[Rinshō ketsueki] The Japanese journal of clinical hematology
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The principle of hemophilia treatment is replacement therapy with factor VIII and factor IX concentrates. Recently, extended half-life factor VIII and factor IX concentrates have been developed. With these concentrates, improvements in patient QOL can be expected. ⋯ ACE910 (emicizumab) is a humanized bispecific antibody recognizing factor IXa and X mimicking factor VIII function. The half-life is reportedly 4-5 weeks and remarkably decreased annual bleeding rates have been achieved with subcutaneous weekly injections in the phase 1 clinical trial. Clinical trials of anti-antithrombin therapeutics based on siRNA (ALN-AT3) and anti-TFPI antibody are currently ongoing and the results are eagerly anticipated.
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Genetically modified T-cells with forced expression of anti-CD19 chimeric antigen receptor (CD19 CAR) have demonstrated promising clinical results for relapsed and refractory B cell malignancies in early clinical trial settings. The first beneficial tumor regressions were identified among approximately half of CLL patients in 2011. Similarly, CD19 CAR T-cells achieved remissions in about 80% of aggressive B-cell lymphomas in 2012. ⋯ However, there are significant toxicities. Cytokine releasing syndrome and neurotoxicity are recognized as life-threatening adverse events. Although phase I/II clinical trials have just started in Japan, given the exciting results obtained to date, this cellular therapy is expected to be a novel breakthrough immunotherapy for treating refractory B-cell malignancies.
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Immuno-checkpoint inhibitors are one of the most promising immunotherapies for various advanced cancers including hematologic malignancies. Recently, enhanced signaling of the PD-1/CTLA4 pathway has emerged as a critical mechanism by which tumors can escape the anti-tumor immune response. ⋯ Currently, several clinical trials including single agent or combination therapies for hematologic malignancies, such as Hodgkin lymphoma, B-cell lymphomas and multiple myeloma, are ongoing. The results of ongoing and future clinical trials may establish a new treatment paradigm for hematologic malignancies.
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Acquired bone marrow failure syndromes consist of aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS). Clonal hematopoiesis is frequently observed in non-neoplastic disorders, aplastic anemia and PNH as well as a neoplastic phenotype, MDS. ⋯ Recent advancements in next generation sequencing technology have revealed a diverse clonal structure in these bone marrow failure syndromes, as well as in age-related clonal hematopoiesis in healthy people. In this review article, we describe gene mutations in bone marrow failure syndromes, together with those detected in healthy people.
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In the past decade, previously approved novel agents, such as proteasome inhibitors (bortezomib) and immunomodulatory drugs ([IMiDs]; e.g., lenalidomide), have led to significant improvement in the treatment of multiple myeloma in Japan. However, almost all patients will ultimately relapse, even when they have achieved a deep and prolonged therapeutic response with initial treatment. Next-generation IMiDs (pomalidomide) and deacetylase inhibitors (panobinostat) were approved for use as salvage therapy for refractory and relapsed multiple myeloma [RRMM] within the last year. ⋯ Therefore, relapse management requires an individual approach based on assessments of patient-, disease-, and treatment-related factors. The primary considerations when selecting an appropriate treatment are patient-related factors such as frailty, comorbidity, disability, quality of life, and the overall goals of care. We hope that these novel agents that appear promising in Japan, such as monoclonal antibodies (e.g., elotuzumab, daratumumab) and next-generation proteasome inhibitors (e.g., carfilzomib, ixazomib) will improve the outcomes of patients with this incurable disease in the near future.