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sure in plasma was not significantly different from that in single-agent studies. In conclusion, clofara- bine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub)clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
Clofarabine in pediatric AML
Introduction
Despite enhanced cure rates for pediatric acute myeloid leukemia (AML), relapsed patients still suffer from poor clinical outcome,1 especially those who relapse within one year of diagnosis.2 Recently, a randomized phase III study in relapsed/refractory AML revealed an improved early treatment response when liposomal daunorubicin (DNX) was added to the FLAG (fludarabine, cytarabine and gran- ulocyte-colony stimulating factor (G-CSF)) regimen.2 Although this did not translate into a survival benefit [4- year probability of survival (pOS) of 38±3%], in Europe, the combination of FLAG and DNX (FLAG-DNX) fol- lowed by stem cell transplantation (SCT) was considered the standard treatment for children with AML in first relapse.2,3 For several reasons, including data obtained in adults, subsequently G-CSF priming was deleted from the FLAG regimen4,5 and the current standard is FLA-DNX. Intensified relapse therapy increased survival over time,6 but insufficient cure rates in the 70% range (pOS),3 and potential long-term toxicities such as anthracycline car- diomyopathy when cumulative dosages exceed 300-400 mg/m2,7,8 mean that novel chemotherapy combinations must be developed.
Clofarabine, a structural hybrid of fludarabine and cladribine, was developed to enhance efficacy and stabili- ty of the drug, while reducing the formation of toxic com- pounds like 2-F adenine compared to previous nucleoside analogs.9,10 Inhibition of DNA polymerase and ribonu- cleotide reductase as well as induction of apoptosis,10 and enhanced accumulation of cytarabine may contribute to the drug's high antitumor activity.11
The first pediatric phase I study of clofarabine identified a maximum tolerated dose (MTD) of 52 mg/m2/day, with reversible hepatotoxicity and skin rash as dose-limiting toxicities.12 Based on a phase II study, clofarabine was approved in 2004 for relapsed pediatric ALL.13 However, in relapsed pediatric AML, activity of clofarabine was not confirmed, with a response rate of only 26%, mainly con- sisting of partial responses, probably due to the inclusion of heavily pre-treated patients.13 In contrast, in adult AML, clofarabine showed antileukemic activity in several early phase studies.14-16 Randomized data showed that, even though remission rates were improved in untreated older patients with AML and high-risk myelodysplastic syn- drome (MDS), no survival benefit of clofarabine (20 mg/m2/d for 5 days) over low-dose cytarabine was shown.17 Moreover, another randomized study comparing cytarabine with clofarabine (20 mg/m2/d for 5 days) in induction courses I and II in elderly AML also failed to show a survival benefit.18 However, a recent study by the HOVON-group did show a survival advantage for patients randomized to clofarabine in intermediate-risk AML sub- sets, albeit at a very low dose of 10 mg/m2/d for five days added to induction courses I and II.19
In pediatric ALL, clofarabine combination therapy was developed to overcome resistance, e.g. combinations with cyclophosphamide, or etoposide and cyclophos- phamide, or topotecan, vinorelbine and thiopeta.20-23 In children with relapsed/refractory AML, clofarabine (52 mg/m2/d for 5 days) with cytarabine (1 g/m2/d for 5 days) resulted in a 3-year pOS of 46%±27% in responders.24 In the CLOUD study, 9 children with relapsed/refractory AML were treated with clofarabine (30 mg/m2/d for 5 days) and liposomal daunorubicin (60 mg/m2, days 1, 3 and 5); 33% obtained complete remission (CR) and were subsequently transplanted.25
In this study, we aimed to combine clofarabine with high-dose cytarabine and liposomal daunorubicin as in the FLA-DNX regimen, replacing fludarabine with clofarabine assuming that this may have greater anti-leukemic poten- tial when tolerable. The treatment schedule was based on an adapted ‘Faderl regimen’ developed in adult AML.26,27
Methods
Study ITCC-020 (EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880) was an investigator-initiated open-label phase IB dose-escalation study sponsored by Erasmus MC, Rotterdam, the Netherlands. Patients were enrolled in 15 centers in 5 countries within the Innovative Therapies for Children with Cancer (ITCC) consortium.
Study design
The primary objective was to establish the MTD and recom- mended phase II dose (RP2D) of clofarabine in combination with cytarabine and DNX in relapsed/refractory pediatric AML. Dose- limiting toxicities were evaluated in the first course only. Secondary objectives included tabulation of additional safety and tolerability data across both treatment courses, preliminary esti- mation of response, event-free survival (EFS), and overall survival (OS), and the pharmacokinetics (PK) of clofarabine in this combi- nation [serum and cerebrospinal fluid (CSF)]. A classical 3+3 design was used with dose escalation to MTD, after which the cohort was expanded (n=10) at the RP2D. Separate expansion cohorts were planned for dose level (DL) 1-4 and for DL5 (in early 1 first relapse only), respectively, when considered safe.
Patient eligibility
Pediatric patients below 19 years of age with early 1st relapse (within 12 months from initial diagnosis), refractory 1st relapse (≥ 20% blasts in the bone marrow after the first course of standard re-induction therapy), or those with at least a second relapsed AML were eligible. Only patients with early 1st relapse without prior SCT were eligible for DL5. Inclusion and exclusion criteria are described in Online Supplementary Methods S1, and included recovery from prior organ toxicity. An amendment in November 2011 excluded patients with evidence for subclinical fungal infec- tions using high-resolution computed tomography (CT) scan of
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