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MRD-negative remission in CLL is achievable with alemtuzumab, leading to an improved overall and treatment-free survival.

Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/ CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10 4 to 10 5 leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 ؋ 10 9 /L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P ‫؍‬ .0001) and overall survival (P ‫؍‬ . IntroductionThe goal of conventional therapy for chronic lymphocytic leukemia (CLL) is to control the disease and rarely results in the complete eradication of detectable tumor cells. 1,2 Even purine analogue therapy, which is the most effective conventional therapy for inducing complete remission, 3 results in a return of normal polyclonal B lymphocytes in only 40% of patients. 4 This is the principle reason why the assessment of minimal residual disease (MRD) in CLL has not been considered to be important and why the criteria for response to therapy have defined "complete" remissions when there is likely to be a significant level of disease detectable by modern techniques. 5 The application of novel therapies, such as allogeneic or autologous hematopoietic stem cell transplantation 6 and monoclonal antibodies, 7,8 have resulted in a significant proportion of patients attaining much more profound responses. There is evidence to suggest that such responses may be associated with improved outcomes. 9,10 The current development of newer agents, the potential of immunomodulatory therapies, and the possible combination of 2 or more of these therapies promises to make the goal of eradicating detectable disease by the most sensitive techniques a realistic one.CAMPATH-1H (alemtuzumab) is a humanized monoclonal antibody specific for the CD52 antigen. The antigen is expressed on all lymphocytes as well as monocytes, macrophages, and spermatozoa. 11,12 CAMPATH-1H is extremely effective at killing lymphocytes in vitro and in vivo. 11,12 The humanization of the antibody has abrogated potential human antimurine antibody (HAMA) responses [13][14][15] and resulted in an agent that is extremely effective at inducing remission in patients with CLL. 8,16 Similarly, treatment with autologous transplantation has been shown to induce complete remissi...

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Alemtuzumab is a humanized anti-CD52 antibody licensed for refractory B-cell chronic lymphocytic leukemia (B-CLL), when given intravenously at 30 mg thrice weekly. However, the intravenous route is associated with infusion-related reactions and is inconvenient. We measured blood concentrations in 30 relapsed patients treated with intravenous alemtuzumab and in 20 patients from a previously untreated group who received similar doses subcutaneously. Highest trough samples in the intravenous group were less than 0.5 microg/mL to 18.3 microg/mL (mean 5.4 microg/mL). The cumulative dose required to reach 1.0 microg/mL was 13 mg to 316 mg (mean 90 mg). Higher blood concentrations correlated with the achievement of better clinical responses and minimal residual disease. The highest measured concentrations in the subcutaneous group were similar (0.6 microg/mL to 24.8 microg/mL, mean 5.4 microg/mL). However, the cumulative dose to reach 1.0 microg/mL was higher: 146 mg to 1106 mg (mean 551 mg). No antiglobulin responses were detected in 30 patients given intravenous alemtuzumab whereas 2 of 32 patients given subcutaneous alemtuzumab made substantial anti-idiotype responses. Thus, subcutaneous alemtuzumab achieved concentrations similar to those for intravenous alemtuzumab, although with slightly higher cumulative doses. Subcutaneous alemtuzumab is more convenient and better tolerated but may be associated with some patients forming anti-alemtuzumab antibodies, particularly those patients who were previously untreated.

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