New Strategies in Acute Promyelocytic Leukemia: Moving to an Entirely Oral, Chemotherapy-Free Upfront Management Approach

Abstract

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.

Acute promyelocytic leukemia: where did we start, where are we now, and the future

“… 95 In summary, the oral formulation of ATO exhibit excellent activity and combinations with ATRA provide an opportunity for a completely oral, chemotherapy-free regimen for treating APL. 96 Although oral ATO is an attractive therapeutic approach, longer-term follow-up is needed, and it is not yet readily available in the United States.…”

Therapy-related myelodysplastic syndrome after successful treatment of acute promyelocytic leukemia: case report and literature review

“…APL presents a particular sensitivity to the differentiating effect of alltrans-retinoic acid (ATRA) and to the apoptotic effect of arsenic trioxide (ATO) by targeting and inducting differentiation of leukemia initiating cells (LIC) [8,9]. New data supports the view that the main mechanism of action of ATRA and ATO in eliminating leukemia initiating cells is by degrading the PML-RARA gene fusion product [10].…”

Fighting against hematological malignancy in China: from unique system to global impact

“…Recently, a prospective, multi-center, randomized, controlled study led by the Shanghai and Beijing groups proved that oral RIF achieved a high rate of remission and survival comparable with that of intravenous ATO as a front-line treatment for newly diagnosed APL, the 3-year overall survival rate (OS) was 99.1% (RIF) and 96.6% (ATO) (Table 1) [5]. Later, in a single-arm study of non-high-risk patients by the Beijing group [31,32], oral RIF and ATRA were administered to patients in a largely home-based treatment protocol, promoting the new era to "Cure leukemia in out-patient department".…”