NEW HYDE PARK, N.Y.--A study of patients with untreated chronic lymphocytic leukemia has confirmed that fludarabine offers higher response rates than chlorambucil plus longer remissions and progression-free survival.
The randomized North American trial documented that fludarabine has several superior qualities as a first-line agent for CLL, though the drug did not lead to a longer overall survival than chlorambucil did.
Nevertheless, Dr. Kanti Rai of the Long Island Jewish Medical Center here, the lead author, was encouraged. He said the results validated the common off-label use of fludarabine (Fludara, Berlex) as a way to achieve "a quick and complete remission" for a longer period for younger patients, giving them freedom from repeated physicians visits and additional chemotherapy.
He and his co-authors, reporting for several cooperative trial groups in the Dec. 14 New England Journal of Medicine, noted that the inconvenience of fludarabine's IV use, compared with chlorambucil's oral administration, may influence the choice of therapy for older patients. And fludarabine was significantly more toxic than chlorambucil.
So despite fludarabine's better response rate, "patients and their physicians still confront a decision about which drug to try first" for previously untreated progressive CLL, they concluded.
The trial's results were similar to those of two other randomized trials, known as the French study and the European study. In the North American trial, 509 previously untreated CLL patients were randomized to either of the drugs. An arm treated with both drugs was halted because of toxicity.
Among 170 patients given fludarabine, 20% had a complete response and 43% a partial response. In contrast, 4% of 181 patients given chlorambucil had a complete response and 33% a partial.
The median remission for the fludarabine group was 25 months, and for progression-free survival it was 20 months. Both were 14 months for chlorambucil. Overall survival was 66 months with fludarabine and 56 months with chlorambucil, not significantly different.
Severe infections and neutropenia were significantly more frequent with fludarabine than chlorambucil.
In an accompanying editorial, Dr. Guillaume Dighiero of Institut Pasteur and Dr. Jacques-Louis Binet of Hopital Pitie Salpetriere, both in Paris, said that if overall survival doesn't lengthen in the face of improved response, there's a need to look elsewhere with randomized trials, particularly at intensification procedures aimed at complete molecular remissions.
In the meantime, though, they recommended observation for early-stage disease, and trials with aggressive intensification strategies for those younger than 65 with advanced CLL. For older patients with comorbidities, they recommended chlorambucil for palliation. For patients in other categories, they noted that fludarabine is the best option for disease that is refractory to alkylating agents.