Fludarabine Effective as First-Line CLL Therapy

ORLANDO--Fludarabine (Flu-dara) improves response, duration of response,and progression-free survival over standard therapy in previously untreatedpatients with active B-cell chronic lymphocytic leukemia (CLL), and itshould be included in the list of drugs for first-line treatment of thisdisease, Kanti R. Rai, MD, said at the 38th Annual Meeting of the AmericanSociety of Hematology (ASH).

Dr. Rai, chief of the Division of Hematology-Oncology, Long Island JewishMedical Center, New Hyde Park, and professor of medicine, Albert EinsteinCollege of Medicine, New York, presented data from a 6-year randomizedstudy of the nucleoside analogue fludarabine vs chlorambucil (Leukeran),the standard therapy for CLL.

Sponsored by the National Cancer Institute (NCI), the Intergroup studywas performed cooperatively by the Cancer and Leukemia Group B (CALGB)consortium and investigators from the Southwest Oncology Group, EasternCooperative Oncology Group, and NCI-Canada's Clinical Trials Group.

A total of 544 previously untreated patients with stage I or stage IIB-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 intravenouslydaily for 5 days each month, for up to 12 months. Patients in the chlorambucilarm received 40 mg/m² orally on day 1 every 4 weeks, for up to 12months. Nonresponders or responders who showed disease progression within6 months were crossed over to the other study arm.

A third study arm randomized patients to receive a combination of thetwo agents and was halted early due to the development of toxicities, includinga significant incidence of infections, compared with either of the single-agentarms.

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 fludarabinearm, a total overall response of 70% (complete response [CR] 27% + partialresponse [PR] 43%) was achieved, compared with 43% (3% CR + 40% PR) of173 patients who could be evaluated in the chlorambucil arm (P less than.0001).

In addition, the median duration of response was significantly longerin 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 andadvanced disease achieving a CR of 34% and 16%, respectively, in the fludarabine-treatedgroup, compared with 5% and 0%, respectively, in the chlorambucil-treatedgroup.

Of 74 patients who crossed from chlorambucil to fludarabine, there wasa salvage rate of 55% (14% CR + 41% PR); of 29 patients who switched fromfludarabine to chlorambucil, the rate of salvage was 17% (0% CR + 17% PR).

No difference, however, was demonstrated in overall survival of patientsin either single-agent arm at a median follow-up of 30 months, althoughthe comparison is complicated by the crossover design of the study. Toxicitiesbetween the two groups were similar.

Because of the lack of difference in overall survival, Dr. Rai believesthat "flu-darabine is a good treatment for some but not all CLL patients."

He suggests it be considered in relatively young CLL patients, "inwhom you want to achieve a rapid, maximally achievable beneficial response,and who may possibly go on to receive peripheral stem cell transplantationor 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 theCR rate by finding other drugs or modalities to combine with fludarabine,with the aim of significantly increasing the overall survival of patientswith this disease."