Safety and Efficacy of Arsenic Trioxide in the Treatment of Newly Diagnosed Pediatric Acute Promyelocytic Leukemia: Results from the JPLSG AML-P13 Study

Aims: Arsenic trioxide (ATO) has shown to be effective in patients with acute promyelocytic leukemia (APL), which has led to a dose reduction of cytotoxic agents in the treatment of APL. To investigate safety and efficacy of ATO in Japanese children with APL, we conducted a nationwide prospective study, JPLSG AML-P13 (jRCTs051180191).

Patients & Methods:

Between December 2014 and November 2018, children (0-18 years old) with newly diagnosed APL were enrolled in the AML-P13 study. All patients received two courses of induction therapy consisting of ATRA, cytarabine, and daunorubicin. Patients who achieved hematological complete remission (HCR) were allocated to the standard risk (SR) group and received three intensification cycles consisting of ATRA and ATO, followed by intermittent ATRA maintenance therapy. Patients who did not obtain HCR after induction courses were allocated to the high risk (HR) group and received intensified schedule of ATO, followed by gemtuzumab ozogamicin monotherapy and maintenance therapy consisting of 6-mercaptopurine and methotrexate.

Results & Discussions:

Among the 32 patients registered, 5 patients were excluded due to a lack of PML::RARA fusion or other reasons, and the remaining 27 patients received the protocol therapy (full analysis set). During induction courses, grade 3 disseminated intravascular coagulation was observed in 9 patients (33.3%). APL differentiation syndrome and induction death were not reported. Two patients were taken off protocol therapy due to a progressive disease (regarded as an event) and a safety issue, respectively. Among the 25 patients who completed induction therapy, 23 patients obtained HCR. During intensification cycles of ATO, grade 3 or higher non-hematological adverse events (AEs) were observed in 3 patients: prolonged QTc interval in 2 and dysesthesia in one. Regarding hematological AEs, 10 to 30% patients exhibited grade 4 neutropenia during each intensification cycles, but no patients experienced severe infectious complications. Two patients who did not obtain HCR received HR regimen without any apparent AEs. All 25 patients including 2 HR patients achieved molecular remission at the end of intensification and molecular remission rate was 100.0% [95% C.I. 86.3-100.0%]. No patients suffered from relapse, and 3-year EFS rate and 3-year OS rate in full analysis set were 96.3% [76.5-99.5%] (Figure) and 100.0% [87.2-100.0%], respectively. We previously reported an inferior outcome of younger children (less than 5 years old) treated with conventional ATRA and chemotherapy in the JPLSG AML-P05 study (Takahashi H. Br J Haematol 2016). However, 4 children under 5 years of age at diagnosis in the AML-P13 study remains in molecular remission, indicating efficacy of ATO in this age group of children.

Interpretations: The AML-P13 study demonstrated an excellent outcome in children with APL and showed that ATO could be administered safely in children with APL.

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