Acute myeloid leukemia after azathioprine treatment for autoimmune diseases: association with -7/7q-

Azathioprine is used as an immunosuppressant in a variety of clinical situations, and its prolonged use is associated with an increased risk of solid malignancies. Three patients (one with rheumatoid arthritis and two with systemic lupus erythematosus) treated with azathioprine for 3 to 7 years developed acute myeloid leukemia (AML). The total cumulative doses of azathioprine varied from 89-260 g. An antecedent prolonged pancytopenic phase suggestive of myelodysplasia developed in all the cases. Morphological analysis showed AML with trilineage myelodysplastic features in residual marrow cells in all the cases. Karyotypic analysis showed deletion of the long arm of chromosome 7 (7q-) in one case and monosomy 7 (-7) in two cases. These were chromosomal aberrations typically associated with mutagen- or therapy-related AML. Fluorescence in situ hybridization with a chromosome-7-specific DNA probe was used to investigate the distribution of the monosomy 7 clone in two cases. Monosomy 7 was demonstrated in both the leukemic blasts and the residual myeloid cells of various stages of differentiation. This finding indicated that the leukemia had evolved from a mutated clone that was capable of terminal differentiation, which was consistent with the biological characteristics of the myelodysplastic syndromes. These cases represented therapy-related AML, as evidenced by clincopathological features, karyotypic aberrations of 7q-/-7, and demonstration of leukemic evolution from an underlying clonal myeloid disorder. The data support the hypothesis that azathioprine might be directly mutagenic.