ORLANDO--Fludarabine (Flu-dara) improves response, duration of response,
and progression-free survival over standard therapy in previously untreated
patients with active B-cell chronic lymphocytic leukemia (CLL), and it
should be included in the list of drugs for first-line treatment of this
disease, Kanti R. Rai, MD, said at the 38th Annual Meeting of the American
Society of Hematology (ASH).
Dr. Rai, chief of the Division of Hematology-Oncology, Long Island Jewish
Medical Center, New Hyde Park, and professor of medicine, Albert Einstein
College of Medicine, New York, presented data from a 6-year randomized
study of the nucleoside analogue fludarabine vs chlorambucil (Leukeran),
the standard therapy for CLL.
Sponsored by the National Cancer Institute (NCI), the Intergroup study
was performed cooperatively by the Cancer and Leukemia Group B (CALGB)
consortium and investigators from the Southwest Oncology Group, Eastern
Cooperative Oncology Group, and NCI-Canada's Clinical Trials Group.
A total of 544 previously untreated patients with stage I or stage II
B-cell CLL who had active disease, and patients with stage III or IV disease,
were randomized to one of three arms.
In the fludarabine arm, patients received 25 mg/m² intravenously
daily for 5 days each month, for up to 12 months. Patients in the chlorambucil
arm received 40 mg/m² orally on day 1 every 4 weeks, for up to 12
months. Nonresponders or responders who showed disease progression within
6 months were crossed over to the other study arm.
A third study arm randomized patients to receive a combination of the
two agents and was halted early due to the development of toxicities, including
a significant incidence of infections, compared with either of the single-agent
Patients in the study were predominantly male, with approximately 10%
between 40 and 49 years of age and 25% older than 70 years.
Higher Overall Response
Of 167 patients who could be evaluated for response in the fludarabine
arm, a total overall response of 70% (complete response [CR] 27% + partial
response [PR] 43%) was achieved, compared with 43% (3% CR + 40% PR) of
173 patients who could be evaluated in the chlorambucil arm (P less than
In addition, the median duration of response was significantly longer
in the fludarabine group than in the chlorambucil group (32 vs 18 months),
as was median progression-free survival (27 vs 17 months).
When analyzed according to intermediate or advanced stage of disease,
differences in response persisted, with patients with intermediate and
advanced disease achieving a CR of 34% and 16%, respectively, in the fludarabine-treated
group, compared with 5% and 0%, respectively, in the chlorambucil-treated
Of 74 patients who crossed from chlorambucil to fludarabine, there was
a salvage rate of 55% (14% CR + 41% PR); of 29 patients who switched from
fludarabine to chlorambucil, the rate of salvage was 17% (0% CR + 17% PR).
No difference, however, was demonstrated in overall survival of patients
in either single-agent arm at a median follow-up of 30 months, although
the comparison is complicated by the crossover design of the study. Toxicities
between the two groups were similar.
Because of the lack of difference in overall survival, Dr. Rai believes
that "flu-darabine is a good treatment for some but not all CLL patients."
He suggests it be considered in relatively young CLL patients, "in
whom you want to achieve a rapid, maximally achievable beneficial response,
and who may possibly go on to receive peripheral stem cell transplantation
or other more aggressive treatment."
In older patients in whom treatment-related morbidity is a major concern,
"it is quite legitimate to try alkylating agents as first-line treatment.
You have to use your clinical judgment," he said.
Dr. Rai added that "we can now attempt to increase further the
CR rate by finding other drugs or modalities to combine with fludarabine,
with the aim of significantly increasing the overall survival of patients
with this disease."