Blood Reviews最新文献

Myelodysplastic syndrome (MDS) is a very heterogeneous clonal disorder. Patients with “higher-risk” MDS, defined by specific recurrent genetic abnormalities, have a poor prognosis because of a high risk of progression to secondary acute myeloid leukemia with low chemosensitivity. Allogeneic hematopoietic stem cell transplantation remains the only treatment that offers durable disease control because the donor immune system allows graft-versus-MDS effects. In terms of preparation steps before transplantation, targeting the malignant clone by increasing the conditioning regimen intensity is still a matter of intense debate. MDS is mainly diagnosed in older patients, and high toxicity related to common myeloablative conditioning regimens has been reported. Efforts to include new drugs in the conditioning regimen to achieve the best malignant clone control without increasing toxicity have been made over the past 20 years. We summarized these retrospective and prospective studies and evaluated the limitations of the available evidence to delineate the ideal conditioning regimen.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disease caused by immune-mediated platelet destruction and decreased platelet production. ITP is characterized by an isolated thrombocytopenia (<100 × 10⁹/L) and increased risk of bleeding. The disease has a complex pathophysiology wherein immune tolerance breakdown leads to platelet and megakaryocyte destruction. Therapeutics such as corticosteroids, intravenous immunoglobulins (IVIg), rituximab, and thrombopoietin receptor agonists (TPO-RAs) aim to increase platelet counts to prevent hemorrhage and increase quality of life. TPO-RAs act via stimulation of TPO receptors on megakaryocytes to directly stimulate platelet production. Romiplostim is a TPO-RA that has become a mainstay in the treatment of ITP. Treatment significantly increases megakaryocyte maturation and growth leading to improved platelet production and it has recently been shown to have additional immunomodulatory effects in treated patients. This review will highlight the complex pathophysiology of ITP and discuss the usage of Romiplostim in ITP and its ability to potentially immunomodulate autoimmunity.

Despite recent therapeutic advancements in the general field of non-Hodgkin lymphoma, effective treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL) remains a challenge. The development of Bruton tyrosine kinase (BTK) inhibitors has revolutionized the field and these agents are now the mainstay of R/R MCL management. However, BTK inhibitors are not curative, and as they are increasingly being incorporated into frontline regimens, the shifting treatment landscape for R/R disease presents new challenges. Here we review data for commonly employed treatment strategies including BTK inhibitors, the BCL2-inhibitor venetoclax, lenalidomide-based regimens, and chimeric antigen receptor T-cell therapy. We additionally review data for promising novel agents including antibody-drug conjugates and bispecific antibodies before highlighting some emerging targeted agents that continue to bring promise for improved outcomes in R/R MCL.

Although immunotherapy is expanding treatment options for cancer patients, the prognosis of advanced cancer remains poor, and these patients must contend with both cancers and cancer-related thrombotic events. In particular, immune checkpoint inhibitors are associated with an increased risk of atherosclerotic thrombotic events. Given the fundamental role of platelets in atherothrombosis, co-administration of antiplatelet agents is always indicated. Platelets are also involved in all steps of cancer progression. Classical antithrombotic drugs can cause inevitable hemorrhagic side effects due to blocking integrin β3 bidirectional signaling, which regulates simultaneously thrombosis and hemostasis. Meanwhile, many promising new targets are emerging with minimal bleeding risk and desirable anti-tumor effects. This review will focus on the issue of thrombosis during immune checkpoint inhibitor treatment and the role of platelet activation in cancer progression as well as explore the mechanisms by which novel antiplatelet therapies may exert both antithrombotic and antitumor effects without excessive bleeding risk.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by excessive reticuloendothelial platelet destruction and inadequate compensatory platelet production. However, the pathogenesis of ITP is relatively complex, and its exact mechanisms and etiology have not been definitively established. The gut microbiome, namely a diverse community of symbiotic microorganisms residing in the gastrointestinal system, affects health through involvement in human metabolism, immune modulation, and maintaining physiological balance. Emerging evidence reveals that the gut microbiome composition differs in patients with ITP compared to healthy individuals, which is related with platelet count, disease duration, and response to treatment. These findings suggest that the microbiome and metabolome profiles of individuals could unveil a new pathway for aiding diagnosis, predicting prognosis, assessing treatment response, and formulating personalized therapeutic approaches for ITP. However, due to controversial reports, definitive conclusions cannot be drawn, and further investigations are needed.

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with a variety of manifestations. Currently, the methods for treating PNH include anti-C5 treatments (eculizumab and ravulizumab) and pegcetacoplan (a targeted C3 inhibitor). On December 5, 2023, the US FDA approved a factor B inhibitor called Fabhalta® (iptacopan), previously known as LNP023, for the treatment of adult patients with PNH, including those who have previously received anti-C5 therapy. The main objective of this review was to elucidate the clinical efficacy and safety of the newly approved factor B inhibitor, iptacopan. Iptacopan plays a proximal role in the alternative complement pathway to control extravascular hemolysis mediated by C3b and intravascular hemolysis mediated by terminal complement. The recommended dosage is 200 mg orally twice daily. The 24-week results of the pivotal phase III open-label trial, APPLY-PNH, demonstrated that among PNH patients who had previously received anti-C5 therapy, 51/60 (estimated percentages 82%) of patients in the iptacopan group showed an increase in hemoglobin of ≥2 g/dL compared to 0/35 (estimated percentages 2%) in the standard treatment group, also, 69% of iptacopan-treated patients achieved hemoglobin levels ≥12 g/dL, while no patients in the standard treatment group reached this level (both p < 0.001). The 48-week results were similar to those observed at 24 weeks. The most common adverse events were headache, infection and diarrhea. There were almost no clinical breakthrough hemolysis. Trials evaluating the long-term safety and efficacy of iptacopan are currently recruiting.

Since the discovery of the Philadelphia chromosome in 1960, cytogenetic studies have been instrumental in detecting chromosomal abnormalities that can inform cancer diagnosis, treatment, and risk assessment efforts. The initial expansion of cancer cytogenetics was with fluorescence in situ hybridization (FISH) to assess submicroscopic alterations in dividing or non-dividing cells and has grown into the incorporation of chromosomal microarrays (CMA), and next generation sequencing (NGS). These molecular technologies add additional dimensions to the genomic assessment of cancers by uncovering cytogenetically invisible molecular markers. Rapid technological and bioinformatic advances in NGS are so promising that the idea of performing whole genome sequencing as part of routine patient care may soon become economically and logistically feasible. However, for now cytogenetic studies continue to play a major role in the diagnostic testing and subsequent assessments in leukemia with other genomic studies serving as complementary testing options for detection of actionable genomic abnormalities. In this review, we discuss the role of conventional cytogenetics (karyotyping, chromosome analysis) and FISH studies in hematological malignancies, highlighting the continued clinical utility of these techniques, the subtleties and complexities that are relevant to treating physicians and the unique strengths of cytogenetics that cannot yet be paralleled by the current high-throughput molecular technologies. Additionally, we describe how CMA, optical genome mapping (OGM), and NGS detect abnormalities that were beyond the capacity of cytogenetic studies and how an integrated approach (broad molecular testing) can contribute to the detection of actionable targets and variants in malignancies. Finally, we discuss advances in the field of genomic testing that are bridging the advantages of individual (single) cell based cytogenetic testing and broad genomic testing.

There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the introduction of new immunotherapies and targeted agents, adoption of pediatric-type chemotherapy protocols in younger adults as well as chemotherapy light approaches in older adults and the incorporation of measurable residual disease (MRD) testing to inform clinical decision making. With this, treatment outcomes in adult Ph- ALL have improved across all age groups. However, a subset of patients will still develop relapsed disease, which can be challenging to treat and associated with poor outcomes. Here we review the treatment of Ph- ALL in both younger and older adults, including the latest advancements and future directions.

Amyloid light-chain (AL) amyloidosis is a rare hematological disease that produces abnormal monoclonal immunoglobulin light chains to form amyloid fibrils that are deposited in tissues, resulting in organ damage and dysfunction. Advanced AL amyloidosis has a very poor prognosis with a high risk of early mortality. The combination of anti-plasma cell therapy and amyloid fibrils clearance is the optimal treatment strategy, which takes into account both symptoms and root causes. However, research on anti-amyloid fibrils lags far behind research on anti-plasma cells, and there is currently no approved treatment that could clear amyloid fibrils. Nevertheless, anti-amyloid fibril therapies are being actively investigated recently and have shown potential in clinical trials. In this review, we aim to outline the preclinical work and clinical efficacy of fibril-directed therapies for AL amyloidosis.