Yaacov Cass

Initial clinical studies with doxorubicin entrapped in the bilayer of phosphatidylglycerol-rich liposomes were hindered by the avid reticuloendothelial system (RES) uptake and by drug leakage from circulating liposomes. In contrast, recent tests of a doxorubicin formulation of polyethyleneglycol-coated liposomes (Doxil) in cancer patients indicate that the drug pharmacokinetic properties are significantly altered, with a prolonged distribution half-life of approximately 2 days. Plasma fractionation studies show that nearly all the drug measured in plasma is in liposome-encapsulated form. The dose of Doxil has been escalated from 25 to 60 mg/m2. Stomatitis is the most significant toxicity, and skin toxicity, in the form of hand-foot syndrome, may complicate the repeated administration of Doxil. A number of objective antitumor responses in a variety of malignancies have been observed, indicating that Doxil is an active antitumor compound. Polyethyleneglycol-coated liposomes show a distinct advantage over previous liposome formulations directed at the RES and appear to be a promising drug delivery system for doxorubicin.

Twenty four patients with refractory chronic lymphocytic leukemia (CLL) and advanced low grade lymphoma (LGL) were treated with Fludarabine given at a dose of 25 mg/m2, intravenously daily for 5 days, every 28 days. Ten of the patients with LGL were in terminal leukemic phase. All patients had received previous chemotherapy, most with multiple regimens. Patients received a mean of 5.1 cycles (range 1-9). 4 patients--one with CLL and 3 with LGL--achieved a complete remission, while 7 LGL and 3 CLL patients had a partial response. Two patients remain in complete remission 23 and 25 months after completion of therapy. One patient underwent successful autologous bone marrow transplantation after achieving a complete remission, while two others had marrow cryopreserved during complete remission. The drug was well tolerated and toxicity was mild. In 9 of the 122 given cycles patients required hospitalization. In conclusion, Fludarabine is active in refractory patients with CLL and LGL and induces complete and partial remissions in some. It seems that Fludarabine could be used as primary therapy in these disorders in the future.