Liposomal daunorubicin versus standard daunorubicin: long term follow-up of the GIMEMA GSI 103 AMLE randomized trial in patients older than 60 years with acute myelogenous leukaemia

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m(2) days 1-3) or DNX (80 mg/m(2) days 1-3) plus cytarabine (AraC; 100 mg/m(2) days 1-7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51.0%) achieved CR, 55 (35.9%) were resistant and 20 (13.1%) died during induction. Among 148 patients in the DNX arm, 73 (49.3%) achieved CR, 47 (31.8%) were resistant and 28 (18.9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12.5% vs. 2.6% at 6 months, P = 0.053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0.064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses.     

A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours

Anthracyclines are widely used in paediatric oncology, but their use is limited by the risk of cumulative cardiac toxicity. Encapsulating anthracyclines in liposomes may reduce cardiac toxicity and possibly increase drug availability to tumours. A phase I study in paediatric patients was designed to establish the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) after a single course of liposomal daunorubicin, 'DaunoXome', as a 1 h infusion on day 1 of a 21 day cycle. Patients were stratified into two groups according to prior treatment: Group A (conventional) and group B (heavily pretreated patients). Dose limiting toxicity was expected to be haematological, and a two-step escalation was planned, with and without G-CSF support. Pharmacokinetic studies were carried out in parallel. In all, 48 patients aged from 1 to 18 years were treated. Dose limiting toxicity was neutropenia for both groups. Maximum tolerated dose was defined as 155 mg m(-2) for Group A and 100 mg m(-2) for Group B. The second phase with G-CSF was interrupted because of evidence of cumulative cardiac toxicity. Cardiac toxicity was reported in a total of 15 patients in this study. DaunoXome shares the early cardiotoxicity of conventional anthracyclines in paediatric oncology. This study has successfully defined a haematological MTD for DaunoXome, but the significance of this is limited given the concerns of delayed cardiac toxicity. The importance of longer-term follow-up in patients enrolled into phase I studies has been underestimated previously, and may lead to an under-recognition of important adverse events.     

Liposomal encapsulation diminishes daunorubicin-induced generation of reactive oxygen species, depletion of ATP and necrotic cell death in human leukaemic cells

In this study, we tested the mechanisms of daunorubicin (DNR)- and the liposomal encapsulated daunorubicin (DaunoXome or DNX)-induced killing in three human leukaemic cell lines, K562, K/Bax and CEM. DNX showed less cytotoxicity in leukaemic cells than conventional DNR. The intracellular accumulation of DNX was 10 times less than conventional DNR during exposure to drugs for up to 5 h. Cell cycle analysis indicated that DNR induced concentration-dependent G2/M arrest, apoptosis and necrosis. However, DNX induced G2/M arrest and apoptosis but not necrotic cell death, even at a higher concentration. DNR- or DNX-induced activation of caspase-9 and -3 was detected at concentrations that induced apoptosis and necrosis. The sensitivity of leukaemic cells to DNR- and DNX-induced apoptosis correlated with the activation of caspases and the reduction of mitochondrial membrane potential (DeltaPsim), but not the depletion of ATP and the generation of reactive oxidative species (ROS). DNX did not provoke ROS generation and ATP depletion in leukaemic cells. We conclude that the liposomal encapsulation of DNR restricts the intracellular accumulation speed and therefore diminishes ROS generation, ATP depletion and necrotic cell death. This may have implications for the cause of cardiotoxicity seen with DNR, its main dose-limiting step.     

Sequential continuous infusion of fludarabine and cytarabine associated with liposomal daunorubicin (DaunoXome) (FLAD) in primary refractory or relapsed adult acute myeloid leukemia patients

A large proportion of adult patients with acute myeloid leukemia (AML) relapse after treatment, and some of them are resistant to primary induction chemotherapy. Sixty-one patients from seven hematological centers with poor-risk AML, primary refractory (n = 16), or relapsed (n = 45) were treated with a salvage regimen, including fludarabine (2 days) and cytarabine (3 days) in a sequential continuous infusion, associated with liposomal daunorubicin (3 days) (FLAD). Complete response rate was 44% and 56% for refractory and relapsed patients, respectively, with an overall response rate of 52% (32 of 61). Twenty-two patients (36%) were resistant to the salvage therapy. Seven patients (12%) died early during chemotherapy, four of them because of sepsis. Nineteen patients in complete remission (CR) underwent a stem-cell transplant (SCT) procedure: five autologous, nine from a HL-A identical sibling, and five from HL-A matched unrelated donors. Post-treatment aplasia and mucositis were major toxicities. Twenty patients (62.5%) relapsed after this treatment in a median of 7.3 months; ten patients relapsed after a SCT procedure. Nine patients are alive and disease free; three of them were rescued after a further cytotoxic treatment. The FLAD regimen proved to be an effective and well-tolerated treatment, with acceptable toxicity in this group of high-risk patients. A better response rate was obtained in the subgroup of relapsed patients, compared to patients treated for refractory disease. More then half (five of nine) of long-surviving patients are those who were submitted to a transplant procedure; thus, the main indication for FLAD seems to be to try to induce a rapid CR with minimum toxicity in order to perform a transplant as soon as possible.     

Phase II studies with DaunoXome in patients with nonresectable hepatocellular carcinoma: clinical and pharmacokinetic outcomes

A total of 14 Chinese patients with inoperable hepatocellular carcinoma received a liposomal formulation of daunorubicin (DaunoXome) at a dose equivalent to 100 mg/m² of the free drug every 3 weeks. Altogether, 12 patients were assessable for response; 2 patients had stable disease for 8 weeks, but all eventually developed progressive disease and there was no responder. The drug was well tolerated, with no evidence of cardiac toxicity being observed. Deterioration of liver-function tests was attributed to progressive tumors in the terminal stage of the disease. Pharmacokinetics studies revealed a biexponential decay for daunorubicin in association with mean initial and terminal half-lives of 1.8 and 7.4 h, respectively, and a mean total clearance of 15.0 ± 5.5 ml/min. The AUC ratio between the metabolite daunorubicinol and daunorubicin was 0.07. These data differ markedly from the pharmacokinetics of the free drug. Received: 13 August 1998 / Accepted: 13 January 1999     

The use of liposomal daunorubicin (DaunoXome) in acute myeloid leukemia

Altered pharmacokinetics of liposomal formulations of drugs can diminish toxicity and allow the administration of the encapsulated drug at high doses. The liposomal formulation of daunorubicin (DaunoXome, L-DNR) has been reported to produce high mean area under the plasma curve (AUC) levels due to a slow distribution of the liposomal moiety into the body and also to reduce the conversion of daunorubicin to the toxic, but inactive, daunorubicinol. Animal and in vitro studies have shown increased intratumor and intracellular levels of the drug, resulting in enhanced cytotoxicity, even in multidrug-resistant cell lines, while normal tissue toxicity, including cardiotoxicity, may be reduced. L-DNR has been tested as a single agent or in combination with arabinosyl cytosine in the treatment of patients with acute myeloid leukemia (AML) in relapse or in patients with newly diagnosed AML or with disease failing initial remission-induction therapy. The results have indicated that L-DNR can be used at high doses, up to 150 mg/m² for 3 days, safely with acceptable toxicity. The anti-leukemia activity has been reported to be at least equal or superior to that of free daunorubicin. Mucositis appeared more frequently than cardiotoxicity and high complete remission rates have been reported in patients with AML in first relapse. However, the superiority of L-DNR with regard to efficacy and toxicity will only be shown by prospective clinical studies comparing L-DNR with free daunorubicin or other regimens. Two comparative trials are currently active in AML patients, one in children and another in the elderly, run by the international BFM and GIMEMA groups, respectively.     

Management of AIDS-related Kaposi’s sarcoma: advances in target discovery and treatment

Kaposi’s sarcoma is the most common tumor arising in HIV-infected patients and is an AIDS-defining illness by the Centers for Disease Control guidelines. Recent advances in the elucidation of the pathogenesis of KS are uncovering potential targets for KS therapies. Such targets include the processes of angiogenesis and cellular differentiation and the Kaposi’s sarcoma herpesvirus/human herpesvirus-8. With the increasing recognition that effective antiretroviral regimens are associated with both a decreased proportion of new AIDS-defining Kaposi’s sarcoma cases and a regression in the size of existing Kaposi’s sarcoma lesions, most, if not all, Kaposi’s sarcoma patients should be advised to take antiretroviral drugs that will maximally decrease HIV-1 viral load. Five agents are currently approved by the US FDA for the treatment of Kaposi’s sarcoma; alitretinoin gel for topical administration; and liposomal daunorubicin, liposomal doxorubicin, paclitaxel and interferon-α for systemic administration. Many more agents, particularly angiogenesis inhibitors and other pathogenesis-targeted therapies are in early clinical development. Over the next 5 years, we may see even more of these pathogenesis-targeted therapies in trials and just as important we may identify, develop and validate clinically practical tools for assessing the biological effects of these therapies. The next 5 years may also bring a better understanding of the pharmacokinetic interactions among the many agents in the Kaposi’s sarcoma and AIDS armamentariums.     

A phase I dose-escalating study of DaunoXome,liposomal daunorubicin,in metastatic breast cancer

The aims of this phase I study were to establish the maximum tolerated dose, safety profile and activity of liposomal daunorubicin, DaunoXome (NeXstar Pharmaceuticals), in the treatment of metastatic breast cancer. DaunoXome was administered intravenously over 2 h in 21 day cycles and doses were increased from 80 to 100, 120 and 150 mg m(2). Sixteen patients were enrolled. A total of 70 cycles of DaunoXome were administered. The maximum tolerated dose was 120 mg m(2), the dose-limiting toxicity being prolonged grade 4 neutropenia or neutropenic pyrexia necessitating dose reductions at 120 and 150 mg m(2). Asymptomatic cardiotoxicity was observed in three patients: grade 1 in one treated with a cumulative dose of 800 mg m(2) and grade 2 in two, one who received a cumulative dose of 960 mg m(2) and the other a cumulative dose of 600 mg m(2) with a previous neoadjuvant doxorubicin chemotherapy of 300 mg m(2). Tumour response was evaluable in 15 patients, of whom two had objective responses, six had stable disease and seven had progressive disease. In conclusion, DaunoXome is associated with mild, manageable toxicities and has anti-tumour activity in metastatic breast cancer. The findings support further phase II evaluation of DaunoXome alone and in combination with other standard non-anthracycline cytotoxic or novel targeted agents. Although the dose-limiting toxicity for DaunoXome was febrile neutropenia at 120 mg m(2), we would recommend this dose for further evaluation, as the febrile neutropenia occurred after four or more cycles in three of the four episodes seen, was short lived and uncomplicated.