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

The iPLAT1 study was conducted from 2019 to 2020 as the first-in-human clinical trial of iPS cell-derived platelet products (iPSC-PLTs). The subject was a patient with aplastic anemia refractory to anti-HPA-1a antibody-induced platelet transfusions who had no matched HPA-1b/1b donor. Autologous iPSC-PLTs were manufactured from a megakaryocyte cell line, imMKCL, established from the patient's iPSCs. High-efficiency manufacturing of iPSC-PLTs was achieved by incorporating the concept of turbulent flow in bioreactor tanks to mimic in vivo conditions. After comprehensive non-clinical studies, the iPLAT1 study was conducted as a dose-escalation study and achieved the primary endpoint of safety. However, an increase in the platelet count after transfusion was not observed, raising the possibility of a failure in post-transfusion measurement or defective circulation of transfused iPSC-PLTs. Since then, my research team and I have been conducting reverse-translational research to improve imMKCLs and developing a larger-scale manufacturing system to improve turbulent flow in bioreactor tanks. We have also recently demonstrated properties of subset of immune megakaryocytes in imMKCLs. Building upon such efforts, we have newly begun R&D for next-generation iPSC-PLTs.

Immune thrombocytopenia (ITP) is defined as acquired thrombocytopenia with a platelet count of less than 100,000/ml and is caused by increased platelet destruction and decreased platelet production by immune mechanisms. ITP is essentially a diagnosis of exclusion, made when other thrombocytopenic diseases are ruled out. The goal of ITP treatment is not to return platelet counts to normal, but to improve bleeding symptoms and prevent serious bleeding. Indications for treatment should be based on platelet counts, severity of bleeding symptoms, patient characteristics, and lifestyle.

A 75-year-old man diagnosed with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia did not respond to standard induction chemotherapy, but was successfully treated with inotuzumab ozogamicin (InO). Although ascites developed after three cycles of InO, the clinical criteria for sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) were not met due to the absence of jaundice and hepatomegaly. However, an increase in the HokUS-6 score from 1 to 4 led us to discontinue InO, considering the risk of SOS/VOD. Three months later, the ascites recurred and a transjugular liver biopsy (TJLB) was performed, resulting in a pathological diagnosis of SOS/VOD. Although the symptoms associated with SOS/VOD temporarily improved with recombinant thrombomodulin and other supportive care, the ascites returned 1 month later along with jaundice. The patient died of liver failure progression that showed no improvement with defibrotide. Pathological examination at autopsy revealed enlarged endothelial cells and fibrosis of the central hepatic vein. In cases where the diagnosis of SOS/VOD is inconclusive based on clinical findings and HokUS scores, TJLB may facilitate earlier diagnosis and effective therapeutic decision-making for SOS/VOD.

Antibodies directed against red blood cell antigens other than those of the ABO system are referred to as irregular antibodies. Among these, IgG-type immune antibodies that are active at 37°C are considered to have high clinical significance. Irregular antibodies are typically detected using the indirect anti-globulin test (IAT), which offers high sensitivity for IgG detection. Although detection of irregular antibodies in the IAT is considered clinically significant, not all IAT-positive antibodies cause hemolytic transfusion reactions (HTR) or hemolytic disease of the fetus and newborn (HDFN). IgG is classified into four subclasses-IgG1 through IgG4. In this study, the characteristics of irregular antibodies were analyzed according to their subclasses using flow cytometry, and a monocyte phagocytosis assay was performed. The results revealed that both the IgG3-only and the IgG1+IgG3 combination types were strongly associated with adverse hemolytic effects and had high clinical relevance. Furthermore, in cases of HDFN, higher levels of IgG3 on fetal red blood cells correlated with increased phagocytosis rates and more severe disease progression. These findings suggest that IgG subclass analysis may serve as an important indicator for predicting the severity of HTR and HDFN.

T-cell acute lymphocytic leukemia (T-ALL) with SPI1 fusion, a leukemia subtype first identified in Japan, has a very poor prognosis. A 7-year-old boy was admitted to our hospital with fever, cervical lymphadenopathy, eyelid edema, and purpura. White blood cell count was markedly increased (551,000/µl). Flow cytometric analysis revealed cyCD3, CD1a, CD8, and HLA-DR positive T-ALL, and fusion gene screening identified TCF7::SPI1 fusion. The patient was treated according to the JPLSG ALL-T11 protocol. He responded poorly to prednisolone, but favorably to L-asparaginase. After completion of early intensification therapy, molecular remission was confirmed. However, due to the patient's poor response to prednisolone, and the presence of the SPI1 fusion gene, hematopoietic stem cell transplantation from an HLA-matched unrelated donor was performed in first remission. So far, the patient has been in remission for 36 months from the time of onset. Hematopoietic stem cell transplantation in first remission may be effective treatment for patients with T-ALL and SPI1 fusion.

The advent of anti-CD19 chimeric antigen receptor-T cell therapy has dramatically changed the treatment strategy for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Three products are recently available in Japan, but to the best of our knowledge, real-world data are only available for tisagenlecleucel. This study was a retrospective analysis of 27 patients who received axicabtagene ciloleucel (axi-cel) for R/R DLBCL at our institution. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 24 (88.9%) and 8 patients (29.6%), respectively, and corticosteroids were used in 19 patients (70.4%). The median follow-up period was 8.1 months (range, 1.0-23.2), and the 6-month progression-free survival and overall survival rates were 80.2% (95% confidence interval [CI], 58.8-91.3) and 92.0% (95%CI, 71.6-97.9), respectively. Although our study was limited by its small sample size and short follow-up period, it demonstrated that axi-cel was highly effective and safe at our institution.

Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection. The prothrombotic/antithrombotic balance within blood vessels can be shifted toward prothrombotic in infectious diseases. This is a physiological defense mechanism intended to contain the disturbance in peripheral tissues and prevent it from reaching the central systems. However, in severe infections where this response does not remain localized, extensive ischemic organ damage leads to sepsis-associated disseminated intravascular coagulation (DIC) with multiple organ failure. In such cases, anticoagulation therapy can alleviate ischemic organ damage. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2024 and the Clinical Practice Guidelines for Management of DIC in Japan 2024 recommend antithrombin or recombinant thrombomodulin for sepsis-associated DIC. Further discussion is needed to determine the optimal candidates and methods for treatment.