Of the proposed methods for accurate dosing of chemotherapy agents, only therapeutic drug monitoring has been studied in the HCT setting.12 If a CY/TBI regimen must be used for a patient at risk for fatal SOS, modifications should be considered for both CY and TBI dosing. The total dose of CY should be 90-110 mg/kg range21 and TBI doses should not exceed 12 Gy unless there is an oncologic imperative for higher doses.20 Shielding the liver during TBI will lessen liver injury but leads to relapse of underlying hematological disease. Accurate methods are available to target CY doses to a metabolic endpoint,

based on exposure to the CY metabolites buy CHIR-99021 4-hydroxyCY and carboxyethylphosphoramide mustard.21 If a BU/CY regimen must be used for a

patient at risk for fatal SOS, liver toxicity may be less frequent if CY is given before targeted BU or if dosing of CY is delayed for 1-2 days after completion of BU. BU and phenytoin to prevent BU-related seizures result in increased exposure to toxic CY metabolites BMN 673 clinical trial when CY is given second in order, compared to giving CY first in order.22 A lower incidence of SOS has been reported following iv BU/CY, compared to oral BU/CY, when neither BU formulation was adjusted for metabolism. The metabolic profile of intravenously administered

BU is variable, with a several-fold range in the area under the curve for BU (AUCBU), a problem that can be addressed by therapeutic drug monitoring.33 Pharmaceutical prevention of SOS has been achieved in animal models of sinusoidal injury17 but these strategies (repletion of intracellular glutathione or inhibition of matrix metalloproteinase enzymes) have not been studied in the clinical setting. Infusion of defibrotide has been reported to be effective as prophylaxis; preliminary results from a large randomized trial in children reported less liver disease and better outcomes in those receiving defibrotide.34 Prospective studies have shown 上海皓元医药股份有限公司 no benefit from use of prophylactic heparin or antithrombin III in preventing fatal SOS. A meta analysis suggests that ursodiol may prevent SOS, but SOS was not differentiated from cholestatic liver disease in these studies and a large randomized trial showed no effect of ursodiol on the frequency of SOS.2 For >70% of patients with SOS who will recover spontaneously, treatment involves management of sodium and water balance, preservation of renal blood flow, and repeated paracenteses for ascites that is associated with discomfort or pulmonary compromise.