Retrospective Comparison of Phenytoin and Levetiracetam as Seizure Prophylaxis With High Dose Busulfan During Allogeneic Stem Cell Transplant

Busulfan is an alkylating agent commonly used in preparative regimens for hematopoietic stem cell transplant (HSCT). Early clinical trials, prior to the use of seizure prophylaxis, revealed a high degree of neurotoxicity associated with myeloablative doses of this agent. Phenytoin has been widely used as seizure prophylaxis with busulfan. However, potential concerns with its use include the length of time to achieve a therapeutic steady state, risk of hepatotoxicity, and drug-drug interactions with busulfan and other agents used during conditioning. Alternatively, levetiracetam is highly bioavailable in both oral and intravenous forms, with a short half life it rapidly achieves steady state and is renally eliminated with limited drug interactions. The main objective of this study was to compare the incidence of seizures with phenytoin and levetiracetam. Secondary objectives were to compare VOD incidence, assess busulfan and phenytoin pharmacokinetics, and toxicity of the prophylactic agents. All patients ≥ 18 years of age receiving busulfan in a preparative regimen prior to HSCT between 6/1/08-6/30/09 were included in this retrospective analysis. Patient information was collected from the pharmacy database and electronic medical records. Data included age, disease, preparative regimen, type of transplant, busulfan dose, busulfan AUC, survival status, incidence of relapse, and hepatic panels. 54 patients were included in this analysis with 22 receiving phenytoin and 32 receiving levetiracetam as seizure prophylaxis. Phenytoin was dosed with a 1000 mg loading dose and 300 mg daily maintenance dose. Levetiracetam was dosed at 500 mg twice daily. Of the 54 patients there were no reports of seizures in either group. There were also no reports of VOD in either group. Elevation in liver enzymes occurred in 3 (9%) patients who received levetiracetam compared to 7 (32%) patients who received phenytoin. A therapeutic steady state of phenytoin was achieved in 12 (55%) patients. Twenty patients (63%) receiving levetiracetam needed busulfan dose adjustments based on pharmacokinetic analysis versus 11 (50%) receiving phenytoin. Rates of relapse were similar in both groups. Levetiracetam is a safe and effective alternative to phenytoin for busulfan seizure prophylaxis. With low hepatoxicity, no pharmacokinetic monitoring, and limited drug-drug interactions it is an attractive option in the HSCT population.