New strategies in acute promyelocytic leukemia: moving to an entirely oral, chemotherapy-free upfront management approach.
New strategies in acute promyelocytic leukemia: moving to an entirely oral, chemotherapy-free upfront management approach.
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DOI：
10.1158/1078-0432.ccr-13-2725
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发表时间：
2014-10-01
期刊：
影响因子：
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通讯作者：
Gore SD
中科院分区：
文献类型：
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作者：
Zeidan AM;Gore SD
将全反式维甲酸（ATRA）和三氧化二砷（ATO）纳入急性早幼粒细胞白血病（APL）的治疗模式，可显著改善预后。对APL发病机制的研究取得了重要进展。ATO与ATRA相反，能够根除APL起始细胞并可导致治愈。临床前和临床数据证实了ATO和ATRA的协同作用，ATRA-ATO联合治疗在非高危APL患者中被证明不劣于标准ATRA化疗方案。砷的口服制剂在先进的临床试验中表现出优异的活性，它们与ATRA的组合为完全口服、无化疗方案治疗APL提供了机会。然而，仍然存在重大挑战。减少因出血并发症导致的早期死亡是一个重要的未满足需求领域。数据表明，在怀疑APL后延迟启动ATRA继续发生在社区，并导致早期死亡。关于砷在治疗顺序中的最佳位置和时间表以及口服制剂的作用仍然存在问题。完善微小残留病在指导治疗决策中的作用是重要的。开发新的靶向药物治疗复发性疾病需要更深入地了解ATRA和ATO的继发性耐药机制。
Incorporation of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) into the management paradigms of acute promyelocytic leukemia (APL) has markedly improved outcomes. Significant progress occurred in understanding the molecular pathogenesis of APL. ATO, in contrast with ATRA, is capable of eradicating the APL-initiating cells and can result in cure. Preclinical and clinical data confirmed the synergy of ATO and ATRA, and the ATRA–ATO combination was proved noninferior to a standard ATRA–chemotherapy regimen in patients with non–high-risk APL. Oral formulations of arsenic exhibited excellent activity in advanced clinical testing and their combinations with ATRA offer an opportunity for a completely oral, chemotherapy-free regimen for curing APL. Nonetheless, significant challenges remain. Reducing early death due to bleeding complications is an important area of unmet need. Data suggest that delays in initiation of ATRA upon suspecting APL continue to occur in the community and contribute to early mortality. Questions remain about the optimal place and schedule of arsenic in the therapeutic sequence and the role of the oral formulations. Refining the role of minimal residual disease in directing treatment decisions is important. Development of novel targeted agents to treat relapsed disease requires deeper understanding of the secondary resistance mechanisms to ATRA and ATO.