慢性髓性白血病患者对伊马替尼（格列卫）反应的分子监测：沙特阿拉伯一家三级医疗医院的经验。

Molecular monitoring of response to imatinib (Glivec) in chronic myeloid leukemia patients: experience at a tertiary care hospital in Saudi Arabia.

作者信息

Khalil Salem H, Abu-Amero Khaled K, Al Mohareb Fahad, Chaudhri Naeem A

机构信息

Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

出版信息

Genet Test Mol Biomarkers. 2010 Feb;14(1):67-74. doi: 10.1089/gtmb.2009.0126.

DOI:10.1089/gtmb.2009.0126

PMID:19943786

Abstract

AIM

The aim of this study was to evaluate the response and resistance of cases to chronic myeloid leukemia (CML) therapy with tyrosine kinase (TK) inhibitors (imatinib mesylate) and to search for mutations in the breakpoint cluster region (BCR)-Abelson murine leukemia (ABL) kinase domain prior to and during therapy.

METHODS

Molecular response was assessed with real-time quantitative reverse transcription-polymerase chain reaction and was expressed as the ratio between BCR-ABL and ABL (k562 cell line) x 100. In addition, we searched for mutations in BCR-ABL kinase domain by amplification and direct sequencing of cDNA products of archived RNA samples.

RESULTS

There were 85 cases of CML Philadelphia-chromosome-positive patients. Major molecular response [corrected] (MMR) of 0.05% was achieved in 40 (47%) of 85 patients and 3-log reduction was achieved in 37 (44%) after 6 months of imatinib therapy. When molecular monitoring was extended to 12 months in a subset of delayed responsive cases (17 cases) who did not achieve an MMR at 6 months, significant changes in BCR-ABL/ABL ratio were noticed. Fifteen de novo CML patients were started directly on treatment and were monitored for BCR-ABL/ABL ratio for a further period of up to 24 months. Their median of BCR-ABL/ABL ratio was 18% at diagnosis, 0.3% after 6 months, 0.2% after 12 months, and 0.01% after 18 and 24 months. Four (27%) of 15 patients achieved MMR as 3-log reduction after 6 months, 6 (40%) after 12 months, 9 (60%) after 18 months, and 7 (46%) after 24 months. No mutation(s) or polymorphism(s) were detected in all tested patients at diagnosis, at 6 months following imatinib and following 12 months for patients showing delayed response.

CONCLUSION

BCR-ABL mutations are rare in early chronic phase and increases with CML disease progression. Therefore, search for other causes in resistant cases at this phase should be sought.

摘要

目的

本研究旨在评估慢性髓性白血病（CML）患者对酪氨酸激酶（TK）抑制剂（甲磺酸伊马替尼）治疗的反应和耐药情况，并在治疗前和治疗期间寻找断点簇区域（BCR）-阿贝尔森鼠白血病（ABL）激酶结构域的突变。

方法

采用实时定量逆转录-聚合酶链反应评估分子反应，并以BCR-ABL与ABL（K562细胞系）的比值×100表示。此外，我们通过对存档RNA样本的cDNA产物进行扩增和直接测序，来寻找BCR-ABL激酶结构域的突变。

结果

共有85例CML费城染色体阳性患者。85例患者中有40例（47%）在伊马替尼治疗6个月后达到了0.05%的主要分子反应[校正后]（MMR），37例（44%）达到了3对数级的降低。当对6个月时未达到MMR的部分延迟反应病例（17例）进行长达12个月的分子监测时，发现BCR-ABL/ABL比值有显著变化。15例初发CML患者直接开始治疗，并对其BCR-ABL/ABL比值进行了长达24个月的进一步监测。他们诊断时BCR-ABL/ABL比值的中位数为18%，6个月后为0.3%，12个月后为0.2%，18个月和24个月后为0.01%。15例患者中有4例（27%）在6个月后达到了3对数级降低的MMR，12个月后为6例（40%），18个月后为9例（60%），24个月后为7例（46%）。在所有检测患者的诊断时、伊马替尼治疗6个月后以及对延迟反应患者治疗12个月后，均未检测到突变或多态性。