Pharmacokinetics of arsenic trioxide in patients with acute promyelocytic leukemia
ABO Blood-Group System
Blood Component Removal
Blood Group Incompatibility
Hematopoietic Stem Cells
Recent studies indicate arsenic dioxide (As203) as a potent agent in the treatment of acute promyelocytic leukemia (APL). APL is characterized by the reciprocal chromosomal translocations of the gene encoding a retinoic acid receptor (RAR-α) on chromosome 17, and a transcription factor, PML, on chromosome 15. The PML/RAR-α fusion gene encodes a chimeric protein that arrests myeloid cell development at the promyelocyte stage. These cells express CD33, an antigen associated with immature myeloid cells. It has been demonstrated that As203 induces partial differentiation (a decrease in the proportion of CD33 cells and an increase in CD11b, an antigen associated with mature myeloid cells) and apoptosis (the expression and activation of several caspases). Subsequently, we began pharmacokinetic (PK) studies of As203 in twelve patients treated for APL. These patients received As203 at a median dose of 0.16 mg/kg per day. One patient expired from a series of intracranial hemorrhages after five days on study. The remaining eleven patients achieved complete remission after a median treatment period of 33 days. The drug has been well tolerated; adverse effects included skin rash, lightheadedness during infusion, fatigue and muscloskeletal pain. Currently, the PK and biological activity of As203 is being evaluated by examining the blood and urine concentrations of elemental As in the treated patients. Parallel elimination curves suggest that the distribution of As between plasma and RBC fractions of whole blood is freely exchangable, with the mean half life of ∼60mins. The mean AUC on day 1 was ∼400nghr/ml and approximately 20% of the administered dose was recovered in urine within the first 24hrs. Ongoing studies are further assessing the therapeutic value of As203 as treatment for APL and other neoplastic diseases.