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

A 58-year-old woman received chimeric antigen receptor T-cell (CAR-T) therapy for triple-class refractory multiple myeloma. Following CAR-T infusion, she developed severe cytokine release syndrome (CRS) and was promptly admitted to the intensive care unit (ICU). Subsequently, she developed immune effector cell-associated neurotoxicity syndrome (ICANS), and then progressed to cardiac arrest. This life-threatening complication was successfully managed with intensive multidisciplinary treatment including mechanical ventilation, vasopressor support, and continuous renal replacement therapy. The patient's high tumor burden at the time of CAR-T infusion likely contributed to the severity of CRS and ICANS. Early intervention with dexamethasone and steroid pulse therapy, along with timely ICU admission, played a pivotal role in the success of treatment. This case highlights the importance of identifying high tumor burden as a risk factor for severe CAR-T-related complications and working closely with medical teams.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) in first complete remission (CR1) has been the standard treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia. However, the introduction of imatinib, a first-generation tyrosine kinase inhibitor (TKI), dramatically improved outcomes. The subsequent development of next-generation TKIs like dasatinib and ponatinib, as well as the antibody therapy blinatumomab, has further diversified treatment strategies. There is an increasing shift toward avoiding allo-SCT in pediatric patients, both in Japan and internationally. For elderly patients ineligible for allo-SCT, chemotherapy-free regimens combining TKIs and blinatumomab show promise for improving outcomes. Moreover, international studies suggest that young adults may also be able to avoid allo-SCT in CR1. In contrast, current data in Japan are insufficient to support the avoidance of allo-SCT in CR1, and caution is needed when applying findings from overseas. Future efforts should focus on establishing personalized treatment approaches, including risk-stratified transplantation eligibility.

In recent years, chimeric antigen receptor (CAR)-engineered cellular therapy has brought remarkable advancements in cancer immunotherapy and autoimmune disease treatment. CAR T-cell therapy has demonstrated high efficacy in multiple myeloma (MM), but its durability is limited due to immune suppression within the tumor microenvironment (TME). This study elucidates how cancer-associated fibroblasts (CAFs) impair BCMA CAR T-cell function, and describes development of dual-specific CAR T-cells targeting CAFs. The results showed that CAFs promoted CAR T-cell exhaustion via TGF-β, PD-L1, IL-10, and the FAS/FASL pathway. BCMA-FAP and BCMA-CS1 CAR T cells exhibited enhanced cytotoxicity against MM cells and CAFs, overcoming TME-mediated suppression. E-cadherin-targeting CAR MSCs (Ecad CAR-MSCs) to address graft-versus-host disease (GvHD) were also developed for this study. These CAR MSCs significantly reduced GvHD by selectively accumulating in the intestinal epithelium, suppressing T-cell activation via IL-10 and galectin-9 while promoting Treg induction. These findings suggest that CAF-targeting dual-specific CAR T cells enhance the efficacy of MM immunotherapy, while Ecad CAR-MSCs offer a novel approach to treating GvHD. These approaches hold promise for clinical translation to improve outcomes in cellular therapy.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder characterized by complement-mediated hemolysis, thrombosis, and bone marrow failure. Eculizumab (Ecu), a C5 inhibitor, blocks intravascular hemolysis (IVH) and improves prognosis. Ravulizumab and crovalimab have longer half-lives, and reduce treatment burden. Crovalimab is effective in patients with C5 polymorphism resistant to Ecu. Despite C5 inhibition, approximately 70% of patients remain anemic due to bone marrow failure and extravascular hemolysis (EVH) from C3 deposition. Upstream complement inhibition can address both IVH and EVH. Pegcetacoplan (C3 inhibitor) improves anemia better than Ecu. Danicopan (factor D inhibitor) and ipracopan (factor B inhibitor) also improve anemia and fatigue. Proximal inhibitors offer better anemia control but pose a risk of breakthrough hemolysis (BTH), especially under complement-amplifying conditions. In addition, long-term real-world infection data remain necessary. While IVH control has improved PNH prognosis, future therapies should focus on patients with persistent anemia or insufficient improvement in quality of life, and should aim to enhance hemoglobin levels and overall well-being while managing BTH for optimal care.

Introduction: As life expectancy in hemophilia improves, chronic comorbidities and treatment-related challenges demand greater attention.

Objective: To characterize comorbidities, medication use, and cardiovascular risk factors in Japanese adults (≥40 years) with hemophilia enrolled in a prospective, multicenter cohort study (ADVANCE Japan cohort).

Methods: A subanalysis was conducted in participants who completed at least one follow-up visit between 2019 and 2023.

Results: Seventeen of the 599 participants died (2.8%), mainly from liver disease, intracranial hemorrhage, and malignancy. Thirty-two cancers were documented, with hepatocellular carcinoma being the most common. Compared with the general male population, hypertension was more common in the hemophilia cohort (OR 1.51, 95%CI: 1.17-1.93), whereas dyslipidemia (OR 0.48, 95%CI: 0.37-0.62), chronic kidney disease (OR 0.53, 95%CI: 0.38-0.76), obesity (OR 0.50, 95%CI: 0.40-0.64), and smoking (OR 0.74, 95%CI: 0.59-0.93) were less common. Non-steroidal anti-inflammatory drugs were frequently prescribed despite guideline recommendations, reflecting likely chronic pain from advanced hemophilic arthropathy. Four patients developed new factor VIII/IX inhibitors, including two without prior history.

Conclusion: This interim analysis reveals distinctive patterns of comorbidity, medication use, and cardiovascular risk among aging Japanese adults with hemophilia, underscoring the need for tailored long-term care strategies.

Acquired pure red cell aplasia (PRCA), characterized by anemia, reticulocytopenia, and erythroid hypoplasia in the marrow, is a bone marrow failure syndrome that mainly affects elderly adults. Underlying T-cell dysregulations, often associated with clonality and/or STAT3 gene mutation, have been a rationale for using cyclosporin and other directed immunosuppressive therapies in most of the disease subtypes, namely, thymoma-associated PRCA, large granular lymphocytic leukemia-associated PRCA, and idiopathic PRCA. Although the epidemiologic rarity of PRCA has precluded comparative clinical trials that could demonstrate the superiority of one immunosuppressive agent over another, some retrospective studies have demonstrated the significance of maintenance therapies to avoid blood transfusion dependency, a factor that may lead to poorer prognosis in patients with PRCA. This review primarily discusses clinical aspects of PRCA in line with recently updated clinical guidelines.

The advent of the C5 inhibitor eculizumab marked a paradigm shift in the management of PNH, transforming it from "a rare disease with a poor prognosis" to "a manageable disease". However, emerging challenges such as primary nonresponse due to C5 gene polymorphisms and residual extravascular hemolysis have prompted the development of new therapeutic agents. Three C5 inhibitors and three proximal complement inhibitors are now available. For complement inhibitor-naïve patients with PNH, C5 inhibitors are the first-line therapy. Selection of eculizumab, ravulizumab, or crovalimab should be based on factors such as dosing frequency, route of administration, C5 gene polymorphisms, and pregnancy status. When C5 inhibitor therapy does not yield sufficient improvement in anemia or quality of life, second-line treatment with proximal complement inhibitors should be considered. Selection of pegcetacoplan, danicopan, or iptacopan should be guided by the underlying pathology of anemia, lifestyle factors, and treatment adherence. This article provides an overview of the pharmacological mechanisms, efficacy, safety, and clinical applications of each drug, along with the future outlook, based on the latest findings.

Coagulation function tests that comprehensively evaluate blood coagulation performance are difficult to standardize and are often used in research. Rotational thromboelastometry (ROTEM) is one of the most common tests used in clinical practice. It involves dynamic stimulation of blood, with recording and evaluation of changes in viscosity over time as coagulation progresses. ROTEM is used for point-of-care monitoring in the operating room. In contrast, coagulation waveform analysis (CWA) provides more usable data. Fully automated blood coagulation analyzers measure the change in turbidity over time as fibrinogen changes to fibrin, and CWA is used to analyze the coagulation reaction curve obtained in this process. One advantage of CWA is that it facilitates collection of large amounts of sample data. Our group developed a diagnostic tool for dysfibrinogenemia using CWA and implemented it as an application in Sysmex's automated blood coagulation analyzer.