复发和难治性儿童t细胞急性淋巴细胞白血病治疗的潜在生物学、挑战和新兴概念

IF 13.4 1区 医学 Q1 HEMATOLOGY
Patrícia Amaral, Rhona Christie, Daisy O. F. Gresham, Emma J. M. Lucas, Luyao Kevin Xu, Lena Behrmann, Jonathan Bond, Sofie Degerman, Frederik W. van Delft, Steven Goossens, Melanie Hagleitner, Chris Halsey, Nicholas Jones, Tim Lammens, Frank N. van Leeuwen, Marc R. Mansour, Panagiotis Ntziachristos, David O’Connor, João T. Barata
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引用次数: 0

摘要

儿童t细胞急性淋巴细胞白血病(R/R T-ALL)的复发和难治性疾病仍然是一个主要的临床挑战。复发或对初始治疗表现出耐药性的儿童的结局令人沮丧,尽管积极治疗,生存率往往低于25%。考虑到T-ALL具有遗传、表观遗传和转录后异质性以及器官和生态位特异性(如中枢神经系统)的特点,所有这些都是疾病进展和治疗耐药性的基础,为了最大限度地减少毒性和改善结果,针对R/R T-ALL潜在生物学的个体化精准医学方法尤为重要。在这里,我们总结了目前对儿童T-ALL生物学复杂性的理解以及这些知识如何在临床中得到利用,强调需要创新的治疗途径来改善R/R T-ALL儿童的预后。新兴的方法有希望或显示明显的结果,包括蛋白酶体抑制剂、BCL-2拮抗剂、JAK(用于JAK和il - 7r驱动的病例)、ABL和SRC家族酪氨酸激酶(用于lck激活的病例)、MEK或PI3K-mTOR抑制剂。myc靶向药物、DNA去甲基化药物、组蛋白去乙酰化酶抑制剂、剪接调节剂或探索T-ALL代谢脆弱性的药物是潜在的药物干预的其他例子。免疫疗法,特别是靶向CD7和其他标记物的CAR - t细胞产品,以及生物制剂(例如靶向CD38)正在开发中,并且越来越受到关注。这些药物应该合理地整合到精确的药物联合治疗中,根据遗传、表观遗传和转录后的见解,这将是完善风险分层和最小化耐药风险所必需的。利用人工智能和机器学习的新策略可以加速发现和优化治疗框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Underlying biology, challenges and emergent concepts in the treatment of relapsed and refractory pediatric T-cell acute lymphoblastic leukemia

Underlying biology, challenges and emergent concepts in the treatment of relapsed and refractory pediatric T-cell acute lymphoblastic leukemia

Relapsed and refractory disease in children with T-cell acute lymphoblastic leukemia (R/R T-ALL) remains a major clinical challenge. Outcomes for children who relapse or exhibit resistance to initial treatments are dismal, with survival rates frequently below 25% despite aggressive therapy. To minimize toxicities and improve outcomes, individualized precision medicine approaches targeting the underlying biology of R/R T-ALL are especially important, considering that T-ALL is characterized by genetic, epigenetic and posttranscriptional heterogeneity, and organ and niche specificities (e.g. the central nervous system), all of which underlie disease progression and therapy resistance. Here, we summarize the current understanding of the complexity of pediatric T-ALL biology and how such knowledge may be clinically leveraged, emphasizing the need for innovative therapeutic routes to improve outcomes for children with R/R T-ALL. Emerging approaches that hold promise or show palpable results include proteasome inhibitors, BCL-2 antagonists, and JAK (for JAK- and IL-7R-driven cases), ABL and SRC family tyrosine kinase (for LCK-activated cases), MEK or PI3K-mTOR inhibitors. MYC-targeting agents, DNA demethylating agents, histone deacetylase inhibitors, splicing modulators, or drugs exploring T-ALL metabolic vulnerabilities, are other examples for potential pharmacological intervention. Immunotherapies, particularly CAR T-cell products targeting CD7 and other markers, but also biologics (e.g. targeting CD38), are under development and increasing interest. These agents should be rationally integrated into precision medicine combination therapies informed by genetic, epigenetic, and posttranscriptional insights that will be essential to refine risk stratification and minimize the risk of resistance. Novel strategies leveraging artificial intelligence and machine learning could accelerate discovery and optimize treatment frameworks.

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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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