[Rinsho ketsueki] The Japanese journal of clinical hematology最新文献

A 53-year-old man was presented with fever, eyelid edema, and thrombocytopenia. Based on examination outcomes, he was diagnosed with immune thrombocytopenia. He was prescribed prednisolone (PSL) at 0.5 mg/kg/day; subsequently, his platelet count improved and fever improved. PSL dose was tapered and stopped without relapse. However, 1 month later, the patient presented to our hospital with fever, generalized edema, thrombocytopenia, and acute renal failure. Computed tomography revealed multiple lymphadenopathies, hepatomegaly, pleural effusion, and ascites. Bone marrow biopsy indicated reticulin fibrosis, and lymph node biopsy revealed mixed-type Castleman disease. Based on these findings, he was diagnosed with grade 5 TAFRO syndrome (very severe). Steroid pulse therapy and tocilizumab were ineffective in improving his condition. Therefore, rituximab was administered instead of tocilizumab, and his condition eventually improved. The optimal treatment for TAFRO syndrome is yet to be established. If tocilizumab is ineffective as the second-line treatment, then rituximab might be effective.

The patient is a 45-year-old man who was diagnosed with severe hemophilia A during childhood and received FVIII replacement therapy, which became ineffective due to inhibitor production (5-225 BU/ml). After initiating emicizumab therapy, bleeding symptoms markedly improved, but he developed an intramuscular hematoma at the right thigh due to a fall. He was hospitalized and maintained on bed rest; however, the size of the hematoma increased, and anemia developed. Since the inhibitor level was markedly decreased at 0.6 BU/ml, a recombinant FVIII preparation was administered, and the size of the hematoma decreased along with an increase in FVIII activity. Levels of the inhibitor increased to 54.2 BU/ml, but tended to decrease during continued emicizumab treatment. Emicizumab therapy seems useful in hemophilia A patients with inhibitor production.

Aortic regurgitation, a thoracoabdominal aortic aneurysm, chronic myeloid leukemia, and chronic kidney disease were all being treated at two hospitals for an 83-year-old man. He was admitted to the Department of Orthopedics at our hospital with a lumbar compression fracture. Later, he experienced melena, for which the Department of Internal Medicine was consulted. Due to the aberrant results of PT-INR (7.1) and a PTT > 200 seconds on a coagulation test, we suspected the presence of an autoimmune coagulation factor deficiency, and prednisolone immunosuppressive therapy medication was started right away. Due to a sharp decline in FV/5 activity, the presence of FV/5 inhibitors, and the presence of anti-FV/5 autoantibodies, a final diagnosis of autoimmune coagulation factor V (FV/5) deficiency was made. After the start of immunosuppressive therapy, the FV/5 inhibitor and anti-FV/5 autoantibodies disappeared, and the FV/5 activity progressively returned to normal. Disseminated intravascular coagulation-which may have been caused by a known aortic aneurysm-worsened while tapering off prednisolone. Due to the patient's advanced age and other problems, the aneurysm was extensive and inappropriate for surgical repair. The coagulation test findings improved gradually upon initiation of warfarin therapy. Herein, the patient had autoimmune FV/5 deficiency, a rare disorder that made diagnosis and therapy difficult because of the patient's several coexisting conditions.

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.

Coagulation factor V (FV) is both procoagulant and anticoagulant functions. Congenital FV abnormality, which are caused by mutations in the FV gene, are characterized by a tendency to bleed. However, FV-R506Q (FV_Leiden) is the most common FV abnormality that eliminates an activated protein C (APC) cleavage site, resulting in the occurrence of deep venous thrombosis (DVT). In Japan, the thrombotic predisposition caused by FV_Leiden and FV molecular abnormalities was believed to be nonexistent. We did, however, report the first case in Japan of a young patient with FV abnormality-related thrombosis. The recurrent DVT in this case was caused by a novel mutation of FV-W1920R (FV_Nara), located in the C1 domain and far from the APC cleavage sites. We considered the possibility that there were cases of FV-related thrombotic predisposition that had gone undetected in Japan. We thoroughly examined FV-related anticoagulant function to understand the pathogenesis of thrombosis caused by FV abnormality. Furthermore, using recombinant thrombomodulin, we successfully developed a novel assay with clot waveform analysis for the rapid detection of FV deficiency with APC resistance. Other FV abnormality-related thrombosis has been reported in Japan in recent years, and we hope to further clarify the FV-related thrombotic predisposition in the future.

Acute myeloid leukemia (AML) is a heterogeneous disease, and the accumulation of various chromosomal and genetic abnormalities is considerably involved in its pathogenesis and prognosis. Recently, the disease classification based on molecular abnormalities and novel molecular-targeting therapies has been developed. In Europe and the United States, several agents have been approved for AML and incorporated into guidelines as the standard treatment depending on comorbid genetic mutations combined with conventional chemotherapy or monotherapy since 2017. The combination therapy of FLT3 inhibitor midostaurin and intensive chemotherapy has improved the prognosis of patients with FLT3-ITD-positive AML, which has been considered a poor prognosis for a long period. In addition to small-molecule compounds, various novel therapies for AML are under clinical investigation, including antibody therapies targeting CD47 and TIM-3, bispecific antibodies, and CAR-T-cell therapies. Considering the treatment strategies with diverse therapeutic modalities, the pathogenesis and clonal selection process of refractory AML, including the surrounding environment of residual leukemia cells, should be clarified. The combination of new therapies and chemotherapies is highly expected to improve the prognosis of patients with AML in the near future.

Multiple myeloma (MM) is characterized by genomic instability, which causes multiple genetic and chromosomal alterations and leads to disease progression and therapeutic resistance. Overlapping mechanisms, including defective genome repair machinery such as the loss of TP53 activity, as well as chromosomal segregation error represented by the abnormality of mitotic checkpoint kinases such as BUB1, cell cycle dysregulation, and tumor environment, cause structural and numerical chromosomal abnormalities. Cytogenetic abnormalities are important prognostic factors, and they are also linked to the use of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and the BCL2 inhibitor venetoclax. We developed new diagnostic modalities for chromosomal analysis to improve the sensitivity and convenience of chromosomal diagnosis. The immunophenotyped-suspension-multiplex (ISM)-fluorescence in situ hybridization (FISH) can use imaging flow to examine three IGH-related chromosomal translocations at the same time. We also created a new FISH method called amplified FISH (amFISH) to detect microdeletion involving narrow chromosomal regions (approximately<100 kb), such as the microdeletions of 1p32 (CDKN2C) or of 14q32 (TRAF3), by using a fluorescent antibody to amplify the signals of small probes. Even in the era of clinical sequencing, these convenient modalities may hasten the cytogenetics-oriented therapeutic approach for MM.

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.