Laboratory of Molecular Diagnostics, Hungarian National Blood Transfusion Service, St. István-St. László Hospital, Budapest, Hungary.
Acta Haematol. 2012;127(1):34-42. doi: 10.1159/000331472. Epub 2011 Oct 14.
Additional chromosome abnormalities (ACAs), mutations of the BCR-ABL tyrosine kinase domain (TKD) and BCR-ABL splice variants may cause resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoid leukemia (ALL).
Karyotyping and BCR-ABL TKD mutation screening were performed in 71 imatinib-resistant CML patients and 6 Ph+ ALL patients. A total of 56 out of these 77 patients received second-generation TKI.
ACAs were present in 30 of 65 imatinib-resistant patients (46%). In 27 of 74 imatinib-resistant patients (36%), 15 different BCR-ABL TKD mutations were detected. Mutations were found in 25% of chronic-phase patients (12/47), 33% of accelerated-phase patients (5/15), 71% of blast crisis CML patients (5/7) and 100% of ALL patients. In nilotinib-resistant patients, Y253H, T315I and F359I/V mutations were detected; in dasatinib-resistant patients, L248M, E279K and T315I mutations were detected. T315I was found more frequently in patients on dasatinib than on imatinib therapy. The presence of ACAs predicted shorter survival during first- and second-generation TKI therapy, while TKD mutations only influenced survival during second-generation TKI therapy.
For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.
在慢性髓性白血病（CML）和费城阳性（Ph+）急性淋巴细胞白血病（ALL）中，额外的染色体异常（ACAs）、BCR-ABL 酪氨酸激酶结构域（TKD）突变和 BCR-ABL 剪接变异体可能导致对第一代和第二代酪氨酸激酶抑制剂（TKIs）的耐药。
对 71 例伊马替尼耐药的 CML 患者和 6 例 Ph+ALL 患者进行了染色体核型分析和 BCR-ABL TKD 突变筛查。共有 56 例患者接受了第二代 TKI 治疗。
在 65 例伊马替尼耐药的患者中有 30 例（46%）存在 ACAs。在 74 例伊马替尼耐药的患者中有 15 例（20%）检测到 15 种不同的 BCR-ABL TKD 突变。突变发生在慢性期患者中的比例为 25%（12/47），加速期患者中的比例为 33%（5/15），急变期 CML 患者中的比例为 71%（5/7），ALL 患者中的比例为 100%。在尼洛替尼耐药的患者中，检测到 Y253H、T315I 和 F359I/V 突变；在达沙替尼耐药的患者中，检测到 L248M、E279K 和 T315I 突变。在接受达沙替尼治疗的患者中，T315I 的检出率高于接受伊马替尼治疗的患者。ACAs 的存在预测了第一代和第二代 TKI 治疗期间的生存较短，而 TKD 突变仅影响第二代 TKI 治疗期间的生存。
对于 TKI 耐药的患者，突变和 ACA 筛查可能有助于识别预后较差的患者。
