Myeloproliferative neoplasms (MPNs), which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis (PMF), have been identified as having a notable association with renal impairment. Among these, MPN-related glomerulopathy has garnered particular attention due to its prevalence in patients with PMF. Chronic kidney disease has a significant impact on the general population and is also associated with a substantial risk of thrombosis and poorer overall survival in MPN patients. Emerging evidence suggests that treatments such as cytoreductive therapy and ruxolitinib may help improve renal function in these patients. Given the significant implications of renal impairment on prognosis and disease outcomes, thorough renal function assessment is essential in the clinical management of MPNs. Collaboration with nephrologists is strongly recommended to ensure comprehensive care, particularly in patients with confirmed or suspected renal complications.

Autologous stem cell transplantation (ASCT) with thiotepa-based conditioning is known to be frequently associated with skin complications in children, but there are no comprehensive reports on skin reactions in adults. We retrospectively analyzed skin problems in 44 patients who underwent ASCT with thiotepa-based conditioning at our institution between January 2017 and April 2023. Skin problems were observed in 19 patients (43.1%), and included blisters or erythema of grade 2 or higher in 8 patients (18.1%). Edema was observed in 8 patients (42%), blisters in 8 patients (42%), and blisters and erythema in 3 patients (16%). These skin changes showed a late onset pattern, ranging from days 22 to 101 (median day 53) post ASCT. In all cases, these skin problems gradually improved with symptomatic treatment. No factors significantly associated with skin problems were identified. A better understanding of the mechanisms involved in the development of these skin problems in thiotepa-conditioned adult patients should lead to better prevention and treatment.

Follicular lymphoma (FL) is the second most common lymphoma subtype diagnosed in Japan. Although FL is not curable, it generally has an indolent clinical course in the absence of histologic transformation to aggressive B-cell lymphoma. However, subsets of patients, including those with progression of disease within 24 months (POD24) and those refractory to rituximab and/or alkylators, have a worse prognosis when treated with conventional cytotoxic chemotherapies. Currently, several novel immunotherapies including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibody (BsAb) therapy are under development for the treatment of B-cell non-Hodgkin lymphomas. Several randomized studies in relapsed/refractory diffuse large B-cell lymphoma have already demonstrated the superiority of novel immunotherapies over cytotoxic chemotherapy. Several single-arm pivotal studies of CAR T-cell therapies and BsAb therapies for relapsed/refractory FL have been conducted recently. Some of these agents have already been approved for the treatment of relapsed/refractory FL and are changing clinical practice dramatically. This manuscript summarizes available clinical data on CAR T-cell therapy and BsAb therapy for FL and briefly discusses future prospects.

While many cases of large B-cell lymphoma (LBCL) can be cured with initial treatment, some patients experience relapse or are refractory to treatment. Chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies can be used for relapsed or chemotherapy-refractory LBCL. This review highlights the latest evidence regarding CAR T-cell therapy and bispecific antibodies for relapsed or refractory LBCL.

Multiple myeloma has conventionally been treated with three major classes of drugs, including immunomodulatory drugs, proteasome inhibitors and anti-CD38 antibodies, but T-cell redirection therapies (CAR-T cell therapy and bispecific antibodies) targeting B-cell maturation antigen (BCMA), which is highly expressed on the surface of myeloma cells, have now been adopted as a new modality. In Japan, CAR-T therapy is indicated as a third-line treatment for patients who have already received three classes of drugs, and bispecific antibodies are also indicated for patients who have already received three lines of therapy. Regimens combining antibody-drug conjugates targeting BCMA with bortezomib or pomalidomide have also demonstrated efficacy. GPRC5D is also attracting attention as a new target, and bispecific antibodies should soon become available for clinical use. Although these are very effective treatments, they are not curative. Therefore, determining how to sequence conventional treatments (combinations of the three classes) and these new treatments will be an important clinical challenge.

Adult T-cell leukemia/lymphoma (ATL) has a very poor prognosis with conventional multidrug chemotherapy. Lenalidomide, an oral anticancer drug classified as an immunomodulator, showed an overall response rate of 46% in a phase II clinical trial in relapsed ATL. The antibody therapy mogamulizumab showed an overall response rate of 50% in a phase II trial of relapsed C-C motif chemokine receptor 4-positive ATL. Brentuximab vedotin has yet to show clear evidence of efficacy due to the limited number of patients enrolled in phase II trials. Epigenetic therapy has also been investigated. The EZH1/2 inhibitor valemetostat showed a response rate of 48% in a phase II trial in relapsed/refractory aggressive ATL. The histone acetylation inhibitor tucidinostat also exhibited efficacy in ATL, with an objective response rate of 30.4%. This review focuses on the abovementioned molecular-targeted agents, which are all currently used in Japan.

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.

Gene therapies for hemophilia A and B were approved in the US and EU in 2022. A single infusion of adeno-associated virus vector containing FVIII and FIX gene increases clotting factor levels within a few weeks. Around 90% of hemophilia patients treated with gene therapy no longer need clotting factor injections and show a reduced annual bleeding rate. Gene therapy vectors for hemophilia have strong liver tropism and use liver-specific promoters. This review discusses the history of hemophilia gene therapy, phase 3 trials, and unmet needs.

Immune thrombocytopenia (ITP) is a thrombocytopenic disorder in which anti-platelet antibodies accelerate platelet destruction and impair platelet production. Treatment consists of first-line steroids, followed by second-line therapy if the patient is unresponsive or intolerant to steroids. Thrombopoietin receptor agonists, rituximab, and splenectomy have been the main second-line options. However, the Syk inhibitor fostamatinib and the FcRn inhibitor efgartigimod, two novel agents that are expected to improve platelet counts through a new mechanism of action, have recently been added as second-line treatment options in Japan as well. Many new therapeutic agents for ITP such as BTK inhibitors, BAFF receptor inhibitors, and anti-CD38 antibody agents are also under development. It is hoped that these novel treatment options with different effects will improve the management of ITP in the future.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic disorder. Immune-mediated TTP is caused by autoantibodies against ADAMTS13, an enzyme responsible for cleaving von Willebrand factor (VWF). Therapeutic plasma exchange (TPE) combined with corticosteroids has historically been the standard treatment, and has significantly improved patient survival. Caplacizumab, a nanobody targeting the VWF A1 domain, inhibits platelet-VWF interactions. Addition of caplacizumab to standard therapy has led to rapid platelet count recovery and prevention of thrombotic events in acute phases. Caplacizumab combined with immunosuppressive therapy has been effective in patients unable to undergo TPE due to clinical or logistical challenges, such as anaphylaxis to fresh frozen plasma or religious restrictions. A retrospective study in 2024 reported that 90.5% of patients achieved clinical response without TPE, highlighting the potential for plasma exchange-free management of acute immune-mediated TTP. These findings underscore the growing importance of caplacizumab in modern TTP therapy. Currently, a phase 3 clinical trial (MAYARI) is evaluating the efficacy of caplacizumab and immunosuppressive therapy without TPE in treating acute immune-mediated TTP. This trial aims to validate a simplified treatment paradigm, potentially transforming the management of TTP by offering safe and effective alternatives to TPE.

Conventional treatments for hemophilia have focused on replacing the missing coagulation factor, but a new treatment concept called rebalancing therapy has recently emerged. Rebalancing therapy corrects bleeding tendency by adjusting the balance between coagulation and anticoagulation, and specifically targets TFPI, AT and APC. The anti-TFPI agents concizumab and marstacimab are administered subcutaneously and have been approved for use in Japan. They are monoclonal antibodies that target the K2 domain of TFPI, and improve hemostatic function by inhibiting the binding of TFPI to FXa and TF/FVIIa complexes. The siRNA drug fitusiran is used as an anti-AT agent that reduces the synthesis of AT, and SerpinPC as an anti-APC agent that specifically inhibits APC. This article will outline the concept of rebalancing therapy and the results of clinical trials, as well as precautions and potential issues during treatment.

Inherited thrombophilia is a rare disorder that increases risk of thrombotic events. The risk of venous thromboembolism (VTE) increases during pregnancy and the postpartum period. Type I antithrombin (AT) deficiency in particular confers a higher risk compared to protein C (PC) or protein S (PS) deficiency. Comprehensive assessment of VTE risk is recommended for pregnant women with hereditary thrombophilia, and should include the type of thrombophilia (AT/PC/PS deficiency), subtype (type I/type II), site of the genetic mutation, prior history of VTE, family history, and other existing or pregnancy-specific risk factors. However, aspects of management during pregnancy, such as the necessity of prophylactic anticoagulation therapy, the appropriate dosing of heparin, and the role of AT replacement therapy, remain insufficiently defined due to limited research data. Heparin is the first-line drug for both prevention and treatment of VTE. In patients with a history of VTE, therapeutic-dose heparin is recommended throughout pregnancy and the postpartum period.

Recent advances in molecular genetic research, driven by the development of genomic analysis technologies, have significantly improved treatment outcomes for leukemia. In recent years, mounting evidence indicates that germline genetic background influences drug sensitivity and the risk of adverse effects, underscoring the growing importance of personalized treatment strategies. In particular, the NUDT15 polymorphism, which determines sensitivity to 6-mercaptopurine, has garnered significant attention. Notably, a low-activity variant of this polymorphism, prevalent in Asian countries, has been shown to substantially increase the risk of bone marrow suppression and other adverse effects. Pre-treatment analysis of the NUDT15 polymorphism has demonstrated utility in dose adjustment, helping to mitigate the risk of treatment-related toxicities. Studies have also explored the relationship between genetic background and late complications of leukemia treatment. Optimization of therapeutic strategies based on pharmacogenetic insights holds promise for minimizing complications while maximizing treatment efficacy for each individual patient.

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.

Granulocyte transfusion therapy (GTX) is a treatment for severe infections in patients with neutropenia, but is not widely used because it requires repeated apheresis from healthy donors to harvest sufficient neutrophils. Induced pluripotent stem cell (iPSC)-derived neutrophils are considered a promising solution to this problem, and several groups have reported methods for differentiating iPSCs into neutrophils. However, the differentiation process takes more than 14 days, and an expansion culture method that yields sufficient neutrophils for effective GTX must be developed. We have recently established iPSC-derived granulocyte progenitor cell lines that can be expanded in vitro, which could serve as a starting point for supplying sufficient iPSC-derived neutrophils in 4 days when GTX treatment is required. However, before this manufacturing method is ready for clinical use, its efficacy and safety must be evaluated and the method must be improved to comply with quality control standards for regenerative medicine products.