Recently, novel drugs like venetoclax plus 5-azacytidine (VA) were reported to have promising efficacy in refractory acute myeloid leukemia (AML). However, there are still some cases presented with novel drugs resistance, and its genetics composition and clinical phenotype are urging to study. We described a 58-year-old patient who was resistant to intensive chemotherapy. This refractory AML was presented with the persistence of RUNX1, IDH1 and DNMT3A mutations. RUNX1 mutations disappeared and leukemia cutis ensued after multiple chemotherapies. Leukemia cutis exhibited NRAS mutations in addition to IDH1 and DNMT3A mutations. With the VA salvage treatment, platelets were recovered to the normal level and blasts in bone marrow and peripheral blood were moderately controlled. However, leukemia cutis did not resolve. Unexpectedly, BM blasts obtained the new NRAS mutations after VA treatment, and consequently experienced leukostasis with two distinct leukemia clones. After survival of 230 days, this patient died because of spontaneous cerebral hemorrhage. This case highlights presentation of leukemia cutis with simultaneous mutations of IDH1, DNMT3A and NRAS in AML patients might act as a resistant niche to avoid the toxicity of multiple drugs including VA. There is unmet need to validate this result in the clinical trials or a large cohort of patients in the future.

中文翻译：

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具有IDH1，DNMT3A和NRAS突变的角质层白血病可赋予难治性AML患者耐Venetoclax加5-氮杂胞苷的耐药性

近来，据报道，诸如venetoclax加5-氮杂胞苷（VA）的新药在难治性急性髓细胞性白血病（AML）中具有良好的疗效。然而，仍然有一些病例出现了新药耐药性，并敦促对其遗传学组成和临床表型进行研究。我们描述了一位对强化化疗有抵抗力的58岁患者。这种顽固性AML具有RUNX1，IDH1和DNMT3A突变的持久性。经过多次化学疗法后，RUNX1突变消失，随后发生了皮肤角质白血病。除了IDH1和DNMT3A突变外，皮肤角质病还显示NRAS突变。通过VA抢救治疗，血小板恢复到正常水平，并适度控制了骨髓和外周血中的原始细胞。但是，角质层白血病没有解决。不料，BM处理后的BM blasts获得了新的NRAS突变，因此经历了两个不同的白血病克隆的白细胞停滞。存活230天后，该患者因自发性脑出血死亡。该病例突显出AML患者中出现IDH1，DNMT3A和NRAS同时突变的皮肤角质病，可能是一种耐药性市场，以避免包括VA在内的多种药物的毒性。在未来的临床试验或大量患者中验证此结果的需求尚未得到满足。AML患者中的DNMT3A和NRAS可能是一种耐药性小生境，以避免多种药物（包括VA）的毒性。在未来的临床试验或大量患者中验证此结果的需求尚未得到满足。AML患者中的DNMT3A和NRAS可能是一种耐药性小生境，以避免多种药物（包括VA）的毒性。在未来的临床试验或大量患者中验证此结果的需求尚未得到满足。