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N.K.A. van Eijkelenburg et al.
the thorax, and elevated serum levels of galactomannan.
All patients/parents had to provide written informed consent according to local law and regulations, after the institutional review boards of the participating institutes approved the study. The study was conducted in accordance with good clinical prac-
tice guidelines and the Declaration of Helsinki.
Treatment
Clofarabine and DNX dosages were escalated from 20-40 mg/m2/day at days 1-5, and 40-80 mg/m2/day at days 1, 3 and 5, respectively, whereas the dose of cytarabine was fixed at 2 g/m2/d for days 1-5 (Table 1, detailed information in Online Supplementary Methods S2). DL5 (DNX 80 mg/m2/day at days 1, 3 and 5) was con- sidered as a separate cohort with restricted inclusion criteria. This cohort was added as up-front pediatric AML protocols use DNX at this dose level rather than 60 mg/m2/d28 (Figure 1).
Safety and efficacy evaluations
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events v.3.0. Dose Limiting Toxicities (DLT) were defined as grade 3 or 4 non-hematologic AEs and hematologic AEs lasting longer than 42 days, limited to the first course, and at least possibly drug-related, with some exceptions (definitions and efficacy evaluation in Online Supplementary Methods S3 and Table S1).
Statistical analysis
Dosing and efficacy were analyzed using descriptive statistics. Survival estimates were computed by Kaplan-Meier. The database lock for this analysis was set at 11th February 2018. All analyses were performed with Stata v.13.1.
Further information concerning pharmacokinetics and statistical analysis is available in Online Supplementary Methods S4, Methods S5 and Table S2.
Table 1. Dose levels of clofarabine, liposomal daunorubicin and cytarabine.
Age ≥ 1 year (Age < 1 year)
Dose level -1
Dose level 1 (starting dose)
Dose level 2
Dose level 3A
Dose level 3B*
Dose level 4
Dose level 5**
Clofarabine
15 mg/m2/d x 5 d
(0.5 mg/kg/d x5 d)
20 mg/m2/d x 5 d
(0.7 mg/kg/d x 5 d)
30 mg/m2/d x 5 d
(1.0 mg/kg/d x 5 d)
30 mg/m2/d x 5 d
(1.0 mg/kg/d x 5 d)
30 mg/m2/d x 5 d
(1.0 mg/kg/d x 5 d)
40 mg/m2/day x 5 d
(1.3 mg/kg/day x 5 d)
40 mg/m2/day x 5 d
DNX
40 mg/m2/day 1-3-5
(1.3 mg/kg/d 1-3-5)
40 mg/m2/d 1-3-5
(1.3 mg/kg/d 1-3-5)
40 mg/m2/d 1-3-5
(1.3 mg/kg/d 1-3-5)
60 mg/m2/d 1-3-5
(2.0 mg/kg/d 1-3-5)
60 mg/m2/d 1-3-5
(2.0 mg/kg/d 1-3-5)
60 mg/m2/d 1-3-5
(2.0 mg/kg/d 1-3-5)
80 mg/m2/d 1-3-5
Ara-C
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2gr/m2/dx5d
(70 mg/kg/d x 5 d)
2 gr/m2/d x 5 d
Ara-C: cytarabine; DNX:liposomal daunorubicin. *Dose level 3B: cohort 3 was repeated after an amendment implementing screening for subclinical fungal infections. **Dose level 5: this cohort was open for patients with early 1st relapse of acute myeloid leukemia without prior stem cell transplantation only. Dosages in brackets are for children below 1 year of age or below 10 kg body weight.
Figure 1. Treatment schedule. Clofarabine was administered intravenously (IV) in 2 hours (h) (days 1-5); liposomal daunoru- bicin (DNX) in 1 h (days 1, 3, 5); DNX in 1 h (days 1, 3, 5), starting 30 minutes after the end of clofarabine; cytarabine was adminis- tered (IV) in 3 h (days 1-5), starting 3 h after the end of clofarabine. Intrathecal therapy was administered at day 6 with cytarabine for prophylaxis, or triple therapy (cytarabine and methotrexate and prednisolone) with age-adjusted dosages in case of central nervous system involvement. G-CSF: granu- locyte-colony stimulating factor.
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