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

Red cell disorders may present with overlapping clinical presentation and laboratory findings; in addition, complete phenotypic characterization of the patients' red cells is more challenging in the most severe cases, which are typically transfusion-dependent. The increasing availability of next-generation sequencing over the past 2 decades, initially with focused gene panels for certain disease groups, optimized to include the known coding and noncoding pathogenic variants for those diseases, has improved the accuracy and timeliness of diagnosis. The ongoing expansion to whole-exome and genome sequencing has been revealing unexpected, rare, overlooked, or previously unknown genetic disorders and expands our knowledge on the pathophysiology of known and novel human diseases. The vast information gained by genetic sequencing should still be checked against the phenotype to confirm agreement. A positive result does not always guarantee that the cause of the patient's symptoms has been identified; phenotype-genotype correlation is critical. In our era of targeted treatments and progress in gene therapy, utilization of genetic workup to improve the timing and precision of diagnosis is crucial to ensure that patients receive effective management, improving their outcome.

After decades of research, gene therapy for hemophilia is now commercially available for both hemophilia A and B. Currently, two products, valoctocogene roxaparvovec (for hemophilia A) and etranacogene dezaparvovec (for hemophilia B), have been licensed following approval in the United States and several other countries. Therefore, clinicians must familiarize themselves with these novel treatment options just as they do with other newly available products in order to provide their patients the opportunity to consider which treatment may suit them best. Undoubtedly, gene therapy is a novel platform for treating human disease, and unlike other hemophilia treatments, its biology, mechanisms, and administration logistics are quite complex. Furthermore, additional products using different approaches have entered clinical trials, with more in the preclinical stages of development. This review's aims are (1) to deconstruct gene therapy in hemophilia and provide a basic framework for understanding its components and processes, including the transgene, the vector, and the delivery systems, in order to help clinicians present gene therapy as a treatment option in a shared decision-making model, better understand the clinical data, and explain gene therapy to their patients; (2) to gain knowledge of the currently approved gene therapies for hemophilia A and B, including their eligibility and exclusion criteria and the range of expected outcomes; and (3) to comprehend the shared decision-making process for these therapies and their implementation in clinical practice. In addition, a brief review of the currently approved products and those in clinical trials is presented, followed by a discussion of practical considerations for implementing gene therapy in practice.

The therapeutic landscape of multiple myeloma has undergone a profound transformation with the incorporation of anti-CD38 monoclonal antibody (mAb)-based quadruplet regimens in the frontline setting and T-cell redirecting immunotherapies in the relapsed setting. In this article, we synthesize evidence from pivotal trials to guide treatment decisions and sequencing across the disease trajectory. For transplant-eligible, transplant-deferred, and fit transplant-ineligible patients who are younger than 80 years old, we use anti-CD38 mAb-, lenalidomide-, and bortezomib/carfilzomib-based quadruplets as an induction regimen. For early relapse (1-3 prior lines), chimeric antigen receptor T-cell therapies targeting B-cell maturation antigen (BCMA) have demonstrated superiority over standard regimens, with ciltacabtagene autoleucel (cilta-cel) being the most efficacious product currently, albeit with some unique toxicities such as parkinsomism. Belantamab mafadotin-based triplets have shown impressive efficacy in lenalidomide and anti-CD38 mAb-refractory patients, although ocular toxicity remains a concern. Anti-CD38 mAb and carfilzomib-based triplets remain an essential therapeutic option in patients not refractory to anti-CD38 mAb. In late relapse (≥4 prior lines), bispecific antibodies (BsAbs) targeting BCMA (teclistamab, elranatamab, and linvoseltamab) and GPRC5D (talquetamab) have demonstrated impressive single-agent activity with distinct toxicity profiles. Emerging evidence supports prioritizing chimeric antigen receptor T-cell therapy before BsAbs when clinically feasible, as sequential efficacy appears compromised in the reverse sequence. For patients with BCMA- and GPRC5D-refractory disease, FcRH5-targeting BsAb (cevostamab), BCL2 inhibitors for t(11;14)-positive disease, and novel trispecific antibodies (BCMAXCD38; BCMAXGPRC5D) offer promising options. Strategic sequencing trials represent a critical unmet need, with PFS (progression-free survival)-2 potentially serving as a valuable intermediate end point to guide clinical decision-making while waiting for mature survival data.

Active malignancy is a known prothrombotic state, first described by Armand Trousseau as thrombophlebitis occurring in a patient with metastatic gastric cancer. The most common presentation of cancer-associated thrombosis (CAT) is venous thromboembolism, inclusive of deep venous thrombosis and pulmonary embolism. With advances in survival of many cancers, the incidence of CAT is increasing, and an estimated 15% to 20% of all patients with cancer will experience venous thromboembolism during their treatment. Consequently, management and prevention strategies for CAT are paramount for comprehensive clinical care of patients with active malignancy. Direct oral anticoagulants, which have fixed drug dosing, few drug-drug interactions, lack of monitoring requirements, and ease of oral administration, have emerged as the preferred option for CAT, with significant clinical trial data supporting their use. Here, we review the current treatment and prevention paradigms for patients with CAT, the specific role of direct oral anticoagulants for CAT, and ongoing challenges in CAT treatment.

Cold agglutinin disease (CAD) is an autoimmune hemolytic anemia, a specific clonal B-cell disorder of the bone marrow, and a monoclonal gammopathy of clinical significance. Thus, CAD should be distinguished from cold agglutinin syndrome, a more heterogeneous cold hemolytic syndrome that occurs secondary to other clinical disease. Cold agglutinins in CAD are usually of the immunoglobulin M kappa class with a heavy chain variable region encoded by the IGHV4-34 gene segment. The hemolytic anemia is entirely mediated by classical complement activation, which also explains some additional clinical features, such as fatigue and acute exacerbations. Non-complement-mediated steps in pathogenesis are also essential, such as erythrocyte agglutination and, probably, coexistent cryoglobulin activity in some patients, resulting in cold-induced circulatory symptoms. Based on this heterogeneity, different clinical phenotypes can be defined and used to guide individualized treatment. Established therapies aim at targeting the pathogenic B-cell clone or the classical complement activation pathway. Novel and investigational therapies include Bruton's tyrosine kinase inhibitors, plasma cell-directed therapies, novel complement inhibitors, and entirely new approaches such as cytokine inhibitors and, possibly, antibodies specific for the VH4-34 protein sequence. Patients with CAD requiring therapy should be considered for clinical trials.

While lenalidomide has been the established standard of care for maintenance after autologous stem cell transplantation in newly diagnosed multiple myeloma, risk-adapted maintenance strategies with the addition of proteasome inhibitors can provide additional benefit in high-risk disease. The widespread use of anti-CD38 monoclonal antibodies (mAbs) in induction and consolidation has further disrupted this paradigm, offering the use of anti-CD38 mAbs in maintenance. Novel immunotherapeutic approaches and minimal residual disease-guided maintenance strategies are being actively investigated. The evolution of maintenance strategies provides a window to a future where maintenance therapy is not only more effective at sustaining deep and durable responses but also more dynamic with careful de-escalation strategies.

Recent clinical trials have shown that the addition of immunotherapy has substantially improved cure rates for children and adolescents newly diagnosed with B-acute lymphoblastic leukemia. Most of these patients now have outcomes similar to those previously seen in only the most favorable subgroups. As such, efforts are underway to study whether the incorporation of immunotherapy can allow for elements of traditional toxic chemotherapy to be removed while maintaining excellent outcomes. In this article, we discuss important considerations for such studies, including those related to which patients are appropriate targets of deintensification efforts and which elements of therapy are or are not appropriate candidates for omission.

The term cryptogenic strokes refers to ischemic strokes that, after thorough evaluation, do not meet criteria for any of 4 designated major subtypes: stenosis due to large or medium artery atherosclerosis, cardiac pathology that could lead to embolism, presumed intracranial small artery disease (lacunar stroke), and other less common specific conditions. The term embolic strokes of undetermined source (ESUS) was introduced to further refine this classification by specifying the necessary diagnostic evaluation and exclusionary conditions. In patients with cryptogenic stroke/ESUS, nonstenotic atherosclerosis and its attendant risk factors are common. Randomized controlled trials have demonstrated no benefit of oral anticoagulants over aspirin in preventing recurrent stroke in these patients. Patients with cryptogenic stroke/ESUS should be treated with aspirin and aggressive atherosclerosis risk factor management.

Low- and intermediate-risk myelodysplastic syndromes (LR-MDS and Int-MDS, respectively) are characterized by ineffective hematopoiesis, along with the presence of at least 10% dysplasia in one cell line, accompanied by a low number and depth of peripheral blood cytopenias, a low bone marrow blast percentage, and a score of ≤0 on the Molecular International Prognostic Scoring System (IPSS-M). The information gleaned from mutational profiles at the time of myelodysplastic syndrome (MDS) diagnosis and over subsequent time points help with classification and prognosis, guiding therapeutic decisions. In LR-MDS, these decisions are initially focused on improving symptom control and optimizing hematologic parameters. New therapeutic options to reduce the red blood cell (RBC) transfusion burden have emerged since 2020 and include luspatercept and imetelstat. Erythropoiesis-stimulating agents and lenalidomide also address anemia and are generally recommended to start at the time of transfusion dependency, although emerging data suggest that an earlier start of these interventions might offer clinical benefits. Patients can derive years of benefit from these approaches in LR-MDS, but despite these therapies, ultimately MDS will evolve into higher-risk MDS (HR-MDS)/acute myeloid leukemia. Even though most LR-MDS patients present with anemia, patients can have isolated thrombocytopenia for which thrombopoietin receptor analogues can be used if blasts are low. Immunosuppressive therapy such as antithymocyte globulin is favored in the hypocellular MDS setting. Dose-modified hypomethylating agent use can be considered for LR-MDS, although neither overall survival (OS) nor progression-free survival (PFS) has been shown to improve with this approach. Targeted therapy directed to the presence of an IDH1 mutation is U.S. Food and Drug Administration (FDA) approved for the rare IDH1 mutated MDS (<10% of the time) and consideration to use an IDH2 inhibitor for IDH2 mutated MDS (<5% of the time) is reasonable. Interestingly, IDH mutations seem to appear with increased frequency in older patients and in patients with underlying autoimmune/rheumatological disorders.1.

Inherited and acquired disorders that qualitatively impair platelet function represent important and commonly encountered conditions. While some rare, well-characterized conditions (eg, Glanzmann thrombasthenia and Bernard-Soulier syndrome) have pathognomonic findings and glycoprotein deficiencies, the more commonly encountered platelet function disorders are much more heterogeneous and challenging to diagnose. Qualitative platelet disorders typically present with mild to moderate, mucocutaneous, and challenge-related bleeding, particularly for hemostatic challenges prior to diagnosis. Diagnostic tests should assess platelet counts and size; platelet morphology by light microscopy; platelet function in aggregation assays (a "gold standard" test for qualitative platelet disorders); platelet-dense granule numbers, granule contents, and/or release; and, less commonly, platelet glycoproteins, procoagulant function, α-granule release, or ultrastructure. Genetic tests can be helpful, but the chances of finding a diagnostic, disease-causing, pathogenic mutation with a platelet disorder genetic test panel is much lower if there is not an a priori suspected cause and/or inherited thrombocytopenia. Commonly, the diagnosis of a qualitative platelet disorder is made after confirming impaired platelet aggregation responses to multiple agonists, with a pattern that excludes rare disorders (eg, Glanzmann thrombasthenia and Bernard-Soulier syndrome), and/or platelet-dense granule deficiency; both findings are highly predictive of a bleeding disorder. To communicate and discuss diagnostic test findings with patients and optimize care, it is also important to have knowledge of the bleeding risks for qualitative platelet disorders and their typical responses to therapies.