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Fludarabine Followed by Alemtuzumab Produces High Response Rates in Previously Untreated CLL

Fludarabine Followed by Alemtuzumab Produces High Response Rates in Previously Untreated CLL

NEW HYDE PARK, New York-Single-agent fludarabine (Fludara) is an active front-line therapy for chronic lymphocytic leukemia (CLL) and has resulted in overall response rates of 63% to 71%.[1,2] Slightly higher response rates (approximately 87%) in previously untreated patients with CLL have been reported for subcutaneous alemtuzumab (Campath-1H), an anti-CD52 monoclonal antibody.[3] As part of the ongoing quest to improve response rates for patients with CLL, the Cancer and Leukemia Group B (CALGB) conducted a study using sequential administration of fludarabine followed by alemtuzumab. Kanti R. Rai, MD, of Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York, presented results of the phase II trial (ASH abstract 772).[4] The primary goal of the study was to determine the toxicity and response rates of fludarabine plus alemtuzumab in treatment-naive patients with CLL. Patients were administered fludarabine 25 mg/m2 per day intravenously for 5 days and monthly thereafter for 4 months. Those who achieved stable disease or better were then treated with a 6-week course of alemtuzumab 30 mg three times per week intravenously, with the antibody first given at 3 mg, then progressively increased as tolerated during the first week, up to 30 mg. Patients were also treated with prophylactic trimethoprim-sulfamethoxazole double strength (DS) and acyclovir (Zovirax) during and for 6 months after alemtuzumab therapy. Final response results were evaluated 2 months after completion of therapy. Effective as Combination A total of 57 patients were enrolled in the trial. One patient died before initiation of fludarabine therapy; safety and efficacy evaluations are therefore based on 56 patients. During fludarabine therapy, 11 patients required parenteral antibiotics and/or hospitalization for serious infections, and 1 patient died of septicemia. After fludarabine therapy, three (5%) patients achieved a complete response and 28 (50%) achieved a partial response. Of the 56 patients who received fludarabine, 17 were not treated with alemtuzumab either because of no response (7 patients) or progressive disease (10 patients). Thus, 39 patients received alemtuzumab and were evaluable for response. The combination of alemtuzumab and fludarabine proved highly effective. The overall response rate among 39 patients who received alemtuzumab was 92% (36 patients), including a 36% complete response rate and 56% partial response rate, according to National Cancer Institute-Working Group 1996 criteria. Among the 56 intent-to-treat patients enrolled in the study, the complete response rate was 25% and the partial response rate was 40%. Of the 12 patients who had stable disease after fludarabine treatment, two (17%) achieved a complete response after alemtuzumab therapy. After a median follow-up of 10 months, 87% of the 56 intent-to-treat patients were still alive. Improved CMV Recognition Alemtuzumab infusion reactions were manageable and in most cases were limited to grade 1 or 2. Twelve patients had grade 3 or higher infections requiring parenteral antibiotics or hospitalization. Infection with cytomegalovirus (CMV) occurred in eight patients during or within 4 months of alemtuzumab therapy. Complete or partial resolution of CMV occurred in six of these patients. Persistent CMV occurred in one patient, and one patient died. Following the fatality, weekly qualitative polymerase chain reactionbased testing for CMV was initiated to improve early recognition of CMV and to allow both discontinuation of alemtuzumab and initiation of antiviral therapy. These results compare favorably with those of a similar trial conducted with sequential fludarabine and ritdarabine, uximab (Rituxan).[5] In that trial, 53 previously untreated CLL patients received 6 monthly courses of fludarabine followed 2 months later with rituximab. The overall response rate with sequential administration of fludarabine and rituximab was 77% (41 patients), including 28% complete and 49% partial response rates (95% confidence interval, 0.66, 0.89). Although these early results with alemtuzumab in combination with fludarabine are encouraging, Dr. Rai cautioned that longer follow-up will be necessary to determine whether alemtuzumab has a positive influence on survival in patients who have received initial therapy with fludarabine.


1. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000.
2. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of flu- ritdarabine, CAP, and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319-2325, 2001.
3. Lundin J, Kimby E, Bjorkholm M, et al: Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as firstline treatment for patients with B-cell chronic lymphocytic leukemia (BCLL). Blood 100:768-773, 2002.
4. Rai KR, Byrd JC, Peterson BL, Larson RA. A phase II trial of fludarabine followed by alemtuzumab (Campath- 1H) in previously untreated chronic lymphocytic leukemia (CLL) patients with active disease: Cancer and Leukemia Group B (CALGB) study 19901 (abstract 772). Blood 100:205a-206a, 2002.
5. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6-14, 2003.
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