Retinoic acid and arsenic trioxide improves the outcomes of non-high-risk APL patients compared to retinoic acid and chemotherapy: phase III APL0406 trial

Combination of All-Trans-Retinoic acid (ATRA) and Chemotherapy (CHT) has since been the standard treatment for Acute Promyelocytic Leukemia (APL). However, this combination is associated with severe hematologic toxicity and development of secondary myeloid neoplasms. Treatment of APL patients with Arsenic Trioxide (ATO) has resulted with high remission and survival outcomes. In newly diagnosed APL patients, CHT-free regimens based on ATO with or without ATRA has proven effective.¹

Uwe Platzbecker from the Carl Gustav Carus University Hospital, Dresden, Germany, and colleagues published their final results from the phase III APL0406 (NCT00482833) trial in the Journal of Clinical Oncology. APL0406 is a prospective, multicenter, randomized, phase III trial conducted by the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), the Acute Myeloid Leukemia Study Group (AMLSG), and the Study Alliance Group (SAL)².

In this phase III study, the combination of ATRA-ATO and ATRA-CHT was compared in 276 newly diagnosed APL patients between October 2007 and January 2013. In total, 266 APL patients were enrolled (10 patients were excluded) on an intent-to-treat basis. Patients were randomly assigned to receive treatment with either ATRA-ATO (n = 129) or ATRA-CHT (n = 137).²

The primary endpoint of the study was to compare the Event Free Survival (EFS) at 2 years of the two treatment arms. The secondary endpoints of the study were Overall survival (OS), rate of Hematological Complete Remission (HCR), and Disease Free Survival (DFS). Of the 263 evaluable patients, initial results from the APL0406 trial have revealed that the ATRA-ATO improved the 2-year EFS, OS, and DFS with less hematological toxicity compared to the ATRA-CHT regimen.²

The final results of the study were²:

• At median follow-up of 40.6 months, 50-month EFS in patients that received ATRA-ATO and ATRA-CHT; 97.3% vs 80.0%, P < 0.001
• 50-month OS in patients that received ATRA-ATO and ATRA-CHT; 99.2% vs 92.6%, P = 0.073
• 50-month DFS in patients that received ATRA-ATO and ATRA-CHT; 97.3% vs 82.6%, P < 0.001
• 50-month Cumulative Incidence of Relapse (CIR) in patients that received ATRA-ATO and ATRA-CHT; 1.9 vs 13.9, P = 0.0013
• HCR in patients that received ATRA-ATO and ATRA-CHT; 100% vs 97%, P = 0.12
• Post-induction events in the ATRA-ATO arm were death in CR (n = 1), relapses (n = 2), and molecular resistance after third consolidation (n = 2)
• Post-induction events in the ATRA-CHT arm were death in CR (n = 5) and relapses (n = 15)
• Two patients developed therapy-related myeloid neoplasms in the ATRA-CHT arm

The final results of the APL0406 trial shows that ATRA-ATO combination significantly improved the survival and relapse risk of patients with newly diagnosed, low–intermediate-risk APL compared to ATRA-CHT.

The authors concluded by stating “these results show that the advantages of ATRA-ATO over ATRA-chemotherapy increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATRA-ATO compared with ATRA-chemotherapy in low- and intermediate-risk APL.” The authors further stated that their results support the use of ATRA-ATO in newly diagnosed APL patients and proposed that this combination should be the new standard of care for low–intermediate-risk APL patients.

This combination of ATRA and ATO (Trisenox®) was recently approved by the European Medicines Agency (EMA) for first line treatment of low to intermediate risk APL patients.

Abstract

Purpose

The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial.

Patients and Methods

The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 109/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013.

Results

Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm.

Conclusion

These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.