Background: Secondary acute myelogenous leukemia (AML) carries a poor prognosis when compared to de novo AML. Therapeutic options are typically limited as patients are often elderly with comorbidities that preclude intensive chemotherapy. Moreover, resistance to therapy is common. Studies have shown that methyltransferase inhibitors (MTI) have activity in myeloid malignancy. It is not known if addition of histone deacetylase (HDAC) inhibitors improves or prolongs the activity of MTI. We present our experience of 3 elderly patients with secondary AML treated with MTI (azacitidine or decitabine) in combination with an HDAC inhibitor (vorinostat). Methods: Patients include 2 males and 1 female, ages 78 yrs, 82 yrs and 71 yrs. All were initially diagnosed with high-grade myelodysplastic syndrome (MDS), which transformed to CD34+ secondary AML at 33, 14 and 4 months from diagnosis of MDS, respectively. One patient had trisomy 8. Patients received 8, 3 and 4 cycles of MTI before leukemic transformation, respectively. At transformation, one patient failed standard induction therapy and 1 patient failed arsenic trioxide. Both of these patients were then placed back on MTI as maintenance therapy. Vorinostat was added at a dosage of 400 mg daily at MTI cycles 8, 3 and 1 post transformation, respectively. The number of cycles of combination therapy was 6, 9 and 4. Gastrointestinal intolerance was an issue in 2 of these patients: nausea (n=2), diarrhea (n=2), vomiting (n=1) and loss of appetite (n=1). Dose reduction to 100mg in one patient and 300 mg in another resulted in some symptomatic relief. The addition of 5-HT3 antagonists or low dose prednisone allowed dose escalation. One patient had 50% reduction in marrow blasts, 1 had near clearance of the peripheral blasts and 1 had a transient minor platelet response. All 3 patients are alive at 14, 10 and 9 months post transformation (6, 8 and 7 months after addition of vorinostat) with no disease progression, respectively. Conclusion: The combination of MTI and HDAC could be an option in elderly patients with secondary AML without increasing morbidity and mortality. Treatment appears well tolerated when premedication with 5-HT3 antagonists is employed. As the treatment options are limited in high-risk elderly patients with secondary AML, larger studies are needed to investigate the utility of this combination.