline chemoimmunotherapy, those who relapse or are refractory have typically had poor outcomes. Early efforts to tailor treatment based on molecular subtypes categorized by gene expression profiling (germinal center-like and activated B-cell-like) or approximation by immunochemistry algorithms did not substantially impact therapy in DLBCL. Genomic profiling led to the discovery of up to 7 subtypes with shared genetic alterations. The LymphGen and DLBclass are classifiers that assign patients to these subtypes. A clinical trial is under design to specifically treat subtypes of DLBCL in the frontline setting with targeted therapies in combination with standard treatment. Importantly, some of the most efficacious therapeutic approaches in relapsed/refractory DLBCL (chimeric antigen-receptor T cells and bispecific antibodies) appear to work independently of molecular subtype, although these agents' effectiveness may be impacted by the tumor microenvironment. Bispecific antibodies are being studied in newly diagnosed patients in combination with standard chemoimmunotherapy regimens. While future treatment may incorporate drugs with novel mechanisms and/or immunotherapies in the frontline setting, targeting by molecular subtype continues to hold promise as our treatment regimens evolve. Potential strategies could include escalation with specific therapies when response is inadequate, de-escalation of chemotherapy with continuation or addition of targeted agents in those with early complete responses, and refined algorithms to select appropriate treatment in high-risk or relapsed/refractory disease.

Patients with active malignancy frequently require anticoagulation for a variety of indications, including thrombosis, atrial fibrillation, or mechanical heart valves. Cancer-associated thrombosis is associated with significant morbidity and mortality and necessitates extended anticoagulation for the duration of active cancer. However, the bleeding risk in this population is heightened due to tumor-related factors such as cancer site (eg, primary or secondary brain tumors), invasive procedures (surgeries, biopsies, etc), and side effects of cancer-directed therapies such as thrombocytopenia. Moreover, there are specific bleeding risk factors unique to individual patients, including medications and preexisting bleeding disorders. Together, these factors substantially increase the likelihood of bleeding events in patients receiving anticoagulation for cancer-associated thrombosis. In this review, we outline the various risk factors contributing to increased bleeding risk in patients with cancer and thrombosis and describe management strategies to ensure safe anticoagulation aimed at minimizing thrombotic complications and hemorrhagic risk.

The challenges associated with achieving a clear diagnosis in patients with a suspected bleeding disorder are evident in those who end up categorized as bleeding disorder of unknown cause (BDUC), which can contribute to uncertainty in management and suboptimal care. BDUC is a diagnosis of exclusion, with nondiagnostic first-line hemostatic laboratory testing not meeting the criteria of an inherited mild bleeding disorder, despite the patient having a positive bleeding phenotype and/or positive family history. An abnormal bleeding phenotype, an important diagnostic criterion for BDUC, should be assessed through the use of standardized bleeding assessment tools, allowing for the quantification of bleeding symptoms as well as through clinical gestalt and judgment. The first-line laboratory workup must include a minimum set of hemostasis assays with normal results, including complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, fibrinogen, von Willebrand disease testing, factor VIII, platelet aggregation testing, and, if available, platelet-dense granule assessment. Following normal results of initial laboratory testing, specialized tests may be ordered based on examination in addition to the patient's clinical history, including measurement of individual clotting factor assays to identify other rare bleeding causes, and in rarer cases, additional platelet assays and fibrinolysis assays may be performed. Genetic testing involving targeted genomic sequencing of known genes associated with bleeding and platelet dysfunction is not currently part of the standard line of care, primarily due to the cost and low diagnostic yield.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare but life-threatening disease caused by an autoantibody-mediated mechanism of deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Novel therapeutic principles have challenged the standard of care, consisting of therapeutic plasma exchange (TPE), glucocorticoids, and adjunct immunosuppressants. Anti-VWF therapy with caplacizumab has been shown to be effective in halting thrombotic microangiopathy earlier, preventing early relapses, and potentially lowering TTP-associated mortality. It has also opened avenues toward a more tailored treatment approach guided by ADAMTS13 activity levels and a treatment algorithm forgoing TPE. This article highlights the importance of an early diagnosis and early therapeutic interventions indiscriminate of the initial clinical presentation that ultimately enable a TPE-free treatment. Moreover, it discusses the approach to handling immunosuppression and anti-VWF therapy in cases with prolonged autoimmunity. Timely diagnosis and therapy are based on on-site ADAMTS13 testing and the immediate availability of anti-VWF therapy in an emergency situation while close monitoring of the clinical and laboratory response to anti-VWF-therapy informs the decision to forgo TPE. A novel standard of care comprising anti-VWF-therapy, glucocorticoids, and early immunosuppression with anti-CD20-agents with or without TPE in selected cases based on cases series and the MAYARI trial (NCT05468320) is currently being established.

The advent of T-cell redirecting strategies, including chimeric antigen receptor T cells and bispecific antibodies, has significantly improved the prognosis of patients with relapsed/refractory large B-cell lymphoma. Current, ongoing clinical trials are exploring their role in earlier treatment lines, rapidly reshaping the treatment landscape of this disease entity. The field has shifted from the concept of transplant-eligible to chimeric antigen receptor T-cell eligible, albeit current trials still consider the former to define the target patient population. Here, we discuss 2 clinical cases to deliberately illustrate this dynamic era of T-cell redirecting strategies, highlighting the main learning points but also presenting the opportunities and open questions to be addressed in the future.

Advances in the development of safe and effective treatments for hemophilia over the past century have significantly increased the life expectancy of persons with hemophilia (PwH). As a result, clinicians are now encountering age-related comorbidities that were previously uncommon in hemophilia care, including cardiovascular disease, malignancy, and renal disease. Managing this aging population of PwH requires addressing both the complications of hemophilia and the multifaceted effects of aging. Their care needs have become increasingly complex, requiring attention to broader aspects of health, such as liver and bone health, fall and fracture risk, and frailty. However, preventive care, including routine monitoring and treatment of these conditions, is a gap in the current care model for this population. Inadequate access to primary care physicians negatively impacts the management and prevention of chronic diseases in PwH, resulting in medical vulnerability. The focus of this review is to examine prevalent complications in the aging PwH. Case studies presented focus on identifying and reducing cardiovascular disease risk, weighing bleeding risk with stroke risk in the management of atrial fibrillation, and ensuring a multidisciplinary approach to address frailty, bone health, and orthopedic surgery in the aging PwH. As we enter a new era of therapeutics, hemophilia treatment centers will play an integral role in closing care gaps in helping PwH achieve optimal outcomes.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vasculopathy that results in dysregulated angiogenesis leading to the development of mucocutaneous telangiectasias and visceral organ arteriovenous malformations. HHT is the second most common inherited bleeding disorder. Recurrent, spontaneous epistaxis occurs in over 90% of affected individuals and is the hallmark of this disorder. Epistaxis and gastrointestinal bleeding result in the development of iron deficiency anemia in nearly half of all affected individuals. Considerable advances have been made in the understanding of the pathobiology, manifestations, and treatment of HHT in the last decade. International consensus treatment guidelines have been developed. Medical therapeutics have become the primary approach for treating HHT-related bleeding. The initial clinical studies evaluating medications for the treatment of HHT have involved repurposing drugs that were previously approved for other indications. In the wake of these efforts, several therapies specifically for HHT are currently being developed and are in preclinical studies and early phase human trials or may soon start pivotal phase III trials. The landscape of HHT is changing fast with increased awareness and diagnosis and the development of new and novel therapies, all of which will decrease morbidity and improve the quality of life of affected individuals.