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.
Note. The name FluCam has been used for a regimen of alemtuzumab with fiudarabine. Distinguish from Flucam, which is ampiroxicam.
Adverse Effects, Treatment, and Precautions
For general discussions, see Antineoplastics.
Alemtuzumab commonly causes bone marrow depression, which may be severe and prolonged; fatalities have occurred. Auto-immune anaemia and autoimmune thrombocytopenia and haemolytic anaemia have been reported less commonly; however, fatalities have been reported. Single doses greater than 30 mg, or cumulative weekly doses greater than 90 mg should not be used, because of the increased incidence of pancytopenia. Complete blood and platelet counts should be measured weekly during alemtuzumab therapy, and more frequently if anaemia, neutropenia, or thrombocytopenia occur.
Treatment should be interrupted if severe myelosuppression or evidence of haematological toxicity are seen and stopped permanently if autoimmune anaemia or auto-immune thrombocytopenia develops. Lymphopenia may be profound with alemtuzumab therapy, and opportunistic infections are common, and occasionally life-threatening. Antimicrobial prophylaxis is recommended from the start of therapy until after completion; if serious infection occurs, treatment should be interrupted. Recovery of lymphocyte counts may take 6 months or longer after stopping treatment.
Alemtuzumab commonly causes an acute cytokine release syndrome. The reaction usually includes rigors, fever, nausea and vomiting, hypotension, rash, urticaria, pruritus, shortness of breath, headache, and diarrhoea. Rarer, more serious reactions may include bronchospasm, syncope, pulmonary infiltrates, acute respiratory distress syndrome, respiratory arrest, myocardial infarction, and cardiac arrest. Cardiac adverse effects have been fatal in some instances. These infusion-related reactions are most common at the start of therapy: the dose must be increased gradually when beginning treatment, or if it is interrupted for 7 days or more. Pre-medication with an oral or intravenous cor-ticosteroid, oral antihistamine, and analgesic should also be used, particularly before the first dose, and with dose increases. If acute infusion reactions persist, the infusion time may be extended to 8 hours from the time ofreconstitution.
Other adverse effects include fatigue, anorexia, asthenia, malaise, arthralgia, myalgia, bone pain, back pain, chest pain, hypertension, cyanosis, and bradycardia or tachycardia. Localised oedema, stomatitis, mucositis, and abdominal pain have been reported, as have dizziness, paraesthesia, tremor, and taste loss. Confusion, insomnia or somnolence, depression, or anxiety may occur. Electrolyte disturbances include hyponatraemia and hypocalcaemia. Coughing, haemoptysis, sinusitis, bronchitis, and pharyngitis have been reported. Alemtuzumab is contra-indicated for patients with active systemic infection, or underlying immunodeficiency
Reactivation of hepatitis B and CMV has been reported with the use of alemtuzumab. Patients who have been pre-treated with purine analogues or those with advanced disease and not responding to alemtuzumab therapy appear to be at highest risk for infectious complications. Recommendations for screening and prophylaxis and guidelines for management have been published. Six infection-related deaths have been reported after previously untreated patients with B-cell chronic lymphocytic leukaemia were treated with fiudarabine and rituximab, followed by alemtuzumab. These deaths may have resulted from a prolonged period of immunosuppression due to the sequencing of these drugs without sufficient recovery time. In the EU, alemtuzumab is licensed for use in patients for whom fiudarabine combination chemotherapy is not appropriate.
There are no formal interaction studies with alemtuzumab; however, it is recommended that it should not be given within 3 weeks of other chemotherapy drugs, and that patients should not receive live viral vaccines for at least 12 months after receiving alemtuzumab.
In patients with B-cell chronic lymphocytic leukaemia, distribution of alemtuzumab is mainly to the extracellular fluid and plasma. Over 12 weeks, clearance has been found to decrease with repeated dosing, with consequent accumulation in plasma, and the rate of elimination to approach zero-order kinetics. The half-life is reported to be 8 hours after a first dose of 30 mg, and 6 days after the last 30 mg dose. Steady-state concentrations are reached after about 6 weeks of therapy.
Uses and Administration
Alemtuzumab is a humanised derivative of campath-1G, a rat monoclonal antibody to the CD52 antigen found on lymphocytes. Alemtuzumab is used in the treatment of B-cell chronic lymphocytic leukaemia. The dose of alemtuzumab must be increased gradually to avoid infusion-related reactions (see above). Alemtuzumab should be diluted in 100 niL sodium chloride 0.9% or glucose 5%. The initial dose is 3 mg daily, given as an intravenous infusion over 2 hours (it may be increased up to 8 hours in some patients, see above). This dose should be repeated daily until it is tolerated; the dose should then be increased to 10 mg daily. When this dose is tolerated, the maintenance dose of 30 mg can be started; this dose escalation usually takes 3 to 7 days. A maximum maintenance dose of 30 mg given three times weekly on alternate days can then be used for up to 12 weeks. The dose should be modified according to haematological toxicity.
Alemtuzumab is under investigation for induction therapy in transplantation (see Organ and Tissue Transplantation). It is also under investigation for the treatment of multiple sclerosis.
Subcutaneous use of alemtuzumab has been investigated as a means of reducing adverse infusion reactions associated with intravenous dosage. Studies have found it to be safe and effective. Similar blood concentrations are achieved to those after intravenous use, although accumulation in the blood took longer to achieve with subcutaneous use, and higher cumulative doses were required. Prolonged treatment with subcutaneous low-dose alemtuzumab (10 mg three times weekly for 18 weeks) has been reported to be as effective as intravenous infusion in patients with chronic lymphocytic leukaemia and a poor prognosis.
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
South Africa: MabCampath;
United Kingdom: MabCampath;
United States: Campath