Trial Information

A Randomized Phase III Study of the Treatment of Children and Adolescents With Refractory or Relapsed Acute Myeloid Leukemia

Secondary objectives of this trial are:

- To determine the toxicity of liposomal daunorubicin when added to FLAG, in terms of
mucosal toxicity, bone marrow aplasia, short- and long-term cardiotoxicity and other
side effects as compared to patients treated with FLAG only.

- To determine the long-term clinical outcome prospectively in a large group of children
with refractory and relapsed acute myeloid leukemia.

- To determine the changes in minimal residual disease over time, and the prognostic
significance of minimal residual disease determined at various time-points.

- To determine the relation between in vitro cellular drug resistance and clinical and
cell biological features, minimal residual disease and clinical outcome in this patient
group

- To determine the pharmacokinetics of liposomal daunorubicin in relation to its toxicity
and efficacy

Reinduction treatment will be done with 2 courses of combination chemotherapy, with FLAG
(fludarabine, ara-C and G-CSF) in both courses as standard treatment. In the first course
there will be a randomisation for liposomal daunorubicin (DaunoXome®) to be added or not.
The second course should always concern FLAG. If patients have > 20% of blasts in the bone
marrow after the 1st course, or if they are not in complete remission (CR) after the 2nd
course, they will go off protocol. Patients in CR after reinduction treatment can
immediately proceed to stem cell transplantation. Consolidation chemotherapy should be given
if SCT is delayed. A 3rd course of intensive chemotherapy (VP16 and continuous infusion with
cytarabine) is the general recommendation. In selected patients, a low intensity
consolidation may be preferred, and such a schedule is described as well. The type of SCT is
based on the risk-group. Preferably, a matched sibling donor (MSD) SCT is performed. If a
MSD is not available all patients are candidates for a matched unrelated donor (MUD) SCT. If
a MUD is also not available, patients with primary refractory disease, early relapse (within
1 year from diagnosis), or greater than or equal to 2nd relapse, are candidates for the more
experimental haplo-identical donor (HID) SCT in view of the dismal prognosis. However,
patients with a late relapse (>1 year from initial diagnosis) have a better prognosis and
should be offered an autologous SCT if a MSD or MUD SCT is not possible. Only in case of
autologous SCT, maintenance treatment and/or adjuvant immunotherapy could be considered.