This trial demonstrates that the combination of ATRA and ATO is non-inferior to ATRA-ATO plus CHT not only in non-high-risk APL, but also in high-risk APL patients. The addition of chemotherapy to ATRA-ATO did not significantly improve the durable anti-leukemia efficacy in these patients. Therefore, a chemotherapy-free regimen combining ATRA plus ATO is a feasible approach to cure all-risk APL patients.
The conventional treatment for APL combined ATRA and anthracycline-based chemotherapy to induce remission, followed by consolidation chemotherapy and ATRA maintenance over ten years ago [6, 30–32]. Compared with this classical combination strategy, C9710 study showed that the addition of ATO as initial consolidation therapy for adult patients with all-risk newly diagnosed APL significantly improved EFS and DFS [18]. Later on, APML4 study introduced ATO to ATRA and anthracycline induction, and eliminated chemotherapy from consolidation, utilizing 2 cycles of ATRA-ATO followed by maintenance therapy with ATRA, 6-mercaptopurine, and methotrexate for 2 years [19]. The incorporation of ATO in initial therapy induction and consolidation for all APL patients reduced the relapse rate when compared with historical controls of APML3 study, which was the ATRA-CHT without ATO strategy [20]. APL2012 trial from China demonstrated that ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA-CHT [13]. In above study, ATO was also added in maintenance therapy. The results of C9710, APML4 and APL2012 strongly supported the application of ATO in all APL patients. AML17 trial, a randomized controlled phase 3 trial, explored the combination of ATO and ATO without chemotherapy for APL for all-risk patients. The results showed that, ATRA and ATO is effective in low-risk and high-risk patients, with a high cure rate, less relapse, and a low incidence of liver toxicity when compared with ATRA-CHT group [7, 33]. However, this study added GO to high-risk patients and low-risk patient with leukocytosis in the ATRA-ATO arm. In many countries where chemotherapy is much more affordable than GO, the combination of ATRA-ATO plus chemotherapy is the conventional treatment option. Therefore, we performed a controlled trial to test the efficacy of ATRA-ATO without chemotherapy and GO for all-risk patients. The results showed that the cure rates and survival rates in the ATRA-ATO group are not different to the ATRA-ATO plus CHT group for all-risk patients. When compared with APML4 and AML17 trial, the outcomes in the ATRA-ATO group in our study were similar to those. This is the first study that reported all APL patients could be curable without chemotherapy or GO.
For low-risk patients, APL0406 trial showed that chemotherapy could be replaced by ATO [8]. ATRA-ATO strategy became the standard of care for patients with low-risk APL. However, the frontline treatment was ATRA-ATO with CHT or GO for high-risk patients according to other studies [7, 15, 19, 34]. In the single-arm study conducted by MD Anderson Cancer Center, induction with ATRA-ATO plus GO and followed with ATRA-ATO conduction therapy, the 5-year event-free survival rate was 81% and overall survival rate was 86% for high-risk patients. While they were 83% and 87% in the APML4 with the ATRA-ATO plus CHT strategy. In our study, the 2-year event-free and overall survival were 85% and 85% in the non-CHT group. The outcomes were not inferior to CHT group in our study or historical study of ATRA-ATO plus GO treatment in MD Anderson Cancer Center or ATRA-ATO plus CHT strategy in APML4 trial. In addition, patients in the CHT group had more cardiac toxicities in our study compared with the non-CHT group. Therefore, we propose that chemotherapy can be removed from the induction and consolidation treatment for high-risk patients with APL. In addition to the combination of ATRA and intravenous arsenic, another study in China is exploring to use oral arsenic realgar-indigo naturalis to replace or reduce CHT in high-risk patients [9].
Hydroxyurea has been shown to significantly reduce WBC counts [35]. The APL0406 trial reported that non-high-risk patients with hyperleukocytosis were successfully treated with hydroxyurea [16]. In this trial, we increased the maximum dose to 0.1 g/kg/d, which has been shown to be safe in previous studies [36]. The administration of hydroxyurea may achieve the same treatment efficacy as chemotherapy or GO in reducing the WBC count and the mortality rate in high-risk patients with APL. Compared with anthracyclines-based chemotherapy, the hydroxyurea dose can be adjusted easily according to the WBC count. In terms of safety, no additional hematological or non-hematological toxicity from hydroxyurea was observed. Hydroxyurea can be a good option in controlling leukocytosis in CHT-free regimens also in the high-risk setting, or in countries where GO is not available or too expensive. High-risk APL patients have an increased risk of CNS relapse [37]. Because ATRA and ATO poorly penetrate the BBB, intrathecal chemotherapy has been the major treatment for CNS prophylaxis. However, its use is still controversial due to the requirement for an invasive procedure and insufficient long term follow-up outcome data [37]. Mannitol has been reported to allow arsenic to better penetrate the BBB and reach therapeutically effective levels in the CSF [38]. In this trial, mannitol was used in high-risk patients to prevent CNS relapse. There were no patients with CNS relapse in the non-CHT group in our study. The use of mannitol in combination with arsenic as a noninvasive CNS prophylaxis strategy may be considered as a new prevention approach of CNS relapse in high-risk APL.
In conclusion, our results showed that ATRA and ATO without CHT or GO was effective and safe for all-risk APL, suggesting that chemotherapy might be unnecessary for high-risk patients. This work may lead to a new treatment strategy for APL patients, particularly for the high-risk patients. However, more research centers and participants are still needed to further verify this conclusion.