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bcl-2 Antisense as Monotherapy for Refractory Chronic Lymphocytic Leukemia

bcl-2 Antisense as Monotherapy for Refractory Chronic Lymphocytic Leukemia

Wild-type bcl-2 protein is normally found within the bilaminar membrane of the mitochondrion, where it is believed to negatively regulate the release of cytochrome C into the cytoplasm after an apoptotic signal has triggered dimerization of bax protein. Thus, high levels of bcl-2 decrease apoptosis by preventing or slowing downstream activation of caspases via cytochrome C. Preclinical studies have shown that antisense-mediated reduction of bcl-2 consistently amplifies the cytotoxic activity of many chemotherapeutic agents across a broad range of hematologic malignancies and solid tumors. However, homologous recombination has generated a murine bcl-2 -/- knockout that displays profound immunodeficiency due to lymphoid hypoplasia, suggesting that the presence of bcl-2 itself is an essential viability factor for lymphoid cells.

bcl-2 is commonly overexpressed in chronic lymphocytic leukemia (CLL) cells, and recent in vitro data indicate that antisense-mediated reduction of bcl-2 protein directly induces apoptosis of CLL cells in the absence of other agents. Therefore, concurrent with a randomized trial that uses bcl-2 antisense (Genasense) combined with fludarabine (Fludara)/cyclophosphamide (Cytoxan, Neosar), we initiated a clinical study to evaluate its pharmacokinetics in CLL patients, biokinetics of bcl-2 protein down-regulation, and reexpression in CLL cells, and to examine whether this drug exhibited single-agent activity independent of its chemosensitizing effects.

To date, 14 patients have been treated with bcl-2 antisense administered as a continuous IV infusion at doses ranging from 3 to 7 mg/kg/d for 5 to 7 days every 3 weeks. At the 5- and 7-mg/kg/d dose levels, 6 patients experienced high fever; 6 patients had hypotension (2 severe) and hypoglycemia requiring intensive care unit admission. One patient developed transient acral cyanosis due to development of a cold agglutinin during the first course, and one patient developed severe sacral pain and a Coombs-positive hemolytic anemia during the second course. Several patients achieved reduction of peripheral leukocytosis, one of whom had tumor lysis syndrome.

CONCLUSION: In summary, unlike patients with solid tumors who routinely tolerate doses of 7 mg/kg/d (but similar to patients with non-Hodgkin’s lymphoma), patients with CLL appear markedly more sensitive to bcl-2 antisense. Whether this decreased tolerance is due to the differing biology of bcl-2 in lymphoid cells is unclear. Because of these reactions, all current studies in CLL have reduced initial drug dose to 3 mg/kg/d, used prednisone (10 mg/d × 3 days) to ameliorate early febrile response, and employed appropriate prophylaxis against tumor lysis. bcl-2 antisense may exert single-agent activity in CLL that does not depend upon chemosensitization to other cytotoxic drugs.

Click here to read Dr. Bruce Cheson's commentary on this abstract.

 
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