Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia
Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia
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DOI：
10.1007/s12185-013-1365-1
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发表时间：
2013-06-01
影响因子：
2.1
通讯作者：
Takeshita, Akihiro
中科院分区：
文献类型：
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作者：
Takeshita, Akihiro
70% - 80%的急性髓性白血病（AML）患者在接受强化化疗后达到完全缓解，但超过50%的缓解患者随后复发，这通常与临床耐药有关。基于单克隆抗体（mAb）的治疗已经被开发出来，通过与单克隆抗体偶联来增加细胞毒性药物的选择性。Gemtuzumab ozogamicin （GO）是细胞毒性药物（calicheamicin衍生物）的偶联物，与靶向CD33抗原的重组人源化单抗相连，CD33抗原在90%以上的AML患者的白血病细胞上表达。该偶联单抗是在I期和II期研究取得令人满意的结果后推出的。然而，最初的III期研究并未证实氧化石墨烯与常规化疗联合使用的疗效。随后的几项III期研究显示了氧化石墨烯在有利和中等风险AML中的疗效。已经报道了几种针对氧化石墨烯的抗性机制。多药耐药p -糖蛋白（P-gp）是一种跨膜糖蛋白，可从细胞中泵出许多抗白血病药物，也会影响氧化石墨烯。因此，氧化石墨烯已与耐多药调节剂（如环孢素）联合使用，并在没有P-gp的情况下使用。一些研究者已经报道了氧化石墨烯在急性早幼粒细胞白血病（APL）中使用的成功结果。氧化石墨烯也被认为对全反式维甲酸（ATRA）、砷酸和常规化疗药物治疗后复发的病例有效。氧化石墨烯的疗效将主要研究在有利风险的AML，如核心结合因子白血病和APL。此外，应讨论与其他化疗的合适组合和给药计划。
Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed.