A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation
A Case of Tyrosine Kinase Inhibitor-Resistant Chronic Myeloid Leukemia, Chronic Phase with ASXL1 Mutation
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DOI：
10.1159/000506452
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发表时间：
2020-04
影响因子：
0.8
通讯作者：
O. Imataki;Tomoya Ishida;H. Kubo;Makiko Uemura;Yasuhito Nanya;K. Kawakami;S. Ogawa;N. Kadowaki
中科院分区：
文献类型：
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作者：
O. Imataki;Tomoya Ishida;H. Kubo;Makiko Uemura;Yasuhito Nanya;K. Kawakami;S. Ogawa;N. Kadowaki
血液恶性肿瘤，包括慢性粒细胞白血病（CML），表现出ASXL 1突变;然而，这些突变的功能和分子机制仍不清楚。ASXL 1最初被鉴定为肿瘤抑制基因，其功能丧失导致骨髓增生异常综合征（MDS）。ASXL 1突变在骨髓恶性肿瘤（包括MDS、急性髓性白血病）中很常见，并与疾病进展相关，在CML中也类似。在MDS中，ASXL 1突变与不良预后相关;然而，ASXL 1突变对CML的影响尚未得到充分描述。一名31岁男性被诊断为CML慢性期（CP）。实验室检查结果显示白色血细胞计数为187，200/µL，伴无症状脾肿大。外周血原始细胞计数为5.0%，骨髓为7.3%。染色体分析除t（9;22）（q34;q11.2）外，无其他染色体异常。在发病时，索卡尔评分为1.4，表明高风险。患者接受酪氨酸激酶抑制剂（TKI）治疗，包括尼洛替尼600 mg/天、博舒替尼600 mg/天、泊那替尼45 mg/天和达沙替尼100 mg/天。然而，在连续TKI治疗1.5年后，最佳结局是血液学缓解。尽管在TKI治疗前和治疗期间反复分析了额外的染色体畸变和ABL 1激酶突变，但未检测到已知的遗传异常。此后，患者接受了来自HLA 7/8匹配的无关供体（HLA-Cw 1位点错配，移植物抗宿主方向）的骨髓移植。患者在移植后18天实现中性粒细胞植入，导致完全缓解，BCR-ABL 1 mRNA水平检测不到。然而，患者在121天后死于移植物抗宿主病和血栓性微血管病。在干细胞移植前对他的CML细胞进行基因序列分析，发现ASXL 1突变。在生理上，ASXL 1有助于表观遗传调控。在本病例报告的CML-CP患者中，ASXL 1突变通过不明确的耐药机制赋予TKI耐药。尽管CML中ASXL 1突变中TKI耐药的分子机制仍不清楚，但表观遗传调节是CML疾病进展的合理模式。强调了ASXL 1对CML的临床影响，包括预后。ASXL 1突变CML的治疗策略尚未确立。对该病例的讨论有望促进治疗选择。
Hematological malignancies, including chronic myeloid leukemia (CML), exhibit ASXL1 mutations; however, the function and molecular mechanism of these mutations remain unclear. ASXL1 was originally identified as tumor suppressor gene, in which loss of function causes myelodysplastic syndrome (MDS). ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described. A 31-year-old male was diagnosed as CML-chronic phase (CP). Laboratory findings showed a white blood cell count of 187,200/µL, with asymptomatic splenomegaly. Blast count was 5.0% in peripheral blood and 7.3% in bone marrow. There was no additional chromosomal abnormality except for t(9;22)(q34;q11.2) by chromosomal analysis. At onset, the Sokal score was 1.4, indicating high risk. The patient received tyrosine kinase inhibitor (TKI) therapy, comprising nilotinib ∼600 mg/day, bosutinib ∼600 mg/day, ponatinib ∼45 mg/day, and dasatinib ∼100 mg/day. Nevertheless, after 1.5 years of continuous TKI therapy, the best outcome was a hematological response. Although additional chromosomal aberrations and ABL1 kinase mutations were analyzed repeatedly before and during TKI therapy, known genetic abnormalities were not detected. Thereafter, the patient underwent bone marrow transplantation from an HLA 7/8 matched unrelated donor (HLA-Cw 1 locus mismatch, graft-versus-host direction). The patient achieved neutrophil engraftment, 18 days after transplantation, leading to complete remission with an undetectable level of BCR-ABL1 mRNA. The patient, however, died from graft-versus-host disease and thrombotic microangiopathy after 121 days. Gene sequence analysis of his CML cell before stem cell transplantation revealed ASXL1 mutations. Physiologically, ASXL1 contributes to epigenetic regulation. In the CML-CP patient in this case report, ASXL1 mutation conferred resistance to TKI through obscure resistance mechanisms. Even though a molecular mechanism for TKI resistance in ASXL1 mutation in CML has remained obscure, epigenetic modulation is a plausible mode of CML disease progression. The clinical impact including prognosis of ASXL1 for CML is underscored. And the treatment strategy of CML with ASXL1 mutation has not been established. A discussion of this case was expected to facilitate treatment options.