Background: Fludarabine is an effective treatment for chronic lymphocytic l
eukemia that does not respond to initial treatment with chlorambucil. We co
mpared the efficacy of fludarabine with that of chlorambucil in the primary
treatment of chronic lymphocytic leukemia.
Methods: Between 1990 and 1994, we randomly assigned 509 previously untreat
ed patients with chronic lymphocytic leukemia to one of the following treat
ments: fludarabine (25 mg per square meter of body-surface area, administer
ed intravenously daily for 5 days every 28 days), chlorambucil (40 mg per s
quare meter, given orally every 28 days), or fludarabine (20 mg per square
meter per day for 5 days every 28 days) plus chlorambucil (20 mg per square
meter every 28 days). Patients with an additional response at each monthly
evaluation continued to receive the assigned treatment for a maximum of 12
cycles.
Results: Assignment of patients to the fludarabine-plus-chlorambucil group
was stopped when a planned interim analysis revealed excessive toxicity and
a response rate that was not better than the rate with fludarabine alone.
Among the other two groups, the response rate was significantly higher for
fludarabine alone than for chlorambucil alone. Among 170 patients treated w
ith fludarabine, 20 percent had a complete remission, and 43 percent had a
partial remission. The corresponding values for 181 patients treated with c
hlorambucil were 4 percent and 33 percent (P<0.001 for both comparisons). T
he median duration of remission and the median progression-free survival in
the fludarabine group were 25 months and 20 months, respectively, whereas
both values were 14 months in the chlorambucil group (P<0.001 for both comp
arisons). The median overall survival among patients treated with fludarabi
ne was 66 months, which was not significantly different from the overall su
rvival in the other two groups (56 months with chlorambucil and 55 months w
ith combined treatment). Severe infections and neutropenia were more freque
nt with fludarabine than with chlorambucil (P=0.08), although, overall, tox
ic effects were tolerable with the two single-drug regimens.
Conclusions: When used as the initial treatment for chronic lymphocytic leu
kemia, fludarabine yields higher response rates and a longer duration of re
mission and progression-free survival than chlorambucil; overall survival i
s not enhanced. (N Engl J Med 2000;343:1750-7.) (C) 2000, Massachusetts Med
ical Society.