bcl-2 Antisense as Monotherapy for Refractory Chronic Lymphocytic Leukemia

Wild-type bcl-2 protein is normally found within the bilaminar membrane ofthe mitochondrion, where it is believed to negatively regulate the release ofcytochrome C into the cytoplasm after an apoptotic signal has triggereddimerization of bax protein. Thus, high levels of bcl-2 decrease apoptosis bypreventing or slowing downstream activation of caspases via cytochrome C.Preclinical studies have shown that antisense-mediated reduction of bcl-2consistently amplifies the cytotoxic activity of many chemotherapeutic agentsacross a broad range of hematologic malignancies and solid tumors. However,homologous recombination has generated a murine bcl-2 -/- knockout that displaysprofound immunodeficiency due to lymphoid hypoplasia, suggesting that thepresence 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-2protein 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), weinitiated a clinical study to evaluate its pharmacokinetics in CLL patients,biokinetics of bcl-2 protein down-regulation, and reexpression in CLL cells, andto examine whether this drug exhibited single-agent activity independent of itschemosensitizing effects.

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

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

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