Liposomal Daunorubicin Causes Only Low Cardiotoxicity in Pediatric AML Patients.

Anthracyclines are effective and important antineoplastic drugs in the treatment of acute myelogenous leukemia (AML). However, their use is limited by their cardiomyopathic effect, which occurs in children already at cumulative doses of 300 mg/m² (given as daunorubicin [DNR] dosages). A clear correlation between acute cardiotoxicity and late cardiomyopathy has been shown. Liposomal daunorubicin (DaunoXome™, L-DNR) is a modified formulation of DNR with a unilamellar liposomal transport system. Several preclinical data show that L-DNR has less cardiotoxic effects than free DNR (Forssen, 1994)

Therapy: L-DNR was used during induction in the relapse study AML-BFM 97 (3x60mg/m², 1-hour infusion, combined with cytarabine), in the ongoing international study Relapsed AML 2001/01 (3x60mg/m², 1-hour infusion, combined with fludarabine, cytarabine, G-CSF) and in the ongoing study AML-BFM 2004 (3x80mg/m², 2-hour infusion, combined with cytarabine, etoposide). All included patients were <18 years.

Method: To evaluate anthracycline-associated cardiomyopathy, the incidence of early and late (</>1 year after intensive AML chemotherapy) subclinical (NCI criteria grade I–II) and clinical (grade III–V) cardiotoxicity was analyzed (late cardiotoxicity only in study relapse AML-BFM 97). Cumulative anthracycline doses were in the range of 600mg/m² for relapse patients [calculated as equivalence dose to DNR using a dose ratio of 1:5 for idarubicin and mitoxantrone; this ratio was the preferred dosage of the AML Collaborative Group (AML Collaborative Group, BJH 1998) and represents proven equivalent doses concerning toxicity (Creutzig, 2001)].

Results:Early cardiotoxicity:

1. Relapse study AML-BFM 97 (n = 69): No subclinical or clinical cardiotoxicity was reported after induction.

2. International study Relapsed AML 2001/01 (AML-BFM patients only): 85 patients were treated with L-DNR; early subclinical cardiotoxicity was reported in 6 patients, clinical cardiotoxicity with reduced cardiac function and/or arrhythmia (grade III) occurred in 3 patients (3.5%) after induction.

3. AML-BFM 2004: Early subclinical cardiotoxicity of grade 1 was seen in 8 L-DNR and in 6 idarubicin patients and reduced cardiac function or arrhythmia (grade III/IV) in 2 out of 124 L-DNR patients (1.6%) compared to 5 of 135 (3.7%) patients treated with idarubicin after induction (p_Fisher 0.44).

All patients with early clinical cardiotoxicity suffered concurrently from grade II–IV infections. Late cardiotoxicity: Study relapse AML-BFM 97: One of 13 longterm survivors (median 9 years) presented with clinical cardiomyopathy after relapse (persistent decreased shortening fraction [SF] of <28% after a cumulative anthracycline dose of 490mg/m², but SF normalized within 14 months. When comparing early clinical cardiotoxicity after induction with L-DNR (3x80mg/m²) to that seen after DNR (3x60mg/m²) or idarubicin in the AML BFM93/98 studies (n=885 patients), the incidence rate was low (both 1.6%). Furthermore, early clinical cardiotoxicity seen after relapse treatment was low despite high cumulative anthracycline doses.

Conclusion: Preliminary data on L-DNR during induction in de novo and relapsed AML patients do not show significant early clinical cardiotoxicity. As early cardiotoxicity is a risk factor for the occurrence of late cardiotoxicity, our results may indicate also a lower risk for late cardiomyopathy after administration of L-DNR.