[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

Restrictive red blood cell (RBC) transfusions with a trigger hemoglobin value of 6-7 g/dl are recommended for anemic patients with bone marrow failure diseases, such as aplastic anemia or myelodysplastic neoplasms (MDS). However, frequent transfusions can lead to iron overload, which can damage various organs through the production of reactive oxygen species. Higher ferritin levels are also known to be a negative prognostic factor for lower-risk MDS. Therefore, in transfusion-dependent patients, iron chelation therapy (ICT) is considered to prevent and reduce organ damage due to iron overload and to improve the prognosis of lower-risk MDS. When regular RBC transfusions are started, it is recommended to monitor serum ferritin levels regularly. Transfusional iron overload is diagnosed when ferritin levels exceed 500 ng/ml and cumulative RBC transfusion volume exceeds 20 units. ICT should be started when ferritin levels exceed 1,000 ng/ml, and should be continued to maintain ferritin levels below 500 ng/ml.

We retrospectively analyzed the efficacy of tixagevimab/cilgavimab (Tix/Cil) in 142 patients (total of 157 injections) with hematological disorders. Fifteen patients (9.5%) were infected with coronavirus disease (COVID-19), and 3 of these remained infected even after repeated administration of Tix/Cil. Malignant lymphoma and multiple myeloma were the most frequent underlying disorders (frequencies of 18.9% and 17.5%, respectively). Whole genome sequencing of the Omicron variant was performed in 11 patients, and revealed sensitivity to Tix/Cil in only 2. In both cases, the severity of COVID-19 was moderate I or II. Since April 2023, when a Tix/Cil-resistant variant became dominant (frequency >70%), the incidence of breakthrough infections increased from 4% to 35%, and none responded to Tix/Cil. Vaccination, together with daily precautions against infection, is the current approach used to prevent COVID-19, particularly in patients with lymphoid malignancies, because Tix/Cil is no longer effective as prophylaxis.

Disseminated intravascular coagulation (DIC) associated with critical obstetrical hemorrhage and severe trauma is classified as fibrinolytic DIC in terms of pathology and acute DIC in terms of progression. Obstetrical DIC is triggered by the influx of tissue factors from the placenta, amniotic fluid, and decidua into the maternal circulation. In contrast, trauma-related DIC is caused by vascular endothelial damage and exposure of subendothelial tissue. Specifically, in traumatic brain injury, tissue factors produced in the adventitia of cerebral blood vessels and astrocytes enter the circulation and lead to DIC. A common feature of both forms of DIC is the coexistence of consumptive coagulopathy and hyperfibrinolysis, which exacerbates massive bleeding. Therefore, the primary treatment strategy is coagulation factor replacement. In addition, antifibrinolytic therapy is effective in controlling excessive fibrinolysis. Appropriate therapeutic interventions can help reduce excessive bleeding in DIC and improve survival.

Peripheral T-cell lymphoma (PTCL) is a highly heterogenous disease that accounts for 10 to 15% of malignant lymphomas. It encompasses a wide range of disease types, including nodal, extranodal, and leukemic forms. Recent molecular genetic findings about PTCL have significantly deepened our understanding of the disease, leading to the reclassification of previously distinct subtypes under a unified entity (e.g., T-follicular helper lymphoma). In terms of treatment, CHOP or CHOP-like therapy have been widely adopted as a first-line regimen. However, even in ALK-positive anaplastic large cell lymphoma, which generally has favorable outcomes, the prognosis of PTCL remains unsatisfactory. The extremely poor outcomes of relapsed and refractory disease have highlighted an urgent need for breakthrough therapies. In recent years, novel therapeutic approaches, including antibody-drug conjugates, epigenetic modifiers, and immune cell therapies, have improved clinical outcomes for some patients with PTCL. However, the optimal use of novel approaches remains unclear, and stratification based on molecular genetic findings is crucial to achieve more effective and precisely targeted treatment.

Sideroblastic anemias (SAs) represent a diverse group of congenital and acquired disorders, characterized by anemia and the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia (CSA) arises from genetic mutations that disrupt heme and iron metabolism within mitochondria. The most common form of CSA is X-linked sideroblastic anemia (XLSA), caused by mutations in the erythroid-specific aminolevulinate synthase 2 (ALAS2) gene, a key enzyme in the heme biosynthesis pathway in erythroid cells. On the other hand, the most common form of acquired SA is myelodysplastic syndrome with ring sideroblasts (MDS-RS). The review explores the current understanding and emerging perspectives on the pathophysiology of SAs, with a particular focus on XLSA and MDS-RS.

My research group developed cytotoxic T lymphocytes (CTLs) redifferentiated from iPS cells (iPSC) established from antigen-specific CTLs that are rejuvenated, exhibiting a younger memory T cell phenotype with robust tumor-killing activity, and can be produced in unlimited quantities. We later introduced a chimeric antigen receptor (CAR) into these iPSC-derived rejuvenated CTLs (rejTs) to mitigate tumor antigen escape. These dual-antigen receptor rejTs can recognize both CD19 via CAR and MHC class I-presented LMP2 antigen via endogenous T cell receptors, and show a synergistic antitumor effect against EBV-associated lymphomas and longer persistence in vivo. We also generated HLA class I-edited virus-specific rejTs using CRISPR/Cas9 genome editing technology. These rejTs not only minimize recipient immune rejection, but also retain more robust cytotoxicity against virus-associated tumors compared to the original CTLs. We believe that these next-generation T cells offer a sustainable and promising approach to "off-the-shelf" T cell therapy.

Autoimmune hemolytic anemia (AIHA), which is caused by autoantibodies for red blood cell membrane antigens, is categorized into two forms: warm AIHA, which involves warm antibodies, and cold agglutinin disease (CAD), which involves hemolysis and red blood cell agglutination due to cold agglutinins. The first-line therapy for wAIHA is corticosteroids. Clinical guidelines by the British Society for Haematology recommend rituximab as second-line therapy, but Japanese national health insurance does not cover rituximab for wAIHA. Several new drugs with different mechanisms of action are in clinical development for refractory cases. Some of these drugs inhibit antibody production or promote antibody clearance, while others inhibit erythrophagocytosis. In CAD, anti-complement drugs targeting C1s improve anemia but do not treat peripheral circulatory failure due to erythrocyte aggregation. B-cell-targeted therapies should be used for patients with severe symptoms of these conditions.