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
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.