New Drugs for the Treament of Chronic Lymphocytic Leukemia

Novel strategies are needed to improve the prognosis of patients with chronic lymphocytic leukemia CLL). One approach is to identify new drugs with unique mechanisms of action. Compound GW506U78, the prodrug for arabinosylguanine, is an interesting new purine analog, which induces responses in about one-third of patients with relapsed or refractory CLL. A multicenter study is currently evaluating patients with CLL who have failed treatment with both fludarabine and an alkylating agent. Other agents in clinical development include retinoids and arsenicals which induce apoptosis, farnesyl transferase inhibitors, proteasome inhibitors and the signal transduction modulators, bryostatin and UCN-01. UCN-01 not only inhibits protein kinase C, but also modulates the G2 checkpoint. In vitro synergy has been demonstrated with fludarabine and a phase I trial of this combination is ongoing at the National Cancer Institute, USA. Flavopiridol is a semisynthetic flavone derivative which is active against cycling as well as noncycling cells. It inhibits a variety of cyclins and induces apoptosis. The histone deacetylase inhibitor depsipeptide has selective activity against CLL cells in vitro. An increasing body of evidence has implicated angiogenesis in hematologic malignancies, such as multiple myeloma, lymphoma and CLL. Several angiogenesis inhibitors are currently in clinical trials, including thalidomide, SU5416 and SU6668. Future strategies must be directed at appropriate therapeutic targets using rational combinations of these drugs and other new compounds with the goal of curing patients with CLL.