Combination of liposomal daunorubicin (daunoxome), fludarabine and cytarabine as salvage therapy in relapsed and refractory acute leukemia

Daunorubicin is one of the most important cytotoxic agent in the treatment of acute leukemia (AL). Its use is usually limited by drug induced cardiotoxicity depending on the cumulative dose administerd. Liposomal daunorubicine (daunoXome,DNX,Nexstar) compared to unencapsulated anthracyclines, is characterized by a higher tumor cell delivery with improved pharmacokinetic and therapeutic indices, resulting in a reduced toxicity profile.In previously reported experiences, hématologie toxicity of DNX given alone was not assessable but non hemathologic toxicity was not seen, suggesting that DNX could be given in combination with other drugs. Therefore we use Fludarabine 30/mg m 2 followed after 4 hours by Cytarabine 2g/m 2 (infused in 4 hours) and DNX 100 nig/m2 (infused in 2 hours)x 3days(FLAD) To investigate the toxicity, safety and efficacy of FLAD in heavily pretreated patients, we currently conduct a phase I study including 5 patients with relapsed or refractory myeloid acute leukemia (AML)( 4 cases )and acute lymphoblastic leukemia (ALL) (1 case). In one post-MDS AML we used FLAD as first-line theraphy. Median age was 53 years (range, 13 to 76), median number of prior regimen was 3 (range, 0 to 5), median cumulative doses of mitoxantrone was 18 mg/m1 (range 0 to 120),of idarubycin was 30 mg/ m ! (range 0 to 60). One patients had received daunorubicin with total cumulative dose of 255mg/m; and another one doxorubicine at total dose of 140/m2. Toxicities included :nausea/ vomiting (WHO 1-2) in 2 cases and mucositis (WHO 1-2) in all the cases. There was no clinical evidence of cardiac toxicity. All patients become cytopenic, needed hospitalitation and required transfusional support.Two AML patients died:l in aplastic phase of disseminated bronco-pneumonitis at +9 day, the other one at +79 day of disease progression.Four patients are alive: 2 have been rescued by allogeneic marrow transplantation during the aplastic phase , 1 has a stable disease and 1 reached a complete response. Our preliminary report shows that FLAD is a feasible treatment in poor prognosis AL and is associated with acceptable tolerability and does not preclude the safety and the feasibility of successive high dose procedure.