Daunorubicin (DNR) is one of the most active drugs for childhood acute lymphoblastic leukemia (ALL). However its use is limited due to the increasingly recognized occurrence of late-onset ventricular impairment. Daunoxome (DNX) is a liposomal form of DNR entrapped into small unilamellar vesicles composed by di-stearyl-phosphatidyl-choline and cholesterol. Preclinical studies have suggested a reduced cardiotoxicity of DNX compared to DNR. We have conducted a phase I-II study in children with advanced ALL in order to assess the tolerance and pharmacokinetics (PK) of DNX and to obtain preliminary data on effectiveness. Data on PK are detailed elsewhere (Robert et al, ASH 98). The study design included a weekly infusion of DNX (max = 4), a bone marrow (BM) evaluation at D14, D28 and recovery, a cardiosonography at the beginning and at the end of trial. To date 21 relapsed pts (Â³ 2nd marrow relapse: 18 pts or 1st relapse after BMT: 3 pts) have been enrolled in 8 centers. All have been previously exposed to anthracyclins. Added bad prognosis criteria at relapse included T-cell phenotype (7 pts), Ph1 + ALL (4 pts), prednisone-poor response at diagnosis (4/11 evaluable pts). Median age at inclusion is 9 y (5 y-18 y). Dose escalation has been studied through 40 mg/m2/w (7 pts), 60 mg/m2/w (4 pts), 80 mg/m2/w (3 pts) 100 mg/m2/w (7 pts). WHO Grade III-IV adverse effects are: septicemia: 3 pts, aspergillosis: 2 pts, pneumonia: 2 pts. No mucositis Â³ grade I has been observed. Only one pt experimented a moderate and reversible decrease in shortening fraction. Complete response (defined by BM complete clearing of blast cells) has been obtained at D36 (2 pts) and D45 (1 pt). The objective response rate in 18 evaluable pts is 33% (3 complete and 3 partial BM responses). Median survival after inclusion is 4 m (1-18). 3 pts are alive: 1 in complete remission (4 m+), 1 in partial remission (5 m+), 1 in blastic phase (5 m+). Conclusions: DNX is feasible even in that cohort of heavily pretreated pts. The absence of significant extrahematological toxicity is to note. The MID has not been reached yet. Objective responses have been observed. The 120 mg/m2/w dose level is currently under investigation.
Full conference title:
40th Annual Meeting of the American Society of Hematology.
- ASH 40th (1999)