A Phase II Study Of Aprepitant As Anti-Emetic Prophylaxis In Patients Receiving Induction Chemotherapy For AML

Standard AML induction chemotherapy includes an anthracycline plus cytarabine (3+7); the former is considered moderately emetogenic. Such patients typically received anti-emetic prophylaxis using a 5-HT3 antagonist; however, many patients continue to experience chemotherapy-induced nausea and vomiting (CINV) requiring additional therapy. Aprepitant is a neurokinin inhibitor with documented efficacy against CINV, but has not been evaluated to date in the setting of AML induction therapy.

Patients with previously untreated AML, receiving induction chemotherapy with daunorubicin 60 mg/m² IV daily on Days 1-3 plus cytarabine 200 mg/m² IV daily (100 mg/m² for patients age 60 and over) as a continuous IV infusion x 7 days, were enrolled in a Phase II single arm open label study. All patients received 5-HT3 antagonist prophylaxis using either granisetron 1 mg IV daily or ondansetron 8 mg IV q12h on the 3 daunorubicin dosing days. In addition, patients received aprepitant 125 mg PO on Day 1 followed by 80 mg PO daily on Days 2-5. No corticosteroids were used. Additional anti-emetic therapy was given as needed, at the discretion of the medical staff, for any nausea or vomiting. The primary endpoint was any vomiting or retching, while secondary endpoints included nausea requiring supplemental anti-emetics. Results were compared to a retrospective cohort of 40 patients who had received the same AML induction chemotherapy and 5-HT3 antagonist prophylaxis, but without aprepitant.

At a pre-planned interim analysis, 27 patients receiving aprepitant on study were evaluated. By the end of Day 5, 3/27 patients (11%) had experienced at least one episode of vomiting or retching, while by the end of Day 8 four additional patients had experienced vomiting/retching, for a cumulative incidence of 26%. In comparison, the cumulative incidence of vomiting or retching by the end of Day 5 in the retrospective cohort was 50% (20/40), and 53% by Day 8. The proportion of patients experiencing vomiting was below 8% per day on aprepitant dosing days, but increased to11% on Day 6.  The cumulative incidence of nausea and/or vomiting in the aprepitant group was 52% by the end of Day 5 and 60% at the end of Day 8, as compared to 78% at both time points in the retrospective cohort. There were no toxicities attributable to aprepitant.

The results indicate that aprepitant is highly effective, when combined with a 5-HT3 antagonist, in preventing vomiting in patients receiving AML induction chemotherapy with 3+7. The combination appears less effective in controlling nausea. The results warrant further evaluation in a Phase III randomized placebo controlled study.

Brandwein:Merck: Honoraria, Research Funding. Off Label Use: Aprepitant as anti-emetic prophylaxis for AML induction. Seki:Merck: Honoraria.