Sequential Fludarabine/Alemtuzumab in High-Risk CLL

February 1, 2003

PHILADELPHIA-Early results of a phase II trial of sequential fludarabine (Fludara)/alemtuzumab (Campath) therapy in patients with high-risk chronic lymphocytic leukemia (CLL) are encouraging in that the monoclonal antibody appears to improve the rate of flu-darabine-induced responses, Dr. Kanti R. Rai said at the 44th Annual Meeting of the American Society of Hematology (abstract 772). This study is one of several Cancer and Leukemia Group B (CALGB) trials investigating the combination of fludarabine, an effective single-agent therapy for CLL, with various antineoplastic monoclonal antibody agents.

PHILADELPHIA—Early results of a phase II trial of sequential fludarabine (Fludara)/alemtuzumab (Campath) therapy in patients with high-risk chronic lymphocytic leukemia (CLL) are encouraging in that the monoclonal antibody appears to improve the rate of flu-darabine-induced responses, Dr. Kanti R. Rai said at the 44th Annual Meeting of the American Society of Hematology (abstract 772). This study is one of several Cancer and Leukemia Group B (CALGB) trials investigating the combination of fludarabine, an effective single-agent therapy for CLL, with various antineoplastic monoclonal antibody agents.

Dr. Rai reported on an open-label, prospective study of sequential fludara-bine/alemtuzumab in 57 patients with previously untreated CLL of advanced stage (III or IV) or with active stage I or II disease. Fludarabine (25 mg/m2 IV for 5 days every 4 weeks) was administered for four cycles. After 2 months’ observation, patients who had a response (stable disease or better) received 6 weeks of alemtuzumab, stepped up to a maximum dose of 30 mg IV three times a week.

The fludarabine regimen resulted in 3 complete responses, 28 partial responses, and 18 instances of stable disease. Ten patients eligible for alemtuzu-mab withdrew, leaving 39 to receive further therapy, said Dr. Rai, chief of hematology/oncology, Long Island Jewish Medical Center, New Hyde Park, NY, and professor of medicine, Albert Einstein College of Medicine, Bronx, NY.

Responses to alemtuzumab were assessed 2 months after the last treatment. Of 24 patients with a partial response to fludarabine, 9 had a complete response to the antibody. Of 12 patients beginning treatment with stable disease, 2 had a complete response with alemtuzumab and 7 had a partial response. Of all patients who received alemtuzumab, 36% had a complete response and 92% were either complete or partial responders. One fourth of all patients who began the trial had a complete response to fludara-bine alone or to the sequential regimen.

Major infections requiring parenteral antibiotics or hospitalization (grade 3-4 toxicity) occurred in 12 patients during alemtuzumab therapy. Following one case of fatal cytomegalovirus (CMV) infection, a protocol revision requiring weekly surveillance for CMV was instituted. A total of 9 CMV cases ocurred, of which 5 were CMV disease and 4 were seroconversions without evidence of disease. All were promptly controlled with IV ganciclovir (Cytovene) and discontinuation of alemtuzumab.

Thrombocytopenia and neutropenia each occurred in about one fourth of patients during the alemtuzumab phase. The antibody also was associated with a high rate of mostly low-grade infusion-site reactions, which subsided over several weeks as patients became better able to tolerate the infusions.

From this study, "we learned that fludarabine for 4 months is inadequate to produce an optimum response," Dr. Rai said. Six cycles of fludarabine are probably optimal, he added. Alemtuzu-mab appears to improve patients’ responses to fludarabine, he said, but longer follow-up is needed to determine whether the sequential regimen truly improves the natural history of CLL.

"We learned that CMV surveillance is necessary to reduce the morbidity and mortality associated with this treatment. And finally, subcutaneous Campath deserves investigation to improve the user-friendliness of this agent by bypassing IV-related problems," he said.