Publication Date:
2005-11-16
Description:
Patients with fludarabine refractory CLL have a median survival of 10 months with conventional chemotherapy. Intravenous (IV) alemtuzumab is approved in fludarabine refractory CLL resulting in 33 to 50% responses. Combined alemtuzumab and fludarabine can induce responses in CLL refractory to both agents. Infusion reactions and 2-hour infusions 3x a week for 12 weeks are problems with IV alemtuzumab. Subcutaneous (SC) alemtuzumab is more convenient but pharmacokinetics suggest the need for prolonged therapy with little efficacy data in fludarabine-refractory CLL. We report on the UKCLL02 study to assess the safety and effectiveness of SC alemtuzumab in fludarabine-refractory CLL. SC alemtuzumab was given at a dose of 30mg 3x a week (after dose escalation) for up to 24 weeks depending on 6-weekly marrow assessments. Patients failing to respond to alemtuzumab in the trial could receive oral fludarabine (40mg/m2/day for 3 days every 4 weeks) combined with SC alemtuzumab. In this planned interim analysis of the first 44 patients (median age 66, range 41 to 79) 2 patients died before receiving alemtuzumab, and 5 remain on therapy. Of the remaining 37 patients, one withdrew consent and 36 patients have completed therapy. Responses to alemtuzumab monotherapy (n=36) were 2 MRD negative CR, 1 MRD positive CR, 11 PR (including 1 MRD negative patient who remained cytopenic), 20 NR and 2 died. Alemtuzumab was given for a median 12 weeks (range: 2–24) with a median dose of 913mg (range 106 to 2173mg). 12 patients (8 NR and 4 PR) received concurrent fludarabine and SC alemtuzumab (median 2.5 courses fludarabine [range 1–3]). 2 non-responders achieved a PR and one of the partial reponders achieved a CR (MRD positive). Therefore the overall response rate for the whole cohort was 16/36 (44%) including 3 MRD negative patients (2 CRs and 1 PR). IgVH gene was unmutated (〉98% homology to germ line DNA) in 11/14. FISH revealed poor risk deletions (11q and/or 17p) in 21/34 patients (17p- in 9; 11q- in 6 and both in 6). p53 functional analysis is available for 23. 20/23 had p53/ATM dysfunction or deletion. 10/21 evaluable cases with del (11q23)/del (17p) responded to therapy. The initial alemtuzumab dose was associated with localised erythematous skin reactions in 20 patients (diameter 1 to 18cm), fever in 7 and rigors in 3. All reactions subsided in
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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