The Case for Laboratory Developed Procedures: Quality and Positive Impact on Patient Care

Kaul, Karen L.; Sabatini, Linda M.; Tsongalis, Gregory J.; Caliendo, Angela M.; Olsen, Randall J.; Ashwood, Edward R.; Bale, Sherri; Benirschke, Robert; Carlow, Dean; Funke, Birgit H.; Grody, Wayne W.; Hayden, Randall T.; Hegde, Madhuri; Lyon, Elaine; Murata, Kazunori; Pessin, Melissa; Press, Richard D.; Thomson, Richard B.

Busulfan is a bifunctional DNA alkylating agent typically given to patients as a conditioning agent prior to hematopoietic cell transplantation (HCT) for the treatment of hematologic malignancies. Therapeutic drug monitoring (TDM) is crucial for the safe and efficacious use of busulfan due to a narrow therapeutic index based on area under the curve (AUC) calculations. Too low a dose places the patient at risk of either graft failure or early relapse. 139, 140 On the other hand, too high a dose increases the risk of neurotoxicity 141 as well as a severe and life-threatening complication termed hepatic sinusoidal obstruction syndrome (SOS). 139, 142 Hepatic SOS, previously termed hepatic veno-occlusive disease (VOD), refers to the occlusion of terminal hepatic venules and hepatic sinusoids. Severe cases of VOD can lead to hepatorenal syndrome, causing multi-organ failure, hepatic encephalopathy, and death. Veno-occlusive disease typically occurs in the context of HCT, particularly after administration of conditioning regimens prior to HCT. It is one of the most feared complications of HCT and accounts for a significant fraction of HCT-related mortality. 143 Severe cases, which account for approximately 25% to 30% of SOS, are almost always fatal. 142, 144, 145 Despite a clear need for busulfan TDM, there are currently no FDA-approved assays available for the quantitation of busulfan in blood. For this reason, various bioanalytical methods have been developed 146 and are currently in use by multiple laboratories. Data from a busulfan proficiency program organized by the University of Washington/Seattle Cancer Care Alliance show a total of 24 participating laboratories at the present time. Of these, 6 laboratories use gas chromatography (GC) methods, 3 use HPLC methods, and 14 use liquid chromatography-tandem mass spectrometry (MS) methods. 147 All of these methods are non-FDA-approved tests independently developed and validated for clinical use by their respective clinical laboratories. The use of these methods is also driven by the need for high precision and accuracy. Current criteria for acceptable laboratory performance in the analysis of busulfan is +10% of the known concentrations for medium and high concentrations and within +15% of the known concentration for low concentrations. 147 This is due to the fact that dosing change decisions are based on AUC calculations, which depend on blood concentrations of busulfan measured from multiple timed blood draws. Multiple small analytical errors can easily add up to big differences in calculated AUC values.