Fludarabine used as the initial treatment for chronic lymphocytic leukemia (CLL) produces more and longer remissions than chlorambucil, according to the findings of a multicenter clinical trial for patients with high- and intermediate-risk CLL. The study's findings appear in the December 14, 2000, issue of the New England Journal of Medicine.
Earlier trials have shown that fludarabine could be effective as second-line therapy, producing responses in patients who had not responded to chlorambucil. The new trial tested the drug in previously untreated patients and compared it to chlorambucil, which has long been considered the standard initial therapy for CLL.
The results show that "fludarabine yields higher response rates and a longer duration of remission" conclude the researchers, who were led by Kanti R. Rai of the Long Island Jewish Medical Center, New Hyde Park, N.Y. The trial was conducted by the Cancer and Leukemia Group B and other Clinical Trials Cooperative Groups, which are networks of cancer researchers sponsored by the National Cancer Institute.
However, fludarabine did not improve overall survival rates and produced more side effects than chlorambucil. The investigators note that CLL patients and their physicians "still confront a decision about which drug to try first," but that "the information from this trial provides a framework for making such decisions."
The trial included 509 patients who were randomly assigned to receive chlorambucil, fludarabine, or the two drugs together. The investigators stopped assigning patients to the two-drug arm of the trial when they found that the combination was producing an excessive number of side effects and a response rate that was no better than the rate with fludarabine alone.
Among the patients who received only fludarabine, 20 percent had a complete remission, compared to 4 percent of those taking chlorambucil. Forty-three percent of the fludarabine group had a partial remission versus 33 percent in the chlorambucil group. The median length of remission was 25 months for fludarabine and 14 months for chlorambucil, while the time before the disease progressed was 20 months for fludarabine and 14 months for chlorambucil.
Severe infections and low blood counts (neutropenia) were more frequent with fludarabine than chlorambucil, but overall toxic effects were tolerable, say the authors.
In an accompanying editorial, Guillaume Dighiero, M.D., of the Institut Pasteur and Jacques-Louis Binet, M.D., of the Hopital Pitie-Salpetriere, both in Paris, discuss other approaches to CLL that are now in clinical trials. These include treatments known as intensification procedures, which may involve bone marrow transplants, administration of monoclonal antibodies, or both.
In their article, Rai and his colleagues also emphasize the importance of continued research: "The challenge before us is to find other effective agents that, when combined with fludarabine, will lead to more incremental advances and, ultimately, to increased survival among patients with CLL."