Evolving Chemotherapy Free Regimens for Acute Promyelocytic Leukemia

Abstract

With the treatment advances over the last three decades, acute promyelocytic leukemia (APL) has evolved from being the most malignant form of acute leukemia to a leukemia with excellent long term survival rates. In the present review, we have summarized data leading to the development of the currently used treatment regimens for APL, which incorporate either none or minimal chemotherapeutic drugs. We have discussed the historical aspects of APL treatment along with the challenges associated with chemotherapy-based approaches and our experience with the use of single agent arsenic trioxide (ATO) which was one of the first successful, non-chemotherapy approaches used for APL. Subsequently, we have reviewed the data from major clinical trials in low-intermediate risk APL and high risk APL which guide the current clinical practice in APL management. With accumulating data on oral ATO, we postulate that the treatment for low-intermediate risk APL will be a completely oral ATO + ATRA regimen in the future. While for high-risk APL, we believe that minimal anthracycline use with ATO + ATRA might become the standard of care soon. A number of promising non-chemotherapy drugs with pre-clinical data would merit clinical testing in the high risk and relapsed setting, with potential to translate to a complete oral chemotherapy free combination regimen in combination with ATO and ATRA.

Keywords: acute promyelocytic leukemia; all-trans retinoid acid (ATRA); arsenic trioxide; differentiation therapy; non-chemotherapeutic treatment.

Figure 1

Synergy between arsenic trioxide (ATO) and bortezomib in the treatment of acute promyelocytic leukemia. 1. There is a significant contribution of microenvironment mediated resistance to ATO at relapse (41). 2. This resistance is mediated predominantly by the NF-kB pathway (41). 3. Preclinical studies show a synergistic effect of bortezomib and ATO in overcoming ATO resistance (42). 4. With the combination of ATO and bortezomib, the PML-RARA oncoprotein is cleared through a p62-dependent autophagy pathway (42). 5. The mechanism of the synergy between ATO and bortezomib involved downregulation of the NF-kB pathway, increased unfolded protein response, and an increased generation of reactive oxygen species in the malignant cell (42). 6. This work has been translated to a phase 2 clinical trial for relapsed APL wherein we have demonstrated that the combination of ATO, ATRA, and anthracycline with the addition of bortezomib is safe (43).