A phase II study of clofarabine in combination with cytarabine and daunoxome for children with acute myeloid leukemia withour other treatment options.

AML is a rare disease, and accounts for approximately 20% of pediatric leukemias. Treatment with intensive chemotherapy results in approximately 60-70% survival in newly diagnosed patients.


Prognosis at relapse is worse, and is in the 30-40% range. A couple of years ago an international relapse study was opened asking a randomized question in relapsed/refractory AML (study relapsed AML 2001/01). This randomization concerned the superiority of the FLAG regimen in combination with DaunoXome® (liposomal daunorubicine) versus FLAG alone, and is still ongoing. Overall results show that poor response to the 1st course of therapy (>20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients, and more often in early relapses (31%) than in late relapses (15%). Early death occurred in 6% of patients. Complete remission (CR) was achieved in 63% of patients after 2 courses, and these patients have a probability of survival at 3 years of 47%, compared to 33% for the total group, and only 8% for patients not achieving CR. Compared to early relapses, patients with late relapse had higher CR rates (76 vs. 51%), and higher 3-yr probability of survival of 42% vs. 23%. Clearly, nor the induction nor the consolidation chemotherapy is effective enough - and we need new and better treatment options for these children.



Cytarabine (Ara-C) and the anthracyclines are the back-bone of pediatric AML treatment. Cytarabine can be given in various different schedules, including higher-dose regimens such as 1-3 gr/m2 IV every 12 hours for 3 consecutive days, but also as a lower dose continuous IV schedule (0.5 gr/m2 CI over 24 hours x 4 days). Cytarabine has been used in combination with fludarabine and cladribine, with the aim to induce synergism by increasing Ara-CTP accumulation, which can be seen as a surrogate marker for cytarabine induced cell-kill.
In the current European relapsed AML study, the FLAG (fludarabine 30 mg/m2/day x5 days, Ara-C 2 gr/m2 bolus IV in 3 hours, 4 hours following fludarabine, for 5 days; plus GCSF) regimen is used as standard re-induction therapy. Synergy with cytarabine can also be achieved with clofarabine, which is a potent inhibitor of ribonucleotide reductase, leading to a depletion of normal deoxynucleotides and subsequently to increased Ara-CTP levels. In the experimental arm of the European relapsed AML protocol liposomal daunorubicin is added. This drug was chosen for its favorable toxicity profile, in particular the expected lack of long-term cardiac toxicity, which is of serious concern for those who survive relapsed AML given the cumulative anthracycline dose these patients may have received during their treatment. The current dose we use is 60 mg/m2 on days 1, 3 and 5 of the FLAG-regimen.


Clofarabine has been tested in phase I/II studies in children with AML. For clofarabine, the DLT was hepatic toxicity and rash, and the MTD for children was defined as 52 mg/m2/day x 5 days per block. Clofarabine is myelo-suppressive, and minimal neurotoxicity has also been reported. The response rate to clofarabine as a single agent in children with AML was relatively low, but this is probably related to the very heavy pre-treatment status of these children, and patients were transplanted in aplasia before proper response determination could take place. Adult AML data do show that the drug is active in AML, even at dosages from 15-20 mg/m2 onwards. Clofarabine has also been studied in combination with cytarabine in adults.



Several pediatric studies are ongoing in the US, evaluating clofarabine in combination with 1) cyclophosphamide; 2) cyclophosphamide and etoposide and 3) cytarabine 1 gram/m2 x 5 days, either in ALL or AML. The combination studies with cyclophosphamide have caused some toxicity concerns, especially hepatotoxicity.


We aim at developing a combination of clofarabine, cytarabine and DaunoXome®, based on the FLAG regimen, which is a combination that may be taken forward in the new European relapsed AML protocol, or in other studies.


In the adult studies the combination of cytarabine and clofarabine has been safe, using cytarabine 1 gr/m2 for 5 consecutive days on day 1-5, and clofarabine at 40 mg/m2 for 5 days on day 2-6. This is the same schedule as the COG is currently testing in children. No data on combination studies with anthracyclines are available as yet, but there is extensive experience with the FLAG regimen in combination with anthracyclines such as idarubicin or DaunoXome®.


We propose to use the cytarabine dose as administered in the FLAG regimen (2 gram/m2 bolus IV) – which will also allow a fair comparison with the FLAG regimen in later studies. This regimen is currently being tested in a trial in the USA in adults with relapsed/refractory AML by Agura et al., with a dosing regimen of cytarabine 2 gr/m2/day IV over 3 hours with clofarabine 40 mg/m2/day over 2 hours, daily, for 5 consecutive days. Considering GCSF priming, there are only data available in adults, with various results. As we expect that priming will in the future be done with CXCR4 inhibitors, and given the lack of hard evidence that GCSF priming works, we decided against using GCSF priming in this study.



Participating countries:

1. Austria (Vienna);

2. Czech Republic (Prague);

3. France (Lyon, Paris (Trousseau and St Louis));

4. Germany (Berlin, Frankfurt, Freiburg, Hannover, Munich, Munster);

5. Italy (Monza, Pavia).

This is a dose-escalation study to determine the safe dose of clofarabine given in combination with cytarabine and liposomal daunorubicin.

CR rate after 1 course of treatment.

Patients will be treated with a combination of clofarabine, liposomal daunorubicina nd cytarabine. Clofarabine is the IMP in this study.