Personalized Medicine in Histiocytic Disorders: Novel Targets in Patients Without MAPK Alterations.

IF 5.3 2区 医学 Q1 ONCOLOGY
JCO precision oncology Pub Date : 2024-11-01 Epub Date: 2024-11-22 DOI:10.1200/PO-24-00471
Katherine E R Smith, Aldo A Acosta-Medina, Surendra Dasari, Wasantha Ranatunga, Karen L Rech, Aishwarya Ravindran, Jason R Young, Patrick W McGarrah, Gordon J Ruan, Saurabh S Zanwar, Jenny J Li, Julio C Sartori-Valinotti, Jessica N Snider, Thomas E Witzig, Gaurav Goyal, Ronald S Go, Jithma P Abeykoon
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引用次数: 0

Abstract

Purpose: BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective.

Methods: We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations.

Results: Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months.

Conclusion: We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.

组织细胞疾病的个性化医疗:无 MAPK 改变患者的新靶点
目的:BRAF和MEK抑制剂是组织细胞疾病(如埃尔德海姆-切斯特病(ECD))的标准治疗方法。有些患者缺乏 MAPK 通路改变,因此这些治疗方法的效果较差:我们描述了三名组织细胞疾病患者,他们都有新的非MAPK通路改变。在适当的情况下,我们通过基因组和硅学分析对这些改变进行了研究,然后根据基因组的改变合理选择标签外药物进行治疗:结果:患者1的ECD进展迅速,累及中枢神经系统。发现了 CSF1R 框内缺失(p.S560_P566del),硅学建模预测为功能增益突变。针对这一突变使用了培西达替尼,结果在2个月内获得了临床完全应答(CR),3个月后通过影像学检查获得了部分应答(PR)。15 个月后,该病对培西达替尼产生耐药性,并转化为组织细胞肉瘤。患者2患有仅累及皮肤的黄疽性肉瘤疾病。通过 RNA 测序确定了 KIF5B-FGFR1 融合,并用培美加替尼进行靶向治疗。随访 24 个月后,她仍处于临床 PR 阶段。患者3的ECD累及骨髓、胃肠道和皮下组织。经鉴定,患者体内存在 MEF2C-FLT3 融合基因,并以索拉非尼为靶向药物。他在3个月内达到了临床CR和影像学PR,并持续了30个月:我们报告了三名患有组织细胞疾病且携带新型变异的患者,他们对标签外的组织细胞疾病特异性激酶抑制剂产生了持续反应。MAPK通路以外的致病变体,包括意义不明的变体,都可以用现成的小分子药物作为靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
9.10
自引率
4.30%
发文量
363
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