Results from the APL 2006 trial of arsenic trioxide in patients with acute promyelocytic leukemia

The role of arsenic trioxide (ATO) in the frontline treatment of higher risk acute promyelocytic leukemia (APL) is not well understood. A group of researchers from the French, Belgian, Swiss APL group conducted a randomized phase III APL 2006 trial (NCT00378365), which is comparing consolidation treatment (after ATRA-chemotherapy induction treatment) with ATO, all-trans retinoic acid (ATRA) and the AraC in standard-risk APL, and evaluated the addition of ATO during consolidation in higher risk APL. The results of this study were reported in the July 2018 issue of Haematologica by Lionel Adès et al.

Seven hundred and ninety-five patients with confirmed diagnosis of APL were included in this study. Of these, 581 patients had standard risk (baseline white blood cell [WBC] < 10 G/L) APL and 214 had high risk (baseline WBC > 10 G/L) APL. Patients were administered induction treatment consisting of ATRA (45 mg/m²/d) with idarubicin (12 mg/m² for 3 days) and AraC (200 mg/m² for 7 days, starting on day 3) until complete remission (CR). The primary endpoint of the study was event-free survival (EFS) from CR achievement. The secondary endpoints of the study were cumulative incidence of relapse (CIR), survival, side effects of the treatment and duration of hospitalization.

Patients with standard-risk APL

Five-hundred and seventy patients (98.1% [570/581]) with standard-risk APL achieved CR after induction therapy. Of the 570 patients in CR, 538 patients were randomized for consolidation between three treatment groups including AraC (n = 178), ATO (n = 180) or ATRA (n = 180).

Results presented below are representative of AraC vs ATO vs ATRA, respectively

• 5-year EFS: 88.7% vs 95.7% vs 85.4%, P = 0.0067
• 5-year CIR: 5.1% vs 0% vs 8.2%, P = 0.001
• 5-year overall survival (OS): 93.6% vs 95.7% vs 91.9%, P = 0.349
• Median duration of hospitalization after the first consolidation: 31.5 vs 32.2 vs 19.5 days, P < 0.0001

Patients with higher risk APL

Two-hundred and five patients (95.9% [205/214]) with higher risk APL achieved CR after induction therapy. Of the 205 patients in CR, 197 patients were randomized for consolidation between two treatment groups including chemotherapy alone (n = 99) and chemotherapy plus ATO (n = 98).

Results presented below are representative of chemotherapy alone vs chemotherapy plus ATO, respectively

• 5-year EFS: 85.5% vs 92.1%, P = 0.38
• 5-year CIR: 4.6% vs 3.5%, P = 0.99
• 5-year OS: 90% vs 93%, P = 0.62

Prolonged myelosuppression was seen in the chemotherapy plus ATO arm. The protocol was amended to exclude AraC during consolidation cycles in the chemotherapy plus ATO group.

Results presented below are representative of chemotherapy alone vs chemotherapy plus ATO with AraC and chemotherapy plus ATO without AraC, respectively

• 5-year CIR: 4.6% vs 5.3% vs 2.7%, P = 0.61
• Median time to ANC >1 G/L after second consolidation: 22 vs 25 vs 18 days, P < 0.001
• Median duration of hospitalization after the first consolidation: 29 vs 34 vs 33 days, P < 0.0001

Conclusion

The researchers concluded that the results of their study demonstrate that “in standard-risk APL, the addition of ATO to ATRA chemotherapy regimen further reduces the incidence of relapse”.  They further added that the addition of ATO to an already “highly effective ATRA chemotherapy regimen may further improve its anti-leukemic effect and that ATO may not be dispensable in the treatment of standard risk APL”.

Furthermore, in high-risk APL, AraC can be replaced by ATO, without increasing the risk of relapse and a limited myelosuppression, thus “potentially reducing the risk of death in CR”.