Biology Reference
In-Depth Information
concentrations are generally proportional to the dose of
fludarine given.
Initial studies with pretreated CLL patients showed
that the complete and partial response rates with fludar-
abine treatment alone were slightly greater than 50%.
186
However, the complete and partial response rates for
na¨ve CLL patients were between 75 to 80%. More
impressive, both response rates were essentially inde-
pendent of the inclusion of prednisone in the regimen.
186
In addition, approximately 60% of patients with follic-
ular lymphoma responded to fludarabine when admin-
istered as a single agent. Many of these patients undergo
complete remissions despite having received extensive
prior therapy.
The efficacy of fludarabine versus chlorambucil
monotherapy was compared in a long-term randomized,
multicenter trial published by Rai
et al.
187
This study con-
sisted of 509 patients with various stages of CLL. Patients
were randomly assigned to treatment arms consisting of
fludarabine (25 mg/m
2
daily for 5 days) or chlorambucil
(40 mg/m
2
every 28 days). Among these two groups, the
overall response rate was significantly higher using flu-
darabine (63%) compared to chlorambucil (37%). In addi-
tion, the complete response rate was higher in the
fludarabine group (20%) than in the chlorambucil group
(4%). The median duration of response and median
progression-free survival of patients treated with fludar-
abine were 25 months and 20 months, respectively. In
contrast, these values were 14 months in the chlorambu-
cil group. However, therewas only amodest difference in
the median overall survival in patients treated with flu-
darabine (66 months) versus those treated with chloram-
bucil (56 months).
above by Rai
et al.
initially included a third arm consist-
ing of fludarabine (20 mg/m
2
/day 1) combined with
chlorambucil (20 mg/m
2
/day 1) every 28 days.
187
Unfortunately, this arm of the study was discontinued
as patients receiving fludarabine and chlorambucil did
not show a response rate that was better than fludara-
bine monotherapy and showed evidence of excessive
hematological toxicity. A similar study of CLL patients
using a combination of 20 mg/m
2
chlorambucil on day
1 and 14 with escalating doses of fludarabine starting
at 10 mg/m
2
on days 1 though 5 produced high levels
of hematological toxicity as early as the entry dose.
189
A similar study performed by Elias
et al.
used 15mg/m
2
chlorambucil on day 1 with 20 mg/m
2
fludarabine on
days 1 through 5.
190
Again, this study was closed after 91
patients displayed unacceptable hematological tox-
icity.
187
Nearly identical complications have been experi-
enced with the combination of cladribine and
chlorambucil.
191
In this case, a schedule of 30 mg/m
2
chlorambucil every 2 weeks with 7-day continuous infu-
sion of cladribine was used to establish 2 mg/m
2
/day as
the maximum tolerated dose. However, hematological
toxicity was again a limiting factor in prolonged
treatment.
191
Alkylating agents other than chlorambucil have also
been tested for effective synergism when combined
with fludarabine. One particular agent is cyclophospha-
mide, a bifunctional alkylating agent that produces
similar cytotoxic activities to chlorambucil.
192
However,
cyclophosphamide generally produces less hematolog-
ical side effects and is often used to treat CLL when
chlorambucil is poorly tolerated. A study performed
by O'Brien
et al.
treated 128 CLL patients with fludara-
bine and cyclophosphamide for 3 days.
193
Included in
this study were na
¨
ve patients as well as those previ-
ously treated with alkylating agents or fludarabine.
The combination of fludarabine and cyclophosphamide
produced an 80% response rate in patients that were not
refractory to fludarabine alone and a response rate of
38% in patients who were refractory to fludarabine
given previously as monotherapy. In na¨ve patients,
the complete response rate of 35% was similar to that
observed earlier in CLL patients treated with fludara-
bine alone. However, residual disease was seen in only
8% in na¨ve patients treated with fludarabine and cyclo-
phosphamide that displayed a complete response.
Higher efficacy combining fludarabine and cyclo-
phosphamide compared with fludarabine monotherapy
has been confirmed in other phase III trials in the treat-
ment of na¨ve patients with advanced CLL.
194
Results
from the German CLL Study Group treated 375 patients
with advanced CLL and who were younger than
66 years old.
194
Patients were randomly assigned to
two treatment arms that included fludarabine mono-
therapy (25 mg/m
2
/day for 5 days) or fludarabine
Clinical and Biochemical Studies of Fludarabine
Combined with DNA Damaging Agents
The primary cytotoxic effect of nucleoside analogs is
thought to be through the inhibition of chromosomal
replication, which occurs exclusively during the S phase
of the cell-cycle.
188
It is therefore surprising that nucleo-
side analogs such as F-ara-A and cladribine showed
significant cytotoxic effects against cells with low
growth fractions such as indolent lymphomas. Since
these cells are not actively replicating, the cytotoxic
effects caused by incorporation into DNA suggests
that they effectively inhibit the low level of maintenance
DNA repair that occurs in quiescent cells. This ability of
these analogs to inhibit DNA repair predicted that
combining DNA damaging agents with nucleoside
analogs should produce a synergistic cytotoxic effect
via the inhibition of DNA repair. While this approach
works in preclinical models, the development of appro-
priate combinations in clinical applications has met with
significant difficulties. For example, the study described