In rheumatology practice, anti-tumor necrosis factor (TNF) alpha agents are frequently used medications, more so in ankylosing spondylitis (AS). There are case reports, besides their adverse effects, such as infection and injection site reaction, suggesting these agents may cause solid or hematologic malignancies. Acute leukemia secondary to anti-TNF alpha agents has been rarely reported in patients with AS. In this case report, based on a patient who developed acute leukemia while on the treatment with etanercept, we will discuss whether it is possible to predict acute leukemia by monitoring the mean corpuscular volume in light of the literature.