Early Estimates of Safety for Alemtuzumab Combined with Fludarabine for the Treatment of Relapsed/Refractory B-Cell Chronic Lymphocytic Leukemia: Phase II Multicenter Study.

Background. Alemtuzumab (CAMPATH) is the most effective single-agent therapy available for the treatment of chronic lymphocytic leukemia (CLL). Previous pre-clinical and clinical studies suggest possible synergistic activity between alemtuzumab and purine analogues. A recent phase 2 study reported an overall response rate of 83% (complete response 30%) in patients (pts) with relapsed and/or refractory CLL treated with intravenous (IV) alemtuzumab combined with IV fludarabine for up to 6 cycles (Elter JCO 2005). We evaluated the safety and efficacy of alemtuzumab administered in a subcutaneous (SC) manner combined with IV fludarabine in pts with previously treated CLL. Safety data are presented based on interim analysis from this study.

Patients and Methods: Pts with active CLL who received at least 1 prior therapy were eligible to receive combination treatment with SC alemtuzumab 30 mg days 1–5 and IV fludarabine 25 mg/m² days 1–5 every 28 days for up to 6 cycles. All pts received prophylaxis with trimethoprim-sulfamethoxazole and famciclovir (or equivalent) from initiation of therapy until ≥2 months following therapy discontinuation. Pts were monitored for cytomegalovirus (CMV) reactivation using polymerase chain reaction (PCR) assays every 2 weeks, and preemptive therapy with oral valganciclovir 900 mg (or equivalent) was administered in cases of PCR-positivity (≥100 copies/mL). Adverse events (AEs) were graded using the NCI Common Toxicity Criteria (version 3.0).

Results. To date, 45 pts of a target 60 pts, have been accrued and safety evaluations are available for 40 pts (median age 63 years; range 45–86) of whom 13 completed 4 cycles, 7 completed 5 cycles and 4 completed 6 cycles of therapy. Most pts had ECOG PS 0 or 1 (82%), 56% had Rai stage ≥3. Ninety percent of pts had received a prior therapeutic regimen that included fludarabine. The most common (≥ 10%) grade 3 or 4 AEs were hematological toxicities including thrombocytopenia in 11 pts (27.5 %), and anemia in 7 pts (17.5 %). Although neutropenia was documented in 13 pts (32.5 %), grade 3 febrile neutropenia was only observed in 1 patient (2.5%). Grade 3 or 4 infections occurred in 6 pts (15 %), which included 1 case of grade 3 fungal sinusitis. CMV reactivation (by PCR) was documented in 42% of patients at a median of 4 weeks (range: 2–8 weeks) after start of therapy. Other commonly observed AEs were infusion or administration-related, and were primarily grade 1 or 2 in severity. One patient died from presumed aspiration pneumonia. No other deaths due to AEs occurred.

Conclusions. Combination therapy with SC alemtuzumab and IV fludarabine at the dose schedule employed is feasible and well tolerated, with manageable toxicities.