Fludarabine and Alemtuzumab Versus Fludarabine and Rituximab in the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia: Results from a Phase II Study.

Although single-agent fludarabine is associated with high response rates (60%–80%) in patients with previously untreated B-cell chronic lymphocytic leukemia (B-CLL), this therapy is not curative and patients will relapse from persistence of minimal residual disease. Response rates to subsequent lines of therapy drop dramatically, as does survival. Antibodies including alemtuzumab and rituximab act in synergy with fludarabine and improve responses in salvage CLL therapy. In an effort to identify an effective chemoimmunotherapy regimen for patients with relapsed CLL, a phase II, multicenter, open-label, randomized trial was initiated. B-CLL patients who had failed prior therapy were randomized to treatment with either fludarabine combined with alemtuzumab or fludarabine combined with rituximab. Four patients randomized to the cohort received fludarabine 25 mg/m² IV and alemtuzumab 30 mg SC, on Days 1–5. Eight patients received fludarabine 25 mg/m² IV on Days 1–5, and rituximab 375 mg/m² IV on Days 1 and 4 of the first cycle, followed by fludarabine 25 mg/m² IV on Days 1–5, and rituximab 375 mg/m² IV on Day 1 in subsequent cycles. Patients were assessed monthly for response while on therapy, and interim restaging occurred at cycle 4. Those who achieved a CR received no further therapy, whereas those who achieved a PR or SD received 2 additional cycles. 12 patients (7 male and 5 female) participated in this trial and the median age was 67 years. Nine patients had Rai III/IV (2 patients in alemtuzumab arm and 7 patients in rituximab arm). All patients had failed 1 course of therapy; 9 had failed treatment with a fludarabine-based regimen, and 3 had failed treatment with alkylating agents. In the alemtuzumab arm, 2 patients developed a CMV reactivation, one of whom developed CMV viremia, which was successfully treated with gancyclovir. Of the 8 patients in the rituximab plus fludarabine arm, 6 withdrew due to adverse events and 2 patients died while on study. In the alemtuzumab plus fludarabine arm, 1 person withdrew due to adverse events and 1 patient died after the trial was closed. Overall, 3 of 4 patients in the alemtuzumab arm responded (2 complete response [CR], 1 partial response [PR]), and 3 of 7 patients in the rituximab arm (1 CR, 2 PR). Recently published data has prompted a shift in CLL therapy. Increased numbers of patients are receiving chemoimmunotherapy combinations earlier in treatment. An increased use of FR and FCR in the first-line setting made further recruitment difficult. The potential of randomizing patients to the FR arm of the study prompted low accrual and the subsequent closing of the study.