[Liposomal daunorubicine combined with cytarabine in the treatment of relapsed/refractory acute myeloid leukemia in children].
BACKGROUND
First-line treatment in AML commonly included high cumulative doses of anthracyclines with an increasing risk of cardiotoxicity. Liposomal daunorubicin (L-DNR) is thought to be less cardiotoxic without impairment of efficacy.


METHODS
The AML-BFM REZ 97 study included two reinduction blocks with L-DNR (2 x 60 mg/m (2) n = 38, since 2/1999 3 x 60 mg/m (2) n = 31) combined with cytarabine (500 mg/m (2) 4 d). Children who achieved a second blast clearance were allocated to allogeneic stem cell transplantation either from a matched related (MRD) or a matched unrelated donor (MUD). Lack of a donor justified haploidentical SCT in early relapse (1st remission < 1 year) and autologous SCT in late relapse.


METHODS
Between 1/1997 and 9/2001, 69 children were enrolled in the AML-BFM 97 relapse study. The median duration of first remission was 0.9 years. Forty-one patients had a remission of less than one year, 28 of more than a year.


RESULTS
46 children (67 %) achieved a second remission, defined as clearance of blasts in bone marrow and at least a partial hematological reconstitution. Seventeen of these children are alive (12 of 25 children receiving allogeneic SCT (MFD/MUD); 1 of 8 children after haploidentical SCT; 1 of 4 patients after autologous SCT and 3 of 9 patients treated with chemotherapy only). Further three children without 2nd remission survived after MFD-SCT (n = 2) or chemotherapy (n = 1; follow-up 0.3 to 0.7 years). Duration of first remission remains a significant prognostic factor. The pharmacokinetic investigation showed a high overall AUC of 234.6 mg/l h at a dose of 60 mg/m (2), and a volume of distribution of 1.98 l/m (2), which is much lower in comparison to conventional Daunorubicin. Regarding toxicity, the combination of L-DNR and cytarabine followed by SCT was feasible in experienced centers, however, acute complications like infection or septicemia in aplasia, mucositis and GvHD were common. By contrast, no clinical relevant cardiotoxicity was seen so far, but definitive results in long-term cardiotoxicity await a longer follow-up. In conclusion, L-DNR/cytarabine treatment induced a 2nd remission in most of the children with relapsed or refractory AML. It has to be followed by allogeneic SCT which enables long-term survival.
Reinhardt
D
D
Pädiatrische Hämatologie/Onkologie, Universität Münster, Germany. drein@uni-muenster.de
Hempel
G
G
Fleischhack
G
G
Schulz
A
A
Boos
J
J
Creutzig
U
U
D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality; D008081:Liposomes; D008297:Male; D012074:Remission Induction; D033581:Stem Cell Transplantation; D015996:Survival Rate
D008081:Liposomes; D003561:Cytarabine; D003630:Daunorubicin