Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial

Abstract

Background: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children.

Methods: We performed a randomized controlled trial in paediatric APL patients (≤14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6-mercaptopurine, and methotrexate for 1.5 years.

Results: Among the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months.

Conclusions: Overall, ATO and ATRA are safe and effective for paediatric APL patients and Ara-C could be omitted when ATO is used for two courses.

Trial registration: ClinicalTrials.gov ( NCT01191541 , retrospectively registered on 18 August 2010).

Keywords: Acute promyelocytic leukaemia; All-trans retinoic acid; Arsenic trioxide; Cytarabine; Paediatric.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Medical Ethics Committee of the Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Written informed consent was obtained from the parents of the study participants before enrollment in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

The CCAPL 2010 regimen and MRD test results. BM, bone marrow aspiration; IT, intrathecal injection; ATRA, all-trans-retinoic acid; ATO, arsenic trioxide; DNR, daunorubicin; Ara-C, cytosine arabinoside; MTX, methotrexate; 6-MP, 6-mercaptopurine

Fig. 2

Arsenic concentrations in the plasma (a), urine (b), hair (c) and nail (d) samples obtained from the different groups. m, months. * indicates a P value less than 0.05 in a comparison with the control group