BACKGROUND: Isocitrate dehydrogenase 2 (IDH2) mutations have been reported in 8% to 28% of patients with acute myeloid leukemia (AML). Enasidenib is a small-molecule inhibitor of the IDH2 mutation with a reported overall response rate of 40.3% in relapsed or refractory disease, and 19.3% of patients reaching complete remission at the approved dose of 100 mg orally daily. We report on 2 patients with AML and IDH2 mutation who received an escalated dose of enasidenib. OBJECTIVE: To generate a hypothesis for optimizing the response to IDH2 inhibitors using a dose-escalation strategy to prolong relapse-free survival in patients with relapsed or refractory AML. DISCUSSION: This article is based on retrospective observations of patients with relapsed or refractory AML and IDH2 mutation who received enasidenib therapy since 2017. We report the outcomes of 2 patients with relapsed or refractory AML and IDH2 mutation at the Stephenson Cancer Center, University of Oklahoma, who received escalated-dose enasidenib (200 mg orally daily). The patients' disease had relapsed after first-line treatment with intensive chemotherapy. At the time of the relapse, bone marrow evaluation revealed the presence of IDH2 mutation. The 2 patients started therapy with standard-dose enasidenib 100 mg daily. After 3 to 6 months of therapy, the patients showed tolerability and response to treatment. The enasidenib dose was then increased to 200 mg daily, after obtaining patient informed consent and counseling about the off-label dosing. The results showed a more durable response with the escalated dose. CONCLUSION: Our limited data show that initial response to standard-dose enasidenib could be optimized by escalating the dose to 200 mg daily. [ABSTRACT FROM AUTHOR]