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Novel therapeutic strategies for essential thrombocythemia/polycythemia vera. 原发性血小板增多症/真性红细胞增多症的新治疗策略。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023013
Seug Yun Yoon, Jong-Ho Won

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.

骨髓增生性肿瘤(mpn)是造血干细胞的克隆性疾病;这些包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)。mpn是炎症性癌症,其中恶性克隆产生细胞因子,维持炎症驱动在一个自我延续的恶性循环。mpn的病程遵循生物学连续体,即从早期癌症阶段(ET/PV)到晚期骨髓纤维化以及即将发生的白血病转化。mpn相关症状,如疲劳、全身无力和瘙痒,是由炎症细胞因子引起的。炎症因子也会加重MPN患者的血栓形成和出血。直到最近,ET和PV治疗的主要目的是通过预防血栓形成来提高生存率。然而,最近有几种药物被证明有能力改变疾病的进程;大多数患者的症状可望得到缓解。此外,人们对低风险PV和ET患者的积极治疗越来越感兴趣。本文将重点介绍ET/PV治疗策略以及临床开发的新治疗方案。
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引用次数: 1
Management of adverse events in young adults and children with acute B-cell lymphoblastic leukemia receiving anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. 接受抗cd19嵌合抗原受体(CAR) t细胞治疗的急性b细胞白血病年轻成人和儿童的不良事件管理
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023026
Jae Won Yoo

With impressive clinical advancements in immune effector cell therapies targeting CD19, chimeric antigen receptor (CAR) T-cell therapy has emerged as a new paradigm for treating relapsed/refractory B-cell malignancies. Currently, three second-generation CAR T-cell therapies have been approved, of which only tisagenlecleucel (tisa-cel) is approved for treating children and young adults with B-cell acute lymphoblastic leukemia (ALL) with durable remission rates of approximately 60‒90%. Although CAR T-cell therapies are considered to treat refractory B-ALL, they are associated with unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The severity of CAR T-cell therapy toxicities can vary according to several clinical factors. In rare cases, severe CRS can progress to a fulminant hyperinflammatory syndrome known as hemophagocytic lymphohistiocytosis, which has a poor prognosis. The first-line treatments for CRS/ICANS include tocilizumab and corticosteroids. When severe CAR T-cell toxicity is resistant to first-line treatment, an additional approach is required to manage the persistent inflammation. In addition to CRS/ICANS, CAR T-cell therapy can cause early and delayed hematological toxicity, which can predispose patients to severe infections. The use of growth factors and anti-infective prophylaxis should follow institutional guidelines according to patient-specific risk factors. This review provides a thorough summary of updated practical recommendations for managing acute and delayed adverse effects following anti-CD19 CAR T-cell therapy in adults and children.

随着靶向CD19的免疫效应细胞疗法取得令人印象深刻的临床进展,嵌合抗原受体(CAR) t细胞疗法已成为治疗复发/难治性b细胞恶性肿瘤的新范例。目前,已经批准了三种第二代CAR - t细胞疗法,其中只有tisagenlecleucel(组织细胞)被批准用于治疗b细胞急性淋巴细胞白血病(ALL)的儿童和年轻人,持久缓解率约为60-90%。尽管CAR - t细胞疗法被认为可以治疗难治性B-ALL,但它们具有独特的毒性,如细胞因子释放综合征(CRS)和免疫效应细胞相关神经毒性综合征(ICANS)。CAR - t细胞疗法毒性的严重程度可以根据几个临床因素而变化。在极少数情况下,严重的CRS可发展为暴发性高炎症综合征,即噬血细胞性淋巴组织细胞增多症,预后较差。CRS/ICANS的一线治疗包括托珠单抗和皮质类固醇。当严重的CAR - t细胞毒性对一线治疗产生耐药性时,需要一种额外的方法来控制持续的炎症。除了CRS/ICANS之外,CAR - t细胞疗法还可能导致早期和延迟的血液毒性,这可能使患者易受严重感染。生长因子和抗感染预防的使用应根据患者特定的危险因素遵循机构指南。这篇综述全面总结了最新的实用建议,用于处理成人和儿童抗cd19 CAR - t细胞治疗后的急性和延迟不良反应。
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引用次数: 1
Mycosis fungoides and Sézary syndrome. 蕈样真菌病和ssamzary综合征。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023023
Hyewon Lee
Mycosis fungoides (MF) and Sézary syndrome (SS) are a distinct disease entity of cutaneous T-cell lymphoma with heterogenous clinical features and prognosis. MF mainly involves skin and usually shows an indolent and favorable clinical course. In patients with advanced-stage disease, extracutaneous involvement including lymph nodes, viscera, and blood, or large cell transformation may be observed. SS is a leukemic form of advanced-stage MF, characterized by generalized erythroderma. Early-stage MF can be treated with skin-directed therapy. However, patients with refractory or advanced-stage disease are associated with severe symptoms or poor prognosis, requiring systemic therapy. Recent progress in understanding the pathogenesis of MF/SS has contributed to advances in the management of these rare diseases. This review aims to describe the clinical manifestations, diagnosis, risk stratification, and treatment strategy of MF/SS, focusing on the recent updates in the management of these diseases.
蕈样真菌病(MF)和ssamzary综合征(SS)是皮肤t细胞淋巴瘤的一种独特的疾病实体,具有异质的临床特征和预后。MF主要累及皮肤,通常表现为无痛和良好的临床过程。在疾病晚期患者中,可观察到包括淋巴结、脏器和血液在内的皮外受累,或大细胞转化。SS是晚期MF的一种白血病形式,以全身性红皮病为特征。早期MF可以通过皮肤定向治疗来治疗。然而,难治性或晚期疾病患者伴有严重症状或预后差,需要全身治疗。最近对MF/SS发病机制的研究进展促进了这些罕见疾病治疗的进展。本文综述了MF/SS的临床表现、诊断、风险分层和治疗策略,并重点介绍了这些疾病的最新管理进展。
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引用次数: 0
Treatment-free remission after discontinuation of imatinib, dasatinib, and nilotinib in patients with chronic myeloid leukemia. 慢性髓性白血病患者停用伊马替尼、达沙替尼和尼洛替尼后的无治疗缓解。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023035
Jae Joon Han

Patients with chronic myeloid leukemia (CML) in the chronic phase receiving tyrosine kinase inhibitor (TKI) therapy are expected to have long-term survival outcomes comparable to those of the general population. Many clinical trials have confirmed that some patients sustain molecular responses without continuing TKI therapy. Treatment-free remission (TFR) is a new goal in treating chronic CML. The safety and outcome of TFR were studied in clinical trials after discontinuing imatinib or the second-generation TKIs dasatinib or nilotinib. TFR was safe in approximately 50% of patients who achieved a deep molecular response to TKI therapy. Patients who relapsed after discontinuing TKI responded immediately to the reintroduction of TKI. The mechanism by which TFR increases the success rate still needs to be understood. The hypothesis that the modulation of immune function and targeting of leukemic stem cells could improve the TFR is under investigation. Despite the remaining questions, the TFR has become a routine consideration for clinicians in the practice of molecular remission in patients with CML.

接受酪氨酸激酶抑制剂(TKI)治疗的慢性髓性白血病(CML)慢性期患者的长期生存结果有望与普通人群相当。许多临床试验证实,一些患者在不继续TKI治疗的情况下仍能维持分子反应。无治疗缓解(TFR)是慢性CML治疗的新目标。在临床试验中研究了停用伊马替尼或第二代TKIs(达沙替尼或尼洛替尼)后TFR的安全性和结局。TFR在约50%对TKI治疗有深度分子反应的患者中是安全的。停用TKI后复发的患者对重新引入TKI立即有反应。TFR增加成功率的机制仍需了解。调节免疫功能和靶向白血病干细胞可以改善TFR的假说正在研究中。尽管仍存在问题,但TFR已成为临床医生在CML患者分子缓解实践中的常规考虑因素。
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引用次数: 1
Novel therapeutics for myelofibrosis. 骨髓纤维化的新疗法。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023012
Sung-Eun Lee

Myelofibrosis (MF) includes primary MF, post-essential thrombocythemia MF, and post-polycythemia vera MF. MF is a progressive myeloid neoplasm characterized by ineffective clonal hematopoiesis, extramedullary hematopoiesis, a reactive bone marrow environment resulting in reticulin deposition and fibrosis, and a propensity for leukemia transformation. The identification of driver mutations in JAK2, CALR, and MPL has contributed to a better understanding of disease pathogenesis and has led to the development of MF-specific therapies, such as JAK2 inhibitors. Despite the fact that ruxolitinib and fedratinib have been clinically developed and approved, their use is limited due to adverse effects such as anemia and thrombocytopenia. Recently, pacritinib has been approved for a group of thrombocytopenic patients with significant unmet clinical needs. In symptomatic and anemic patients with prior JAK inhibitor exposure, momelotinib was superior to danazol in preventing exacerbation of anemia and in controlling MF-associated signs and symptoms, such as spleen size. Although the development of JAK inhibitors is remarkable, modifying the natural course of the disease remains a priority. Therefore, many novel treatments are currently under clinical development. Agents targeting bromodomain and extra-terminal protein, anti-apoptotic protein Bcl-xL, and phosphatidylinositol-3-kinase delta have been studied in combination with JAK inhibitors. These combinations have been employed in both the frontline and "add-on" approaches. In addition, several agents are being studied as monotherapies for ruxolitinib-resistant or -ineligible patients. We reviewed several new MF treatments in the advanced stages of clinical development and treatment options for cytopenic patients.

骨髓纤维化(MF)包括原发性MF、原发性血小板增多症MF和真性红细胞增多症MF。MF是一种进行性髓系肿瘤,其特点是克隆造血、髓外造血无效,骨髓环境反应性导致网状蛋白沉积和纤维化,并倾向于白血病转化。JAK2、CALR和MPL驱动突变的鉴定有助于更好地了解疾病的发病机制,并导致了mf特异性治疗的发展,如JAK2抑制剂。尽管ruxolitinib和federatinib已经被临床开发和批准,但由于贫血和血小板减少等不良反应,它们的使用受到限制。最近,pacritinib已被批准用于一组临床需求未得到满足的血小板减少患者。在既往有JAK抑制剂暴露的有症状的贫血患者中,莫美洛替尼在预防贫血加重和控制mf相关体征和症状(如脾脏大小)方面优于达那唑。尽管JAK抑制剂的发展是显著的,但改变疾病的自然过程仍然是一个优先事项。因此,许多新的治疗方法目前正在临床开发中。靶向溴域和外端蛋白、抗凋亡蛋白Bcl-xL和磷脂酰肌醇-3激酶δ的药物已与JAK抑制剂联合研究。这些组合已被用于前线和“附加”方法。此外,一些药物正在研究作为鲁索利替尼耐药或不合格患者的单药治疗。我们回顾了几种处于临床开发晚期的新的MF治疗方法和细胞减少患者的治疗选择。
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引用次数: 0
Recent advances in diagnosis and therapy in systemic mastocytosis. 系统性肥大细胞增多症的诊断与治疗进展。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023024
Hyun Jung Lee

Mastocytosis is a heterogeneous neoplasm characterized by accumulation of neoplastic mast cells in various organs. There are three main types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. CM mainly affects children and is confined to the skin, whereas SM affects adults and is characterized by extracutaneous involvement, with or without cutaneous involvement. Most cases of SM have an indolent clinical course; however, some types of SM have aggressive behavior and a poor prognosis. Recent advances in the understanding of the molecular changes in SM have changed the diagnosis and treatment of aggressive and advanced SM subtypes. The International Consensus Classification and World Health Organization refined the diagnostic criteria and classification of SM as a result of accumulation of clinical experience and advances in molecular diagnostics. Somatic mutations in the KIT gene, most frequently KIT D816V, are detected in 90% of patients with SM. Expression of CD30 and any KIT mutation were introduced as minor diagnostic criteria after the introduction of highly sensitive screening methods. SM has a wide spectrum of clinical features, and only a few drugs are effective at treating advanced SM. Currently, the mainstay of SM treatment is limited to the management of chronic symptoms related to release of mast cell mediators. Small-molecule kinase inhibitors targeting the KIT-downstream and KIT-independent pathways were recently approved for treating advanced SM. I describe recent advances in diagnosis of SM, and review the currently available and emerging therapeutic options for SM management.

肥大细胞增多症是一种异质性肿瘤,其特征是肿瘤肥大细胞在各器官中积聚。主要有三种类型:皮肤肥大细胞增多症(CM)、全身肥大细胞增多症(SM)和肥大细胞肉瘤。CM主要影响儿童,局限于皮肤,而SM影响成人,其特征是皮外受累,有或没有皮肤受累。大多数SM患者的临床病程为惰性;然而,某些类型的SM具有攻击性行为,预后较差。近年来对SM分子变化的理解已经改变了侵袭性和晚期SM亚型的诊断和治疗。由于临床经验的积累和分子诊断技术的进步,国际共识分类和世界卫生组织完善了SM的诊断标准和分类。在90%的SM患者中检测到KIT基因的体细胞突变,最常见的是KIT D816V。在引入高灵敏度筛选方法后,CD30表达和KIT突变被引入作为次要诊断标准。SM具有广泛的临床特征,只有少数药物对晚期SM有效。目前,主要的SM治疗仅限于管理与肥大细胞介质释放相关的慢性症状。靶向kit下游和kit非依赖性途径的小分子激酶抑制剂最近被批准用于治疗晚期SM。我描述了SM诊断的最新进展,并回顾了目前可用的和新兴的SM管理治疗方案。
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引用次数: 0
Plasmacytoid dendritic cell neoplasms. 浆细胞样树突状细胞肿瘤。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023052
Yoo Jin Lee, Youjin Kim, Sang Hyuk Park, Jae-Cheol Jo

Plasmacytoid dendritic cells (pDCs) are type I interferon-producing cells that modulate immune responses. There are two types of pDC neoplasms: 1) mature pDC proliferation (MPDCP) associated with myeloid neoplasm and 2) blastic pDC neoplasm (BPDCN). MPDCP is a clonal expansion of mature pDCs that is predominantly associated with chronic myelomonocytic leukemia. In contrast, BPDCN is a clinically aggressive myeloid malignancy involving the skin, bone marrow, lymphatic organs, and central nervous system. There are various types of skin lesions, ranging from solitary brown or violaceous to disseminated cutaneous lesions, which often spread throughout the body. The expression of CD4, CD56, CD123, and pDC markers (TCL-1, TCF4, CD303, and CD304, etc.) are typical immunophenotype of BPDCN. Historically, BPDCN treatment has been based on acute leukemia regimens and allogeneic hematopoietic cell transplantation in selected patients. Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms.

浆细胞样树突状细胞(pDCs)是调节免疫反应的I型干扰素产生细胞。pDC肿瘤有两种类型:1)成熟pDC增殖(MPDCP)伴髓系肿瘤和2)母细胞pDC肿瘤(BPDCN)。MPDCP是成熟pDCs的克隆扩增,主要与慢性髓单细胞白血病相关。相比之下,BPDCN是一种临床侵袭性髓系恶性肿瘤,累及皮肤、骨髓、淋巴器官和中枢神经系统。有各种类型的皮肤病变,从孤立的棕色或紫色到弥散性皮肤病变,通常扩散到全身。CD4、CD56、CD123和pDC标记物(TCL-1、TCF4、CD303、CD304等)的表达是BPDCN的典型免疫表型。从历史上看,BPDCN治疗基于急性白血病方案和特定患者的异基因造血细胞移植。分子生物学和遗传学的最新进展导致了靶向药物的发展,如tagraxofusp(一种靶向CD123的重组融合蛋白)、抗CD123 CAR-T细胞、XmAb14045和IMGN632。最后,本文对pDC肿瘤进行了全面的综述。
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引用次数: 2
Treatment after failure of frontline therapy of chronic myeloid leukemia in chronic phase including allogeneic hematopoietic stem cell transplantation. 慢性髓系白血病慢性期一线治疗失败后的治疗包括异基因造血干细胞移植。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023054
Jieun Uhm

The treatment outcomes of chronic myeloid leukemia in chronic phase (CML-CP) have dramatically improved with comparable life-expectancy to average of general population in tyrosine kinase inhibitor (TKI) era. However, less than a half of patients who started with TKI can remain on frontline TKI. The reasons of switching TKI can be either intolerance or the lack of efficacy. Although a kinase domain (KD) mutation can guide to select salvage TKI from the point of view on the efficacy of TKIs, many factors need to be considered before choosing next-line TKI such as the high-risk features of CML, the adverse events with prior TKI, and the comorbidities of patients. The therapeutic options for CML-CP after failing frontline TKI due to treatment failure or suboptimal responses will be reviewed including allogeneic hematopoietic stem cell transplantation.

在酪氨酸激酶抑制剂(TKI)时代,慢性髓系白血病(CML-CP)的治疗结果显著改善,预期寿命与普通人群的平均寿命相当。然而,只有不到一半的TKI患者能够坚持一线TKI治疗。切换TKI的原因可能是不耐受或缺乏疗效。虽然激酶结构域(KD)突变可以从TKI疗效的角度指导补救性TKI的选择,但在选择下一线TKI时需要考虑许多因素,如CML的高危特征、既往TKI的不良事件、患者的合并症等。在一线TKI治疗失败或反应欠佳后,CML-CP的治疗选择将包括异体造血干细胞移植。
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引用次数: 1
Prognostication in myeloproliferative neoplasms, including mutational abnormalities. 骨髓增生性肿瘤的预后,包括突变异常。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023038
Junshik Hong

Increasing knowledge of the molecular features of myeloproliferative neoplasms (MPNs) is being combined with existing prognostic models based on clinical, laboratory, and cytogenetic information. Mutation-enhanced international prognostic systems (MIPSS) for polycythemia vera (PV) and essential thrombocythemia (ET) have improved prognostic assessments. In the case of overt primary myelofibrosis (PMF), the MIPSS70 and its later revisions (MIPSS70+ and MIPSS70+ version 2.0) effectively predicted the overall survival (OS) of patients. Because post-PV and post-ET myelofibrosis have different biological and clinical courses compared to overt PMF, the myelofibrosis secondary to PV and ET-prognostic model was developed. Although these molecular-inspired prognostic models need to be further validated in future studies, they are expected to improve the prognostic power in patients with MPNs in the molecular era. Efforts are being made to predict survival after the use of specific drugs or allogeneic hematopoietic stem cell transplantation. These treatment outcome prediction models enable the establishment of personalized treatment strategies, thereby improving the OS of patients with MPNs.

随着对骨髓增生性肿瘤(mpn)分子特征知识的不断增加,现有的基于临床、实验室和细胞遗传学信息的预后模型正在被结合起来。真性红细胞增多症(PV)和原发性血小板增多症(ET)的突变增强国际预后系统(MIPSS)改善了预后评估。在显性原发性骨髓纤维化(PMF)的情况下,MIPSS70及其后来的修订版(MIPSS70+和MIPSS70+ 2.0版本)有效地预测了患者的总生存期(OS)。由于与明显的PMF相比,PV后和et后骨髓纤维化具有不同的生物学和临床过程,因此建立了PV和et后继发骨髓纤维化预后模型。虽然这些分子启发的预后模型需要在未来的研究中进一步验证,但它们有望在分子时代提高mpn患者的预后能力。人们正在努力预测使用特定药物或同种异体造血干细胞移植后的生存率。这些治疗结果预测模型可以建立个性化的治疗策略,从而提高mpn患者的OS。
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引用次数: 1
Current status of red blood cell manufacturing in 3D culture and bioreactors. 三维培养和生物反应器中红细胞制造的现状。
IF 2.2 Q3 Medicine Pub Date : 2023-04-30 DOI: 10.5045/br.2023.2023008
Soonho Kweon, Suyeon Kim, Eun Jung Baek

Owing to donor-related issues, blood shortages and transfusion-related adverse reactions have become global issues of grave concern. In vitro manufactured red blood cells (RBCs) are promising substitutes for blood donation. In the United Kingdom, a clinical trial for allogeneic mini transfusion of cultured RBCs derived from primary hematopoietic stem cells has recently begun. However, current production quantities are limited and need improved before clinical use. New methods to enhance manufacturing efficiencies have been explored, including different cell sources, bioreactors, and 3-dimensional (3D) materials; however, further research is required. In this review, we discuss various cell sources for blood cell production, recent advances in bioreactor manufacturing processes, and the clinical applications of cultured blood.

由于与献血者有关的问题,血液短缺和与输血有关的不良反应已成为严重关切的全球性问题。体外制造的红细胞(rbc)是很有前途的献血替代品。在英国,最近开始了一项从原发性造血干细胞中提取培养红细胞的异体微量输血的临床试验。然而,目前的生产数量有限,在临床使用之前需要改进。已经探索了提高制造效率的新方法,包括不同的细胞来源,生物反应器和三维(3D)材料;然而,还需要进一步的研究。在这篇综述中,我们讨论了用于血细胞生产的各种细胞来源、生物反应器制造工艺的最新进展以及培养血液的临床应用。
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引用次数: 0
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Blood Research
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