Arsenic Trioxide Consolidation Allows Anthracycline Dose Reduction for Pediatric Patients With Acute Promyelocytic Leukemia: Report From the Children's Oncology Group Phase III Historically Controlled Trial AAML0631

Abstract

Purpose 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. Results 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. Conclusion 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.

Outcome for pediatric acute promyelocytic leukemia patients at Children's Oncology Group sites on the Leukemia Intergroup Study CALGB 9710 (Alliance)

“…The COG AAML0631 trial has now shown that a regimen including ATO consolidation for all children with APL results in a low relapse risk (4% at 3 years). 29 The recent Italian-German APL0406 randomized trial has further demonstrated excellent survival for adult patients with standard risk APL receiving ATRA and ATO without any doses of anthracycline or cytarabine. 14 The role of age in relapse risk remains an outstanding question in pediatric APL.…”

“…This highlights the need for decreasing anthracycline dose through use of other effective therapies. Indeed, anthracycline exposure was significantly decreased on the COG trial AAML0631 along with incorporation of ATO consolidation, which resulted in excellent outcomes (3‐year OS 94% and EFS 91%) …”

“…Only patients age ≥15 years were eligible for the ATO randomization, and there were no relapses among adolescents age 15–17.99 years who received ATO while those age 15–17.99 years randomized to no ATO had a relapse rate of 44%. The COG AAML0631 trial has now shown that a regimen including ATO consolidation for all children with APL results in a low relapse risk (4% at 3 years) . The recent Italian–German APL0406 randomized trial has further demonstrated excellent survival for adult patients with standard risk APL receiving ATRA and ATO without any doses of anthracycline or cytarabine …”

Reduced regulatory T cells (Treg) in bone marrow preferentially associate with the expansion of cytotoxic T lymphocytes in low risk MDS patients

“…Nonetheless, all patients experienced hyperleucocytosis, which required the administration of low-dose cytarabine in 3 cases (plus liposomal daunorubicin in one case). The recently published COG-AAML0631 protocol for newly diagnosed APL, including 101 children given induction therapy with Idarubicin and ATRA, combined ATO and ATRA for consolidation-1 in SR and HR patients (Kutny et al, 2017). This trial demonstrated that ATO consolidation allowed significant reduction in anthracycline doses, while maintaining excellent results, with a 3-year EFS of 91%.…”

Arsenic trioxide and all‐trans retinoic acid treatment for childhood acute promyelocytic leukaemia

“…Nonetheless, all patients experienced hyperleucocytosis, which required the administration of low‐dose cytarabine in 3 cases ( plus liposomal daunorubicin in one case). The recently published COG‐AAML0631 protocol for newly diagnosed APL, including 101 children given induction therapy with Idarubicin and ATRA, combined ATO and ATRA for consolidation‐1 in SR and HR patients (Kutny et al , ). This trial demonstrated that ATO consolidation allowed significant reduction in anthracycline doses, while maintaining excellent results, with a 3‐year EFS of 91%.…”