NEW YORKNovel treatment strategies targeting specific
cytokines may provide an additional therapeutic window for the treatment of
chronic lymphocytic leukemia (CLL), Janice L. Gabrilove, MD, of Mount Sinai
School of Medicine, New York, said at the Chemotherapy Foundation Symposium
Certain cytokines, in vitro, have been shown to promote
enhanced CLL cell proliferation. Others may contribute to resistance to
programmed cell death in response to an apoptotic stimulus (such as a
nucleoside analog). Evidence suggests that delayed apoptosis contributes to the
prolonged cell survival seen in this disease.
"Approaches that take advantage of understanding this
pathway may be of therapeutic benefit," particularly to patients resistant
to standard therapies, Dr. Gabrilove said.
A number of CLL treatments that are accepted today, including
use of the nucleoside analog fludarabine (Fludara), actually work by
interfering with the impaired apoptosis seen in CLL. By inducing programmed
cell death, treatment leads to extinction of the malignant cells.
Tumor necrosis factor-alpha (TNF-alpha) is one cytokine that
contributes to enhanced proliferation of malignant cells. Fibroblast growth
factor (FGF), on the other hand, contributes to the survival of CLL cells by
preventing cell death.
Nine FGF genes have been identified. Dr. Gabrilove and her
colleagues have observed that CLL cells express elevated levels of
intracellular basic FGF (bFGF) that increase with stage of disease. In
vitro, the researchers showed that bFGF contributes to CLL cell resistance to
In vitro CLL cells exposed to fludara-bine had almost all
undergone apoptosis after 5 days of culture; however, with the addition of
bFGF, more CLL cells were still viable, suggesting that bFGF confers a
"growth advantage" by interfering with the cells’ ability to
respond to the apoptotic stimulus provided by the nucleoside analog.
The Bcl-2 protein is commonly over-expressed in CLL, and
upregulation of Bcl-2 is associated with delayed programmed cell death. Thus,
strategies to interfere with Bcl-2, such as use of novel Bcl-2 antisense
compounds, "may prove to be of considerable interest," Dr. Gabrilove
said. Fibroblast growth factor also has the ability to promote cell survival by
upregulating Bcl-2, she said.
Trial of Thalidomide
A clinical trial of thalidomide (Thalomid) has been initiated
by Dr. Gabrilove and her colleagues based on the current understanding of
growth-promoting and survival mechanisms.
In the trial, thalidomide, a potent inhibitor of both TNF-alpha
and FGF-mediated growth, will be given alone or in combination with fludarabine
to CLL patients who have already failed fludarabine treatment or are primarily
resistant to fludarabine.