On 2nd August 2017, in an article published in the Journal of Clinical Oncology, Matthew A. Kutny, from the University of Alabama at Birmingham, Birmingham, Alabama, USA, and colleagues reported results of the Children’s Oncology Group (COG) historically controlled phase III non-randomized AAML0631 trial (NCT00866918), which investigated the combination of arsenic trioxide (ATO) with an approximate 40% reduction in anthracycline dosing compared with the historical control trial, AIDA 0493, in de novo Acute Promyelocytic Leukemia (APL) pediatric patients.
In AAML0631, 101 evaluable patients (median age = 15.04 years; range, 2–21) were risk-stratified based on diagnostic White Blood Cell (WBC) count into two groups including Standard-Risk (SR, WBC < 10,000 cells/µl [n = 66]) and High-Risk (HR, WBC ≥ 10,000 cells/µl [n = 35]). Patients were administered All-Trans Retinoic Acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1. The cumulative anthracycline dosing was 51 mg/m2 and 61 mg/m2 idarubicin for SR and HR patients, respectively, and 20 mg/m2 mitoxantrone.
The historical control trial used in this study was the phase III AIDA 0493 trial, which enrolled 983 patients including 107 pediatric APL patients (SR, n = 69; HR, n = 38). The cumulative anthracycline dosing was 80 mg/m2 and 50 mg/m2 mitoxantrone. The AIDA 0493 trial did not include ATO consolidation.2
The key results from the AAML0631 trial were:
- 3-year Overall Survival (OS) in SR and HR patients; 98% ± 3% vs 86% ± 12%, P = 0.003
- 3-year Event Free Survival (EFS) in SR and HR patients; 95% ± 5% vs 83% ± 13%, P = 0.03
- 3-year Relapse Risk for all patients; 4% ± 4%
- Differentiation syndrome (an APL-associated cardiopulmonary distress syndrome) occurred in 20% of patients during induction therapy
- Causes of death in patients enrolled in the AAML0631 trial included: coagulopathy (n = 2), multi-organ dysfunction (n = 2) during induction, and accidental overdose (n = 1) and sepsis (n = 1)
- 2-year EFS in SR patients in the AAML0631 and AIDA 0493 trial; 97% vs 91%, P = 0.93
In summation, “ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL”.
The Children’s Oncology Group AAML0631 trial for newly diagnosed pediatric acute promyelocytic leukemia (APL) was a phase III historically controlled trial to determine the survival of patients receiving arsenic trioxide (ATO) consolidation and reduced doses of anthracyclines.
Patients and Methods
Patients age 2 to 21 years with de novo APL confirmed by PML-RARα polymerase chain reaction were stratified as standard risk (SR) or high risk (HR) on the basis of diagnostic WBC count. All patients received all-trans retinoic acid (ATRA) during induction, each consolidation course, and maintenance. All patients received two cycles of ATO therapy during consolidation 1, an additional two (SR) or three (HR) consolidation courses that included high-dose cytarabine and anthracycline, and maintenance therapy comprising ATRA, oral methotrexate, and mercaptopurine.
One hundred one patients (66 SR and 35 HR) were evaluable for outcome. The 3-year overall survival was 94%, and event-free survival (EFS) was 91%. For SR and HR patients with APL, the overall survival was 98% versus 86% (P = .003), and EFS was 95% versus 83% (P = .03), respectively. The EFS for SR patients in AAML0631 was noninferior to that of patients in the AIDA 0493 historical control, which used a significantly higher anthracycline dose and did not include ATO consolidation. Relapse risk for patients in AAML0631 from end consolidation 1 (after ATO treatment) was only 4% at 3 years and did not differ significantly between SR and HR patients.
ATO consolidation cycles were well tolerated in pediatric patients with APL and allowed significant reduction in cumulative anthracycline doses while maintaining excellent survival and a low relapse risk for both SR and HR patients with APL.