Although vaccination against coronavirus infection 2019 (COVID-19) has been found to be effective, reports of adverse reactions continue to appear. We report the development of severe aplastic anemia post BTN162b2 mRNA COVID-19 vaccination in patient undergoing dialysis. The pathogenesis and risk factors for post-vaccination aplastic anemia remain unclear. We must remain vigilant to aplastic anemia following COVID-19 vaccination. The risk of aplastic anemia should be identified, and management methods should be established.

The anti-C5 antibody eculizumab was approved in 2007 as the first anti-complement agent for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). While eculizumab’s indication has been expanded to include other diseases, the development of new anti-complement agents has been aggressively pursued for various diseases. In PNH, the anti-C5 recycling antibody ravulizumab, which is an improved version of eculizumab, has been developed, with an extended dosing interval of 2 to 8 weeks, vastly improving convenience. The treatment of PNH with terminal complement inhibitors such as eculizumab and ravulizumab presents a new challenge—extravascular hemolysis. To address this issue, the proximal complement inhibitor, a C3 inhibitor called pegcetacoplan, was approved in the United States of America. Furthermore, the amplification loop inhibitors—a factor B inhibitor iptacopan, and a factor D inhibitor danicopan—are being developed. Recently, the anti-C1s antibody sutimlimab was approved for the treatment of cold agglutinin disease, a type of autoimmune hemolytic anemia. This article discusses novel anti-complement therapies for hemolytic anemia.

Aplastic anemia (AA) is a non-neoplastic bone marrow failure syndrome caused by the destruction of hematopoietic stem and progenitor cells by the immune system. However, in some cases of AA, a small number of specific clones with gene mutations are observed without clinical manifestations. Cases with mutated PIG-A, BCOR/BCORL1, or HLA class I allele clones respond better to immunosuppressive therapies (ISTs). Cases with MDS-related clones, such as DNMT3A or ASXL1 mutations, are at a higher risk for secondary MDS. In this review, I will focus on the clonal hematopoiesis (CH) in AA and discuss its clinical significance, including its impact on disease boundaries and transition. I will also discuss the pathophysiology and diagnosis of hypoplastic MDS, a type of MDS that responds to ISTs.

Large-scale in vitro red blood cell (RBC) production has been attempted in recent years. Potential cell sources for RBC production include hematopoietic stem/progenitor cells, pluripotent stem cells, and immortalized erythroid progenitor cell lines, which can induce enucleated RBCs with characteristics such as oxygen-carrying capacity and deformability. A phase I clinical study of cultured RBCs produced from hematopoietic stem/progenitor cells has revealed a similar in vivo half-life between cultured and native RBCs. Thus, the application of cultured RBCs in blood transfusion is gradually advancing. However, a single transfusion requires a large number of cells, unlike other cell therapies. Therefore, developing a method to mass-produce RBCs from a small culture volume at a low cost is important in the future. This review summarizes the current status and prospects concerning in vitro RBC production using each cell source, which can improve future transfusion medicine.

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.

Adult T-cell leukemia/lymphoma (ATL) is an exceedingly refractory peripheral T-cell lymphoma. Despite the approval of a few new drugs for managing patients with newly diagnosed or relapsed/refractory ATL in recent years, the prognosis has yet to be substantially ameliorated. This study focuses on recent topics on the development of innovative therapies and the identification of prognostic indicators, considering the recent elucidation of the pathogenesisof ATL. Specifically, this study also delineates the advancements in developing novel EZH1/2 inhibitors and comprehensive genetic analysis; the molecular pathogenesis determined through comprehensive gene knockdown and knockout techniques, with its potential as a therapeutic target; the latest discoveries from the analysis of super-enhancer regions; and the prognostic factors extracted from comprehensive genetic analysis.

Classic Hodgkin lymphoma (cHL) is one of the common subtypes of malignant lymphoma in Western countries. Although patients with HL showed unsatisfactory results in the 1960s, the clinical development in radiotherapy and chemotherapy based on several clinical trials over the last 50 years has made cHL a curable disease with a favorable outcome. As a result, late-onset treatment-related toxicities such as second primary malignancies and cardiac events are thought to be a significant issue especially in early-stage patients. To minimize the toxic effects while maximizing the antitumor efficacy, several clinical trials to evaluate response-adapted strategies using interim PET scans and novel agents, such as brentuximab vedotin (BV) and/or immune checkpoint inhibitor (ICI) are currently underway. In this review, the author summarizes currently available data on PET-adapted and BV and/or ICI-containing therapies for untreated cHL, and discusses their future prospects in cHL treatment.

HLA-haploidentical stem cell transplantations using posttransplant cyclophosphamide (PTCy-haplo) rapidly increased worldwide. In Japan, the number of HLA-haploidentical stem cell transplantation cases exceeded related HLA-matched transplants in 2020. Recent retrospective studies using Japanese registry data have reported comparable transplantation outcomes between PTCy-haplo and HLA-matched unrelated and cord blood transplantations. PTCy-haplo was initially developed in the bone marrow transplantation setting after non-myeloablative conditioning but has recently become widely used in peripheral blood stem cell transplantation and myeloablative conditioning. Peripheral blood stem cell transplantation increases the occurrence of graft-versus-host disease but may have more improved transplant outcomes compared with bone marrow transplantation. Other factors, such as the number of infused cluster of differentiation 34-positive cells, donor age, HLA class II mismatch, HLA-B leader, and reduced PTCy dosage, may also contribute to the outcome of PTCy-haplo transplantations. Furthermore, PTCy has been reportedly effective in related/unrelated HLA-matched transplantation and HLA-mismatched unrelated transplantations. A prospective phase II trial using PTCy in patients who underwent HLA-matched and 1-2 allele-mismatched transplantation is ongoing in Japan. Patient enrollment has already been completed, and the results will be revealed soon. Using PTCy to sufficiently reduce the occurrence of graft-versus-host disease will make performing allogeneic transplants with a higher safety level possible.

Several novel agents (e.g., molecularly targeted drug, bispecific antibody, antibody-drug conjugate, chimeric antigen receptor T-cell therapy) have successively emerged in clinical practice and are occasionally used in allogeneic hematopoietic cell transplantation (allo-HCT) settings. These drugs are expected to reduce pretransplant tumors, lower the risk of relapse with posttransplant maintenance therapy, and consequently improve transplant outcomes. Additionally, some molecularly targeted drugs could be adapted to treat steroid-refractory acute and/or chronic graft-versus-host disease (GVHD), which remained the leading cause of nonrelapse mortality after allo-HCT. However, these agents develop an excessive immune reaction, including GVHD, or presented an increased risk of sinusoidal obstruction syndrome (SOS)/veno-occlusive disease (VOD) as their “off-target” effects. Thus, this review aimed to summarize the risk assessment and management of post-posttransplant complications, focusing on GVHD and SOS/VOD, in the era of molecularly targeted therapy. Moreover, recent advances in GVHD or SOS/VOD prophylaxis and treatment using novel agents/devices are also discussed.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.

Acute myeloid leukemia (AML) is one of the most common hematologic malignancies derived from self-renewing and highly propagating leukemic stem cells (LSCs). We have previously identified T-cell immunoglobulin mucin-3 (TIM-3) as an AML LSC-specific surface molecule by comparing the gene expression profiles of LSCs and hematopoietic stem cells (HSCs). TIM-3 expression clearly discriminates LSCs from HSCs within the CD34⁺CD38^- stem cell fraction. Furthermore, AML cells secrete galectin-9 (Gal-9, a TIM-3 ligand) in an autocrine manner, resulting in constitutive TIM-3 signaling, which maintains LSC self-renewal capacity through β-catenin accumulation. In this study, we investigated the LSC-specific mechanisms of TIM-3 signaling. We found that TIM-3 signaling drove the canonical Wnt pathway, which was independent of Wnt ligands, to maintain cancer stemness in LSCs. Gal-9 ligation activated the cytoplasmic Src homology 2 (SH2) binding domain of TIM-3 to recruit hematopoietic cell kinase (HCK), a Src family kinase that is highly expressed in LSCs. HCK phosphorylated p120-catenin to promote the formation of the LDL receptor-related protein 6 (LRP6) signalosome, hijacking the canonical Wnt pathway. This TIM-3/HCK/p120-catenin axis was employed principally in immature LSCs compared to TIM-3-expressing exhausted T-cells.