Glutathione S-transferase genotypes in children who develop treatment-related acute myeloid malignancies

Epipodophyllotoxin-associated secondary myeloid leukemia is a devastating c omplication of acute lymphoblastic leukemia (ALL) therapy. The risk factors for treatment-related myeloid leukemia remain incompletely defined. Geneti c deficiencies in glutathione S-transferase (GST) activities have been link ed to higher frequencies of a number of human malignancies. Our objective w as to determine whether the null genotype for GSTM1, GSTT1, or both, was mo re frequent in children with ALL who developed treatment-related myeloid ma lignancies as compared to those who did not. A PCR technique was used to as say for the null genotype for GSTM1 and GSTT1 in 302 children with ALL, 57 of whom also subsequently developed treatment-related acute myeloid leukemi a or myelodysplastic syndrome. Among children with ALL who did not develop treatment-related myeloid malignancies, the frequencies of GSTM1 and GSTT1 wild-type, GSTM1 null-GSTT1 wild-type, GSTM1 wild-type-GSTT1 null, and GSTM 1 and GSTT1 null genotypes were 40%, 42%, 9% and 9%, respectively. The corr esponding frequencies for patients who developed acute myeloid malignancies were 42%, 32%, 11% and 16%, respectively (P = 0.26). A statistically signi ficant increase in the frequency of the GST null genotype was observed in m ale patients who developed myeloid malignancies as compared to male ALL con trol patients (P = 0.036), but was not observed in female patients (P = 0.5 1). Moreover, a logistic regression analysis of possible predictors for mye loid malignancies, controlling for gender and race, did not reveal an assoc iation of GSTM1 or GSTT1 null genotypes (P = 0.62 and 0.11, respectively) w ith treatment-related malignancies. Our data suggest that GSTM1 and GSTT1 n ull genotypes may not predispose to epipodophyllotoxin-associated myeloid m alignancies.