Important events in transforming APL from being a highly fatal to a highly curable disease
| Recognition of APL as a unique subtype of acute leukemia |
| In 1957, Hillestad1 first reported 3 patients with a highly fatal disease, which he designated as APL. APL was named AML M3100 in 1976. |
| In 1977, t(15;17)(q22;q21) was identified,40 while the PML-RARα fusion gene was cloned41,42 in 1991. The variant translocations, eg, t(11;17)(q23;q21),47,48 t(5;17)(q35;q21),101 t(11;17)(q13;q21),102 and dup(17)(q11;q21),103 were subsequently discovered. |
| Development of curative therapeutic approaches for APL |
| Pre-ATRA period |
| CT was first used against APL in 1967, and anthracycline was introduced to treat APL in 1973.3 |
| Incorporating ATRA in treating APL |
| Early results: ATRA was used to treat APL in 1985. In 1987, its efficacy on the first 6 patients was reported17 ; in 1988, Huang et al18 showed the high CR rate induced by ATRA in 24 APL cases. Clinical results using ATRA in treating APL in Western countries were reported in 1990.19,21 |
| International joint efforts in optimizing ATRA-based regimens: Since 1990, ATRA has been used in combination with CT, resulting in CR rates up to 90%-∼95%, and 5-year DFS up to 74%.24,25,27,,–30,104,105 |
| Studies on mechanisms of action of ATRA: In 1996, PML-RARα was shown to be a direct target of ATRA.106 ATRA-triggered degradation of PML-RARα was then shown to be mediated by caspases54 and proteasome.107 In 2000, gene expression networks underlying ATRA-induced APL cell differentiation were investigated, and many retinoic acid–induced genes were identified.108 |
| Incorporating ATO in treating APL |
| In 1992, Sun et al58 reported the efficacies of Ailing-1—a crude solution of ATO—in treating APL. In the mid-1990s, Chen et al60,61 showed the dose-dependent dual effects of ATO on APL cells, in which degradation of PML-RARα underlay mechanisms of action of ATO. Shen et al62 reported the first controlled trial using purified ATO in treating APL and investigated the pharmacokinetics of ATO in vivo. Efficacies of ATO in treating APL were confirmed worldwide.59,63,109,110 |
| ATRA/ATO combination as a synergistic therapy |
| Since 2000, ATRA/ATO combination has been applied to treat newly diagnosed APL. Shen et al85 and Liu et al86,111 reported that a shorter time to achieve CR, an earlier recovery of platelet count, a more profound reduction in PML-RARα transcript, and a much lower relapse rate of disease were obtained in newly diagnosed APL patients treated with ATRA in combination with ATO compared with therapy using ATRA or ATO alone. Similar results were reported by Estey et al87 and Wang et al.88 |
| Development of new agents |
| Recognition of APL as a unique subtype of acute leukemia |
| In 1957, Hillestad1 first reported 3 patients with a highly fatal disease, which he designated as APL. APL was named AML M3100 in 1976. |
| In 1977, t(15;17)(q22;q21) was identified,40 while the PML-RARα fusion gene was cloned41,42 in 1991. The variant translocations, eg, t(11;17)(q23;q21),47,48 t(5;17)(q35;q21),101 t(11;17)(q13;q21),102 and dup(17)(q11;q21),103 were subsequently discovered. |
| Development of curative therapeutic approaches for APL |
| Pre-ATRA period |
| CT was first used against APL in 1967, and anthracycline was introduced to treat APL in 1973.3 |
| Incorporating ATRA in treating APL |
| Early results: ATRA was used to treat APL in 1985. In 1987, its efficacy on the first 6 patients was reported17 ; in 1988, Huang et al18 showed the high CR rate induced by ATRA in 24 APL cases. Clinical results using ATRA in treating APL in Western countries were reported in 1990.19,21 |
| International joint efforts in optimizing ATRA-based regimens: Since 1990, ATRA has been used in combination with CT, resulting in CR rates up to 90%-∼95%, and 5-year DFS up to 74%.24,25,27,,–30,104,105 |
| Studies on mechanisms of action of ATRA: In 1996, PML-RARα was shown to be a direct target of ATRA.106 ATRA-triggered degradation of PML-RARα was then shown to be mediated by caspases54 and proteasome.107 In 2000, gene expression networks underlying ATRA-induced APL cell differentiation were investigated, and many retinoic acid–induced genes were identified.108 |
| Incorporating ATO in treating APL |
| In 1992, Sun et al58 reported the efficacies of Ailing-1—a crude solution of ATO—in treating APL. In the mid-1990s, Chen et al60,61 showed the dose-dependent dual effects of ATO on APL cells, in which degradation of PML-RARα underlay mechanisms of action of ATO. Shen et al62 reported the first controlled trial using purified ATO in treating APL and investigated the pharmacokinetics of ATO in vivo. Efficacies of ATO in treating APL were confirmed worldwide.59,63,109,110 |
| ATRA/ATO combination as a synergistic therapy |
| Since 2000, ATRA/ATO combination has been applied to treat newly diagnosed APL. Shen et al85 and Liu et al86,111 reported that a shorter time to achieve CR, an earlier recovery of platelet count, a more profound reduction in PML-RARα transcript, and a much lower relapse rate of disease were obtained in newly diagnosed APL patients treated with ATRA in combination with ATO compared with therapy using ATRA or ATO alone. Similar results were reported by Estey et al87 and Wang et al.88 |
| Development of new agents |