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.
©2014 American Association for Cancer Research.