A 62-year-old man was referred to our hospital for leukocytosis with an increase (25.5%) of plasma cell-like cells in the peripheral blood. M-protein was not detected, and no deviation of the κ/λ ratio of free light chain was observed. Bone marrow biopsy showed increased plasma cell-like cell counts; however, immunohistochemical staining was positive only for CD138, and negative for both κ and λ chains. Non-secretory multiple myeloma (MM) was diagnosed based on morphological findings, although differential diagnosis from lymphoplasmacytic lymphoma was difficult. After remission induction treatment, the patient underwent autologous peripheral blood stem cell transplantation and relapsed one year later. The disease was refractory to various chemotherapies. To support the diagnosis, next-generation sequencing was performed on a bone marrow sample obtained at relapse. The analysis showed multiple mutations in driver genes (IRF4, TRAF2 and TRAF3) and 1q gain, which are characteristic of MM. These mutations are associated with a poor prognosis, which is consistent with the clinical course of the present case. This case highlights the potential utility of next-generation sequencing in diagnosis and therapeutic decision-making for MM.

A 57-year-old man presented with neutropenia, circulating blast-like cells, anemia, and fever. Bone marrow examination revealed that 62.8% of nucleated cells were small lymphoid blast-like cells, whose surface markers and immunophenotype were consistent with mantle cell lymphoma (MCL). Because no nodal involvement was detected at the initial visit, leukemic non-nodal MCL (nnMCL) was initially considered. However, ¹⁸F-fluorodeoxyglucose positron emission tomography demonstrated diffuse bone uptake and new nodal lesions that had not been apparent at presentation. The presence of SOX11 positivity, a high Ki-67 index, a complex karyotype, and the rapidly progressive clinical course were atypical for nnMCL and instead resembled conventional MCL. Although differentiation was challenging, a treatment protocol for aggressive conventional MCL was followed. The patient received bendamustine and rituximab, followed by CHASE-R (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab), and then high-dose chemotherapy with autologous peripheral blood stem cell transplantation. This case was considered borderline between conventional MCL and nnMCL. Although a definitive classification was not made, the treatment strategy was determined based on the pathological features, chromosomal abnormalities, and clinical behavior, following the approach typically used for aggressive conventional MCL.

A 26-year-old man presented in 2002 with petechiae, hemolytic anemia, and thrombocytopenia, raising suspicion for thrombotic thrombocytopenic purpura (TTP). His condition improved with plasma exchange, fresh frozen plasma (FFP) transfusion, and prednisolone. He was diagnosed with thrombotic microangiopathy and subsequently experienced multiple relapses, all treated successfully with FFP transfusion and prednisolone. During the sixth relapse in December 2018, a marked reduction in ADAMTS13 activity was detected, confirming the diagnosis of TTP. At the ninth relapse in June 2022, ADAMTS13 inhibitor testing was negative, and congenital TTP was considered as a differential diagnosis. However, repeated testing at another institution confirmed the presence of ADAMTS13 inhibitor, leading to the final diagnosis of immune-mediated TTP. After rituximab therapy, ADAMTS13 inhibitor became undetectable, and the patient has remained in remission for three years. This clinical course is atypical for immune-mediated TTP, as recurrent relapses were successfully managed with FFP transfusion and short-term prednisolone. This case provides important insights into the diagnosis and management of immune-mediated TTP.

A 59-year-old woman was diagnosed with symptomatic Bence Jones protein, lambda (λ) type, associated with multiple myeloma (BJP-λ MM). Considering her renal dysfunction, she initially received bortezomib and dexamethasone. After renal function improved, she received one cycle of bortezomib, lenalidomide, and dexamethasone (BLD) therapy and achieved stringent complete response. She presented with general fatigue and jaundice before the second cycle of BLD. Laboratory testing revealed: total bilirubin, 4.8 mg/dl; indirect bilirubin, 4.1 mg/dl; lactate dehydrogenase, 978 U/l; hemoglobin, 7.4 g/dl; haptoglobin, <10 mg/dl; platelet count, 23,000/µl; and creatinine, 0.96 mg/dl. A hemogram revealed 1% schistocytes. ADAMTS13 activity was undetectable and the ADAMTS13 inhibitor level was 1.8 Bethesda units. A diagnosis of acquired thrombotic thrombocytopenic purpura (aTTP) was made, and treatment was initiated with prednisolone and rituximab. Plasma exchange was not performed because thrombocytopenia did not progress. The first dose of rituximab restored platelet count, and ADAMTS13 inhibitor became undetectable. The clinical course in this case was consistent with drug-induced aTTP.

A 30-year-old man underwent his third allogeneic hematopoietic stem cell transplantation for relapsed B-lymphoblastic leukemia. Watery diarrhea appeared on post-transplant day17, and colonoscopy on day21 revealed acute graft-versus-host disease (GVHD). The disease was refractory to steroid therapy, and hepatocellular injury progressed on day26. The patient died of multiple organ failure on day29. Autopsy demonstrated adenovirus (ADV) infection in the liver and colon, and the plasma ADV DNA load immediately before death was 3.16×10⁹ copies/ml, consistent with disseminated ADV infection. Re-evaluation of the colonic biopsy on day21 revealed not only histological features consistent with GVHD but also positive staining for ADV antigens in the intestinal epithelium. At autopsy, ADV had spread from the intestinal epithelium to the vascular endothelium. These findings suggest that immunohistochemistry in high-risk post-transplant patients may enable earlier detection of ADV infection.

Diamond-Blackfan anemia (DBA) is a classic example of an inherited bone marrow failure syndrome in the category of erythrocyte diseases. DBA mainly occurs due to ribosome dysfunction. In the peripheral blood, reticulocytes are reduced, and in the bone marrow, only erythroid cells are markedly reduced. DBA primarily develops in infants and is often caused by heterozygous allele mutations in ribosomal protein genes. Activation of p53, translation dysfunction, inflammatory signals, and imbalance of hemoglobin/heme synthesis have been shown to contribute to impaired erythropoiesis and decreased red blood cell production. Patients with DBA are primarily treated with steroids; however, half of these patients eventually become unresponsive to long-term steroid treatment and become transfusion-dependent. Hematopoietic cell transplantation is currently the only curative treatment. Recent advances in gene therapy using lentiviral vectors have shown potential in promoting normal hematopoiesis in the treatment of RPS19-deficient DBA.

Iron excretion from the body is minimal due to lack of an active excretion mechanism, and absorption is limited as well, making iron metabolism a semi-closed system. However, loss of iron-containing red blood cells through persistent gastrointestinal or gynecological bleeding depletes iron stores. If the bleeding progresses further, iron stores become insufficient for erythropoiesis, leading to iron deficiency anemia (IDA). IDA accounts for approximately 70% of all anemia cases. Furthermore, it is increasingly recognized that iron deficiency causes various symptoms even in the absence of anemia. Recent research has also revealed that iron-related tests are being underutilized in diagnosis and treatment. In recent years, ferric citrate hydrate has been added as a new oral iron preparation, along with ferric carboxymaltose and ferric derisomaltose as new intravenous options. Multiple clinical trials conducted in Japan have expanded the body of evidence. Alongside established agents, iron preparations are contributing to IDA treatment across a broad range of clinical areas.

Acquired pure red cell aplasia (PRCA) is a bone marrow failure syndrome characterized by anemia, reticulocytopenia, and erythroid hypoplasia in the marrow that mostly affects older adults. Underlying T-cell dysregulation, often associated with clonality and/or STAT3 mutation among CD8+T-cells, provides a rationale for directed immunosuppressive therapies such as cyclosporin in the three most frequent disease subtypes: thymoma-associated PRCA, large granular lymphocytic leukemia-associated PRCA, and idiopathic PRCA. Some retrospective studies have demonstrated the significance of maintenance therapy for avoiding blood transfusion dependency, which is associated with poorer prognosis in patients with PRCA. While treatment options are currently scarce for patients with relapsed or refractory disease after CsA, results of a prospective randomized controlled clinical trial of sirolimus are expected in the near future.

This review outlines the clinical significance of comprehensive genomic profiling (CGP) in patients with hematopoietic failure, including severe unexplained cytopenia. Since March 2025, Japanese National Health Insurance has covered CGP for hematologic malignancies and related disorders, facilitating a genome-based precision medicine approach that complements conventional clinical approaches, including morphologic and cytogenetic analyses. In bone marrow failure phenotypes, CGP supports differentiation of aplastic anemia from myelodysplastic syndromes and related diseases by evaluating genetic alterations. In addition to diagnosis, CGP contributes to prognostic stratification and evaluation of inherited bone marrow failure syndromes, which may present with minimal extra-hematologic features. However, accurate interpretation of CGP results requires not only understanding the genetic pathology of each disease, but also awareness of the characteristics of the CGP and the pitfalls specific to hematopoietic diseases (such as clonal hematopoiesis) and discussions with an expert panel. This review aims to facilitate the interpretation of CGP results to optimize clinical management for patients with hematopoietic failure.

Platelet function is regulated by numerous molecules, and congenital abnormalities of these molecules result in a variety of congenital platelet function disorders. Among these, Glanzmann thrombasthenia (GT), caused by a congenital deficiency or molecular abnormality in GPIIb-IIIa (αIIbβ3), and Bernard-Soulier syndrome (BSS), caused by a congenital deficiency or molecular abnormality in the GPIb-IX-V complex, are representative disorders that manifest as severe bleeding tendency from infancy. GT and BSS are diagnosed mainly by flow cytometry of membrane glycoproteins in addition to conventional light transmission aggregometry. Platelet transfusions are indicated for bleeding refractory to standard hemostatic measures, and recombinant factor VIIa (rFVIIa) has been shown to be effective in GT. rFVIIa has conventionally been used in GT patients refractory to platelet transfusion due to alloantibody production, but is now available in Japan regardless of alloantibody status or platelet transfusion refractoriness. rFVIIa should be considered especially in patients at risk of alloantibody production due to platelet transfusion.

Antiphospholipid syndrome (APS) is characterized by recurrent arteriovenous thrombosis and pregnancy complications associated with persistent antiphospholipid antibodies (aPL). The 2023 ACR/EULAR classification criteria introduced a scoring system incorporating microvascular disease, cardiac valve disease, and thrombocytopenia. However, these criteria are designed for research classification rather than clinical diagnosis. In laboratory testing, the expanding use of automated immunoassays necessitates inter-assay standardization. Risk stratification integrates quantitative aPL assessment, including triple positivity, aPL score, and Global APS Score (GAPSS), with conventional cardiovascular risk factors. For thrombotic APS, direct oral anticoagulants should be avoided in high-risk patients. Disease activity assessment has advanced with the development of EAPSDAS and the monocyte-to-HDL cholesterol ratio. These advances are expected to facilitate a paradigm shift toward precision medicine in APS management.

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by endothelial injury resulting from dysregulated activation of the alternative complement pathway. Clinical outcomes have markedly improved since the anti-complement agent eculizumab, an anti-C5 monoclonal antibody, became available in 2013. However, no established diagnostic method directly assesses complement activation for definitive diagnosis. In practice, diagnosis relies on the evaluation of pathogenic variants in complement-related genes as predisposing factors and on the exclusion of other diseases that can cause TMA. Consequently, distinguishing aHUS from secondary TMA can sometimes be clinically challenging. In particular, secondary TMA associated with hypertensive emergencies or pregnancy may overlap with aHUS, requiring careful diagnostic consideration. In recent years, several novel anti-complement agents have been developed. In addition to therapies targeting the terminal complement pathway downstream of C5, agents that act on the proximal complement cascade are also under development, and further clinical evidence on these strategies is awaited.

Hyperfibrinolysis-related bleeding is well recognized in conditions such as the acute phase of trauma, disseminated intravascular coagulation with hyperfibrinolysis, and acute promyelocytic leukemia. In contrast, whether primary hyperfibrinolysis can directly cause bleeding in the absence of an underlying disorder has not been sufficiently investigated, largely due to the lack of an established disease concept and the limited availability of reliable functional assays. Congenital deficiencies of individual fibrinolysis inhibitors—such as plasminogen activator inhibitor-1 (PAI-1) deficiency, α₂-plasmin inhibitor (α₂-PI) deficiency, and thrombomodulin (TM) disorders leading to impaired activation of thrombin-activatable fibrinolysis inhibitor (TAFI)—are extremely rare but are known to result in severe bleeding manifestations. Based on functional assessment assays for these conditions, we have proposed a novel disease entity, “bleeding disorders caused by hyperfibrinolysis,” and established diagnostic criteria. This entity was designated in Japan as an intractable disease (No. 347), effective April 2025. This review outlines the clinical significance and diagnostic framework of this disorder and highlights the potential contribution of fibrinolytic dysfunction to bleeding disorder of unknown cause (BDUC).

Treatment of relapsed or refractory multiple myeloma (MM) has advanced substantially with the introduction of chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibody therapy targeting B-cell maturation antigen (BCMA). CAR-T therapy induces high complete response rates and deep minimal residual disease negativity after a single infusion. In a subset of patients, remission persists beyond completion of therapy, making treatment-free intervals an achievable therapeutic objective in MM. In contrast, BCMA-directed bispecific antibody therapy can be administered without manufacturing delay and provides rapid and durable responses. It also reduces the cumulative treatment burden by enabling outpatient management and extended dosing intervals. Despite these advances, clinically relevant challenges remain. Sustained T-cell activation may result in hypogammaglobulinemia and increased susceptibility to infections, while antigen loss and T-cell exhaustion represent key mechanisms of relapse. Careful monitoring of immune reconstitution and appropriate infection prophylaxis are therefore essential components of MM management. Future therapeutic strategies should emphasize optimal treatment sequencing, evaluation of fixed-duration approaches, and development of multi-antigen targeting platforms to overcome resistance. Achieving durable remission while preserving functional capacity and improving quality of life has become an important goal in the treatment of MM.

The prognosis of multiple myeloma (MM) has improved dramatically over the past two decades with the introduction of proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and, more recently, immune-based therapies such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies. Quadruplet regimens are now used in the frontline setting, enabling deeper responses and long-term survival, and even making functional cure a realistic goal for some patients. Nevertheless, MM remains a relapsing disease, and outcomes of triple-class-exposed (TCE) patients are still poor. While novel immunotherapies have significantly improved outcomes in relapsed or refractory MM, their extremely high costs may threaten the sustainability of healthcare systems, particularly in countries with universal health coverage, such as Japan. Cost-effectiveness analysis (CEA) using quality-adjusted life years (QALYs) provides a quantitative framework to evaluate the value of high-cost therapies. In this review, we summarize recent advances in immunotherapy for MM and discuss the cost-effectiveness of these therapies based on clinical trials, real-world data, and modeling studies. We also present our own analyses of daratumumab-based quadruplet induction and anti-BCMA CAR-T therapy. Finally, we discuss future strategies to balance innovation and sustainability, including patient selection, subgroup-based treatment optimization, and minimal residual disease-guided treatment discontinuation.