Impact of Glutathione S-Transferase Polymorphisms on Busulfan Pharmacokinetics and Outcomes of Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan (Bu) is an alkylating drug used in many preparative regimens before hematopoietic stem cell transplantation (HSCT). It is conjugated in the liver mainly by glutathione S-transferase isoenzyme A1-1 ( GSTA1 ). Genetic polymorphisms in these isoenzymes may affect the pharmacokinetics of Bu and the clinical outcomes of HSCT. This study aimed to assess the impact of glutathione S-transferase ( GST ) genetic polymorphisms on the clearance of Bu and the clinical outcomes of patients undergoing HSCT. METHODS: This single-center retrospective study included patients who received IV Bu before HSCT at Sultan Qaboos University Hospital (SQUH), Oman from January 2003 to October 2016. Genotyping for polymorphisms was performed for GSTM1 , GSTT1 , GSTA1 , and GSTP1 . Each GST polymorphism was analyzed for its impact on Bu clearance and HSCT outcomes. RESULTS: A total of 135 patients were included. The mean Bu clearance was 3.7 ± 0.98 mL/min/kg. Patients with GSTA1 A-513G heterozygosity (AG) were found to have a higher incidence of graft loss ( P = 0.006). Homozygous double null of GSTM1 and GSTT1 was associated with a higher incidence of acute graft versus host disease ( P = 0.04). Double non-null GSTM1 and GSTT1 and non-null GSTM1 increased the risk of mortality ( P = 0.034 and 0.021, respectively). CONCLUSIONS: GST genotyping before HSCT may predict HSCT outcomes. The results of this preliminary retrospective study need to be confirmed in a larger prospective study.

Maternal complications and the association with baseline variables in pregnant women with sickle cell disease.

Sickle cell disease is an inherited hemoglobinopathy with multi system complications. It has been associated with multiple maternal complications. A retrospective review of 68 consecutive pregnant women with sickle cell disease, followed in a tertiary center, was conducted over 5 years, to estimate the incidence of different maternal complications and the impact of baseline characteristics. Sixty-eight patients were analyzed (mean age 30 years). Sixty-two patients had a Hb SS genotype. The initial mean hemoglobin (Hb) level was 9.5 g/dL. Twelve patients delivered by Cesarean section. Sixty-five patients required admission for sickle cell disease/pregnancy-related complications [96.0%; 95% confidence interval (95% CI) 91-100]. Infection was seen in 17 patients (25.0%, 95% CI 14-36). Blood transfusions were given to 61 patients (90.0%, 95% CI 82-97). Eight patients had gestational hypertension (18.0%, 95% CI 4-20), while five patients (7.0%, 95% CI 1-14) had pre term labor. One patient developed eclampsia and one had a uterine rupture. One patient died due to post partum hemorrhage. The multi variable logistic regression model on the impact on the major maternal complications revealed none of the baseline factors to be statistically significant. Sickle cell disease patients have low mortality and pregnancy-related morbidity but high sickle cell disease-related morbidity. Prospective studies are needed to confirm these results.