Myelopoiesis is a process that produces myeloid cells including granulocytes and mononuclear phagocytes. The differentiation and proliferation of hematopoietic stem and progenitor cells are tightly regulated to meet demands for such myeloid cells both at steady state and under stressed conditions. CCAAT/enhancer-binding protein family transcription factors are involved not only in the appropriate regulation of myelopoiesis but also in dysregulated myelopoiesis. A recent study has revealed that inflammation, in addition to the established concepts or mechanisms of dysregulated myelopoiesis, triggers long-term epigenetic memory in hematopoietic stem/progenitor cells. Further, clonal hematopoiesis develops and impairs host health conditions via inflammatory conditions. Intensive studies covering both the basic and clinical aspects of myelopoiesis are required to establish therapeutic and even prophylactic approaches to different types of human diseases including hematopoietic and nonhematopoietic origins.

Hematopoietic stem and progenitor cells in mammals primarily reside in the bone marrow after birth. There, the cellular dynamics and subsequent fate of those cells are regulated by the adjacent microenvironment, known as the niche, to sustain lifelong blood cell production. To analyze and study physiological hematopoiesis and various hematopoietic disorders, it is essential to deeply understand how the niche regulates hematopoiesis and how niche dysregulation occurs. However, the dynamics of hematopoietic stem and progenitor cells and their interactions with the niche are dynamic and complex, and our knowledge of the spatial organization of bone marrow cells and niche factors is still limited. In this review, I provide an overview of classical techniques for spatiotemporal understanding of the cellular communities in bone marrow, as well as recent advances in bone marrow imaging techniques and valuable animal models, and discuss future prospects in this field.

Hematopoietic cells are a group of cells that first appear in the midembryonic stage of the mouse and are essential for body growth and maintenance. For a long time, their development was widely assumed to be divided into primitive and definitive hematopoiesis. However, erythromyeloid progenitors were identified as the wave between primitive and definitive hematopoiesis, and at least three waves were recognized. An even more multilayered structure of hematopoietic development is becoming evident in recent years, with the progress and spread of lineage tracing experiments. This review will focus on recent advances in the behavior of hematopoietic stem and progenitor cells in the embryo revealed by cell lineage-tracking experiments.

The process of RNA splicing plays a pivotal role in gene expression and genetic information modification by converting pre-mRNA into mature mRNA. Dysregulation of this process has been associated with aberrant gene expression and function, leading to hematopoietic malignancies. Through recent clinical and mouse model analyses, insights have been gained into the mechanisms underlying splicing factor mutations that aid in myelodysplastic syndrome and acute myeloid leukemia. These mutations affect genes that modulate diverse cellular processes, including chromatin regulation, transcription factors, proliferation signaling, and inflammation pathway. The relationship between aberrant splicing and cancer remains unclear despite progress in understanding the functional consequences of splicing factor mutations. This review focuses on the mechanisms of disease development because of splicing factor mutations and their potential mechanism-based therapeutic applications.

In recent years, it has become clear that various diseases are caused by complement (related molecule) abnormalities (complementopathies) or are exacerbated by complement (complement-related diseases), and novel therapeutic agents targeting complement (anti-complement agents) are now being developed. Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis due to a deficiency of complement regulatory factors, making it a perfect candidate for anti-complement agents. In 2007, the anti-C5 monoclonal antibody eculizumab was approved for PNH, as the first anti-complement agent. The indications for eculizumab are expanding, and aggressive development is underway for new anti-complement agents, not only for PNH but also a variety of other diseases. In addition, the anti-C1s antibody sutimlimab was approved last year for the treatment of cold agglutinin disease, a form of autoimmune hemolytic anemia. This presentation overviews novel anti-complement agents for these hemolytic anemias.

The “Reference Guide for the Treatment of Aplastic Anemia” has been revised for the first time in 3 years, and clinical questions have been formulated for the first time. As research demonstrated a benefit to combining antithymocyte globulin (ATG) and cyclosporine with eltrombopag (EPAG), the revised guide recommends that EPAG be started as soon as possible after ATG administration. In addition, it states that starting with immunosuppressive therapy and performing allogeneic bone marrow transplantation in the event of inadequate response or relapse is an option even for young adult patients with severe aplastic anemia who have HLA-matched allogeneic bone marrow donor candidates. The guide also discusses aggressive treatment of non-severe cases, ATG dosage and the maximum age for ATG administration, infection prevention, and G-CSF administration. It is necessary to continue collecting evidence and promoting clinical trials to build evidence in Japan.

Recently, nutritional anemia has been increasing, particularly refractory iron-deficiency anemia, which has become more common not only among older adults but also among relatively young people. Coexisting conditions such as chronic inflammatory disease, gastrointestinal disease, and chronic kidney disease can all complicate diagnosis and treatment. In many cases, appropriate treatment can improve anemia. Same as iron, copper, and zinc are proven to be absorbed from the transporter in the upper gastrointestinal mucosa, but potential zinc and copper deficiencies are increasingly being reported in cases of iron deficiency. Serum zinc deficiency is more common in cases of severe iron-deficiency anemia. This paper provides an overview of refractory iron-deficiency anemia and discusses the molecular groups involved in iron dynamics, zinc, and copper metabolism.

Bone marrow (BM) failure is a condition characterized by peripheral pancytopenia due to decreased BM function. It includes conditions such as acquired aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). AA is characterized by pancytopenia and BM hypoplasia, and is primarily caused by an autoimmune mechanism involving cytotoxic T cells that damage hematopoietic stem cells (HSCs). Recent genomic research has revealed that patients with AA often exhibit clonal hematopoiesis by HSCs with genetic alterations, such as PIGA, DNMT3A, ASXL1, BCOR/BCORL1, copy-number neutral LOH of chromosome 6p (6pLOH), and HLA class I allele mutations. The genomic landscape of AA is distinct from MDS and age-related clonal hematopoiesis. Most notably, the presence of PNH-type cells and HLA class I allele-lacking cells indicates the presence of HSCs that have escaped from autoimmunity. We recently identified a common nonsense mutation at codon19 (c.19C>T, p.R7X) in exon1 (Exon1mut) of different HLA-A and HLA-B alleles, and HLA-DR loss of hematopoietic stem progenitor cells in AA patients carrying HLA-DR15. These results provide important clues for understanding the immune pathophysiology of BM failure.

For approximately 4 billion years after the birth of life, iron, the fourth most abundant metal on earth, has played a critical role in redox reactions. Iron is a trace metal that is required for life activity, and no organism can survive without it. However, it has recently been discovered that iron causes life-threatening toxicity as organisms live longer. Ten years have passed since the discovery of iron-dependent cell death (ferroptosis), and the interest in iron is growing rapidly in various fields. Many diseases, such as neurodegenerative diseases and cancers, have been linked to abnormalities in iron metabolism, and completely new treatment methods based on iron regulation have been developed. In this article, we will assess the secretory mechanism ferritin, an iron storage protein that we recently discovered, as well as the role of secreted ferritin in diseases.

Blood transfusion is an essential supportive treatment in modern medicine and is frequently used. Acute hemolytic transfusion reaction is prevented by conducting a cross-matching test; however, nonhemolytic transfusion reactions are difficult to predict. Furthermore, adverse transfusion reactions are not sufficiently recognized by healthcare workers because they rarely occur, except for urticaria and febrile reactions. Thus, further awareness of adverse reactions, particularly regarding transfusion-associated circulatory overload, is needed. Since the introduction of irradiated blood, no transfusion-associated graft-versus-host-disease (TA-GVHD) case has been reported for over 20 years. However, education on the risk of TA-GVHD is important in facilities where nonirradiated blood is supplied or in situations such as unavoidable in-house blood collection on remote islands. The incidence of transfusion-transmitted hepatitis was significantly decreased by the introduction of nucleic acid amplification tests. Recently, the Japanese Red Cross Society is focusing on the reduction of transfusion-associated bacterial infections, which are rare but serious complications. This review provides an updated overview of adverse transfusion reactions and their management measures. Understanding adverse transfusion reactions will enable healthcare workers to recognize symptoms and take prompt action.

FMS-like tyrosine kinase 3 (FLT3) mutation is present in 25% of acute myeloid leukemia (AML) cases. It is associated with poor prognosis due to a high relapse rate and short remission duration. Consequently, various FLT3 inhibitors were developed. Two second-generation FLT3 inhibitors, including gilteritinib and quizartinib, are used for treating relapsed/refractory FLT3-mutated AML. Additionally, in May 2023, quizartinib was approved for newly-diagnosed FLT3-mutated AML, in combination with standard remission induction, consolidation, and maintenance therapies based on a phase 3 trial. Furthermore, high relapse rates were observed even in patients who underwent allogeneic hematopoietic cell transplantation while in their first complete remission, and post-transplant maintenance therapy using oral FLT3 inhibitors has been tried. This review summarizes breakthroughs in treatments of FLT3-mutated AML aiming for a better prognosis.

Recently, a series of new approvals or expanded indications for small-molecule drugs indicated for acute myeloid leukemia (AML) has occurred. Small-molecule drugs greatly improve AML treatment options and contribute to prolonged prognosis; however, drug resistance is inevitable with long-term use. New modalities that have immune cell therapy should be developed using chimeric antigen receptor (CAR)-T cells which is one of the most promising next-generation cancer therapies for hematological cancers, and with awaited practical application in AML. Although CAR-T cell development that targets various AML-related antigens has progressed so far, products close to practical use have remained unavailable globally due to the AML-specific drug discovery challenges. This article will review the clinical development of CAR-T cells and discuss the developmental issues in AML from the viewpoint of target antigen characteristics and on-target/off-tumor toxicity.

With recent advances in sequencing technologies, novel genes associated with the predisposition to myeloid neoplasms have been discovered, and subsequent studies have shown that the incidence of myeloid neoplasms associated with germline variants is higher than expected. Accordingly, myeloid neoplasms with germline predisposition have represented a unique category in the recent WHO classification and the International Consensus Classification, and DDX41 mutation accounts for 2-5% of myeloid neoplasms. Clonal hematopoiesis commonly occurs in healthy individuals, especially in older people. For patients with germline predisposition, clonal hematopoiesis is frequently observed at a younger age and often associated with disease-specific driver mutations, leading to further understating of the pathogenesis of diseases.

Anthracycline- and cytarabine-based intensive combination chemotherapies are considered the backbone therapy for patients with acute myeloid leukemia (AML). Although chemotherapy leads to long-term remission and cures many patients with AML, it can induce DNA damage/stress due to acute/chronic toxicities, acquired resistance, relapse, and therapy-related malignancies. Introduction of molecularly targeted agents with less systemic toxicities has considerably improved the scope of treatment, particularly in elderly and frail patients. However, outcomes of TP53-mutated myelodysplastic syndrome (MDS) and AML, a distinct group of myeloid disorders, have not improved irrespective of the treatment used (median overall survival, 5-10 months). In this review, we discuss the biological and clinical significance of TP53 mutations in malignancies, while particularly focusing on MDS/AML, and emerging therapies for TP53-mutated MDS/AML. Rationally designed novel treatment strategies are expected to improve the clinical outcomes of TP53-mutated MDS/AML.

Myeloid malignancies are composed of multiple clonal hematopoietic disorders, including myelodysplastic syndrome, myeloproliferative neoplasms, and acute myeloid leukemia. Inflammation is already known to play an important role in the pathogenesis of an extensive variety of malignancies, and its significance in myeloid malignancies is becoming more widely recognized. Specifically, cell-intrinsic and -extrinsic activation of the innate immune signaling pathway, as well as elevation of proinflammatory cytokines via innate immune signaling downstream signaling, have been demonstrated. Furthermore, the inflammatory microenvironment refers to the bone marrow environment rich in inflammatory signaling molecules that surround hematopoietic malignant cells, and its role in the pathogenesis of myeloid malignancies has been extensively studied in recent years. Herein, we present the latest findings and discuss how innate immune signaling activation and the inflammatory bone marrow microenvironment contribute to the pathogenesis of myeloid malignancies.

The discovery of driver genes such as JAK2 in myeloproliferative neoplasms (MPN) led to a better understanding of MPN pathogenesis as a constitutive activation of the JAK/STAT signal. Following these findings, several types of JAK inhibitors have been developed. Ruxolitinib, a JAK1/2 inhibitor licensed for polycythemia vera and myelofibrosis, demonstrated efficacy in regulating hematocrit levels, lowering spleen volume, and relieving MPN-related symptoms. However, some patients with myelofibrosis are refractory to JAK inhibitors, and some are intolerant due to cytopenia. Furthermore, JAK inhibitors did not slow the progression of acute leukemia, indicating the need for new therapeutic methods for myelofibrosis. Novel medicines, including BCL inhibitor, MDM2 inhibitor, LSD1 inhibitor, PI3K inhibitor, BET inhibitor and telomerase inhibitor, are presently being evaluated in clinical studies for myelofibrosis with the potential to enhance clinical outcomes.

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML) in the chronic phase. However, only 50-60% of patients stay on the same TKI for 5 years, and the long-term progression-free survival rate is significantly reduced if an early molecular response is not achieved. Possible mechanisms of therapeutic resistance against BCR::ABL1 dependent clones include point mutations in the ABL1 kinase domain, BCR::ABL1 splicing variants, BCR::ABL1 overexpression, and altered pharmacokinetics by the ABC transporter. Ponatinib, the most potent inhibitor among TKIs, and the STAMP inhibitor asciminib are important drugs for overcoming BCR::ABL1-dependent resistance.

Myelodysplastic syndromes (MDS) are hematopoietic stem cell neoplasms characterized by bone marrow failure with a propensity to develop into acute myeloid leukemia (AML). Recent advances in genome-wide analyses have enabled identification of most somatic gene mutations responsible for MDS, and multiplex gene-panel testing for hematological malignancies will be available soon. Thus, identification of genetic abnormalities is now enabling precise diagnosis and risk-stratification of MDS. Recently, two diagnostic classification systems for MDS have been published as updates to the previous WHO classification of myeloid tumors. The IPSS-M has also been proposed as a new risk-stratification system based on genetic abnormalities and known prognostic factors. Following identification of pathological processes in MDS, therapeutic agents that can alter the course of disease, including azacitidine and lenalidomide, were approved and became available in Japan. Several novel therapeutic agents are under development as well. This paper will discuss updated diagnostic and risk-stratification systems, as well as standard treatment strategies for MDS.

Primary myelofibrosis (PMF) is characterized by the clonal expansion of megakaryocytes and myeloid cells from stem cells with abnormal cytokine expression, resulting in bone marrow fibrosis, angiogenesis, and osteosclerosis. The use of next-generation sequencing revealed that both genetic and epigenetic changes are important in the pathogenesis of PMF. Several epigenetic regulator genes, including TET2, the polycomb-related gene ASXL1, and the polycomb-group gene EZH2, have been found to be targeted by somatic gene mutations in PMF patients. Among these, loss of Ezh2 has been demonstrated to disrupt the function of the polycomb repressive complex 2, promoting the development of JAK2^V617F-induced myelofibrosis in mice. In this analysis, we highlight the role of PRC dysfunction in the pathogenesis of PMF.

Chronic myeloid leukemia (CML) stem cells have been identified to promote CML relapse due to their quiescent cell cycle and tyrosine kinase inhibitor resistance. Therefore, their eradication is important for the cure of CML. We herein identified the quiescent CML stem cell fraction using a G0 marker that can visualize quiescent cells. Whole-transcriptome analysis of imatinib-resistant, quiescent CML stem cells revealed that NF-κB is activated via inflammatory signals in the same cells. The combination of imatinib and an inhibitor of this inflammatory signal (IRAK1/4 inhibitor) effectively eliminated CML stem cells and attenuated PD-L1 expression in CML stem cells. Furthermore, the combination of anti-PD-L1 antibody and imatinib effectively eliminated CML stem cells in the presence of T-cell immunity, indicating the importance of creating an environment in which T cells can attack CML stem cells. Thus, IRAK1/4 inhibitors exert two effects: blocking CML stem cell survival and proliferation signals by inhibiting NF-κB and blocking T cell immune evasion by reducing PD-L1 expression in CML stem cells. Collectively, their combination may be one of the attractive strategies for achieving a radical cure for CML. Discussions regarding the possibility of future medications seem warranted.

Follicular lymphoma (FL) is the most common indolent lymphoma, benefits from anti-CD20 monoclonal antibody therapy, and has a median overall survival of over 15 years. However, it remains incurable in the majority of patients despite the current standard therapeutic strategy. For advanced-stage cases with a low tumor burden, watchful waiting remains the standard treatment. The optimal timing of rituximab monotherapy is a clinical question. For advanced-stage cases with a high tumor burden, the standard of care includes anti-CD20 monoclonal antibody and chemotherapy, followed by maintenance therapy for 2 years in responding cases. The significance of maintenance therapy after bendamustine administration has not been confirmed. Even within the early relapse group, histological transformation is the most important prognostic factor. For refractory FL, anti-CD19 chimeric antigen receptor T-cell therapy and CD20/CD3-bispecific antibodies have shown promising results. This review presents the current FL treatment strategy and prognostic factors.

Diffuse large B-cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease. Remarkable effort has been exerted in the classification of DLBCL and the development of its corresponding treatment. The prognosis of patients with DLBCL receiving rituximab combination chemotherapy significantly improved in the early 2000s. However, approximately 40% of patients still develop recurrence, and the prognosis of these patients is extremely poor. Recently, the use of polatuzumab vedotin and CAR T-cell therapies has improved patient prognosis. However, it is extremely important to identify the patient group who can benefit from the efficacy of these treatments. In relation to this, the molecular pathogenesis of DLBCL should be further evaluated. Recent advancements in the genetic analysis technology have led to the discovery of unknown genetic abnormalities and gene expression patterns. The elucidation and subdivision of the molecular pathology based on these findings will be the foundation of future personalized medicine.

Adult T-cell leukemia/lymphoma (ATL) is an extremely refractory peripheral T-cell lymphoma that develops after persistent human T-lymphotropic virus type 1 (HTLV-1) infection. In recent years, the number of HTLV-1 carriers has decreased due to lifestyle changes and different measures. Rapid progression in comprehensive genetic analysis techniques has revealed the molecular basis of ATL. Therefore, in addition to conventional prognostic indices based on clinical parameters, prognostic indices incorporating genetic mutations have been proposed. The standard treatment for untreated aggressive ATL is combination chemotherapy such as VCAP-AMP-VECP or CHOP, followed by allogeneic hematopoietic stem cell transplantation, as appropriate. Combined mogamulizumab and chemotherapy is a promising first-line treatment option for patients not eligible for transplantation. Salvage treatment with lenalidomide, brentuximab vedotin, tucidinostat, and valemetostat, in addition to mogamulizumab, has been introduced over the last decade. Advancements in allogeneic transplantation therapy, including early induction and transplantation with post-transplant cyclophosphamide for GVHD prophylaxis, have also improved patient outcomes. This article highlights recent developments in the field of ATL.

Correct interpretation of clinical trial results is important. Overall survival was once considered the primary endpoint for neoplastic disease, but surrogate endpoints are increasingly being used for diseases whose prognosis has improved. This is due to the longer trial duration required to obtain conclusions and to poor statistical power. Clinical decision-making in practice is also shifting to using these surrogate endpoints. In clinical trials, eligibility criteria are set to obtain differences between arms. However, this does not mean that results should only be applied to eligible populations, as it is not realistic to conduct a clinical trial in patients with all possible characteristics. Rather, results should be applied to patients who do not meet the eligibility criteria, with careful consideration. A single clinical trial often presents the results of many subgroup analyses, but the main conclusion should not be judged differently by subgroup. The purpose of subgroup analysis is to find potential confounders that interact with the conclusion, and results of subgroup analysis should not be overestimated. Non-inferiority trials have become increasingly common in recent years, and their importance is not limited to demonstrating the non-inferiority of the primary endpoint. Specifically, they are also important for understanding the benefits in the experimental arm outside those in primary analysis. Some secondary endpoints are very important for making conclusions about these benefits.

Single-cell analysis encompasses analyses at the single-cell level. Specifically, DNA sequences, RNA and protein expression levels, and epigenome modifications are currently analyzed at the single-cell level. In recent years, single-cell sequencing technologies have been incorporated into numerous blood studies. This paper introduces an overview of single-cell technologies and further explains achievements in blood research using single-cell analysis.

Information about genetic mutations that accumulate in each subtype of malignant lymphoma has been reported. Identification of mutations is predicted to become more crucial not only for a definitive diagnosis but also for selecting effective targeted therapies and analyzing detectable residual diseases. However, in the clinical environment of malignant lymphoma, DNA samples might be difficult to obtain, and longitudinal sample collection throughout disease development and/or remission is exceedingly difficult compared to leukemia sectors. Liquid biopsy is a new strategy of tumor biopsy that detects aberrant tumor-derived genes from a patient’s plasma, cerebrospinal fluid, or other body fluids. With advances in genetic analysis methods, reports are accumulating on the usefulness of liquid biopsy in diffuse large B-cell lymphoma, central nerves system lymphoma, Hodgkin lymphoma, and other types of lymphoma. This method has the potential to significantly change the way of ML diagnosis and followed up in daily practice, and its development is a great deal of attention.

Treatment outcomes of multiple myeloma (MM) have dramatically improved in the past 20 years. The IFM/DFCI group reported that triplet induction (bortezomib, lenalidomide, and dexamethasone), followed by up-front high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) and maintenance therapy, demonstrated a median progression-free survival (PFS) of 50 months. Therefore, up-front HDM/ASCT is considered standard care even in the era of novel agents. Daratumumab, lenalidomide, and dexamethasone have also been reported to prolong PFS for newly diagnosed transplant-ineligible MM. Quadruplet induction, including anti-CD38 antibody, will be approved even for transplant-eligible MM soon. Conversely, the success of chimeric antigen receptor T-cell therapy revealed that cellular immunotherapy may play an important role in treating MM. This review discussed the current standard of care and future perspectives for transplant-eligible MM.

The use of novel agents has improved the outcomes of patients with multiple myeloma. However, almost all patients eventually relapsed, became resistant to available treatments, and, thus, required further therapy. To improve the outcomes of relapsed and/or refractory, the best efficacy in each line of treatment should be achieved. Currently, the prognosis of patients who became refractory to triple-class agents including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies is extremely poor. Moreover, the best treatment regimen for these patients remains unclear. In Japan, the use of B-cell maturation antigen-targeting chimeric antigen receptor T-cell therapy for this patient group was approved. Furthermore, bispecific T-cell engagers and B-cell maturation-targeting antibody-drug conjugate are currently developed. Since it is challenging to identify the optimal sequences, it is important to apply each treatment individually based on clinical trial results. In the educational session, the framework to choose the most optimal treatment based on evidence of relapsed multiple myeloma therapies in each treatment line will be discussed.

Multiple myeloma (MM) is a hematological malignancy characterized by aberrant clonal plasma cells in the bone marrow. Despite significant advances in the treatment of MM, infection remains a main cause of death. MM patients have an increased risk of infection compared to their healthy counterparts due to several factors related to underlying disease, advanced age, comorbidities, and MM treatment. MM patients are at high risk of infection during the first 3 months after diagnosis and during relapse. Anti-myeloma drugs frequently result in severe immunosuppression and increased risk of infection. Proteasome inhibitors deplete T cells, lenalidomide and pomalidomide induce neutropenia, and CD38 antibodies reduce B cell function. To prevent infection in MM patients, we should take appropriate action by medical prophylaxis and vaccination.

Because of innovative therapeutic agents such as proteasome inhibitors, immunomodulatory medicines, and antibody medications, the prognosis of multiple myeloma (MM) has considerably improved in recent years. However, the prognosis for MM patients with treatment resistance and extramedullary illness remains poor. The interaction between MM cells and their surrounding cells in the bone marrow microenvironment is critical for medication resistance development. Many issues cannot be explained by liquid factors, such as cytokines and chemokines. Extracellular vesicles (EVs) have gained interest due to their role in the advancement of several forms of cancers. In this article, we primarily summarize MM drug resistance and examine the most recent articles on small-EVs (particularly exosomes) that contribute to MM drug resistance acquisition.

With the development of immune checkpoint inhibitors in cancer therapy, tumor microenvironments have attracted the attention of many researchers as a critical compartment of immune therapies. Immune suppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages play important roles in regulating anti-tumor immunity in the bone marrow microenvironment in multiple myeloma, in addition to decreased immunogenicity of tumor cells and increased expression of immune checkpoint molecules. These cells are activated by numerous chemicals released by tumor cells or their surroundings, and they suppress dendritic, tumor-specific cytotoxic T, NK, and NKT cells. Multiple myeloma cells use immunological suppressive effects to escape the patients’ immune surveillance system. In the future, we hope a better understanding of these immune suppressive cells leads to further improvements in immune therapies.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by increased platelet destruction and impaired platelet production from bone marrow megakaryocytes. The details of different platelet destruction mechanisms resulting from differences in autoantibodies and autoantibody-independent direct platelet destruction remain unclear although antiplatelet autoantibodies directed against platelet glycoproteins, such as GPIIb/IIIa and GPIb, play a central role in ITP pathogenesis. ITP is diagnosed by excluding other causes of thrombocytopenia due to the lack of standard tests or biomarkers for its confirmation. Plasma thrombopoietin level measurement and reticulated platelet ratio are useful in distinguishing the cause of thrombocytopenia and will be included in the new “Diagnostic reference guide of adult immune thrombocytopenia.” Currently, the treatment of refractory chronic ITP is mainly based on thrombopoietin receptor agonists, but ITP drugs with novel mechanisms of action are actively developed. New therapeutic agents are expected to be selected based on an accurate diagnosis and tailored to the pathophysiology of each case in ITP treatment.

Autoimmune coagulation factor deficiency (AiCFD) is an acquired bleeding disorder caused by immunoglobulins (autoantibodies) that target a single coagulation factor. Most of these autoantibodies are polyclones and primarily neutralizing antibodies (inhibitors) that inhibit the function of coagulation factors; however, non-neutralizing autoantibodies that enhance clearance are also present. AiCFD has been reported in nearly all coagulation factors and von Willebrand factor, and its representative disease is acquired hemophilia A, which is caused by autoantibodies against coagulation factor VIII. The treatment for AiCFD consists of hemostatic therapy according to the bleeding symptoms and immunosuppressive therapy to eradicate autoantibodies. Hemostatic treatment varies depending on the deficient coagulation factor, and coagulation factor replacement therapy, platelet or fresh frozen plasma transfusions, and bypassing agents are provided. Although AiCFD is a rare disease, raising awareness of this disease is necessary because general physicians may also encounter it.

Thrombotic thrombocytopenic purpura (TTP) is a poor prognosis disease caused by platelet thrombi produced in the microvessels throughout the body. The thrombus is mainly composed of von Willebrand factor (VWF) and platelets. Acquired TTP is an autoimmune disease wherein autoantibodies against ADAMTS13, a VWF-cleaving enzyme, are produced and ADAMTS13 activity is markedly decreased. Plasma exchange using fresh-frozen plasma as a replacement fluid effective against acquired TTP was reported in 1991. Since then, plasma exchange and corticosteroids have been the standard of care in Japan. Caplacizumab, which is a monoclonal antibody against the VWF A1 domain, finally became available for use in 2022, and the number of cases is still increasing in Japan. A clinical trial of recombinant ADAMTS13 product is being conducted for congenital TTP, and an era is expected to come in the future when plasma exchange will no longer be necessary.

The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional de novo PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.

Hematologic malignancies, particularly acute myeloid leukemia, are associated with thrombocytopenia as well as hyperfibrinolytic disseminated intravascular coagulation, which increases the risk of death due to bleeding. Conversely, thromboembolism is known to complicate certain proportions of patients and lead to a poor prognosis; however, prophylaxis and treatment with anticoagulants received little attention. This article discusses the risk factors for thromboembolism in hematologic malignancies, such as acute leukemia, malignant lymphoma, and multiple myeloma, as well as thromboembolism prevention and treatment. Meta-analyses have revealed that second- and third-generation BCR-ABL tyrosine kinase inhibitors increase the risk of cardiovascular events in patients with chronic myeloid leukemia, and this article discusses strategies to prevent these events, which are regarded as a major clinical issue.

The treatment outcomes for adult Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) have improved with the introduction of pediatric protocols. On assessing long-term survivors of chemotherapy who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), it was found that these patients had good performance status and few complications. Therefore, in the first complete remission (1CR) of ALL, allo-HSCT is indicated for patients in whom the results of chemotherapy are predicted to be poor. In adolescent and young adult (AYA) patients with ALL, allo-HSCT is recommended in the 1CR if end of consolidation measurable residual disease (MRD) is positive. In adults with ALL (non-AYA patients), if end of induction MRD is negative, chemotherapy should be continued and allo-HSCT is not recommended. In the future, it is necessary to perform a comprehensive evaluation of individual patients that considers MRD, as well as the initial tumor burden and biological features of leukemic cells.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) grafts have expanded from related human leukocyte antigens (HLA)-matched donors to unrelated HLA-matched donors and umbilical cord blood. Either one of these grafts is now available for almost all patients who need allo-HSCT. Furthermore, an allo-HSCT from an HLA one haplo-mismatched donor can be safely performed with cyclophosphamide administration after transplantation. Graft-versus-host disease (GVHD) and graft-versus-leukemia effects are inextricably linked in allo-HSCT, and a transplant with more GVHD-associated complications is not necessarily a worse transplant as a graft selection indicator. Transplants with severe GVHD have fewer relapses, which offset the negative effects. This study presents data to guide graft selection by comparing transplant outcomes from different donor sources. The current position of post-transplant cyclophosphamide haplo from HLA-one haplo mismatched donor is also discussed based on data presented to date.

The use of human leukocyte antigen (HLA)-incompatible transplantations, in addition to cord blood transplantation, is rapidly increasing due to the development and refinement of graft-versus-host disease prophylactic treatment with post-transplant cyclophosphamide or anti-thymocyte globulin. However, caution must be observed in interpretating the significance of HLA incompatibility because each transplant source differs, which affect the association between HLA compatibility and transplant outcome. In addition, the loci that should be evaluated, the level of matching (antigen/allele), the direction of incompatibility (graft-versus-host or host-versus-graft), and the combination of incompatible HLA alleles must be understood. Notably, the significance of HLA incompatibility changes with the development and improvement of GVHD prophylactic treatment. Factors that should be prioritized in donor selection should be evaluated in the future. This article outlines the significance of HLA incompatibility in each transplant source.

Adenovirus disease can cause disseminated disease or lethal organ damage in patients undergoing hematopoietic cell transplantation (HCT). Renourinary infection is the most common in Japan. The 1-year cumulative incidences of adenovirus disease in children and adults were 0.15% and 0.49%, respectively, after autologous HCT, and 1.52% and 2.99%, respectively, after allogeneic HCT. The annual incidence remained above 100 cases. Viremia or disseminated disease after autologous and allogeneic HCT occurs in 6% and 19%, respectively, in patients with adenovirus disease. Age ≥50 years and lymphoma are associated with adenovirus disease after autologous HCT. Patient age ≥50 years, male patients, adult T-cell leukemia/lymphoma, lymphoma, HCT-specific comorbidity index ≥3, HLA-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, grades II-IV acute graft-versus-host disease (GVHD), and extensive chronic GVHD are associated with adenovirus disease after allogeneic HCT. No regulatory authority has approved an antiviral agent for treating adenovirus disease after HCT. More than half of the patients received only supportive care in Japan. The increased risk of mortality following developing adenovirus disease, even with a single-site infection, after both autologous and allogeneic HCT suggests an urgent unmet need for the development of safe and effective drugs.

Candida species are the second most frequent fungal pathogen of invasive fungal disease after hematopoietic cell transplantation (HCT) following Aspergillus species. Prolonged severe neutropenia and mucocutaneous barrier impairment resulting from the conditioning regimen or central venous catheter placement are major risk factors for invasive candidiasis in the early phase after HCT. Graft-versus-host disease (GVHD) and corticosteroid use affect the development of invasive candidiasis in the post-engraftment phase after allogeneic HCT. Breakthrough candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate although antifungal prophylaxis that covers Candida species is a standard of care in HCT. A multidisciplinary approach is required to treat patients with candidiasis, involving multiple healthcare professionals from different fields, such as transplant physicians, infectious disease specialists, ophthalmologists, nurses, pharmacologists, and laboratory technicians. This review focuses on the epidemiology, risk factors, antifungal prophylaxis, diagnosis, and treatment of invasive candidiasis after HCT. Additionally, the association between Candida species and GVHD in allogeneic HCT is discussed.

Chimeric antigen receptor transgenic T cell (CAR-T) therapy targeting the CD19 antigen was approved for relapsed/refractory acute lymphocytic leukemia in the United States in 2017 and in Japan in 2019. Despite the excellent efficacy of CAR-T therapy, the relapse rate is about 50%. To reduce this rate, it will be important to examine predictive factors for relapse and which patients should receive hematopoietic cell transplantation. In addition, as the high cost of CAR-T cells has become a financial toxicity that threatens the health insurance system in many countries, development of less expensive CAR-T products using non-viral vectors is also underway.

Recent advances with chimeric antigen receptor T-cell (CAR-T) therapy are changing the current landscape of poor-prognosis relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Pivotal trials leading to the FDA approval of three CD19 CAR-T cells, namely, Yescarta^®, Kymriah^®, and Breyanzi^®, demonstrated complete response rates of 40-60%, with a significant subset of patients achieving long-term disease remission, and real-world studies confirm these data. In Japan, CAR-T therapy was approved for R/R DLBCL in 2019 and for R/R follicular lymphoma in 2022. However, guidelines are not clear on which CAR-T agents should be indicated for which patients and at which timing, and currently, institutions decide and operate according to their criteria. To optimize CAR-T therapy under the best conditions, the treatment strategy must be decided with the referring institution in terms of T-cell fitness and tumor volume. Therefore, institutional collaboration to monitor long-term adverse events after CAR-T therapy is important.

Immunotherapies such as immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy are emerging as new treatments for relapsed and/or refractory hematological malignancies. CAR T-cell therapy has attracted attention as a potentially curative treatment for patients incurable by chemotherapy. However, appropriate management is required to avoid serious complications specific to CAR T-cell therapy, such as cytokine release syndrome (CRS), neurotoxicity (ICANS), hypogammaglobulinemia and prolonged cytopenia, as well as post-treatment infections caused by suppressed immune function.

The pathogenesis of inflammatory bowel disease (IBD) may include immune dysregulation. About 20% of inborn errors of immunity (IEIs) are related to IBD, and more than 60 IEIs are known to present IBD. Monogenic IBDs include those that are refractory to traditional treatment and can be cured by allogeneic hematopoietic cell transplantation (HCT), making early diagnosis and treatment essential. In this report, we present a series of monogenic IBDs that are relatively frequently found in Japan, such as interleukin (IL)-10/IL-10 receptor deficiency, chronic granulomatous disease, XIAP deficiency, immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, NEMO deficiency, and A20 haploinsufficiency and will describe the features of each IEI and the indications for HCT.

Central nervous system relapse prevention through intrathecal and intravenous methotrexate (MTX) administration is a crucial aspect of treatment in acute lymphoblastic leukemia. However, neurotoxicity-induced leukoencephalopathy is a significant concern. Neurological symptoms associated with MTX can appear as subacute leukoencephalopathies, which manifest as a stroke-like syndrome, consisting of paralysis, seizures, consciousness disturbances, and dysarthria. These symptoms persist for a few days, presenting with fluctuating severity and location. Characteristic findings in bilateral white matter are observed on diffusion-weighted magnetic resonance imaging. Symptoms typically improve naturally within a few days although supportive therapy remains the primary treatment. The efficacy of drug administration is not established. Therapy should be continued if clinical improvements are achieved following the initial neurological event regarding MTX re-administrations after symptom improvement. However, careful consideration is required for each patient because symptoms may reoccur or persist and long-term effects remained unclear.

Children with acute lymphoblastic leukemia (ALL) now have a five-year survival rate of 80-90% thanks to advances in risk-directed treatment and supportive care. Further, as the number of childhood ALL survivors grows, much emphasis should be directed to their after-treatment life quality, which largely depends on later complications. By removing cranial radiation, the likelihood of severe late problems such as second malignant neoplasm and endocrine disease was reduced. The risk for neurocognitive dysfunction was also reduced. However, among ALL survivors who have only received chemotherapy, there is still a risk of neurocognitive impairment. Although their overall cognitive abilities have been intact, individuals exhibit domain-specific neurocognitive impairment, which needs a thorough evaluation. Therefore, it now became more challenging to elucidate their neurocognitive dysfunction. The neurocognitive function of ALL survivors treated just with chemotherapy will be reviewed.

Recently, utilization of genetic data has become routine in medicine. It is important to consider the use of genetic information in different situations based on the principles of medical ethics. Furthermore, it is necessary to understand the features of genetic information and to adhere to various guidelines in research and clinical practices. In genomic medicine, which will become the mainstream of medicine using comprehensive genetic information, it will be crucial to fully comprehend the suitable handling of secondary results, and to prioritize benefits to the patients. Moreover, developing a system that incorporates appropriate legislation to ensure nondiscrimination of patients on the basis of their genetic information and to provide a forum for ethical issues that will arise in the future is essential.