Expert Review of Hematology最新文献

Introduction: Patients undergoing revascularization of the lower extremities have unacceptably high rates of major adverse cardiac and limb events despite the routine use of antiplatelet therapy. Optimization of antithrombotic therapy provides an opportunity to reduce this risk. Recent large, randomized trials have demonstrated substantial benefit from the combination of low dose rivaroxaban and aspirin compared with aspirin alone. Despite this new evidence, uptake remains limited.

Areas covered: This review will outline the drug profile of rivaroxaban, summarize the key efficacy and safety data for the combination of low dose rivaroxaban and aspirin following lower extremity revascularization, and examine barriers to therapy uptake.

Expert opinion: Combination low dose rivaroxaban and aspirin is the only antithrombotic regimen that has been shown to reduce both cardiac and limb events following peripheral revascularization while maintaining an acceptable bleeding profile. Single or dual antiplatelet therapy have limited randomized evidence for this indication but are commonly used. An important contributor is the failure of major societal guidelines to incorporate this new evidence. Moving forward, there is an urgent need to update these guidelines. Further evaluation of the efficacy and safety of dual antiplatelet therapy will help to inform optimal antithrombotic therapy after lower extremity revascularization.

Introduction: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response.

Areas covered: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge.

Expert opinion: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.

Introduction: Prophylaxis is the recommended management strategy for all persons with hemophilia (PwH), yet its adoption is uneven worldwide.

Areas covered: This analysis examines global disparities in hemophilia care, focusing on global prophylactic coverage and its correlation with the World Bank's world development indicators. It outlines the disproportionate consumption of clotting factors and non-factor concentrates in high-income countries compared to lower-income counterparts and the challenges of expanding prophylaxis coverage in under-resourced settings. The analysis integrates socioeconomic data with global health indicators to understand these disparities and advocates for increased distribution of treatment resources across all income levels, emphasizing the need for policy changes to improve hemophilia care worldwide. Studies addressing the prophylaxis perspectives in hemophilia were selected using PubMed and Google Scholar platforms (unlimited time frame). Articles were supplemented with WFH's annual surveys and guidelines, including the WFH Global Survey 2022, WFH Guidelines for the Management of Hemophilia 2020 and World Bank data.

Expert opinion: Significant disparities in hemophilia care and factor usage exist between high-income and lower-income countries. Standardized, harmonized metrics for different types of factor consumption are critical to accurately assess and compare hemophilia care on an international basis.

Introduction: Von Willebrand disease (VWD) reflects the most common inherited bleeding disorder, arising from defects or deficiencies in the von Willebrand factor (VWF). VWD treatment mostly relies on the replacement of missing or defective VWF, but additional ('adjunct') therapies are useful in select patients/situations. Patients with VWD are often misdiagnosed and therefore non-optimally managed.

Areas covered: We provide a narrative review, following relevant literature searches in PubMed related to the topic up to September 2024. After an overview of VWF, VWD, and current treatments, we explore the use of nonstandard or emerging therapies for VWD. For example, FVIII replacement or antibody-based FVIII bypassing strategies (e.g. emicizumab) may prove useful in some cases or in initial treatment of certain VWD patients, including those with type 2N or 3 VWD, or those with inhibitors. Additional emerging therapies may also be useful, including hemostasis rebalancing agents.

Expert opinion: Just as hemophilia is experiencing a renaissance of treatment options, so too will the landscape of VWD treatment change over time. This will be fueled by the concept of personalized treatment, meaning potentially different treatments for different VWD patients, or for given patients according to treatment aims.

Introduction: Hairy cell leukemia accounts for less than 2% of leukemias. The hairy cells express CD11c, CD25, CD103, and CD123 markers. The BRAF^V600E mutation was detected in 95% of HCL cases. Patients achieve high complete response rate with purine analogues with or without rituximab, but relapses are inevitable. HCL-like disorders including HCL variant, splenic diffuse red pulp lymphoma, and splenic marginal zone lymphoma are BRAF^V600E negative. The CD25 expression is negative. The absence of BRAF^V600E mutation in HCL variant contrasts with the presence of mitogen-activated protein kinase kinase 1 (MAP2K1) mutations in 50% of cases.

Areas covered: We investigated the criteria used to distinguish HCL from HCL-like disorders. Recent discoveries in molecular biology have enabled the introduction of several new drugs in HCL patients. We explore the investigational agents: inhibitors of BRAF, MEK, and Bruton tyrosine kinase and potential future strategies we will use in the future in patients with relapsed/refractory HCL. We also discuss the clinical trials in progress.

Expert opinion: The association of Cladribine (CDA) with rituximab (R) is the standard first-line treatment in fit HCL and HCL variant patients. BRAF and BTK inhibitors are options in relapsed/refractory HCL patients. The optimal treatment sequences remain to be determined.

Introduction: Sickle cell disease is ameliorated, and perhaps can be 'cured' if enough fetal hemoglobin is present in most erythrocytes. Hydroxyurea, which increases fetal hemoglobin levels, is widely available and effective, especially in children. Nevertheless, only cell-based gene therapy can achieve a 'curative' fetal hemoglobin threshold.

Areas covered: We cover the path to modulating fetal hemoglobin gene expression and the use of CRISPR/Cas9 gene editing as a viable clinical modality for treating severe sickle cell disease relying on references obtained from PubMed. Mobilized autologous hematopoietic stem and progenitor cells are engineered with vectors that derepress genes that regulate fetal hemoglobin gene expression. Following myeloablative conditioning gene-edited cells are reinfused, engraft, and make large amounts of fetal hemoglobin. Within months, fetal hemoglobin forms more than 40% of total hemoglobin and hemoglobin levels normalize; symptoms of sickle cell disease disappear.

Expert opinion: Optimistically, these patients are 'cured,' but long term follow up is needed. Although approved by regulatory agencies and highly efficacious, because of its technical imperatives and cost this first gene editing therapeutic will be unavailable to most people with severe sickle cell disease. It is highly likely that improved methods of genomic editing will simplify gene therapy, reduce its costs, and lead to its wider applicability.

Introduction: Mantle cell lymphoma (MCL) is a non-Hodgkin B-cell lymphoma typically regarded as incurable with standard chemotherapy. Ibrutinib has become an accepted second-line treatment for relapsed or refractory MCL. Although venetoclax has shown activity against the disease, these results have not been consistently seen in the post-ibrutinib era. Therefore, there is growing evidence that supports using ibrutinib and venetoclax together in patients with chronic lymphocytic leukemia.

Areas covered: This article looks at the evidence for combining ibrutinib and venetoclax in treating relapsed or refractory MCL, particularly from the AIM and SYMPATICO studies. The phase II AIM study evaluated the ongoing combination of ibrutinib and venetoclax following a run-in period of ibrutinib. The phase III SYMPATICO study started both drugs without a run-in period and included a fixed two-year duration of venetoclax.

Expert opinion: The combination of ibrutinib and venetoclax has shown effectiveness in patients with relapsed/refractory MCL, indicating potential for fixed-duration therapy. The emerging use of measurable residual disease and molecular data may help identify which patients are suitable for stopping treatment. As new information becomes available on ibrutinib in first-line settings and chimeric T-cell therapy, the optimal timing for combining ibrutinib and venetoclax may require further refinement.

Introduction: Allogeneic hemopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD). Exposure to both SCD and HSCT conditioning regimens is associated with late health effects.

Areas covered: This review addresses post-HSCT outcomes and late health effects among individuals with SCD exposed to allogeneic HSCT regimens, summarizes recommendations for long-term care, and identifies future survivorship research needs.

Expert opinion: Individuals with SCD exposed to HSCT and gene therapy require multidisciplinary care to monitor late health effects. To optimize care, multi-disciplinary clinics that include experts in late effects of HSCT exposure, SCD, complex chronic pain, mental health, and social work are needed. Research defining the late effects of exposure is needed to inform patient management and build clinical care infrastructure.

Background: B-cell lymphoma, a diverse malignancy, is intricately regulated by multiple factors. MicroRNAs (miRNAs) have been demonstrated to be important regulators of the initiation and progression of human B-cell lymphoma, but their functions need to be further explored.

Research design and methods: Two B-cell lymphoma cell lines, Romas and HBL-1, were engineered to overexpress miR-451, with cell proliferation assessed via cell counting assays. Flow cytometry was used to study the effects of miR-451 on cell cycle and apoptosis. Bioinformatics analyses were performed using GEO datasets (GSE181063, GSE32918, GSE56315) to identify DEGs, and potential miR-451 target genes were predicted using tools like ENCORI, TargetScan, and R packages. A risk model for DLBCL prognosis was developed using Cox and LASSO regression. qRT-PCR validated the expression of these target genes.

Results: This study revealed that miR-451 inhibited cell proliferation, arrested the cell cycle, and induced apoptosis in human DLBCL cell lines. Bioinformatics analysis identified 9 target genes (MMP9, AQP9, RIN2, EOMES, LCP2, SELPLG, MAL, SOCS5, S1PR3) significantly associated with DLBCL prognosis, suggesting a potential mechanism by which miR-451 suppresses DLBCL development.

Conclusions: Our study indicates that a specific set of miR-451 target genes may significantly influence DLBCL patient outcomes.

Introduction: The disruption of the JAK/STAT signaling pathway is a defining feature of myelofibrosis (MF). The introduction of JAK inhibitors (JAKi) has transformed the therapeutic approach to MF, becoming essential to treatment and reshaping the management landscape. While JAKi are now the preferred first-line treatment for most patients, various management options are available for those who do not respond to initial therapy.

Areas covered: This review focuses on management options for patients with MF, with particular emphasis on therapeutic strategies following the failure of first-line JAKi. It provides a comprehensive overview of the current treatment landscape, including alternative JAKi and other approaches. The review is based on an extensive literature search using available databases (PubMed, Cochrane …) and relevant web resources (clinicaltrials.gov).

Expert opinion: Ruxolitinib benefits in MF often diminish after 3-4 years, with complications like thrombocytopenia and anemia. Three newer JAKi offer alternatives with similar efficacy and varied side effects. Stem cell transplantation is a curative option for a minority, ideally timed at peak response to JAKi. Research aims to enhance first-line treatments and restore responses in resistant patients. Future therapies may include novel combinations or immunotherapies targeting specific mutations, requiring collaboration between patient, clinical, and pharmaceutical communities.