Creutzig U, et al. APL 2017:PO037

First experience with ATO and ATRA treatment in pediatric patients with low-risk APL

Background

Studies in adults with low-risk acute promyelocytic leukemia (APL) showed high cure rates and reduced toxicities after treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO); however, the study of this regimen in pediatric patients is limited.1 At the 7th International Symposium on APL, Creutzig et al. reported on the outcomes of 13 pediatric patients with low-risk APL treated with an ATO and ATRA regimen.2

Study design

  • Since 2013, 13 patients with low-risk APL, aged 1–17 years, were treated with an ATO and ATRA regimen in nine hospitals in Germany and Austria (part of the acute myeloid leukemia [AML]–Berlin-Frankfurt-Münster consortium).
  • A detailed outline of the treatment regimen is described in Figure 1.
  • The following changes were made to the original treatment scheme:
    • ATO was given at a later start (Day 10) to avoid a hyperleukocytosis burst due to simultaneous ATO and ATRA at onset;
    • Patients received a one-week break from ATRA after the first 14 days; and
    • Seven intrathecal therapies with cytarabine (in age-dependent doses) were given every four weeks starting at Day 10 (after blast cell reduction).
  • Two patients received chemotherapy induction because either therapy was started in a hospital not involved in the consortium or the case was initially misdiagnosed as AML with level 2 maturation as classified by the French-American-British system.

Figure 1. Treatment Regimen

Key findings

  • The median follow-up was 2.4 years (range: 1.0–3.8).
  • All patients experienced an increase of white blood cells (WBC) >10,000/μL during the first four weeks.
    • The peak of WBC values was on Day 14 of treatment.
  • In six patients, hyperleukocytosis with clinical signs of differentiation syndrome (DS) occurred.
    • This occurred after starting ATO treatment in four patients (6–9 days after initiation).
    • DS was managed with breaks of ATO, dexamethasone, hydroxyurea, and low-dose cytarabine.
    • One patient experienced posterior reversible encephalopathy syndrome and aseptic osteonecroses, and one patient experienced temporary abducens paresis.
  • Transient grade 1 hepatic toxicities occurred in four patients, temporary grade 1 corrected QT time prolongation occurred in two patients, and facial eczemas were reported in two patients.
  • Only one patient reported a long-term toxicity (psychological problems with headache and partial hair loss, two years after diagnosis).
  • Generally, in-patient treatment duration was one week and all patients required only out-patient care after the induction phase.
  • All patients achieved molecular remission after 7–20 weeks (median 10 weeks).
  • One patient (an infant) was polymerase chain reactionpositive after 16 weeks.

Key conclusions

    • Therapy with ATO and ATRA in pediatric patients with standard-risk APL was well tolerated.
    • Similar to the Lo-Coco trial,1 prophylactic prednisone 0.5 mg/kg/day is recommended during induction to prevent DS.
    • Due to the rising leukocyte counts observed, frequent blood count monitoring is recommended until blood counts drop.
    • The best strategy for the introduction of ATO, whether starting cautiously on Day 10 or at an earlier start with ATRA, remains unclear.
    • This new ATO and ATRA treatment regimen should only be applied in the pediatric setting by experienced clinics, while accompanied by expert consultation.

References: 1. Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369(2):111–21. 2. Creutzig U, Dworzak MN, Bochennek K, et al. First experience with ATO and ATRA treatment in pediatric patients with low risk APL. Intl. Symposium on APL Abstracts 2017:PO037.