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Concurrent vs Sequential Rituximab and Fludarabine Elicits Higher Complete Response in CLL

Concurrent vs Sequential Rituximab and Fludarabine Elicits Higher Complete Response in CLL

COLUMBUS, Ohio—Concurrent administration of rituximab (Rituxan) and
fludarabine (Fludara) produced higher complete response rates in previously
untreated patients with chronic lymphocytic leukemia (CLL) than sequential
administration, according to results of a phase II Cancer and Leukemia Group
B study.

"Hematologic toxicity on the concurrent arm is increased but
manageable, with no consequences with respect to infectious morbidity,"
reported John C. Byrd, MD, assistant professor and director of hematologic
malignancies at Ohio State University in Columbus. Stepped-up dosing, he
noted, could be used to diminish the infusion toxicity that occurred in 20%
of the patients receiving the concurrent treatment.

Induction Therapy

From March 1999 to January 2000, the study enrolled 104 patients—53 in
the sequential arm and 51 in the concurrent arm. Eligible patients had
symptomatic B-cell CLL as defined by the National Cancer Institute working
group, to meet the definition of required therapy, no prior therapy for CLL,
and performance status of 0 to 3. The median age was 64. Modified Rai stage
was 59% intermediate and 41% high risk.

Patients randomized to the sequential arm of the study received six
cycles of fludarabine (25 mg/m² on days 1 to 5, every 28 days). The study
design called for those in the concurrent arm to receive the same
fludarabine therapy, but with rituximab (375 mg/m²) added on days 1 and 4 of
cycle 1, and on day 1 only of cycles 2 to 6. Patients in both arms were
observed for 2 months, assessed for induction response, and given
consolidation therapy of 375 mg/m² of rituximab administered once a week for
4 weeks.

Infusion Reactions Managed

Among the first 44 patients in the concurrent arm, 9 (20%) developed
grade 3 or 4 dyspnea or hypotension with the first full dose of rituximab on
day 1 of treatment. "Although this resolved and usually did not occur
with the second and subsequent cycles," Dr. Byrd reported, these
reactions "required three patients to go off of the study and led to
the hospitalization of five patients. The study was modified with stepped-up
dosing." This meant giving 50 mg/m² on day 1, 325 mg/m² on day 3, and
the full 375 mg/m² on day 5 for the first cycle only. With this stepped-up
dosing, none of the last seven patients treated in the concurrent arm had
grade 3 or 4 dyspnea or hypotension.

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