Alemtuzumab (Schering AG’s Mab Campath, Berlex Laboratories’ Campath) was launched for third-line therapy of chronic lymphocytic leukemia in the United States and Europe in 2001. Early pilot studies indicated that alemtuzumab could cause tumor regression in advanced non-Hodgkin’s lymphoma. However, subsequent studies showed that the therapeutic effect was confined mainly to tumor cells in the blood and bone marrow rather than in lymph nodes, a finding that paved the way for trials in chronic lymphocytic leukemia. Patients who are refractory to fludarabine are left with few treatment options. These difficult-to-treat patients are therefore candidates for therapies such as monoclonal antibodies, whose uptake is growing.
Mechanism Of Action
Alemtuzumab is a chimeric, humanized monoclonal antibodies directed against the cluster of differentiation (CD) molecule 52, a glycosylphosphatidy-linositol-anchored glycoprotein expressed on all mature lymphocytes, monocytes, and spermatozoa but not on hematopoietic stem-cell progenitors. The physiological function of CD52 is unknown. The binding of alemtuzumab to cell-surface CD52 leads to complement-mediated lysis, antibody-dependent cellular cytotoxicity, and opsonization, resulting in cell death. The efficacy of alemtuzumab has been correlated with the density of CD52 on the target cell surface.
An international study investigated the efficacy of alemtuzumab in 93 chronic lymphocytic leukemia patients who had failed at least one alkylating-based regimen and fludarabine treatment. FDA approval was granted largely on the basis of this study’s initial results. Longer-term follow-up reported that 33 out of 93 patients responded (33%), experiencing 2 CRs (2%) and 29 PRs (31%). The authors noted that this result significantly exceeded their target response rate of 20%, and responses were seen in all prognostic subsets: both those who had failed fludarabine and those who had previously had a short response to this agent. However, patients with Rai stage IV and those who had at least one lymph node greater than 5 cm in diameter were less likely to respond. Median TTP among responders was 9.5 months; median survival was 16 months in all patients, which is longer than for historical controls.
Infusion-related reactions were commonly reported adverse events and were mostly grade 1/2. They included rigors (90% in total, 14% grade 3); fever (85% in total, 17% grade 3, 3% grade 4); nausea (53% grade 1/2); vomiting (38% in total, 1% grade 3); and rash (33% grade 1/2). These events declined over the time of treatment. Most patients experienced transient cytopenias. Neutropenia was most common during weeks 5 and 6 (30% of patients) and thrombocytopenia occurred in the first two weeks. These problems had resolved in the majority of patients by two-month follow-up.
This study recorded a high rate of infection (51 patients, 55%), although 53% of patients had a prior history of infection and 33% had infection in the month before alemtuzumab therapy. Twenty-five of 51 patients had a grade 3/4 infection. Grade 3/4 sepsis occurred in ten patients and led to death in two of these cases. A total of nine deaths occurred during treatment or within 30 days of the last alemtuzumab dose, of which five were related to treatment, comparing favorably with the 22% death rate observed in fludarabine trials.
Although alemtuzumab is approved as third-line therapy in chronic lymphocytic leukemia, the literature reports that it has been investigated in previously untreated chronic lymphocytic leukemia patients. Forty-one patients, the majority (90%) of whom were in Rai stage II-IV, were enrolled in a dose-escalation Phase II study of subcutaneous alemtuzumab. Of the 38 evaluable patients, 7 (19%) achieved a CR and 26 (68%) achieved a PR, giving an overall response rate of 87%. The response rate was almost as high in Rai stage III-IV patients as it was in stage I-II, possibly because this antibody is effective in eradicating bone marrow disease, thereby improving or normalizing peripheral blood counts. In addition, the response rates were equally high among older patients.
Acute administration-related reactions such as rigor, nausea, hypotension, and bronchospasm were rare or absent. These reactions are commonly seen when alemtuzumab is administered intravenously, and the reason for the discrepancy is unclear. Hematologic toxicity included transient grade IV neutropenia in 21% of patients; in some patients, repeated or more prolonged episodes required the use of G-CSF so that further treatment was not delayed.
Alemtuzumab is also under investigation in combination with chemotherapy and other monoclonal antibodies. Data presented at the American Society of Clinical Oncology (ASCO) conference in 2003 described the combination of fludarabine and alemtuzumab in relapsed chronic lymphocytic leukemia patients who had received a median number of two prior courses of therapy. Of 14 patients, 9 (64%) achieved a CR and 3 (21%) achieved a PR. Transient grade 3 and 4 hematologic toxicities were observed. Other investigations include using alemtuzumab as consolidation therapy following chemotherapy to further improve responses and eradicate minimal residual disease.
Alemtuzumab’s major limitation is the high level of hematologic toxicity and subsequent infection it induces in these already fragile patients. Physicians are wary of these side effects, but in light of alternative options, alemtuzumab is a popular therapy choice in the third-line setting. Continued investigation is evaluating its worth in earlier treatment settings.