PHILADELPHIA-In patients with chronic lymphocytic leukemia (CLL), the standard regimen for intravenous alemtuzumab(Drug information on alemtuzumab) (Campath- 1H), an anti-CD52 monoclonal antibody, is associated with systemic side effects including hypotension, rigors, fever, shortness of breath, bronchospasm, chills, and rash, which require pretreatment with antihistamines and acetaminophen to ameliorate. Recently, a phase II trial among 41 patients demonstrated that subcutaneous administration of alemtuzumab is effective (87% overall response rate) and appears to reduce the incidence and severity of some of these adverse events. Two independent studies presented at the American Society of Hematology 2002 Annual Meeting tested the efficacy and safety of subcutaneous alemtuzumab in patients with CLL.[3-5] Comparable Blood Levels Geoff Hale, PhD, and colleagues at the University of Oxford and other institutions in the United Kingdom, the United States, and Sweden, evaluated whether therapeutic serum levels of alemtuzumab could be achieved via subcutaneous injection and whether this route of administration would lead to a higher frequency of antiglobulin responses (ASH abstracts 777 and 5011).[3,4] The 30 patients with fludarabinerefractory CLL in the IV group were given the standard IV protocol of alemtuzumab (CAM213), escalating doses from 3, to 10, to 30 mg during week 1 and giving 30 mg three times per week thereafter for up to 12 weeks. Additionally, 20 patients with previ- ously untreated CLL in the SC group were administered the same doses of alemtuzumab via SC injection for up to 18 weeks. Blood samples were collected weekly, before and after dose administration, to determine the free serum levels of alemtuzumab and the presence or absence of anti-alemtuzumab antibodies. In the IV group, the mean maximum serum level of alemtuzumab was 10.7 μg/mL (range, 2.8 to 26.4 μg/mL) and the mean trough concentration (48 hours) was 5.4 μg/ mL (range, < 0.5 to 18.3 μg/mL). In the SC group, peak serum levels of alemtuzumab were comparable to trough levels of alemtuzumab in the IV group (mean, 5.4 μg/mL; range, 0.6 to 24.8 μg/mL). In the SC group, significantly more time was required for patients to achieve an antibody level of 1 μg/mL than for the IV group, requiring a mean cumulative dose of 551 mg alemtuzumab (range, 146 to 1,106 mg), compared with a mean cumulative dose of 90 mg (range, 13 to 316 mg) for the IV group. Dr. Hale and his colleagues speculate that this might be secondary to more effective binding of alemtuzumab to the tumor cells in the SC group. Antiglobulin Responses To detect antiglobulin responses to alemtuzumab, Professor Hale's group used a validated enzyme-linked assay with a lower limit of detection of approximately 0.5 μg/mL. In the IV group, no patient had anti-alemtuzumab antibodies detectable by this method. In the SC group, one patient had a weak, transient response in a single sample taken 14 days after the last dose of alemtuzumab, and one patient had a strong idiotype-specific response high enough to neutralize therapeutic doses of alemtuzumab. In fact, this patient had no detectable free serum alemtuzumab and was the only patient in the SC group to demonstrate no response from alemtuzumab therapy. Most other patients administered alemtuzumab subcutaneously demonstrated measurable clinical benefit. Although these results are encouraging, Dr. Hale cautions against drawing a direct comparison between efficacy in the SC group and that in the IV group, as the SC patients were previously untreated. Interestingly, in the IV group a strong correlation was seen between antibody serum levels and clinical response (as determined by flow cytometry for minimal disease in the bone marrow). This implies that serum levels of alemtuzumab may provide a useful predictive clinical test and warrants further investigation. Upgrading Response Level The results presented by Dr. Hale and colleagues were supported by a small clinical study presented by Mar- co Montillo, MD, of Niguarda Ca' Granda Hospital in Milan Italy (ASH abstract 3175). Twelve patients (nine male, three female) with CLL who responded to fludarabine (Fludara) treatment received sequential SC alemtuzumab three times per week for 6 weeks in escalating doses up to 10 mg. All patients had monoclonal rearrangement of the gene for immunoglobulin H before receiving alemtuzumab. All patients also received prophylactic acyclovir (Zovirax), cotrimoxazole, and bone marrow stimulants prior to peripheral blood stem cell harvest. After fludarabine treatment, two patients achieved a complete response, six experienced a nodular partial response, and four experienced a partial response. After alemtuzumab, all four patients who previously had a partial response experienced a complete response and two also achieved molecular remission. Among the six patients with a previous nodular partial response, five experienced a complete response, with polyclonal rearrangement of the gene for immunoglobulin H in 1 patient. Finally, of the two patients who had a complete response before alemtuzumab treatment, one converted to a molecular complete response. Overall, after sequential administration of fludarabine and SC alemtuzumab, 11 of 12 patients achieved a complete response, including 3 who achieved molecular remission. All 12 patients were evaluable for toxicity. No infectious episodes were reported. Five patients experienced cytomegalovirus reactivation, and four were successfully treated with oral ganciclovir(Drug information on ganciclovir) (Cytovene) without pneumonia. A skin reaction (grade 1 to 2 by World Health Organization standards) was observed in 50% of the patients at the injection site. Preliminary Results Indicate Efficacy Taken together, these results present exciting new preliminary evidence that SC administration of alemtuzumab may provide efficacy similar to that of IV administration while decreasing the incidence of severe complications associated with IV administration. It will be important to confirm that SC alemtuzumab remains as effective as IV alemtuzumab in a large, multicenter, randomized clinical trial.