PDF(Pubmed)
Abstract：
We performed sequential molecular analyses of a 75-year-old woman with de novo FLT3-ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, FLT3-ITD, NPM1, DNMT3A, and IDH2 mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. FLT3-ITD and NPM1 mutations were persistently positive, and the patient received gilteritinib therapy. Although the FLT3-ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and CBL mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the FLT3-ITD clone was detected again. Gilteritinib treatment was restarted, and FLT3-ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) FLT3-ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.
摘要：
我们对一名接受gilteritinib治疗43个月的从头FLT3-ITD阳性急性髓细胞性白血病（AML）的75岁女性进行了序贯分子分析。在诊断的时候,她的核型是正常的，然而，FLT3-ITD,NPM1,DNMT3A,并检测到IDH2突变。她接受了柔红霉素和阿糖胞苷的诱导治疗，并实现了血液学完全缓解（HCR）。在达到HCR之后,她接受了氮杂胞苷或阿糖胞苷的巩固治疗，阿克拉比星，和粒细胞集落刺激因子。然而,AML在第一次HCR后八个月复发。FLT3-ITD和NPM1突变持续阳性，患者接受了gilteritinib治疗.尽管在gilteritinib治疗期间未检测到FLT3-ITD克隆，出现了具有单体7和CBL突变的克隆。gilteritinib治疗后15、24和32个月的骨髓检查显示多谱系血细胞发育不良，但成髓细胞没有增加。经过33个月的治疗，gilteritinib因为肠梗阻发展而停药两个月，并且再次检测到FLT3-ITD克隆。Gilteritinib治疗重新开始，FLT3-ITD变为阴性。我们的分析表明：（1）来自吉特替尼耐药克隆的造血是通过长期吉特替尼治疗产生的，和(2)FLT3-ITD克隆在不存在FLT3抑制的情况下重新获得克隆优势。这些发现表明gilteritinib影响克隆造血过程中显性克隆的选择。
