A phase 2 study of decitabine with or without carboplatin and arsenic trioxide in patients with MDS and AML

Although decitabine (DAC) shows activity against myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), patient responses are limited, and prognoses remain poor. Preclinical studies have indicated that arsenic trioxide (ATO) and carboplatin (Carbo) enhance DAC's epigenetic gene derepression. Consequently, we initiated a randomized phase 2 clinical trial evaluating DAC alone, or with Carbo or ATO, in patients with MDS/AML. Thirty patients were initially randomized to receive DAC alone (20 mg/m², days 1-5), DAC plus Carbo (AUC 5, day 8), or DAC plus ATO (0.15 mg/kg, days 1-5), followed by adaptive randomization of 61 patients, based on response rates, for at least three 28-day cycles. The primary endpoint was composite response rate; secondary endpoints included 1-year median survival, safety, and epigenetic effects. Among 91 patients (44 relapsed/refractory), no significant grade 3 or 4 toxicities were observed. Response rates were 26.7% for DAC alone, 14.3% for DAC/Carbo, and 32.3% for DAC/ATO, with DAC/ATO achieving significantly higher responses (P = .041) and more stable disease (P = .018). MDS diagnosis and prior treatment status were key response predictors. Patients with MDS receiving DAC/ATO had the longest survival (16.5 months), compared to DAC/Carbo (4.6 months) and DAC alone (9.3 months) (P = .039). Epigenetic effects were similar across groups. DAC/ATO was well tolerated and improved clinical responses and survival, compared to DAC or DAC/Carbo, particularly in MDS or chronic myelomonocytic leukemia patients. This trial was registered at www.clinicaltrials.gov as #NCT02190695.