Consolidation therapy with Alemtuzumab

This is another section on consolidation therapy to follow on from the section on bone marrow transplantion.

An alternative approach with potentially less hazard is to attempt to consolidate the remission using monoclonal antibodies. Alemtuzumab is particularly suited to this task because it is able to kill CLL cells in a caspase-independent manner that is not inhibited by loss of p53 [10] and is therefore able to eliminate chemotherapy-resistant cells [11]. In a study [12] of 91 previously treated patients, 44 of whom were refractory to purine analogues, NCI defined [Cheson 1996 previously referenced] complete remissions were achieved in 32%, 56% of whom had no disease detectable by a four-color flow technique for detecting minimal residual disease (MRD)[13]. Those patients who became MRD negative had significantly longer treatment-free and overall survivals than those who did not.

In a prospective phase III study conducted in Germany [14] patients were randomized to receive or not receive Alemtuzumab 30mg intravenously thrice weekly for 12 weeks beginning a median of 67 days after the last dose of induction chemotherapy, which was fludarabine with or without cyclophosphamide. Although recruitment to this trial was halted because of severe infections in the Alemtuzumab arm, even with only 21 patients in the trial, those receiving Alemtuzumab had a significantly longer progression-free survival. Using a very sensitive PCR-based assay with sequence-specific primers to detect MRD, 5/6 patients tested became MRD negative.

A phase II study [15] of Alemtuzumab given in doses of 10mg subcutaneously three times a week for six weeks beginning not less than eight weeks after the discontinuation of fludarabine induction chemotherapy proved that this regimen was safer and capable of turning partial remissions into complete remissions. MRD was tested for using the less sensitive PCR technique with consensus primers, but using this, patients with mutated VH genes were more likely to become MRD negative than those with unmutated VH genes. Reactivation of cytomegalovirus occurred in 53% but was successfully treated with oral Ganciclovir. 53% of patients successfully underwent autologous stem cell transplantation, but no follow-up information is available.

At present, immunological consolidation with Alemtuzumab following chemotherapy appears safer than with allogeneic transplantation but we await a comparison of efficacy.

References

10. Mone AP, Cheney C, Banks AL et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia 2006; 20:272-9.
11. Lozanski G, Heerema NA, Flinn IW et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103:3278-81.
12. Moreton P, Kennedy B, Lucas G et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after Alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23:2971-9.
13. Rawstron AC, Kennedy B, Evans PA et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98:29-35.
14. Wedtner C-M, Ritgen M, Schweighofer CD et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLCG) Leukemia 2004; 18:1093-1101.
15. Montillo M, Tedeschi A, Miqueleiz S et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24:2337-42.