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[Veno-venous extracorporeal membrane oxygenation for capillary leak syndrome during induction chemotherapy in acute myeloid leukemia]. [静脉-静脉体外膜氧合治疗急性髓性白血病诱导化疗期间的毛细血管渗漏综合征]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.169
Tadashi Okamura, Shogo Murata, Kyohei Miyamoto, Misato Tane, Yuka Okabe, Satomi Takeda, Shotaro Tabata, Hideki Kosako, Yoshikazu Hori, Yusuke Yamashita, Toshiki Mushino, Hiroki Hosoi, Takashi Sonoki

A 44-year-old woman was diagnosed with acute myeloid leukemia (RUNX1::RUNX1T1 translocation) and received induction chemotherapy with idarubicin hydrochloride and cytosine arabinoside. The pneumonia that had been present since admission worsened, and a drug-induced skin rash appeared. On day 17, she presented with respiratory failure and shock, complicated by hemoconcentration and hypoalbuminemia. This was considered capillary leak syndrome due to pneumonia and drug allergy, so she was started on pulse steroid therapy and IVIG, and was intubated on the same day. On day 18, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was started due to worsening blood gas parameters despite ventilatory management. Bronchoalveolar lavage fluid was serous, and both blood and sputum cultures yielded negative. The patient was weaned from VV-ECMO on day 26 as the pneumonia improved with recovery of hematopoiesis. She was disoriented, and a CT scan on day 28 revealed cerebral hemorrhage. Her strength recovered with rehabilitation. After induction chemotherapy, RUNX1::RUNX1T1 mRNA was not detected in bone marrow. The patient received consolidation chemotherapy, and has maintained complete remission. Severe respiratory failure during induction chemotherapy for acute leukemia can be fatal, but VV-ECMO may be lifesaving.

一名 44 岁女性被诊断为急性髓性白血病(RUNX1::RUNX1T1 易位),并接受了盐酸伊达比星和阿糖胞苷的诱导化疗。入院后一直存在的肺炎恶化,并出现了药物引起的皮疹。第 17 天,她出现呼吸衰竭和休克,并伴有血液浓缩和低白蛋白血症。这被认为是肺炎和药物过敏导致的毛细血管渗漏综合征,因此她开始接受脉冲类固醇治疗和 IVIG,并于当天进行了插管。第 18 天,尽管进行了通气管理,但由于血气参数恶化,于是开始静脉体外膜肺氧合(VV-ECMO)。支气管肺泡灌洗液呈浆液性,血液和痰培养结果均为阴性。第 26 天,随着造血功能的恢复,肺炎有所好转,患者脱离了 VV-ECMO。她神志不清,第 28 天的 CT 扫描显示她有脑出血。经过康复治疗,她的体力有所恢复。诱导化疗后,骨髓中未检测到 RUNX1::RUNX1T1 mRNA。患者接受了巩固化疗,并保持完全缓解。急性白血病诱导化疗期间的严重呼吸衰竭可能会致命,但VV-ECMO可以挽救生命。
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引用次数: 0
[Molecular profiling of myeloid/natural killer (NK) cell precursor acute leukemia]. [髓系/自然杀伤(NK)细胞前体急性白血病的分子特征]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.1179
Masatoshi Takagi, Akira Nishimura

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described based on its clinical phenotype and immunophenotype, and proposed as a unique leukemia entity. However, due to its rarity and lack of defined distinctive molecular characteristics, there is currently no international consensus on this disease concept. We performed multi-omics analysis and revealed that MNKPL is distinct from acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia. NOTCH1 and RUNX3 activation and BCL11B downregulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, our single-cell analysis using MNKPL cells suggested that NK cells and myeloid cells share common progenitor cells. Our retrospective case study uncovered that outcomes of MNKPL are unsatisfactory, even with hematopoietic cell transplantation. Multi-omics analysis and in vitro drug sensitivity assays revealed increased sensitivity to L-asparaginase and reduced levels of asparagine synthetase, supporting the clinically observed effectiveness of L-asparaginase.

髓系/自然杀伤(NK)细胞前体急性白血病(MNKPL)根据其临床表型和免疫表型被描述为一种独特的白血病实体。然而,由于其罕见性和缺乏明确的分子特征,目前国际上尚未就这一疾病概念达成共识。我们进行了多组学分析,发现MNKPL有别于急性髓细胞白血病、T细胞急性淋巴细胞白血病和混合表型急性白血病。NOTCH1和RUNX3激活以及BCL11B下调是MNKPL的特征。尽管NK细胞一直被认为是源自淋巴系,但我们使用MNKPL细胞进行的单细胞分析表明,NK细胞和髓系细胞拥有共同的祖细胞。我们的回顾性病例研究发现,即使进行造血细胞移植,MNKPL 的治疗效果也不理想。多组学分析和体外药物敏感性测定显示,患者对L-天冬酰胺酶的敏感性增加,天冬酰胺合成酶水平降低,这支持了临床观察到的L-天冬酰胺酶的有效性。
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引用次数: 0
[Update on treatment strategies for mantle cell lymphoma]. [套细胞淋巴瘤治疗策略的最新进展]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.1012
Suguru Fukuhara

Mantle cell lymphoma (MCL) is a type of lymphoid malignancy that is rare in Japan. MCL is refractory to conventional chemotherapy and has dismal outcomes. Nonetheless, the prognosis of MCL has gradually improved with the advent of autologous stem cell transplantation and BTK inhibitors. First-line therapies incorporating BTK inhibitors are currently under development, and are expected to further improve the prognosis. Nevertheless, subsets with poor prognosis have been identified, including p53 abnormalities (TP53 mutations or deletions), blastoid variant, high MIPI-c, and POD24, and these show resistance to conventional treatments including BTK inhibitors. To overcome these challenges, novel therapies such as CAR-T therapy and combination therapy with BTK and BCL2 inhibitors are being developed, and should soon become clinically available in Japan. The therapeutic landscape for MCL is evolving dynamically, and this article will discuss the future of MCL treatment strategies in Japan.

套细胞淋巴瘤(MCL)是一种淋巴恶性肿瘤,在日本非常罕见。套细胞淋巴瘤对常规化疗难治,疗效不佳。不过,随着自体干细胞移植和BTK抑制剂的出现,MCL的预后逐渐得到改善。含有BTK抑制剂的一线疗法目前正在开发中,有望进一步改善预后。然而,预后不良的亚群已被确定,包括p53异常(TP53突变或缺失)、blastoid变异、高MIPI-c和POD24,这些亚群对包括BTK抑制剂在内的常规治疗表现出耐药性。为了克服这些挑战,目前正在开发 CAR-T 疗法以及 BTK 和 BCL2 抑制剂联合疗法等新型疗法,这些疗法不久将在日本投入临床使用。MCL的治疗格局正在动态演变,本文将讨论日本MCL治疗策略的未来。
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引用次数: 0
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.1245
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引用次数: 0
[Genetic abnormalities in bone marrow failure]. [骨髓衰竭的遗传异常]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.1277
Kohei Hosokawa

Bone marrow (BM) failure is a condition characterized by peripheral pancytopenia resulting from decreased hematopoiesis in the BM. It includes congenital disorders such as Fanconi anemia (FA), as well as acquired conditions such as acquired aplastic anemia (AA), myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria (PNH). AA presents with pancytopenia and BM hypoplasia, primarily triggered by an autoimmune mechanism involving T cells that damage hematopoietic stem cells (HSCs). Genomic investigations utilizing next-generation sequencing or SNP arrays have revealed that clonal hematopoiesis by HSCs with genetic aberrations, including PIGA, DNMT3A, ASXL1, BCOR/BCORL1, copy-number neutral LOH of chromosome 6p (6pLOH), and somatic mutations in HLA class I alleles are prevalent in AA patients. Recent studies have identified somatic mutations in genes associated with the JAK-STAT and MAPK pathways in T cells of AA patients. Genomic abnormalities in AA differ from those observed in MDS and age-related clonal hematopoiesis. Notably, the presence of PNH-type cells and HLA class I allele-lacking cells represent two major instances of escape hematopoiesis, which indicate the presence of HSCs evading autoimmune T cell attacks. These findings provide crucial insights into the immune pathophysiology of BM failure.

骨髓(BM)衰竭是一种因骨髓造血功能减退而导致的外周泛发性贫血。它包括范可尼贫血(FA)等先天性疾病,以及获得性再生障碍性贫血(AA)、骨髓增生异常综合征(MDS)和阵发性夜间血红蛋白尿(PNH)等后天性疾病。再生障碍性贫血表现为全血细胞减少和BM发育不良,主要由T细胞损伤造血干细胞(HSCs)的自身免疫机制引发。利用下一代测序或SNP阵列进行的基因组学调查显示,AA患者中普遍存在造血干细胞克隆性造血,并伴有基因畸变,包括PIGA、DNMT3A、ASXL1、BCOR/BCORL1、染色体6p的拷贝数中性LOH(6pLOH)以及HLA I类等位基因的体细胞突变。最近的研究发现,在 AA 患者的 T 细胞中,与 JAK-STAT 和 MAPK 通路相关的基因发生了体细胞突变。AA 基因组异常与在 MDS 和年龄相关克隆性造血中观察到的异常不同。值得注意的是,PNH 型细胞和缺乏 HLA I 类等位基因细胞的存在代表了逃避性造血的两大实例,这表明存在逃避自身免疫 T 细胞攻击的造血干细胞。这些研究结果为了解造血干细胞衰竭的免疫病理生理学提供了重要的启示。
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引用次数: 0
[Recent advances in bone marrow pathology for myeloproliferative neoplasms diagnosis]. [骨髓病理学在骨髓增生性肿瘤诊断中的最新进展]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.778
Masafumi Ito

Identification of driver genes and pathological bone marrow diagnosis were considered essential for subclassification of MPN in the revised 4th edition of the WHO classification, and this remained nearly unchanged in the 5th edition. Pathological diagnosis of primary myelofibrosis/pre-fibrotic stage by biopsy is now feasible and is becoming standardized. Progressive myelofibrosis and blast transformation are the advanced forms of MPN, and various therapeutic interventions for these forms have been devised. Observation of activated megakaryocytes on evaluation of megakaryocyte morphology could predict the progression of myelofibrosis. This paper describes recent progress in pathological diagnosis of MPN and how it is performed in practice.

在修订后的第四版世卫组织分类中,驱动基因的鉴定和病理骨髓诊断被认为是骨髓增生性疾病亚分类的关键,这一点在第五版中几乎没有改变。现在,通过活检对原发性骨髓纤维化/纤维化前期进行病理诊断是可行的,而且正在逐渐标准化。进行性骨髓纤维化和爆破转化是骨髓增生性疾病的晚期形式,针对这些形式已设计出各种治疗干预措施。通过评估巨核细胞形态观察活化的巨核细胞可预测骨髓纤维化的进展。本文介绍了多发性骨髓瘤病理诊断的最新进展以及实际操作方法。
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引用次数: 0
[Treatment strategies for low-risk polycythemia vera]. [低风险红细胞增多症的治疗策略]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.810
Shuichi Ota

Treatment selection for patients with polycythemia vera (PV) is based on patient age and history of thrombosis. The standard treatment is low-dose aspirin and phlebotomy for low-risk PV, with cytoreductive therapy added for high-risk PV. Thrombotic events and disease progression due to PV clone expansion affect the prognosis of PV. Although phlebotomy is effective in controlling hematocrit level, it has no effect on disease progression or PV-related symptoms. In Western countries, interferon (IFN) has been used as a cytoreductive therapy for PV. Long-term IFN therapy has been shown to result in sustained hematologic remission and molecular responses. Ropeginterferon-α-2b (ropeg-IFN), which is administered every two weeks, has recently become available. Clinical trials in patients with PV have shown that ropeg-IFN treatment is safe and efficacious, reducing JAK2V617F allele burden. Ropeg-IFN could ultimately affect long-term hematologic remission and molecular response in younger patients with low-risk PV, and may even offer a cure.

多发性红细胞症(PV)患者的治疗选择取决于患者的年龄和血栓形成史。标准治疗方法是低剂量阿司匹林和抽血术治疗低风险的红细胞增多症,高风险的红细胞增多症则需进行细胞再生治疗。血栓事件和 PV 克隆扩张导致的疾病进展会影响 PV 的预后。虽然抽血疗法能有效控制血细胞比容水平,但对疾病进展或与 PV 相关的症状没有影响。在西方国家,干扰素(IFN)一直被用作 PV 的细胞再生疗法。长期的 IFN 治疗已被证明可导致持续的血液学缓解和分子反应。每两周给药一次的罗匹干扰素-α-2b(罗匹干扰素-IFN)最近已经上市。对多发性骨髓瘤患者进行的临床试验表明,Ropeg-IFN 治疗安全有效,可减少 JAK2V617F 等位基因的负担。Ropeg-IFN最终可能会影响年轻的低风险PV患者的长期血液学缓解和分子反应,甚至有可能治愈。
{"title":"[Treatment strategies for low-risk polycythemia vera].","authors":"Shuichi Ota","doi":"10.11406/rinketsu.65.810","DOIUrl":"10.11406/rinketsu.65.810","url":null,"abstract":"<p><p>Treatment selection for patients with polycythemia vera (PV) is based on patient age and history of thrombosis. The standard treatment is low-dose aspirin and phlebotomy for low-risk PV, with cytoreductive therapy added for high-risk PV. Thrombotic events and disease progression due to PV clone expansion affect the prognosis of PV. Although phlebotomy is effective in controlling hematocrit level, it has no effect on disease progression or PV-related symptoms. In Western countries, interferon (IFN) has been used as a cytoreductive therapy for PV. Long-term IFN therapy has been shown to result in sustained hematologic remission and molecular responses. Ropeginterferon-α-2b (ropeg-IFN), which is administered every two weeks, has recently become available. Clinical trials in patients with PV have shown that ropeg-IFN treatment is safe and efficacious, reducing JAK2V617F allele burden. Ropeg-IFN could ultimately affect long-term hematologic remission and molecular response in younger patients with low-risk PV, and may even offer a cure.</p>","PeriodicalId":93844,"journal":{"name":"[Rinsho ketsueki] The Japanese journal of clinical hematology","volume":"65 8","pages":"810-818"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
[Appropriate use of the ELN guidelines based on results of real-world genetic analysis in Japanese patients with AML]. [根据日本急性髓细胞性白血病患者的实际基因分析结果合理使用 ELN 指南]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.676
Satoshi Wakita

Researchers in the field of acute myeloid leukemia have long sought to establish a prognostic stratification system for clinical use that combines multiple genetic mutations. In 2022, the European LeukemiaNet (ELN) proposed a new prognostic model incorporating new genetic mutations. However, Japanese National Health insurance only recently began covering clinical genetic analysis for AML. We established the Multi-center Collaborative Program for Gene Sequencing of Japanese AML (GS-JAML) to contribute to clinical practice by providing rapid genetic analysis results. Retrospective analysis of this research program revealed (1) the clinical significance of CEBPA-bZIP mutations, and (2) the clinical significance of DNMT3A mutations in NPM1 mutated AML.

长期以来,急性髓性白血病领域的研究人员一直在寻求建立一个结合多种基因突变的预后分层系统,供临床使用。2022 年,欧洲白血病网络(ELN)提出了一种结合新基因突变的新预后模型。然而,日本国民健康保险最近才开始覆盖急性髓细胞白血病的临床基因分析。我们建立了日本急性髓细胞性白血病基因测序多中心合作计划(GS-JAML),通过提供快速的基因分析结果,为临床实践做出贡献。对该研究项目的回顾性分析表明:(1) CEBPA-bZIP 突变具有临床意义;(2) DNMT3A 突变在 NPM1 突变 AML 中具有临床意义。
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引用次数: 0
[Budd-Chiari syndrome and JAK2 gene mutation]. [布德-奇异综合征与 JAK2 基因突变]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.790
Shuichi Shirane

Budd-Chiari syndrome (BCS) is a rare vascular disorder characterized by obstruction of hepatic venous outflow, culminating in elevated hepatic and portal venous pressure. BCS is associated with myeloproliferative neoplasms (MPN) in 40% of cases, which is significantly higher than the rate observed in other venous thrombotic conditions, and suggests that MPN may contribute to the etiology of BCS. In particular, the JAK2 V617F mutation has recently attracted substantial attention, given its profound association with thrombogenesis, mechanically implicated through endothelial damage, increased blood cell adhesion, and facilitation of neutrophil extracellular trap formation. A common treatment approach consists of anticoagulation for prevention and treatment of thrombosis, and cytoreductive therapy targeting MPN. However, as no definitive evidence exists for this approach, a bespoke therapeutic strategy tailored to individual patient profiles is required.

巴德-恰里综合征(BCS)是一种罕见的血管疾病,其特点是肝静脉流出受阻,最终导致肝静脉和门静脉压力升高。40%的病例与骨髓增生性肿瘤(MPN)有关,明显高于其他静脉血栓性疾病,这表明骨髓增生性肿瘤可能是 BCS 的病因之一。特别是,JAK2 V617F突变最近引起了广泛关注,因为它与血栓形成密切相关,通过内皮损伤、血细胞粘附性增加和促进中性粒细胞胞外陷阱的形成而产生机械性牵连。常见的治疗方法包括抗凝以预防和治疗血栓形成,以及针对 MPN 的细胞再生疗法。然而,由于这种方法尚无确切的证据,因此需要根据患者的具体情况量身定制治疗策略。
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引用次数: 0
[Development and prospects of bispecific antibodies for multiple myeloma]. [多发性骨髓瘤双特异性抗体的发展与前景]。
Pub Date : 2024-01-01 DOI: 10.11406/rinketsu.65.1049
Junichiro Yuda

Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.

三类难治性多发性骨髓瘤患者的预后曾一度很差,但最近开发的针对B细胞成熟抗原(BCMA)、G蛋白偶联受体5D(GPRC5D)和Fc受体同源体5(FcRH5)的双特异性抗体(bsAbs)在这些患者中显示出了显著的临床活性。然而,对 bsAbs 的反应并不普遍,在治疗过程中往往会出现耐药性。产生耐药性的机制可能是肿瘤内在的,也可能是免疫依赖的。肿瘤内在因素包括靶基因缺失或突变导致的抗原缺失(双拷贝或功能性)、可溶性 BCMA 增加(针对 BCMA 靶向 bsAbs)、高肿瘤负荷和髓外疾病。免疫介导的抗药性在很大程度上取决于 T 细胞的适应性和抗药性免疫环境。本文介绍了目前正在开发的针对多发性骨髓瘤的双特异性抗体。
{"title":"[Development and prospects of bispecific antibodies for multiple myeloma].","authors":"Junichiro Yuda","doi":"10.11406/rinketsu.65.1049","DOIUrl":"10.11406/rinketsu.65.1049","url":null,"abstract":"<p><p>Patients with triple-class refractory multiple myeloma once had a poor prognosis, but recently developed bispecific antibodies (bsAbs) targeting B-cell maturation antigen (BCMA), G protein-coupled receptor 5D (GPRC5D), and Fc receptor-homolog 5 (FcRH5) have shown significant clinical activity in these patients. However, responses to bsAbs are not universal, and resistance often develops during therapy. Mechanisms that mediate resistance may be tumor-intrinsic or immune-dependent. Tumor-intrinsic factors include antigen loss (biallelic or functional) due to deletion or mutation of target genes, increased soluble BCMA (for BCMA targeting bsAbs), high tumor burden, and extramedullary disease. Immune-mediated resistance highly depends on T cell fitness and the resistant immune environment. This article describes bispecific antibodies against multiple myeloma that are currently being developed.</p>","PeriodicalId":93844,"journal":{"name":"[Rinsho ketsueki] The Japanese journal of clinical hematology","volume":"65 9","pages":"1049-1057"},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
[Rinsho ketsueki] The Japanese journal of clinical hematology
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