Influence of Glutathione S-Transferase A1 and P1 Polymorphisms on the Outcome of Hematopoietic Stem Cell Transplantation with Busulfan Based Conditioning Regimen In Children.

Abstract

3492 Introduction: Busulfan has narrow therapeutic range. High exposure is associated with systemic toxicity such as veno-occlusive disease (VOD) while underexposure results in graft failure or relapse. In children, pharmacokinetic variability was found to be high even after the introduction of intravenous busulfan. Busulfan is metabolized via liver through conjugation with glutathione S-transferase (GST) family, and inter-individual variability may be explained by GST polymorphisms. Thus, we investigated the influence of GST polymorphisms on the clinical outcomes of hematopoietic stem cell transplantation (HSCT) with busulfan based conditioning regimen in children. Patients and methods: We studied patients who underwent HSCT at Seoul National University Children's Hospital from November, 2001 to November, 2008. IV busulfan (0.8 mg/kg/dose for patients≥10 kg and 1.1 mg/kg/dose for patients <10 kg, q 6hr for 4 days) was used in combination with cyclophosphamide or fludarabine as conditioning regimen. Etoposide was added for acute lymphocytic leukemia (ALL). GST polymorphisms (GSTA1 375 A > G, -52 G > A, -567 G > T, -631 G > T, -69 C > T, GSTM1 deletion, GSTT1 deletion, and GSTP1 313 A > G) were analyzed by multiplex PCR amplification and SNP genotyping. Results: A total of 70 patients (48 male, 22 female) were analyzed. The diagnoses were ALL in 32, AML in 26, and other diseases in 12 patients. Median age at HSCT was 8.8 years (range 1.0–19.0 years). Bone marrow or peripheral blood stem cell transplantations (BMT/PBSCT) were conducted in 42 patients, and cord blood transplantations (CBT) in 28 patients. Graft failure occurred in 11 (15.7%) patients (1 (2.4%) in BMT/PBSCT, 10 (35.7%) in CBT) and relapse occurred in 15 (21.4%) patients (12 (28.6%) in BMT/PBSCT, 3 (10.7%) in CBT) after HSCT. Patients having GSTA1 *A/*A and GSTP1 313 A/A genotype (N=33) showed higher incidence of graft failure than the others (N=37) (27.3% vs 5.4%, P =.01). Conversely, the incidence of hyperbilirubinemia over grade 3 was significantly lower in the patients with GSTA1 *A/*A and GSTP1 313 A/A genotype than the other patients (6.1% vs 24.3%, P =.05). Event free survival (EFS) of patients with GSTA1 *A/*A and GSTP1 313 A/A genotype was significantly lower than the EFS of the other patients in both BMT/PBSCT and CBT, and the main causes of event were graft failure in CBT and relapse in BMT/PBSCT. Conclusions: In children undergoing HSCT with busulfan based conditioning regimen, GST A1 and P1 polymorphisms seem to have influence on the graft failure, relapse and complications. To confirm our results, further studies about the influence of GST A1 and P1 polymorphisms on the pharmacokinetics of busulfan are needed. Disclosures: No relevant conflicts of interest to declare.

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

“…In our population, we found that GSTA1 A-513G heterozygous (AG) had a higher incidence of graft loss than the wild-type (AA) (40% versus 8%; P = 0.006). A study by Lee et al 25 found that the GSTP1 A313G mutant homozygous (AA) allele was associated with increased risk of graft loss ( P = 0.01). Low Bu exposure is thought to be the most common factor influencing graft loss.…”