Age-related clonal hematopoiesis and myeloid malignancies arise from hematopoietic stem cells and progenitors with genetic abnormalities. Advances in next-generation sequencing technology have led to the identification of a wide variety of genetic alterations involved in disease onset. However, it remains unclear how diverse genetic alterations, lacking disease specificity, lead to the development of myeloid malignancies and the progression of clonal hematopoiesis. Mitochondrial abnormalities and their roles in various pathological conditions such as aging, inflammation, neurological diseases, cardiac diseases, and cancer have recently been revealed, and have garnered attention as new therapeutic targets. This review focuses on regulation of mitochondrial dynamics and outlines the role of mitochondria in myeloid malignancies and clonal hematopoiesis.

Sustaining lifelong hematopoiesis requires maintenance, proliferation, and differentiation of hematopoietic stem cells. Thrombopoietin is a cytokine essential for regulation of hematopoietic stem cells as well as differentiation and maturation of megakaryocytes required for platelet production. Due to these properties, thrombopoietin agonists have been used to treat bone marrow failure syndromes such as aplastic anemia. Through analysis of thrombopoietin gene-deficient mice, my colleagues and I have demonstrated the mechanism of action of thrombopoietin receptor agonists in hematopoietic stem cell maintenance and differentiation. This review focuses on governance of homeostasis in the hematopoietic system by thrombopoietin signaling.

We found a novel gene, named “transformed follicular lymphoma” (TFL), in a patient who developed diffuse large B-cell lymphoma from follicular lymphoma. TFL modulates several cytokines and chemokines by binding their 3'UTR region of mRNA with its unique RNase motif. TFL is part of a family called zinc finger CCCH-type containing 12A-D. Due to its unique RNase motif, the TFL family is also called regulatory RNase (Regnase 1-4). TFL is expressed in lymphoid tissue and is upregulated by an inflammatory response, contributing to autoimmune diseases such as multiple sclerosis via IL-17 in CNS and worsening inflammation (cachexia) due to lymphoma progression through CXCL-13. Loss of TFL expression is reported to be a valuable biomarker for various cancers, including lung adenocarcinoma, endometrial cancer, and possibly lymphoma. In addition to its mRNA modulation function, Regnase1 is known to have deubiquitinase activity for TRAF2, 3, and 6, attenuating JNK and NFκB activity, and TFL captures and transports naked nonvesicular extracellular mRNA of IL-1β to the nucleus, enhancing the tumor-killing activity in NK cells. Based on its potential to modulate inflammation, TFL could be a future treatment target for autoimmune diseases and cancer.

Myelodysplastic neoplasms (MDS) are clonal hematological malignancies arising from gene mutations. Immunosuppressive therapies (IST) are effective in lower-risk MDS (LR-MDS) with characteristics such as hypoplastic marrow with low blasts or low ring sideroblasts, and with a small increase of PNH clones or decrease of megakaryocytes. Differential diagnosis of these LR-MDS cases from AA can be difficult, and precise diagnosis requires careful evaluation of bone marrow cellularity and dysplasia. To decide on an appropriate treatment strategy for LR-MDS, it is important to evaluate the underlying pathology, and preferentially select IST as first-line therapy in patients with features that indicate immune-mediated bone marrow failure.

Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies that can be divided into two types—warm and cold—depending on their thermal amplitudes. The pathology differs depending on the type of autoantibody involved; however, the underlying etiology can differ even when the pathology is the same. Therefore, understanding the underlying mechanisms and making an accurate diagnosis is critical, as inappropriate treatment not only results in treatment failure, but can also cause life-threatening complications and reduce patient quality of life. Corticosteroids are the first-line treatment for warm AIHA, but have limited efficacy against cold agglutinin disease (CAD). Moreover, long-term and high-dose administration of corticosteroids increases risk of infection, fracture, and thromboembolism. A novel therapeutic agent for CAD targeting the complement system is effective only against hemolysis, but does not improve symptoms induced by red blood cell aggregation. In addition, elderly patients who present with either warm AIHA or CAD should also be assessed for possible malignancy. This review discusses the etiologies and pathological conditions associated with AIHA and describes the recommendations for diagnosis and treatment according to the Japanese guideline for AIHA revised in 2022.

GATA1, GATA2, and GATA3, collectively known as hematopoietic GATA factors, play a central role in the transcription factor network that governs hematopoietic homeostasis. Dysfunction of these factors leads to various hematopoietic disorders. Aberrant function of GATA1 factor, crucial in erythrocyte and megakaryocyte differentiation, not only causes anemia and thrombocytopenia, but also triggers erythroid leukemia and acute megakaryoblastic leukemia. Similarly, GATA2 factor expression is dynamic in the hematopoietic hierarchy, and dysfunction of GATA2 factor contributes not only to dysfunction of the myeloid and lymphoid lineages but also to the development of diverse hematopoietic neoplasms such as myelodysplastic syndromes, acute myeloid leukemia, and myeloproliferative neoplasms. GATA3, critical for T-lymphocyte differentiation, is relevant to lymphocytic leukemia. This review discusses hematopoietic disorders caused by aberrant GATA transcription functions, with a particular emphasis on hematopoietic malignancies.

Sideroblastic anemias (SAs) are a diverse group of congenital and acquired disorders, characterized by anemia and the presence of ring sideroblasts in bone marrow. Congenital SA is a rare disorder that results from genetic mutations that impair heme biosynthesis, iron-sulfur [Fe-S] cluster biosynthesis, and mitochondrial protein synthesis. The predominant type of congenital SA is X-linked sideroblastic anemia, caused by mutations in the erythroid-specific δ-aminolevulinate synthase (ALAS2) gene, a key enzyme in the heme biosynthesis pathway in erythroid cells. SAs can also arise due to exposure to certain drugs or alcohol or to copper deficiency (secondary SAs). They are also often associated with myelodysplastic syndrome (idiopathic SA), and idiopathic SAs are the most frequently encountered type. This review discusses the current understanding of the pathophysiology underlying SA.

Blood products are biological products derived from human blood. Japan currently meets its domestic needs with red cell products, platelet products, and plasma derivatives produced from blood, but this system could face challenges in the future. Blood transfusion therapy is only a replacement therapy that relieves symptoms, and should not worsen the patient’s outcome. Blood transfusion therapy should also be based on evidence, and the Japan Society of Blood Transfusion and Cell Therapy has created “Blood Transfusion Guidelines Based on Scientific Evidence” and calls for its proper use. Although the transfusion triggers in this guideline are effective for considering the indication for blood transfusion, the necessity of blood transfusion is comprehensively judged by taking into account factors such as the pathology, severity of symptoms, and comorbidities in each patient. Hematologists and pediatricians who frequently use blood products need to be fully aware of the risks they pose and promote safer and more appropriate use.

Acute myeloid leukemia (AML) accounts for approximately 25% of pediatric leukemia cases in Japan, with approximately 150 patients being newly diagnosed with AML annually. Pediatric acute myeloid leukemia is classified into three groups: myeloid leukemia associated with Down syndrome (ML-DS), acute promyelocytic leukemia (APL), and de novo AML. Patients with ML-DS have an event-free survival rate over 80%; however, relapsed patients have dismal outcomes, even if they receive hematopoietic cell transplantation. APL is curable with all-trans retinoic acid and arsenic trioxide. In de novo AML, 10% of patients fail to achieve remission, and approximately 30% of patients who successfully achieve remission subsequently experience AML relapse. This review highlights the therapeutic approach for these three diseases with context from past clinical studies in Japan, and shares promising new therapeutic options for relapsed/refractory de novo AML.

Traditionally, the goal of AML therapy has been to induce remission with intensive chemotherapy, reduce tumor volume as much as possible with consolidation therapy, and achieve cure by allogeneic transplantation in patients with a poor prognosis. However, in elderly patients and patients with co-morbidities, toxicity often outweighs the therapeutic benefit of intensive chemotherapy. Now that low-intensity chemotherapy, such as methylation inhibitors and venetoclax, has emerged as a promising treatment option for elderly patients, it is more important than ever to consider age and comorbidities in treatment selection. The recently proposed comorbidity-based risk stratification system for AML enables prognostic stratification in not only patients who received intensive chemotherapy, but also those who received low-intensity chemotherapy. Optimization of treatment intensity based on such risk stratification should improve both treatment efficacy and safety, and ultimately improve the prognosis of AML.

FLT3 mutations are the most frequently identified genetic abnormalities in adult acute myeloid leukemia (AML) patients, accounting for approximately 30%. FLT3-ITD mutation specifically is considered as a poor prognostic factor in AML, and allogeneic hematopoietic cell transplantation in first remission is recommended for younger patients. The recent clinical introduction of FLT3 inhibitors has been reported to improve the prognosis of patients with FLT3 mutation-positive AML. In Japan, alongside monotherapy with gilteritinib or quizartinib for relapsed/refractory patients, combination of quizartinib with intensive chemotherapy was approved in 2023 for untreated FLT3-ITD mutation-positive AML. Studies to date have demonstrated the utility of measurable/minimal residual disease evaluation targeting FLT3 mutations and the efficacy of maintenance therapy after allogeneic transplantation. However, emergence of additional genetic mutations associated with treatment resistance has been observed. Thus, FLT3 mutations are utilized not only as a prognostic factor in AML but also as a target for treatment and for response assessment. Furthermore, the development of new treatment strategies involving FLT3 inhibitors is highly anticipated to improve clinical outcomes for patients with FLT3 mutation-positive AML.

EVI1 is a zinc finger transcription factor encoded by the MECOM locus and is essential for the development and maintenance of hematopoietic stem cells. However, overexpression of EVI1 in various myeloid malignancies is associated with aggressive clinical behavior and poor outcome. The locus encodes multiple isoforms that are differentially acting and independently regulated. EVI1 interacts with a variety of transcription and epigenetic factors via different domains. It also regulates cell survival, differentiation, and proliferation through a variety of mechanisms, including transcriptional activation and repression, regulation of other transcription factors’ activity, and chromatin remodeling. While the mechanism by which 3q26 translocation leads to high EVI1 expression through enhancer hijacking of genes active in myeloid development is now better understood, regulation of EVI1 expression in the absence of chromosomal translocations and in normal hematopoiesis remains unclear. Recent studies have provided insight into the regulatory mechanisms of EVI1 expression and action, which may lead to development of targeted therapies in the near future.

Mitochondrial metabolic dependencies characteristic of acute myeloid leukemia (AML) have recently been identified, demonstrating that metabolic enzymes regulate AML gene expression and control cell differentiation and stemness. These mitochondrial metabolic adaptations occur independently of underlying genomic abnormalities and contribute to chemotherapy resistance and relapse. Mitochondrial alterations also lead to metabolic vulnerability of AML cells, whose metabolism is characterized by dependence on oxidative phosphorylation, fatty acid oxidation, reactive oxygen species (ROS) production, and mitochondrial dynamics. Currently, mitochondrial properties of AML cells and leukemia stem cells are being investigated, focusing on metabolism, signal transduction, mitochondrial respiration, ROS generation, and mitophagy. In addition, mitochondria-targeted agents have shown promising results in clinical trials. This paper outlines recent findings from preclinical and clinical trials on the utility of agents targeting mitochondria-related molecules and metabolic pathways and their efficacy in combination with existing chemotherapies.

Atypical chronic myeloid leukemia (aCML) is a rare disease classified as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN). Recent advances in gene mutational profiling have clarified the characteristics of aCML as a disease entity relative to other MDS/MPNs. Although some studies suggest the efficacy of DNA demethylating agents and tyrosine kinase inhibitors, data about these agents are limited due to the small number of patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is only therapeutic option that can provide durable remission for aCML and other MDS/MPNs. Retrospective studies from Europe and Japan revealed the clinical results of allo-HSCT for aCML. This review summarizes the pathogenesis of aCML and the development of allo-HSCT and other therapeutic options.

Many patients with chronic myeloid leukemia (CML) can now maintain response thanks to the advent of tyrosine kinase inhibitors (TKIs) and STAMP inhibitors, but adverse events associated with prolonged TKI therapy have become a problem. Adequate management of adverse events is key to successful treatment, as some can significantly impact the patient’s prognosis. The goal of CML treatment was once to prevent acute transformation, but now that many patients achieve deep remission and long-term survival, the goal has shifted to achieving long-term treatment free remission (TFR). It is essential to carefully consider disease risk, patient background, and adverse events of each therapeutic agent in order to make the appropriate choice. This article reviews the treatment of chronic phase CML (CML-CP) as described in the 2023 edition of the Guidelines for Hematopoietic Tumors, focusing on treatment options for first-line CML-CP, dose optimization of ponatinib, outcomes with the new CML drug asciminib, and TFR.

Myelodysplastic syndromes (MDS) are clonal diseases resulting from the accumulation of genetic mutations. In general, MDS is categorized into two risk groups, with management and treatment varying significantly based on this classification. Over the past two decades, allogeneic transplantation and hypomethylating agents (HMAs) have become the standard of care and remain crucial for higher-risk MDS. Unfortunately, no new drugs have emerged to replace HMAs as the standard of care. However, the landscape of practice and research in MDS has evolved. In 2022, the focus of diagnostic classification of MDS shifted significantly from morphology to genetic alterations. As a result, treatment strategies centered on genetic mutations are now already used internationally. Revisions made to the International Working Group (IWG) criteria for assessing treatment response in 2023 are expected to further improve accuracy. Meanwhile, interest has increased in understanding the relationship between inflammation and the development and progression of lower-risk MDS. This year, luspatercept, an anti-anemic agent targeting the TGFβ pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1β, CD33, TLR, IRAK4, and p38MAPK.

Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all malignant lymphomas, making it the most common subtype. Molecular genetic studies have elucidated the pathogenesis of DLBCL and the causes of its poor prognosis. This basic research has led to the development of novel molecularly targeted therapies that target molecules and cellular antigens in relevant signaling pathways or epigenetic enzymes. Treatment with polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone has become the standard of care for newly diagnosed CD20-positive DLBCL with an International Prognostic Index score of 2 to 5, based on its reported efficacy for this indication. In addition, the development of immunotherapy such as anti-CD19-chimeric antigen receptor (CAR)-T therapy and bispecific antibodies such as epcoritamab, mosunetuzumab, and glofitamab has led to a paradigm shift in treatment of relapsed/refractory DLBCL. This review summarizes the evolution of treatment development for DLBCL, as well as the results of the current clinical standard of care and new therapies that are expected to become the standard of care.

Follicular lymphoma (FL) is the most common subtype of indolent lymphoma. Survival outcomes for FL have improved since the introduction of anti-CD20 monoclonal antibodies, such as rituximab, and median overall survival has reached 15-20 years. However, FL is an incurable disease that subsequently progresses or relapses, and progression-free and overall survival tend to shorten with repeated relapses. For patients with limited-stage disease, radiation therapy is generally the treatment of choice and results in a median survival of approximately nearly 20 years. For advanced-stage patients with low tumor burden, watchful waiting continues to be the appropriate strategy at present. It remains unclear whether rituximab monotherapy might change this watchful waiting approach and result in a benefit from early intervention in patients with low tumor burden. For advanced-stage patients with high tumor burden, chemoimmunotherapy including rituximab or obinutuzumab followed by maintenance therapy is the standard treatment. For relapsed or refractory patients, treatment options such as chemoimmunotherapy, lenalidomide-rituximab, tazemetostat, chimeric antigen receptor T-cell therapies, and CD3/CD20 bispecific antibodies are available or in development. This review presents current standard treatments, recent advances, and future perspectives on the management of FL.

Mantle cell lymphoma (MCL) is a type of lymphoid malignancy that is rare in Japan. MCL is refractory to conventional chemotherapy and has dismal outcomes. Nonetheless, the prognosis of MCL has gradually improved with the advent of autologous stem cell transplantation and BTK inhibitors. First-line therapies incorporating BTK inhibitors are currently under development, and are expected to further improve the prognosis. Nevertheless, subsets with poor prognosis have been identified, including p53 abnormalities (TP53 mutations or deletions), blastoid variant, high MIPI-c, and POD24, and these show resistance to conventional treatments including BTK inhibitors. To overcome these challenges, novel therapies such as CAR-T therapy and combination therapy with BTK and BCL2 inhibitors are being developed, and should soon become clinically available in Japan. The therapeutic landscape for MCL is evolving dynamically, and this article will discuss the future of MCL treatment strategies in Japan.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell malignancy caused by human T-cell leukemia virus type-1 (HTLV-1) infection. Genetic alterations are thought to contribute to the pathogenesis of ATLL alongside HTLV-1 products such as Tax and HBZ. Several large-scale genetic analyses have delineated the entire landscape of somatic alterations in ATLL, which is characterized by frequent alterations in T-cell receptor/NF-κB pathways and immune-related molecules. Notably, up to one-fourth of ATLL patients harbor structural variations disrupting the 3′-UTR of the PD-L1 gene, which facilitate escape of tumor cells from anti-tumor immunity. Among these alterations, PRKCB and IRF4 mutations, PD-L1 amplification, and CDKN2A deletion are associated with poor prognosis in ATLL. More recently, several single-cell transcriptome and immune repertoire analyses have revealed phenotypic features of premalignant cells and tumor heterogeneity as well as virus- and tumor-related changes of the non-malignant hematopoietic pool in ATLL. Here we summarize the current understanding of the molecular pathogenesis of ATLL, focusing on recent progress made by genetic, epigenetic, and single-cell analyses. These findings not only provide a deeper understanding of the molecular pathobiology of ATLL, but also have significant implications for diagnostic and therapeutic strategies.

The prognosis of hematopoietic diseases has been improving over the past several decades, and measures to fulfill patients’ wishes to have children are needed to improve survivors’ quality of life. In Japan, the Japan Society for Fertility Preservation has taken the lead in developing guidelines, a national registry, and a nationwide uniform subsidy system. When considering fertility preservation in patients with hematopoietic diseases, interdisciplinary collaboration between oncology and onco-fertility is necessary to solve problems specific to hematopoietic diseases, such as the short time window between the onset of disease and the start of treatment, complications associated with fertility preservation treatment such as bleeding or ovarian hyperstimulation syndrome, and contamination of collected tissue with hematopoietic tumor cells. This article outlines the basic concept of fertility preservation in patients with hematopoietic diseases and recently established strategies for women with chronic myelogenous leukemia. It will also share some treatment innovations that can be considered in cases when fertility preservation treatment may be challenging.

POEMS syndrome is a plasma cell neoplasm that presents with peripheral neuropathy, organomegaly, fluid retention, skin manifestations, osteosclerotic lesions, and λ-type M-proteinemia. The pathogenesis of POEMS syndrome is poorly understood, as the genetic profile of plasma cells in POEMS syndrome differs from that of myeloma. In most cases, POEMS syndrome is difficult to distinguish from chronic inflammatory demyelinating polyneuropathy (CIDP). Consequently, it is essential not to miss characteristic signs of POEMS syndrome such as M-protein, VEGF, pleural effusion, and osteosclerotic lesions. Novel agents for myeloma, such as thalidomide, lenalidomide, and bortezomib, are effective. For younger patients, these agents followed by autologous transplantation with high-dose melphalan is the standard of care. More relapses are now being reported in results of long-term observation, and treatment strategies for relapsed disease must be established.

Immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies have been the three mainstays of myeloma treatment. B-cell maturation antigen (BCMA)-targeted immunotherapy, including chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAbs), is emerging as another important class of treatment. Two BCMA-targeting CAR-T products, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, are approved in Japan, but only ide-cel is available for clinical use. Recently, a randomized phase III study comparing ide-cel with standard therapy in patients with refractory myeloma who had received 2 to 4 prior lines of therapy showed that ide-cel was superior in terms of both response rate and PFS. Based on these results, ide-cel was approved as a third-line therapy. The new availability of bispecific antibodies has also raised new clinical questions regarding how to use CAR-T and BsAbs for each patient, and in what order. Limited data have suggested that favorable responses can be achieved when BsAbs are administered after CAR-T, but responses are suboptimal when CAR-T is administered after BsAbs. Finally, it is important to note that coordination between referring centers and treating centers, including aspects such as timing of patient referral, bridging therapy, and long-term follow-up after CAR-T, is critical to optimization of CAR-T.

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.

Multiple myeloma (MM) is currently treated with combined immunotherapies targeting the immune microenvironment surrounding MM cells. Although novel immunotherapeutic agents for MM have improved complete response rates and survival time, some patients experience repeated relapses and die of MM because its progression is strongly influenced by the immune microenvironment as well as cytogenetic abnormalities of MM cells. Various studies have elucidated the mechanisms underlying the immunosuppressive immune microenvironment of MM. Recently, single-cell RNA sequencing and cytometry by time-of-flight analysis have revealed spatiotemporal crosstalk between MM and immune cells in the bone marrow of patients with MM. These studies showed that immunosuppression appears in the early stages of MM and becomes stronger as the disease progresses, leading to immunotherapy resistance. Understanding the state of the immune microenvironment in patients with MM is important for developing immunotherapeutic strategies for long-term complete response and cure.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. Recent advances in next-generation sequencing technologies have facilitated in-depth genetic exploration of MM, unveiling a more comprehensive genomic landscape that extends beyond classical chromosomal alterations, such as IGH translocations and hyperdiploidy. These studies have elucidated recurrent mutations across various functional pathways including those involving MAPK, NF-κB, cell cycle regulation, and epigenetic modulation. With respect to clinical utility, studies have shown that the number of genetic alterations and biallelic events in TP53 are associated with worse prognosis, and CRBN mutations with resistance to immunomodulatory drugs. We recently analyzed the full landscape of genetic alterations in relapsed and refractory MM using circulating tumor DNA (ctDNA), revealing TP53 mutations as the most frequent driver mutation. Notably, more than half of TP53 mutations were present in only ctDNA, suggesting a subclonal origin. Mutations in six genes, including KRAS and TP53, were associated with poor progression-free survival. In addition, the number of ctDNA mutations was identified as a prognostic factor independent of IGH translocations and clinical factors. Here we summarize recent progress in genetic analysis of MM, focusing on clinical relevance.

Methods in which patient-derived T cells are genetically modified in vitro and administered to patients have been demonstrated effective in the area of cancer immunotherapy. However, these methods have some unresolved issues such as cost, time, and unstable quality. Several groups have developed strategies to overcome these barriers by regenerating T cells from iPSCs. We have been developing a method in which specific TCR genes are introduced into iPSCs and T cells are regenerated from these iPSCs (TCR-iPSC method). We are now using starting iPSCs from the iPSC stock lines provided by CiRA-F, as the iPSC stock cells are less likely to be rejected. A study aimed at application to solid tumors demonstrated the therapeutic effect of regenerated T cells in a patient tissue xenograft model of WT1 antigen-positive renal cell carcinoma. This article will also discuss strategies by other groups to regenerate various types of T cells from iPSCs.

Advances in replacement therapy with clotting factor (F) VIII or FIX product have contributed greatly to reducing the incidence of hemophilic arthropathy and improving quality of life (QOL) in patients with hemophilia. However, frequent intravenous administration of clotting factor products, blood access, and development of alloantibodies (inhibitors) have been important issues. Clinical studies aimed at addressing these issues have been conducted in Japan as well, including a multicenter study to determine factors involved in inhibitor development. Drug development has also progressed: several clotting factor products with extended half-life and non-clotting factor therapies have been introduced in quick succession. Anti-FIX/FX bispecific antibody in particular has a long half-life when administered subcutaneously and controls bleeding in patients with hemophilia A. Anti-antithrombin therapy and anti-TFPI monoclonal antibody products that work by rebalancing coagulation have also been developed. In addition, gene therapy has been approved for adults in U.S. and Europe, where improved vectors and codon optimization have enabled protein expression up to the near-therapeutic hemostatic range. Recent significant developments in hemophilia treatment are expected to overcome long-standing problems and further improve QOL.

Disseminated intravascular coagulation (DIC) is defined as systemic intravascular coagulation activity that has been acquired in the presence of various underlying diseases and is outside local or compensatory control, and is a fatal condition. Although the pathogenesis, diagnosis, and treatment of DIC are well known in Japan, each clinician has a different understanding of DIC, which makes it difficult to standardize diagnosis and treatment. Even at the international level, perception of DIC varies widely. This makes it difficult for residents and novice clinicians to standardize routine care for DIC. To meet the demands of the times, my colleagues and I are currently working on a globally unprecedented project to develop guidelines for the treatment of DIC for each underlying disease (tentative title). This article will also review the status of past guidelines from inside and outside Japan.

Two thrombopoietin receptor agonists (eltrombopag and romiplostim), rituximab or splenectomy have been recommended for the treatment of glucocorticoid-resistant ITP in Japanese guidelines. In addition, the Syk inhibitor fostamatinib and FcRn inhibitor efgartigimod were approved in Japan for refractory ITP in 2023 and 2024, respectively. Clinical trials have also reported promising results for the new thrombopoietin receptor agonist avatrombopag, the BTK inhibitor rilzabrutinib, and the C1s inhibitor sutimlimab. These developments will usher in a new era in the treatment of ITP.

Unlike for anticoagulants, no good monitoring methods exist for antiplatelet agents, and their monitoring is considered unnecessary. In the platelet aggregation test, which is the standard test for platelet function, aggregation is evaluated by adding a platelet activator to platelets in a cuvette. Therefore, it provides information on the maximum potential of platelets to induce aggregation, but not the actual in vivo degree of platelet activation. In vivo platelet activation markers are not widely used because they require a special blood collection method, although some tests are covered by insurance. My colleagues and I identified the platelet activation receptor C-type lectin-like receptor 2 (CLEC-2) and found that CLEC-2 is cleaved and released during platelet activation. We established a plasma-soluble CLEC-2 (sCLEC-2) assay system with the aim of using it as a marker of in vivo platelet activation. Elevation of sCLEC-2 has been reported in various thrombotic diseases. The multi-center prospective cohort study CLECSTRO is now underway to investigate the usefulness of sCLEC-2 for diagnosis, typing, and prognostic estimation in acute ischemic stroke.

Heparin-induced thrombocytopenia (HIT) was widely known as a disease characterized by development of thrombosis with thrombocytopenia after heparin exposure. In addition, vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described as a fatal disease involving simultaneous bleeding and thrombosis after COVID-19 adenovirus vector vaccination. These were caused by HIT antibodies and anti-PF4 antibodies, respectively, but both were autoantibodies that recognized PF4, and were found to have the same pathology with different severities. In recent years, many pathologies in which anti-PF4 antibodies are produced have been reported, and a new concept of anti-PF4 disorder has been proposed. Anti-PF4 disorders are often difficult to identify due to their diverse range of causes, and the prognosis varies greatly depending on whether anti-PF4 antibodies can be measured and early treatment performed after observation of thrombocytopenia of unknown cause or thrombosis at an unusual site. To avoid overlooking anti-PF4 disorders, clinicians should become familiar with the classification of these disorders and accurately select the necessary tests.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, and remains a global issue due to its high incidence and mortality. Many randomized controlled trials have investigated sepsis, but no specific treatments have been established. This is due to “heterogeneity,” which indicates that a diagnosis of sepsis includes various pathophysiological states. To resolve this issue, efforts are being made to identify subclasses of sepsis. Past studies have selected different variables, such as expressed genes, cytokines, and vital signs, and identified subclasses based on clinical or biomarker-expression features. We also identified subclasses of sepsis with different coagulation features, and found that a specific anticoagulant agent (recombinant human thrombomodulin) was associated with improved survival rates in only one subclass. We also developed a model that could predict the subclass. However, none of the reported subclasses had shared characteristics, and they are not in clinical use. Further research is required to identify subclasses that are strongly associated with the pathophysiological mechanism and reproducible in any cohort.

Sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) is a well-known, potentially fatal liver complication. Some clinical diagnostic criteria have been proposed over the years. Defibrotide is the only approved treatment for SOS/VOD and should be administered within two days of diagnosis. Recently, the EBMT 2023 criteria aimed at early diagnosis were published, and the ultrasound diagnostic tool HokUS-10 has attracted worldwide attention. Although the incidence of SOS/VOD is decreasing, it remains a significant complication that must be addressed. Early diagnosis and prompt treatment are crucial, and achieving this requires multidisciplinary teamwork between physicians, nurses, sonographers, pharmacists, and other healthcare professionals. This collaborative approach is essential to optimize treatment and save SOS/VOD patients.

The intestinal microbiota is an important prognostic factor for allogeneic hematopoietic stem cell transplantation (allo-HCT), and decreased diversity of the intestinal microbiota is linked to shorter overall survival, high transplant-related mortality, and acute graft-versus-host disease (GVHD). Major factors that alter the intestinal microbiota during allo-HCT are broad-spectrum antibiotics and intestinal GVHD. Broad-spectrum antibiotics dysregulate the immune system and impair intestinal epithelial regeneration by reducing beneficial commensal bacteria and activating mucus-degrading bacteria, which disrupts the colonic barrier function. Intestinal GVHD leads to decreased secretion of antimicrobial peptides into the intestinal lumen, as well as mitochondrial dysfunction in the intestinal epithelium, altering the intestinal microbiota. Various therapeutic approaches targeting the intestinal microbiota have been investigated in clinical trials. Protecting the intestinal microbiota may further enhance the safety and efficacy of allo-HCT by regulating intestinal immune responses, promoting intestinal epithelial regeneration, and facilitating the production of beneficial metabolites derived from commensal bacteria.

Treatment for chronic graft-versus-host disease, the most important long-term complication of allogeneic hematopoietic cell transplantation, has changed significantly over the past decade. Development of novel targeted therapies has advanced as objective criteria for the diagnosis and evaluation of chronic GVHD have been established and understanding of the biological pathways to pathogenesis has increased. This paradigm shift is driving chronic GVHD practice significantly toward individualized therapy while minimizing exposure to steroids. Treatment using a variety of novel agents, tailored to each individual patient’s condition, is expected to improve quality of life and overall survival by preventing chronic GVHD, controlling disease progression, and maintaining motor and occupational functions. This article reviews the pathogenesis of chronic GVHD and discusses prospects for the treatment of chronic GVHD, along with recently approved drugs and promising drugs in development.

Chimeric antigen receptor (CAR) T-cell therapy is an innovative treatment for B-cell malignancies and multiple myeloma. CAR T-cell therapy is now approved in Japan and has become one of the essential therapeutic options for chemotherapy-resistant disease. It has many unique features that distinguish it from conventional chemotherapies, including the limitations imposed by the production of CAR-T cells from autologous T cells, and the limited availability and mandatory waiting period for treatment. Importantly, each patient has only one opportunity to receive CAR T-cell therapy. To achieve the maximum therapeutic benefit from CAR T-cell therapy, it is necessary to understand all aspects of CAR T-cell therapy, including factors that influence its efficacy. The design of the entire treatment sequence, including before and after CAR T-cell therapy, is also important to optimize clinical outcomes. In addition, since this treatment is only available at a limited number of facilities, effective coordination between local hospitals and treatment centers is also important. This educational session will focus on the practical aspects of CAR T-cell therapy in adults and will provide indispensable knowledge for providing CAR T-cell therapy to patients with B-cell lymphoma and multiple myeloma.

Tisagenlecleucel, a commercially available CD19-targeted CAR-T cell product, has dramatically changed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Tisagenlecleucel infusion has been linked to distinct acute adverse events, including cytokine release syndrome, neurotoxicity, hemophagocytic lymphohistiocytosis and prolonged pancytopenia, which are rare with cytocidal chemotherapy. In addition, recent retrospective studies have revealed pre-infusion prognostic factors including high tumor burden (bone marrow leukemia cell fraction ≥5%) and non-response to blinatumomab, another CD19-targeting agent. Not only physicians providing CAR-T cell therapy but also those referring patients for this therapy should thoroughly understand the indications and limitations, characteristic acute complications, pre-treatment factors affecting prognosis, and late complications. This article outlines the current understanding regarding the use of tisagenlecleucel in children and adolescents with B-ALL.

Hematopoietic stem cell (HSC)-targeted gene therapy is curative for various genetic blood diseases, and its efficacy has been demonstrated in recent clinical trials. HSCs have self-renewal and hematopoietic multipotency; therefore, repairing pathological mutations or defects in HSCs allows for a lifelong cure with a single treatment. Autologous HSC gene therapy has been developed by lentiviral gene addition or gene editing, and is an option for most patients because it does not require a compatible donor. Current HSC gene therapy is based on ex vivo methods, in which patient HSCs are harvested, genetically modified ex vivo, and autologously transplanted into patients. However, the complexity of this process and the high cost of treatment are hindering the spread of gene therapy. Therefore, in vivo HSC gene therapy is being developed to deliver gene therapy tools directly into bone marrow HSCs by administration without ex vivo culture.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.

Recent advancements in treatment have improved the prognosis of hematologic malignancies. However, the increasing cost of therapeutic drugs has become an urgent issue. Cost-effectiveness analysis is performed using the incremental cost-effective ratio (ICER), a value calculated by dividing the incremental cost by the incremental quality-adjusted life year (QALY). The ICER must be compared with the willingness-to-pay (WTP) threshold, which differs between countries. Since the analysis should be made over a long time horizon, it is necessary to model and extrapolate the long-term outcomes of clinical trials to calculate cumulative costs and QALYs. This article discusses several approaches to cost-effectiveness analysis for chronic myelogenous leukemia, multiple myeloma, and CAR-T therapy. As even expensive treatments could be cost-effective if they provide long treatment-free survival, it is essential to judge cost-effectiveness by an appropriate method, rather than price alone.

L-asparaginase is a key drug in the treatment of acute lymphocytic leukemia/lymphoblastic lymphoma and is currently used in treatment regimens for a wide range of age groups, including children, adolescents, young adults, and older adults. Discontinuation of L-asparaginase leads to worse survival outcomes. Strategies such as appropriate prevention and management of asparaginase-specific adverse events such as hypersensitivity reactions and optimizing administration by therapeutic drug monitoring are important to ensure completion of all asparaginase doses planned in each regimen. Two new L-asparaginase preparations with different properties are now available in Japan, and attempts to leverage these properties for more effective and safe administration are attracting attention. This article reviews previous advances in therapy with L-asparaginase and outlines current and future challenges for maximizing the therapeutic efficacy of L-asparaginase.

The new guidelines for pediatric immune thrombocytopenia (ITP) not only include changes to the name and staging of the disease, but also introduce the modified Buchanan’s bleeding score for the assessment of bleeding symptoms. Treatments should aim to improve patients’ health-related quality of life (HRQoL) based on a multidimensional assessment of not only platelet counts but also bleeding symptoms, as well as activity level, lifestyle, and access to healthcare. First-line therapy includes intravenous immunoglobulin therapy (IVIG) and short-term corticosteroids. Second-line therapy includes thrombopoietin receptor agonists, rituximab, and splenectomy. Many novel agents are also in development, with splenic-derived tyrosine kinase (Syk), Bruton’s kinase (BTK), and fetal Fc receptor (FcRn) attracting attention as target molecules. Future developments in the treatment of pediatric ITP are eagerly awaited.

About 100 cases of Langerhans cell histiocytosis (LCH) occur annually in Japan. It predominantly occurs in infants, presenting as multisystem disease or multifocal bone involvement. However, LCH can also occur in adults aged 20 to 40. Single-system skin involvement is rare, with most cases presenting with multisystem disease, including bone lesions, which respond to chemotherapy. In adults, lung lesions that improve with smoking cessation are well-known, although multisystem disease is more common and requires aggressive therapeutic intervention similar to that in children. In some infant cases, progression of liver, spleen, and bone marrow lesions can be difficult to control and can become severe. However, targeted molecular therapies are now available as a lifesaving option. More than 30% of cases of multisystem LCH recur at least once, often leading to long-term complications. In particular, the emergence of central diabetes insipidus, anterior pituitary dysfunction, and central nervous system neurodegenerative disorders several years after the diagnosis of LCH is a unique feature not observed in other diseases. New therapeutic strategies are needed to counter these problems.

Flow cytometry (FCM) remains an essential test in the diagnosis of leukemia despite advances in genomic testing. However, the role of FCM results as a risk factor is already extremely limited. International diagnostic criteria for leukemia already prioritize diagnosis based on genetic abnormalities, with FCM diagnosis only serving as an aid to morphological diagnosis for subtypes without genetic abnormalities. However, rapid lineage diagnosis of leukemia by FCM remains important for selecting initial treatment. FCM is also an important tool for evaluating response to molecular targeted therapy, which requires repeated measurements and rapid results. Furthermore, FCM enables prediction of specific genetic abnormalities by immunophenotypic patterns, which could make it useful for verifying the clinical impact of genetic abnormalities detected by multi-gene panel testing.

Evidence-based medicine (EBM) is “decision-making for better patient care that integrates current evidence, and clinical expertise with patients’ preferences, values and circumstances.” It is important to distinguish research evidence from EBM, which is comprehensive decision-making that takes into account the diversity and individuality of clinical situations while respecting evidence as a general theory. Clinical practice guidelines are “a document that evaluates the total body of evidence through systematic review and presents recommendations that are considered optimal, taking into account the balance of benefits and harms, in order to support decision-making on important health-related issues by healthcare users and providers,” and is useful in the practice of EBM. Shared decision making (SDM), which has been attracting attention in recent years, is “a process in which the patient and the health care provider, through dialogue, decide on a treatment plan that is acceptable to the patient, based on the patient’s own preferences and values, research evidence, and clinical expertise” and must be understood in relation to the above definition of EBM and from the perspective of clinical ethics.

Clinical research is conducted to investigate physicians’ clinical questions and to clarify research hypotheses. When conducting clinical research, it is important to carefully consider the research design in advance. An optimal design that meets the objectives of the study and addresses practical implementation issues is desirable. Randomized comparisons during the final confirmatory phase may be the best tool for comparing treatments. However, not all clinical questions can be answered through randomized controlled trials. This article summarizes the basics of clinical study design and explains the role of randomization. It also introduces a propensity score-based method that has gained attention as a statistical method for comparing treatment groups when randomization is not feasible, and is increasingly being utilized in clinical research.