肥大细胞白血病是一种罕见的侵袭性疾病,主要与KITD816V突变。对常规多化疗反应不佳,肥大细胞白血病对midostaurin治疗的总体反应率(ORR)为50%,但完全缓解率约为0%。因此,midostaurin耐药的潜在机制以及midostaurin对基因表达谱和肥大细胞白血病体内微环境的确切影响对于设计针对肿瘤细胞和肿瘤微环境的定制组合疗法至关重要。在这里,我们报告了一名59岁的男性肥大细胞白血病患者,其KITF522C突变接受了midostaurin治疗。在midostaurin治疗前和治疗后10个月进行外周血单细胞测序和骨髓全外显子组测序(WES)。根据临床反应,与预处理像差相比,肥大细胞的减少和T-的增加,NK,外周血中的B细胞,观察到骨髓中KITF522C突变负荷的降低。同时,RUNX1突变的出现,基因表达上调(RPS27A,RPS6,UBA52,RACK1)对肿瘤细胞,T和NK细胞的TIGIT频率增加,Midostaurin治疗后观察到CTLA4和LAG3的表达,预测该患者的疾病进展。据我们所知,这是第一例报告临床的病例,免疫学,和肥大细胞白血病患者在midostaurin治疗前后的分子变化,说明肥大细胞白血病中midostaurin耐药的体内机制,为开发靶向癌基因成瘾后避免肿瘤进展和延长患者生存期的序贯选择提供重要线索。
Mast cell leukemia is a rare and aggressive disease, predominantly with KIT D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the
midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of
midostaurin resistance and the exact impacts of
midostaurin on both gene expression profile and mast cell leukemia microenvironment in vivo are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with KIT F522C mutation treated with
midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the KIT F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of RUNX1 mutation, upregulations of genes expression (RPS27A, RPS6, UBA52, RACK1) on tumor cells, and increased frequencies of T and NK cells with TIGIT, CTLA4, and LAG3 expression were observed after
midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the in vivo mechanisms of
midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients\' survival.