A 64-year-old man presented with abnormal imaging results on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), showing moderately increased FDG-uptake in the entire bone marrow. Blood tests revealed leukocytosis, thrombocytosis, and increased lactate dehydrogenase levels. Furthermore, the neutrophil alkaline phosphatase score decreased. Bone marrow examination revealed marked hypercellularity of myeloid and megakaryocytic lineages without an excess of blasts. Cytogenetic analysis of the bone marrow demonstrated Philadelphia chromosome, and fluorescence in situ hybridization analysis was positive for BCR-ABL1 fusion genes. Thus, the patient was diagnosed with chronic myeloid leukemia (CML) in the chronic phase and tyrosine kinase inhibitor therapy with 100 mg of dasatinib daily was initiated. Complete cytogenetic response and a major molecular response were achieved at 3 and 12 months post-treatment, respectively. FDG-uptake values of the bone marrow remarkably decreased along with the remission status of the disease. FDG-PET images at pre- and post-treatment of CML are rarely compared, so we report this case as an important reference.

Human T-cell leukemia virus type I (HTLV-1) infection and adult T-cell leukemia-lymphoma (ATL) have been shown to cause immunodeficiency. However, only a few cases have been reported on the development of Epstein-Barr virus positive-diffuse large B-cell lymphoma (EBV-DLBCL) in HTLV-1 carriers or in patients with ATL. Here we report a case of a female HTLV-1 carrier who developed cytomegalovirus (CMV) retinitis. During the CMV retinitis treatment, she developed a liver tumor. The diagnosis of composite ATL and EBV-DLBCL was made by tumor biopsy. The patient also suffered from pulmonary cryptococcosis and invasive pulmonary aspergillosis at the time of chemotherapy initiation. She had repeated CMV antigenemia and bacterial sepsis during the course of chemotherapy, and she died of bacterial sepsis. HTLV-1 carriers who are complicated with opportunistic infections should be carefully observed not only for ATL development but also for the development of EBV-DLBCL and associated infectious complications.

We present the case of a 39-year-old man with a primary diagnosis of mixed phenotype acute leukemia, T/myeloid not otherwise specified (T/M-MPAL). After achieving a complete remission (CR), he underwent allogeneic hematopoietic stem cell transplantation (HSCT). Subsequent evaluation of the cerebrospinal fluid suggested central nervous system graft versus host disease (GVHD); hence, prednisolone therapy was initiated. After 118 days on prednisolone, a routine follow-up thoracic and abdominal computed tomography (CT) revealed extensive pneumatosis in the wall of the colon. We diagnosed his condition as pneumatosis cystoides intestinalis (PCI). The patient was treated conservatively with high concentration oxygen. A CT scan performed 1 week later revealed that the pneumatosis had fully resolved; no relapse has been observed. Various etiologies of PCI have been reported previously. However, there are very few reports of PCI presenting in association with hematologic neoplasms or in response to allogeneic HSCT in adult patients.

We report the case of a patient with fulminant pneumococcal infection along with the presence of Howell-Jolly bodies (HJBs) and splenic hypoplasia at the onset. A 71-year-old man developed fever during outpatient chemotherapy for IgG-κ multiple myeloma and was diagnosed with septic shock due to invasive pneumococcal infection. HJBs were observed on peripheral blood smears at this visit. Computed tomography revealed marked hypoplasia of spleen, suggesting the presence of hyposplenic function. Antibacterial therapy was initiated and the pneumococcal infection was cured; however, there was no notable change in his splenic hypoplasia. Splenic hypoplasia can be associated with fatal infections; hence, care should be taken when it is found in the elderly and in patients with cancer and those receiving immunosuppressive treatment. Even today, when automated hematology analyzers have become common, not all patients with hematological diseases have peripheral blood smears checked with a normal optical microscope. This study suggests that HJBs may be useful for simple and rapid screening of splenic hypofunction. The importance of detecting HJBs in peripheral blood smears with a normal optical microscope should be re-recognized.

Gilteritinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown efficacy in patients with refractory or recurrent adult acute myeloid leukemia (AML) with FLT3 mutations. However, there are limited data for pediatric patients treated with this drug. Herein, we report the clinical courses of two children with FLT3-mutated recurrent AML who received gilteritinib. Case 1: An 11-year-old boy with secondary relapsed AML presented with an FLT3 internal tandem duplication (ITD) since the first recurrence. One week after gilteritinib initiation, blasts, which had comprised 90% of the white blood cells before treatment, almost disappeared from the peripheral blood without tumor lysis syndrome. The patient developed multiple adverse effects and died from the disease 2.5 months after gilteritinib initiation. Case 2: A 12-year-old girl diagnosed with AML was positive for FLT3 ITD. She received gilteritinib during her first relapse post-stem cell transplantation. After the drug was administered, the recipient cell counts increased, as determined by molecular tests (i.e., FISH), whereas microscopically, there was a complete response for 5 months with good performance status. Gilteritinib treatment in children with FLT3-mutated recurrent AML is feasible and effective. As a patient experienced several adverse effects with gilteritinib treatment, clinical trials are required to determine the appropriate pediatric dose of this medication.

An 18-year-old male patient who had been diagnosed with chronic granulomatous disease at 2 years old and suffering from repeated severe infections underwent human leukocyte antigen haploidentical bone marrow transplantation from his mother using reduced intensity conditioning. After engraftment, donor lymphocyte infusion was initiated to decrease donor chimerism on day 96. On day 120, acute graft-versus-host disease occurred; hence, steroid administration was initiated. On day 173, a generalized convulsion occurred; multiple abscesses were observed in the brain, lung, kidney, and prostate. Aspergillus siamensis of unknown pathogenic status was cultured in the abscess fluid from the brain, prostate, and kidney; accordingly, he was diagnosed with disseminated aspergillosis involving the brain, prostate, lungs, and kidney. Despite using a combination of various antifungal drugs, he died of multiple organ failure on day 239. Disseminated aspergillosis following the hematopoietic stem cell transplantation is a fatal complication. If infection symptoms are observed, the presence of any fungal antigens should be examined. Appropriate samples should be promptly collected, and adequate antifungal drugs should be administered based on the fungal species and drug sensitivity results.

For more than two decades, the leukemia stem cell (LSC) model has received considerable attention following the identification of rare engrafting cell subpopulations in patient-derived xenograft assays. LSCs are thought to induce leukemogenesis and recurrence and are considered excellent targets in the development of curative therapies. Experimental support for this model in human malignancy was first achieved for acute myeloid leukemia (AML). Subsequent studies of AML stem cells have revealed a dormant state and enrichment of the CD34⁺CD38^- subpopulation. These cells express specific antigens (e.g., CD123, CD47, TIM-3) and depend on several signaling pathways (e.g., WNT/β-catenin and PI3K/AKT/FOXO pathways) and mitochondrial respiration for growth and survival. More recently, genetic and immunological studies revealed that LSCs are genetically heterogenous and can escape host antitumor immunity. This article summarizes the current knowledge about LSCs and discusses future challenges involving the translation of research findings into real-time benefits for AML patients.

Minimal (measurable) residual disease (MRD) in acute leukemia denotes the presence of leukemic cells detected by multiparameter flow cytometry or various molecular techniques in patients achieving hematological remission. The MRD become an independent, post-diagnosis, prognostic indicator important for risk stratification and treatment planning, in conjunction with other well-established clinical, cytogenetic, and molecular data assessed at diagnosis in acute myeloid leukemia (AML). However, several issues remain with regard to the ideal time point to measure MRD, the clinically significant threshold, the sample (peripheral blood or bone marrow) should be used, and the standardize tests, so that results from different laboratories become comparable. This review gives an overview of the currently available evidence regarding technical issues, prognostic impact, and MRD-directed treatment for AML.

Several chromosomal abnormalities and gene mutations involved in the onset and recurrence of acute myeloid leukemia (AML) were discovered with the recent progress of genome analysis technology. The founding not only have clinical application as prognostic factors and minimal residual disease markers but also contribute to the novel molecular-targeted drug development. Many new drugs such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor have been developed in Europe and the United States. In addition, second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, and the treatment outcome of AML has been improved. However, a large disparity in the drug availability remains between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to the practical use in Japan. In this paper, molecular-targeted drug treatment by gene diagnosis will be considered for AML in Japan, and the future paradigm shift of gene diagnosis and treatment of AML will be outlined.

By intensive efforts of sequencing a large number of genomes from patients with myelodysplastic syndromes (MDS), a comprehensive registry of driver mutations repeatedly found in MDS patients has been identified, providing us with a virtually complete spectrum of driver mutations in this disease. Importantly, significant correlations between driver mutations have been revealed, suggesting that some combinations of genetic events confer strong selective advantages on mutated stem cells. Next-generation sequencing technology has also revealed that clonal hematopoiesis is a common, age-related process, in which a somatically mutated hematopoietic precursor gives rise to a genetically distinct subpopulation in the blood. Furthermore, novel germline mutations have been identified, indicating that mutated stem cells appear long before MDS presentation. Such founding mutations are thought to be acquired and positively selected for in a well-organized manner to allow expansion of the initiating clone to compromise normal hematopoiesis, ultimately resulting in MDS and subsequent transformation into acute myeloid leukemia in many patients.

For the past seven decades, animal models of allogeneic hematopoietic stem cell transplantation (SCT) have contributed to the development of clinical SCT. Murine models are particularly useful to study the pathophysiology of graft-versus-host disease (GVHD) and the mechanism of graft-versus-leukemia (GVL) effects after SCT because of the variety of genetically engineered mice and numerous research reagents for immune profiling. SCT models using non-human primates are useful in preclinical studies to evaluate the efficacy and safety of novel therapies developed in murine models. In the present manuscript, the advantage and disadvantages of each animal SCT model is discussed, mainly focusing on the studies of GVHD and GVL effects.

Biomarkers, which include cells, cytokines/chemokines, and genes, present in patient blood, urine, or tissues, are considered objective indicators of disease progression or treatment response. Recipients of allogeneic hematopoietic cell transplantation often develop acute and/or chronic graft-versus-host disease (GVHD). Biomarkers that could provide precise assessment of temporal inflammatory conditions in transplant recipients could help us to identify recipients at an increased risk of GVHD, determine the severity of GVHD, and decide upon treatment strategies. The current review article summarizes several established biomarkers for acute and chronic GVHD, as well as interesting and novel viewpoints. Biomarkers could be categorized as those associated with an abnormal immune reconstitution, organ damage, or poor wound healing, including inflammation and fibrosis. The investigation of biomarkers for GVHD would shed light on the complicated networks underlying allo-immune responses and is necessary for further advances in our understanding of GVHD pathophysiology. Clinical trials of preemptive interventions or novel drugs based on GVHD biomarkers are warranted. Research on potential biomarkers of GVHD would lead to further progress in diagnosis, treatment, and drug discovery.

The annual number of hematopoietic cell transplantation (HCT) in Japan exceeds 5,500 in recent years, and a steady increase in the HCT activity is observed globally. Transplant Registry Unification Management Program (TRUMP^®) data, the HCT outcome registry data (or real-world data) in Japan, played important roles in improving the therapeutic outcomes of HCT. Registry studies are actively performed by working groups, and >20 papers are published yearly using the TRUMP^® data. The development of shared scripts has contributed to improving the quality of registry data analyses. In January 2020, the TRUMP^® survey items were significantly revised according to the World Health Organization's disease classification revision and addition of new drug information, and >600 survey items were newly added. The quality control system for registry studies should be updated in response to this major change. The HCT registry is becoming HCT and cell therapy registry and is expected to expand the use of registry data, including the international collaborative research.

Mutations in ASXL1, which occur frequently in myeloid neoplasms, often confer poor prognosis. Despite their clinical importance, the precise molecular mechanisms underlying the contribution of mutant ASXL1 to cancer pathogenesis remain to be elucidated. Thus, we analyzed the roles of the hyperactive complex formed by mutant ASXL1 and the deubiquitinase BAP1 in promoting myeloid leukemogenesis. BAP1 expression resulted in the stabilization and increased monoubiquitination of mutant but not wildtype ASXL1. Monoubiquitination of mutant ASXL1 enhanced the catalytic function of BAP1, resulting in a profound reduction in H2AK119ub by counteracting the PRC1 complex. The mutant ASXL1-BAP1 hyperactive complex impaired the multi-lineage differentiation of hematopoietic progenitor cells and accelerated myeloid leukemogenesis. Mechanistically, the mutant ASXL1/BAP1 complex induced the upregulation of HOXA5, HOXA7, HOXA9, and IRF8 via a reduction in H2AK119ub. Importantly, BAP1 depletion inhibited the leukemogenicity of mutant ASXL1-expressing myeloid leukemia cells and MLL-rearranged leukemia cells by reducing the expression levels of HOXA5, HOXA7, and HOXA9. Our findings highlight the potential of BAP1 as a therapeutic target in a broad range of myeloid neoplasms.