APL in children is generally similar to APL in adults, though children have a higher incidence of hyperleukocytosis (defined as white blood cell [WBC] count higher than 10 x 109 /L) and a higher incidence of the microgranular morphologic subtype.[13,14,15,27] Similar to adults, children with WBC count less than 10 x 109 /L at diagnosis have significantly better outcome than patients with higher WBC count.[14,15,28]FLT3 mutations (either internal tandem duplications or kinase domain mutations) are observed in 40% to 50% of APL cases, with presence of FLT3 mutations correlating with higher WBC counts and with the microgranular (M3v) subtype.[29,30,31,32,33] While some reports describe an association of FLT3 mutation with increased risk of treatment failure, this has not been a consistent finding.[29,30,31,32,33]
The standard approach to treating children with APL utilizes induction therapy with ATRA, in conjunction with standard-dose cytarabine and daunorubicin, followed by consolidation therapy with ATRA and daunorubicin.[1,17,34,35] Maintenance therapy, includes ATRA plus 6-mercaptopurine and methotrexate; this combination showed an advantage over ATRA alone in randomized trials in adults.[10,36] European clinical trials groups (Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto-Associazione Italiana Ematologia ed Ocologia Pediatrica [GIMEMA-AIEOP] and Programa de Estudio y Tratamiento de las Hemopatias Malignas [PETHEMA]) have utilized idarubicin and ATRA without cytarabine for remission induction in children with APL.[14,15] Subsequent therapies for these groups include treatment courses with an anthracycline (idarubicin and mitoxantrone) plus ATRA (PETHEMA) or treatment courses with an anthracycline, ATRA, and other agents (GIMEMA-AIEOP), with both groups utilizing maintenance therapy as described above.[14,15] The Berlin-Frankfurt-Munster group has reported 5-year overall survival (OS) rates (89% � 4%) and event-free survival (EFS) rates (73% � 6%) combining ATRA with chemotherapy that included 350mg/m2 of anthracycline. Because of the favorable outcomes observed with chemotherapy plus ATRA (EFS rates of 70%-80%), hematopoietic stem cell transplantation (HSCT) is not recommended in first CR.
Arsenic trioxide has also been identified as an active agent in patients with APL. Approximately 85% of patients in relapse achieve morphologic remission following treatment with this agent.[38,39,40,41,42] Arsenic trioxide is well tolerated in children with relapsed APL. The toxicity profile and response rates in children are similar to that observed in adults. In adults with newly diagnosed APL, the addition of two consolidation courses of arsenic trioxide to a standard APL treatment regimen resulted in a significant improvement in EFS and OS, although the outcome of patients who did not receive arsenic trioxide was inferior to the results obtained in the GIMEMA or PETHEMA trials. The combination of arsenic trioxide and ATRA compared with ATRA alone or arsenic alone during induction therapy followed by conventional consolidation and maintenance therapy has been tested in both adult and pediatric patients with APL. The study in adults showed that the CR rate was the same among all three induction regimens, although CR was achieved sooner with the combination regimen (median 25.5 days) compared with ATRA alone (median 40.5 days) or arsenic alone (median 31 days). Additionally, the combination of ATRA and arsenic resulted in an increased disease-free survival (DFS) compared with the patients treated with the combined results of ATRA alone or arsenic alone; data on OS was not presented. In the pediatric study, the results (EFS, DFS, OS) from the combination of ATRA and arsenic were comparable to the groups treated with ATRA alone or arsenic alone. The OS for the entire group of 65 patients was approximately 91% with a median follow-up of 38 months. These results indicate that ATRA, arsenic, or the combination of ATRA and arsenic are effective remission induction regimens in both adult and pediatric patients although the role of the combination in terms of OS is unclear and will require larger randomized studies. A report on 19 children treated with arsenic alone for newly diagnosed APL showed an EFS of 73% and OS of 84% at 5 years. Because arsenic trioxide causes Q-T interval prolongation that can lead to life-threatening arrhythmias (e.g., torsades de pointes), it is essential to monitor electrolytes closely in patients receiving arsenic trioxide and to maintain potassium and magnesium values at midnormal ranges.