Phenytoin Versus Levetiracetam for Busulfan-Induced Seizure Prophylaxis and Hematopoietic Stem Cell Transplantation Outcomes

Background: Busulfan crosses the blood-brain barrier and at high doses can cause severe neurotoxicity, including seizures that are most commonly tonic-clonic in character. When Busulfan is used in the conditioning of patients undergoing hematopoietic cell transplantation (HSCT), phenytoin, benzodiazepines, or newer anticonvulsants such as levetiracetam are often used for seizure prophylaxis. Phenytoin is a potent inducer of cytochrome P450 hepatic enzymes that leads to higher clearance of Busulfan. Phenytoin is also capable of altering cyclophosphamide levels by affecting its metabolism and formation of hydroxy-cyclophosphamide through uridine glucoronosyltransferase enzymes and may also affect HSCT outcomes such as increased risk of sinusoidal obstructive syndrome (SOS). In this report, we evaluated the impact of levetiracetam versus phenytoin on effectiveness of seizure prophylaxis and development of SOS in our center.

 Methods: We retrospectively reviewed Allogeneic HSCT patients who received intravenous Busulfan for 4 days as part of their conditioning regimen in our center between 2002 and 2013. Primary objective was to study the impact of phenytoin and levetiracetam on effectiveness of seizure prophylaxis and SOS. Demographics and disease-related variables were collected.

 Results: Between 2002 and 2013, 106 patients received Busulfan intravenously once daily for 4 days as part of part of their conditioning regimen for allogeneic HSCT. Median age at diagnosis was 56 (range 19-73). Median OS for all patients was 316 days. Of these 106 patients, seventy-seven patients (73%) received a regimen that included both Busulfan and Cyclophosphamide (BUCY), while twenty-nine patients (27%) received a regimen that included both Busulfan and Fludarabine (FluBu). Median age of patients who received BUCY was 54 while median age of patients who received FluBu was 60.  Sixty-four (60%) patients received phenytoin while 42 (40%) received levetiracetam. Of 106, none developed seizures. Only two patients developed SOS; one who received BUCY and got phenytoin as seizure prophylaxis and the other one received FluBu and got levetiracetam as seizure prophylaxis. Both patients were on Low molecular weight heparin.

 Conclusion: In this small cohort from a single center where Busulfan Kinetics is not monitored, there is low incidence of SOS whether using BUCY or FluBu as conditioning regimen and without any difference between  phenytoin or levetiracetam on effectiveness of seizure prevention or SOS incidence.