Drug Metabolism Gene Polymorphisms and the Risk of Hepatic Sinusoidal Obstruction Syndrome in Children with Inherited Diseases Receiving Haematopoietic Stem Cell Transplantation.

Hepatic Sinusoidal Obstruction Syndrome (SOS) following high dose cytotoxic therapy remains a serious complication after heamatopoietic stem cell transplantation (HSCT). Genetic polymorphisms that interfere with metabolism of drugs used in conditioning regimens have been associated with SOS after HSCT. In order to study this association in children given a HSCT for inherited diseases of the heamatopoietic system we have analyzed candidate genes in 99 children: 35 who developed SOS and in 64 children who did not develop SOS; both groups were transplanted in the same center and matched for year of transplant (from 1998 to 2004). Four families of candidate genes were analyzed: P450 cytochrome [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)], Glutathione-S-Transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Methylenetetrahydrofolate reductase [MTHFR (C677T)] and Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. The most frequent diagnosis was severe combined immunodeficiency. The two groups had no statistical differences for gender, diagnosis, type of transplant and source of stem cells. Conditioning regimen consisted in busulfan and cyclophosphamide in 91% of SOS patients and 87% of non-SOS patients (p=ns). There was no statistical difference on the frequency of all gene polymorphisms studied in both groups of patients, except for the gene CYP2B6*2 (C64T). In fact, the mutant allele T (genotypes CT or TT) was present in 31% of SOS patients and 9% of remainders (p=0.01). CYP2B6 is known to play an important role in the metabolism of chemotherapeutic agents such as cyclophosphamide (CY). In conclusion, we found that the polymorphism in CYP2B6*2 allele of the P450 cytochrome family is more frequent in children with inherited diseases who have developed SOS after HSCT than in those who did not develop SOS. This finding may define better surveillance and prophylaxis of SOS for children with the mutant allele of CYP2B6*2 given a HSCT.