曲美替尼
幼年粒单核细胞白血病
少年
医学
内科学
阿扎胞苷
肿瘤科
耐火材料(行星科学)
变构调节
白血病
癌症研究
生物
干细胞
造血
受体
MAPK/ERK通路
激酶
天体生物学
遗传学
基因表达
基因
DNA甲基化
作者
Elliot Stieglitz,Alex G. Lee,Steven P. Angus,Christopher Davis,Donald A. Barkauskas,David Hall,Scott C. Kogan,Julia Meyer,Steven D. Rhodes,Sarah K. Tasian,Xiaoling Xuei,Kevin Shannon,Mignon L. Loh,Elizabeth Fox,Brenda J. Weigel
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2024-06-11
卷期号:14 (9): 1590-1598
被引量:2
标识
DOI:10.1158/2159-8290.cd-23-1376
摘要
Abstract Juvenile myelomonocytic leukemia (JMML) is a hematologic malignancy of young children caused by mutations that increase Ras signaling output. Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment, but patients with relapsed or refractory (advanced) disease have dismal outcomes. This phase II trial evaluated the safety and efficacy of trametinib, an oral MEK1/2 inhibitor, in patients with advanced JMML. Ten infants and children were enrolled, and the objective response rate was 50%. Four patients with refractory disease proceeded to HSCT after receiving trametinib. Three additional patients completed all 12 cycles permitted on study and continue to receive off-protocol trametinib without HSCT. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Transcriptomic and proteomic analyses provided novel insights into the mechanisms of response and resistance to trametinib in JMML. ClinicalTrials.gov Identifier: NCT03190915. Significance: Trametinib was safe and effective in young children with relapsed or refractory JMML, a lethal disease with poor survival rates. Seven of 10 patients completed the maximum 12 cycles of therapy or used trametinib as a bridge to HSCT and are alive with a median follow-up of 24 months. See related commentary by Ben-Crentsil and Padron, p. 1574
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