Outpatient-Based Therapy with Oral Fludarabine and Alemtuzumab for Asian Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL).

Chronic lymphoproliferative disorders are considered rare in Asian countries. A recent 3-year study of 342 consecutive leukemia patients from 2 regional hospitals in Hong Kong, however, showed that CLL was diagnosed in 19% of Chinese patients with leukemia. Intravenous (IV) alemtuzumab (Campath-1H) in combination with fludarabine has been shown to be an effective chemoimmunotherapy regimen for treatment of CLL, yielding responses even in patients with relapsed/refractory disease who did not respond to therapy with either agent alone. Because alemtuzumab and fludarabine appear to be effective as monotherapy when given subcutaneously and orally, respectively, we performed a phase 2 single-arm clinical study to assess the safety and efficacy of subcutaneous (SC) alemtuzumab in combination with oral fludarabine for the treatment of patients with CLL. Patients with relapsed/refractory CLL who had failed ≥1 prior therapy were eligible to self-administer, on an outpatient basis, SC alemtuzumab 30 mg, 3 times per week on days 1, 3, and 5 and oral fludarabine 40 mg/m²/day on days 1–5, of a 28-day cycle. Depending upon response, patients received 2 to 6 cycles: if hematological CR was attained without molecular remission (assessed by clonal IgH rearrangement), SC alemtuzumab was given only on day 1 with fludarabine for subsequent cycles. Therapy was discontinued if molecular CR was attained. Patients were all males with ages ranging from 60 to 81 (median 72 years). The CLL FISH panel showed that 2 patients had 11q23 (consistent with ATM gene deletion) and trisomy 12 abnormalities, 1 had 17p13.1 deletion (consistent with p53 deletion), 1 had 13q14 deletion, whereas another had no detectable chromosomal aberrations. The baseline mean lymphocyte counts of all patients decreased from 63,610 to 42,610 cells/mL after the first cycle of treatment, and further decreased to a significantly lower mean of 1,500 cells/mL after completion of 2 to 6 cycles of therapy. Both the platelet counts (mean 114,000 cells/mL prior to and 111,400 cells/mL after therapy) and hemoglobin levels (11.7 g/dL prior to and 11.66 g/dL after therapy) remained unaffected. No cytomegalovirus reactivation was documented, but 2 patients developed a rapidly reversible episode of neutropenic sepsis treated with empiric antibiotics and transient administration of G-CSF. 3 patients attained a complete haematological response, while two had a good partial response, as defined by the NCI-WG response criteria. Based on bone marrow assessment and 4-color flow cytometry, 2 patients also attained complete molecular remission. These responses are comparable to those observed with patients from Western countries, who are treated with alemtuzumab and fludarabine combinations. In light of the promising results, the combination of oral fludarabine and SC alemtuzumab should be extended to larger multicenter clinical trials.