Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under treatment with midostaurin
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DOI：
10.1182/blood.2020007626
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发表时间：
2021-06-03
期刊：
影响因子：
20.3
通讯作者：
Bullinger, Lars
中科院分区：
文献类型：
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作者：
Schmalbrock, Laura K.;Dolnik, Anna;Bullinger, Lars
在国际随机3期AML临床试验(对60岁以下患者进行的Flt3AML随机试验)试验中，多激酶抑制剂米哚妥林显著提高了18至59岁的Flt3突变急性髓系白血病(AML)患者的总体无事件存活率。然而，服用米多妥林的患者中，只有59%的患者达到了方案指定的完全缓解(CR)，并且几乎一半的患者实现了CR复发。为了探索耐药的潜在机制，我们研究了Flt3内部串联复制(ITD)阳性AML患者的克隆进化模式，这些患者进入了APECAL或德国-奥地利急性髓系白血病研究组16-10试验，并接受了米多妥林治疗。为此，来自54名患者的配对样本在诊断时和复发或难治性疾病时获得，使用基于基因扫描的传统检测Flt3-ITD和整个外显子组测序进行分析。在疾病抵抗或进展时，几乎一半(46%)的患者Flt3-ITD阴性，但信号通路(如MAPK)发生获得性突变，从而提供了新的增殖优势。在持续存在Flt3-ITD的病例中，11%的耐药ITD克隆被发现为潜在的疾病驱动因素。在32%的病例中，没有观察到Flt3-ITD突变改变，这表明要么是耐药机制绕过了Flt3抑制，要么是由于药物水平不足而失去了米哚妥林的抑制活性。综上所述，我们的研究为突变Flt3-ITD的AML在米哚妥林联合强化化疗治疗下的克隆进化和耐药机制提供了新的见解。
In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlyingmechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian AcuteMyeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD-mutated AML under treatment with midostaurin in combination with intensive chemotherapy.