Abstract 869

Polymorphisms in drug metabolizing enzymes are known to contribute to inter-individual differences in the pharmacokinetics (PK) of the two most commonly used drugs for conditioning for hematopoietic stem cell transplantation (HSCT), busulfan (Bu) and cyclophosphamide (Cy) and their metabolites in plasma. We have previously reported the impact of CYP genes on the PK of Cy, [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 99] and the influence of Cy PK on transplant outcome [Blood (ASH Annual Meeting Abstracts), Nov 2004; 104: 1820]. We have now extended this study to evaluate a total of 19 polymorphisms in 11 genes that are known to be involved in the metabolism of Bu and Cy. 180 of the 276 patients with thalassemia major who underwent HSCT between March 1991 and Dec 2008 and for who genomic DNA was available were included in the study. The following polymorphisms were screened using PCR followed by RFLP and/ or gel electrophoresis: GSTA1*B, GSTM1 and GSTT1 deletion, GSTP1*B, CYP2B6*2, *3, *4, *5 and *6, CYP2C9*2, *3 and *4, CYP2C19*2, *3, CYP3A4*1B, CYP3A5*3, *6 and ALDH1A1*2 and ALDH3A1*2. Polymorphism frequencies were associated with regimen related toxicities, other transplant related complications using Fischer's Exact test and Cox-proportional hazard's model.. Significant associations are shown in the Table. On univariate analysis, CYP2B6*4 variant genotype was associated with incidence of hemorrhagic cystitis (HC); CYP2C9*3 variant genotype was associated with the severity of HC; CYP2C19*3 and 2C9*2 genotypes were associated with overall and even-free survival (OS and EFS) and CYP2C9*2 and CYP2C9*3 genotype was associated with transplant related mortality (TRM). Multivariate analyses performed adjusting for known clinical risk factors still showed these genotypes to be significantly associated with outcome parameters. Variant genotypes of polymorphisms that result in decreased metabolism of Cy are protective against regimen related toxicities while these polymorphisms were risk factors for EFS and OS in the present study. This is the first report on the influence of common GST, CYP and ALDH polymorphisms on outcome of HSCT in patients with thalassaemia major. Screening for these polymorphisms in patients with beta thalassaemia undergoing HSCT can help identify patients at higher risk of complications.

Table:
EndpointGenotypeRelative risk (95% CI)P- value
HC CYP2B6*4 variant 0.3 (0.13-0.889) 0.028  
HC grade 1 vs. HC grade 2-4 CYP2C9*3 variant 0.2 (0.073-0.962) 0.043  
TRM 2C9*2 variant 2.7 (1.08-6.77) 0.034  
 2C9*3 variant 2.3 (1.0-5.7) 0.049  
OS and EFS 2C19*3 variant 3.3 (1.2-9.3) 0.018  
 2C9*2 variant 1.3 (0.93-2.03) 0.070 
EndpointGenotypeRelative risk (95% CI)P- value
HC CYP2B6*4 variant 0.3 (0.13-0.889) 0.028  
HC grade 1 vs. HC grade 2-4 CYP2C9*3 variant 0.2 (0.073-0.962) 0.043  
TRM 2C9*2 variant 2.7 (1.08-6.77) 0.034  
 2C9*3 variant 2.3 (1.0-5.7) 0.049  
OS and EFS 2C19*3 variant 3.3 (1.2-9.3) 0.018  
 2C9*2 variant 1.3 (0.93-2.03) 0.070 
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Disclosures:

No relevant conflicts of interest to declare.

Topics:
cooley's anemia, genes, hematopoietic stem cell transplantation, polymorphism, toxic effect, cyp2c9 protein, human, cytochrome p450 cyp2b6 enzyme, transplantation, cyp2c19 protein, human, aldehyde dehydrogenases

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2009 by The American Society of Hematology
2009
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