"This study shows that fludarabine is superior to what we?ve been using as the gold standard for treating CLL for decades, namely chlorambucil," says Kanti R. Rai, MD, principal author of the study and chief, division of hematology/oncology at Long Island Jewish Medical Center in New York. "As a result of the study, fludarabine will gain strong acceptance by the community of oncologists in the front-line treatment of CLL."

The study, conducted between 1990 and 1999, randomly assigned 509 patients with previously untreated CLL to one of three treatment groups: fludarabine alone, chlorambucil alone, or a combination of the two. Enrollment in the combination fludarabine/chlorambucil group was stopped when results from the first three years of the study showed that the combination caused increased risk of life-threatening side effects without any improvement in response rate.

In the two other groups, fludarabine alone yielded a higher response than for chlorambucil alone. Twenty percent of the 170 patients treated with fludarabine had a complete remission, and 43% had a partial remission. Only 4% of the 181 chlorambucil-treated patients experienced complete remission, and 33% had a partial remission. For the fludarabine group, the remissions lasted an average of 25 months, while the remissions lasted only 14 months for the chlorambucil-treated patients. It also took longer for the leukemia to progress in the fludarabine-treated patients.

While patients taking fludarabine alone lived longest, the differences in overall survival among the three groups were not statistically significant: Patients survived an average of 66 months with fludarabine, 56 months with chlorambucil, and 55 months with a combination of both. Herman Kattlove, MD, medical editor with the American Cancer Society (ACS), says "the study shows that starting treatment with fludarabine doesn?t significantly improve long-term survival rates. But the ability of fludarabine to induce faster and longer-lasting remissions will help improve the quality of life for some patients."

The study maintains that side effects resulting from the treatments were mostly mild to moderate and were well-tolerated. However, severe to life-threatening thrombocytopenia (a bleeding disorder due to a shortage of blood platelets), neotropenia (a shortage of one type of infection-fighting white blood cells), and infections were significantly more common with fludarabine than with chlorambucil. One treatment-related death was reported for a patient who suffered heart and lung complications after fludarabine treatment.

Now that fludarabine has been demonstrated to significantly increase the rate of remission in patients with CLL, researchers believe other agents may be found that, when combined with fludarabine, will lead to new advances in the treatment of CLL.

"Hopefully, this research will lead to further methods of improving results," says Rai. "We have gone from 4% complete remission to 20% complete remission. Other research will build on these findings with incremental advances, a small step at a time, to prolong the lives of patients with CLL. Research is underway to test the use of monoclonal antibodies (lab-made proteins that are designed to seek and destroy some types of cancer cells) in combination with fludarabine. While there is no data yet, there is great promise of further achievements."

An editorial by Guillame Dighiero, MD, PhD, and Jacques-Louis Bonet, MD, of the Institut Pasteur and Hôpital Pitié-Salpetricre in Paris suggested that fludarabine may be the best initial treatment for some but not all people with CLL. They recommend that some patients delay treatment until symptoms occur, and then start with chlorambucil. If chlorambucil loses effectiveness, they suggest switching to fludarabine.