Phase I Study of Liposomal Daunorubicin (DaunoXome) in Relapsed and Refractory Acute Myeloid Leukemia

Abstract

Daunorubicin (DNR) is one of the most important cytotoxic agents in the treatment of acute myeloid leukemia (AML). Its use is usually limited by drug-induced cardiotoxicity depending on the cumulative dose administered. Liposomal encapsulation of DNR (DaunoXome®, DNX) seems to reduce the risk of this severe and sometimes fatal side effect. To investigate the toxicity of DNX in a heavily pretreated patient population, we currently conduct a phase I study including patients (pts) older than 60 years with relapsed or refractory AML. DNX is used at doses of 40, 60, 75, 90 and 100 mg/m2 biweekly. Until now, 13 pts have been treated: median age 69 years (range, 63-77), median number of prior regimen 1,4 (range, 0-2), median cumulative doses of DNR 553.5 mg (range, 0-880), mitoxantrone 16.2 mg (range, 0-60) and idarubicin 33.8 mg (range, 0-80). A total of 47 courses of DNX were administered (3 pts at 40 mg/m2 with a total of 13 courses, 5 at 60 mg/m2 with a total of 20 courses, 4 at 75 mg/m2 with a total of 12 courses and 1 at 90 mg/m2 with a total of 2 courses). Mean cumulative dose of DNX administered was 386,3 mg (range, 120-1200). Hematologic and non-hematologic toxicities were monitored by clinical, laboratory and cardiologic examination (including radionuclide ventriculography and echocardiography) and by a questionaire which was repeatedly filled in by the pts. Grade 1 and 2 elevations of liver enzymes were seen in 2 pts. A 20 % decline in left ventricular ejection fraction (LVEF) without clinical signs and symptoms of heart failure was noticed after a cumulative DNX dose of 480 mg in 2 patients, one with a history of two myocardial infarctions and the other with arterial hypertension. Even at the highest cumulative doses of DNX, no further decline in LVEF was noticed (LVEF prior to DNX: median 53 % (range, 34-67), after last course: median 52,7 % (range, 46-60). Vomiting, alopecia and mucositis were absent. All patients had significant myelosuppression requiring transfusion support. During treatment, 3 pts showed a reduction of leukemic blasts in bone marrow of > 25 %, 8 pts had to be excluded due to AML progression and 2 pts died due to disease-related complications. We conclude from these preliminary data, that DNX might offer a less toxic alternative to DNR and other anthracyclines. We will give a dose recommendation for the palliative treatment of relapsed and refractory AML as soon as our phase I study is finished. A phase II study will then be initiated.