骨髓恶性肿瘤中的Tagraxofusp。

IF 3.3 4区 医学 Q2 HEMATOLOGY
Antonella Bruzzese, Enrica Antonia Martino, Caterina Labanca, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Antonino Neri, Annalisa Imovilli, Fortunato Morabito, Ernesto Vigna, Massimo Gentile
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引用次数: 0

摘要

Tagraxofusp(或SL-401)是一种由人白细胞介素-3组成的重组分子,其结合与截短的白喉毒素(DT)融合的肿瘤细胞上的CD123。Tagraxofusp最显著的成功来自对母细胞浆细胞样树突状细胞肿瘤(BPDCN)患者的研究,这是一种侵袭性疾病,通常对传统化疗难以治愈。Tagraxofusp在BPDCN患者的早期I/II期研究中具有可接受的安全性和高效性。另一项II期研究证实了良好的反应率,导致美国食品药品监督管理局和欧洲药品管理局批准了tagraxofusp用于治疗BPDCN。考虑到其高效性和可控的安全性,tagraxofusp在其他细胞表面CD123高表达的髓系恶性肿瘤中突然被探索出来,无论是单药治疗还是联合治疗。在这些组合中,三联体tagraxofusp氮杂胞苷venetoclax似乎特别令人感兴趣。此外,组合策略可用于克服tagraxofusp抗性。DPH1(白喉酰胺生物合成1)的下调通常与这种抗性现象有关,DPH1是负责将eEF2上的组氨酸715转化为白喉酰胺的酶,然后是ADP核糖基化DT的直接靶标。已经发现阿扎胞苷可以逆转DHP1的表达并恢复对tagraxofusp的敏感性。总之,tagraxofusp在BPDCN中的成功为其在其他CD123阳性恶性肿瘤中的应用铺平了道路。目前,一些正在进行的试验正在探索tagraxofusp在不同骨髓肿瘤中的应用。本综述旨在总结tagraxofusp在BPDCN和其他CD123阳性髓系恶性肿瘤中的实际作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Tagraxofusp in myeloid malignancies

Tagraxofusp in myeloid malignancies

Tagraxofusp (or SL-401) is a recombinant molecule composed of human interleukin-3 that binds CD123 on neoplastic cells fused to a truncated diphtheria toxin (DT). Tagraxofusp's most significant success has come from studies involving patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive disease that is usually refractory to conventional chemotherapy. Tagraxofusp had an acceptable safety profile and high efficacy in early phase I/II studies on patients with BPDCN. Another phase II study confirmed the good response rates, resulting in Food and Drugs Administration and European Medicine Agency approval of tagraxofusp for the treatment of BPDCN. Considering its high efficacy and its manageable safety profile, tagraxofusp has been suddenly explored in other myeloid malignancies with high expression of cell surface CD123, both in monotherapy or combination strategies. The triplet tagraxofusp-azacytidine-venetoclax appears to be of particular interest among these combinations. Furthermore, combination strategies may be used to overcome tagraxofusp resistance. The downregulation of DPH1 (diphthamide biosynthesis 1), the enzyme responsible for the conversion of histidine 715 on eEF2 to diphthamide, which is then the direct target of ADP ribosylation DT, is typically associated with this resistance phenomenon. It has been discovered that azacitidine can reverse DHP1 expression and restore sensitivity to tagraxofusp. In conclusion, the success of tagraxofusp in BPDCN paved the way for its application even in other CD123-positive malignancies. Nowadays, several ongoing trials are exploring the use of tagraxofusp in different myeloid neoplasms. This review aims to summarize the actual role of tagraxofusp in BPDCN and other CD123-positive myeloid malignancies.

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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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