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Sequential Fludarabine/Alemtuzumab in High-Risk CLL

Sequential Fludarabine/Alemtuzumab in High-Risk CLL

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.

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