DNA methyltransferase inhibitors are frequently used to treat patients with acute myeloid leukemia (AML) who are unresponsive or resistant to intensive chemotherapy. Combinations of compounds might improve effectiveness. DNMT induce the recruitment of PARP1 and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). Previously, researchers proved the efficacy of the DNMTi and PARPi combination in AML in vitro and in vivo. Here, they described a phase I clinical trial that combines the DNMTi decitabine and PARPi talazoparib in relapsed/refractory AML. Cycle 1 days 1, 5, and 8 were used in a 3 + 3 design to escalate the decitabine and talazoparib dosages. On cycle 1 days 1 (pretreatment), 5, and 8 blood clots were examined pharmacodynamically. In seven cohorts of 25 patients (all previously treated with DNMTi), decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles, were given as a recommended phase II dose combination.Fever in 19 individuals and lung infections in 15 were identified among Grade 3–5 events. The illnesses were caused by AML.Complete response with absent count recovery was reported in two patients (8%) and hematological improvement in three. The pharmacodynamic studies revealed the expected DNA demethylation, PARP trapping in chromatin, increased γH2AX foci, and reduced HR activity in responderss.The number of γH2AX+ foci in the brain increased significantly as talazoparib doses increased together with 20 mg/m2 decitabine.The combination of decitabine and talazoparib was well tolerated. Expected pharmacodynamic effects were seen, notably in responders.
