Fludarabine Produces CRs as First-Line CLL Therapy

SEATTLE--Fludarabine (Fludara) has demonstrated impressive resultsin previously untreated patients with active chronic lymphocyticleukemia (CLL) when compared with chlorambucil (Leukeran), KantiRai, MD, said at the American Society of Hematology (ASH) annualmeeting.

"Chlorambucil has been the gold standard treatment for CLL,"said Dr. Rai, chief of the Department of Hematology and Oncology,Long Island Jewish Hospital, New Hyde Park, NY. Although chlorambucilproduces response rates of up to 60% to 70%, the great majorityare partial, not complete, responses. "Overall, the naturalhistory of CLL has not been shown to be altered or improved byany treatment, and nothing we did was improving survival,"he said.

Fludarabine is currently indicated for the treatment of patientswith B-cell CLL who have not responded to, or whose disease hasprogressed during, treatment with a regimen containing at leastone standard alkylating agent. A study from M.D. Anderson showedthat fludarabine was significantly more effective in previouslyuntreated patients with active disease, compared with other drugs.

This finding prompted the randomized intergroup study in previouslyuntreated CLL patients with active disease, Dr. Rai said. Thestudy involved the Cancer and Leukemia Group B (CALGB), SouthwestOncology Group (SWOG), National Cancer Institute (NCI), ClinicalTrial Group of the NCI of Canada, and the Eastern CooperativeOncology Group (ECOG).

Over a period of 3½ years (October 1990 through April 1994),more than 450 intermediate-risk and high-risk patients were randomizedto receive either flu-darabine, 25 mg/m² by ½-hour intravenousinfusion daily from days 1 to 5 every 4 weeks, or chlorambucil,40 mg/m² by mouth on day 1 every 4 weeks.

Initially, a third randomized arm combined the two drugs but wasclosed when an interim analysis showed unacceptably high hematologictoxicity and a response rate no better than that achieved by fludarabinealone, Dr. Rai said.

The study, with a primary endpoint of complete remission, wascomprised of two phases: Patients showing continued beneficialresponse received the assigned therapy for a maximum of 12 months,and nonresponding patients and those relapsing within 6 monthswere crossed over to the alternate therapy.

Of 233 evaluable patients who had finished induction therapy,patients in the fludarabine arm experienced a 36% complete remissionrate, compared with 9% with chlorambucil, Dr. Rai said. Fludar-abineachieved a combined complete and partial response rate of 64%.It is too early to compare response duration and survival.

Overall, Dr. Rai said, both drugs were well tolerated, with nosignificant difference between their toxicity profiles.

"Fludarabine is the single most active agent we have againstchronic lymphocytic leukemia," said Bruce Cheson, MD, headof the NCI's Medicine Section Cancer Therapy Evaluation Programand a co-investigator of the study.

A nucleoside analog, fludarabine appears to work by inhibitingDNA synthesis and repair, Dr. Cheson said. It has also been shownto induce apoptosis, an action that may be responsible for itsefficacy in low-grade lymphoma as well as CLL.

Fludarabine's toxicity profile also appears to be acceptable."We thought it would be more toxic than the alkylating agents,but that wasn't the case," Dr. Cheson said.

Dr. Cheson noted that even though chlorambucil has been aroundfor decades, an optimal dosing schedule for the agent has neverbeen devised. "Even under the best of circumstances,"he said, "chlorambucil has achieved few complete remissions,which are necessary to influence the natural history of the diseaseand effect a cure."