Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia
Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia
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DOI：
10.1532/ijh97.04033
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发表时间：
2004-07-01
影响因子：
2.1
通讯作者：
Fujita, S
中科院分区：
文献类型：
--
作者：
Hato, T;Yamanouchi, J;Fujita, S
甲磺酸伊马替尼和利妥昔单抗分别是针对bcr-abl融合蛋白和CD20抗原的分子靶向药物。虽然这些药物具有优异的抗癌效果，但一个主要的问题是耐药性。我们调查了一例患有费城染色体阳性和CD20(+)急性淋巴细胞白血病的患者，他对伊马替尼和利妥昔单抗获得了耐药性。伊马替尼治疗导致迅速的细胞遗传学缓解，但此后不久就出现了耐药性。ABL基因的激活域测序和等位基因特异性聚合酶链式反应分析显示，在治疗前存在一个点突变，导致E255V替换。患者在接受温和化疗后再接受利妥昔单抗治疗，血液学和细胞遗传学缓解持续了5.5个月。经美罗华治疗后复发的白血病细胞不仅出现ABL基因E255V突变，而且由于CD20基因转录受损而导致CD20抗原丢失。双色流式细胞仪分析结果显示，伊马替尼治疗前存在少量CD20(-)白血病细胞。这些结果表明，在治疗前存在携带针对伊马替布和利妥昔单抗的靶分子的遗传扰动的白血病亚克隆。原发耐药克隆的存在提示两种分子靶向药物联合治疗无法克服白血病的耐药性。(C)2004年日本血液病学会。
Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20(+) acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20(-) leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatimb and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia. (C) 2004 The Japanese Society of Hematology.